Treatment of cancer with a KRAS inhibitor

Abstract

Provided herein are compositions and methods for the treatment of cancer. Said compositions comprise a KRAS inhibitor.

Description

TREATMENT OF CANCER WITH A KRAS INHIBITORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application No. 63 / 711579, filed on October 24, 2024; and U.S. Patent Application No. 63 / 774023, filed on March 18, 2025, all of which are hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] KRAS (Kirsten rat sarcoma viral oncogene homologue) is an oncoprotein that is a part of the RAS / MAPK pathway, and relays signals from outside of the cell to the cell’s nucleus. KRAS protein is a GTPase and involved in cellular signaling such as regulation of cell proliferation. KRAS can activate cellular signaling pathways including, but not limited to, the mitogen-activated protein kinase (MAPK) pathway. KRAS was previously considered un-targetable, but recent studies have shown that targeting codon 12 can lead to therapeutic effects. There remains an unmet need to identify and develop novel compounds for KRAS inhibition.BRIEF SUMMARY OF THE INVENTION

[0003] One embodiment provides a method of treating a cancer in a patient in need thereof, the method comprising administering to the patient 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

[0004] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

[0005] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a composition comprising 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one oncology therapeutic selected from a rapidly accelerated fibrosarcoma (RAF) inhibitor, a BRAF inhibitor, a cyclin dependent kinase (CDK) inhibitor, a receptortyrosine kinase (RTK) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor (VEGF) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a KRAS inhibitor, a methyl ethyl ketone (MEK) inhibitor, an immune checkpoint inhibitor, a phosphoinositide 3 -kinase (PI3K) inhibitor, an antibody drug conjugate (ADC), a mammalian target of rapamycin (mTOR) inhibitor, a radiopharmaceutical, a protein arginine methyltransferase 5 (PRMT5) inhibitor, a RAF / MEK dual inhibitor, a SHP2 inhibitor, a Son of Sevenless homolog 1 (S0S1) inhibitor, a focal adhesion kinase (FAK) inhibitor, a famesyltransferase inhibitor, a taxane, or a poly-ADP ribose polymerase (PARP) inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0007] Figure 1 illustrates the time course of inhibition in various cell lines with compound 1 compared to B 1-2493.

[0008] Figure 2 provides the results from the NCI-H2009 lung cancer xenograft, NCI-H358 lung cancer xenograft, and MiaPaca-2 pancreatic cancer xenograft.

[0009] Figure 3 provides the results from the HP AC pancreatic cancer xenograft and AsPC-1 pancreatic cancer xenograft.

[0010] Figure 4 provide the results from the NCI-H441 lung cancer xenograft and NCI-H727 lung cancer xenograft.

[0011] Figure 5 provides the results of a long duration NCI-H441 lung cancer xenograft.

[0012] Figure 6 provides the results of a CTG-1358 NSCLC patient-derived xenograft and a CTG-2803 NSCLC patient-derived xenograft.

[0013] Figure 7 provides the results from a single-dose PK study and a DUSP6 determinations.

[0014] Figure 8 provides the results from rat and dog PK studies.

[0015] Figure 9 provides the results from modeling to predict efficacious human dose.

[0016] Figure 10A and Figure 10B provide the results combination from SW403 colorectal cancer patient-derived xenograft studies.

[0017] Figure HA and Figure 11B provide the results from SW620 colorectal cancer patient-derived xenograft studies.

[0018] Figure 12A and Figure 12B provide the results from GP2d colorectal cancer patient-derived xenograft studies.

[0019] Figure 13A and Figure 13B provide the results from NCI-H727 non-small cell lung cancer patient-derived xenograft studies.

[0020] Figure 14A and Figure 14B provide the results from LoVO colorectal cancer patient-derived xenograft studies.

[0021] Figure 15A and Figure 15B provide the results from LSI 80 colorectal cancer patient-derived xenograft studies.

[0022] Figure 16 provides the results from combination treatment with a pan-KRAS and MEK inhibitor in KRAS G12D cell line.

[0023] Figure 17 provides the results from combination treatment with a pan-KRAS and RAF / MEK inhibitor in KRAS G12D cell line.

[0024] Figure 18 provides the results from combination treatment with a pan-KRAS and MEK inhibitor in KRAS G12V cell line.

[0025] Figure 19 provides the results from combination treatment with a pan-KRAS and RAF / MEK inhibitor in KRAS G12V cell line.

[0026] Figure 20 provides the results from combination treatment with a pan-KRAS and pan-RAS inhibitor in KRAS G12D cell line.

[0027] Figure 21 provides the results from combination treatment with a pan-KRAS and pan-RAS inhibitor in KRAS G12V cell line.

[0028] Figure 22 provides the results from combination treatment with a pan-KRAS and pan-RAS inhibitor in KRAS G12R cell line.

[0029] Figure 23A and Figure 23B provide the results from combination treatment with RMC-6236 in SW403 human colon adenocarcinoma patient-derived xenograft studies.

[0030] Figure 24A and Figure 24B provide the results from combination treatment with RMC-6236 in GP2d human colon adenocarcinoma patient-derived xenograft studies.

[0031] Figure 25A and Figure 25B provide the results from combination treatment with RMC-6236 in NCI-H727 human lung cancer patient-derived xenograft studies.

[0032] Figure 26A and Figure 26B provide the results from combination treatment with RMC-6236 in LoVo human colon adenocarcinoma patient-derived xenograft studies.

[0033] Figure 27A and Figure 27B provide the results from combination treatment with Cetuximab in SW620 human colon adenocarcinoma patient-derived xenograft studies.

[0034] Figure 28A and Figure 28B provide the results from combination treatment with Cetuximab in LoVo human colon adenocarcinoma patient-derived xenograft studies.

[0035] Figure 29A and Figure 29B provide the results from combination treatment with Cetuximab in LSI 80 human colon adenocarcinoma patient-derived xenograft studies.

[0036] Figure 30A and Figure 30B provide the results from Murine Colorectal Syngeneic Cancer Cell line-derived xenograft studies.

[0037] Figure 31A, Figure 31B, Figure 31C, and Figure 31D provide median survival results from Murine Colorectal Syngeneic Cancer Cell line-derived xenograft studies.

[0038] Figure 32A and Figure 32B provide the results from human gastric cancer (KRAS WT amplified) patient-derived xenograft studies.INCORPORATION BY REFERENCE

[0039] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTIONCertain Terminology

[0040] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of' or "consist essentially of' the described features.

[0041] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0042] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of the heterocyclic KRAS inhibitor described herein is intended to encompass all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0043] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids (such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.) and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. etal., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0044] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0045] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0046] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0047] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit. The term “therapeutic benefit” is meant include eradication or amelioration of the underlying disorder being treated. Also, a “therapeutic benefit” is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. In some embodiments, the term “treating” includes slowing or delaying the progression of the disease or disorder to which the term is applied. Additionally, in some embodiments, the term “treating” is applied to one or more of the complications resulting from the disease or disorder to which the term is applied. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. In some embodiments, the treatment provides a partial response. A partial response, or partial remission, is a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. In some embodiments, the treatment provides acomplete response. A complete response, or complete remission, is the disappearance of all signs of cancer in response to treatment. In some embodiments, the treatment provides a slowing of disease progression.

[0048] The term "tumor," or “cancer” as used herein, and unless otherwise specified, refers to a neoplastic cell growth, and includes pre-cancerous and cancerous cells and tissues. Tumors usually present as a lesion or lump. As used herein, “treating” a tumor means that has one or more symptoms of the disease, such as the tumor itself, vascularization of the tumor, or other parameters by which the disease is characterized, are reduced, ameliorated, inhibited, placed in a state of remission, or maintained in a state of remission. “Treating” a tumor also means that one or more hallmarks of the tumor may be eliminated, reduced, or prevented by the treatment. Nonlimiting examples of such hallmarks include uncontrolled degradation of the basement membrane and proximal extracellular matrix, migration, division, and organization of the endothelial cells into new functioning capillaries, and the persistence of such functioning capillaries.

[0049] The term “refractory” or “refractory to therapy” indicates that the patients have never responded to therapy.

[0050] The term “relapsed” or “relapsed after therapy” indicates that patients, after initially responding to prior therapy, have progressive disease due to acquired resistance and / or intolerance.

[0051] The term “resistance to therapy” or “acquired resistance to therapy” indicates the patients, after initially responding to prior therapy, have progressive disease due to clinical or molecular resistance to the therapy. The acquired resistance can result from emergence of resistant mutations in the molecular target of the therapy, or in the development of physiological functions such as efflux pumps.

[0052] The phrase "therapeutically effective amount", as used herein, refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other.

[0053] Other aspects, advantages, and features of the invention will become apparent from the detailed description below.KRAS Protein and Function

[0054] RAS mutation is frequent in cancer, with approximately 19% of patients with cancer harboring RAS mutations (I. A. Prior et al., Cancer Res 2020; 80:2969-74). Ras proteins are important for activating signaling networks for controlling cell differentiation, proliferation, and survival, encoded by three genes HRAS, KRAS, and NRAS. The three genes share significantsequence homology and largely overlapping functions. Activation of RAS is facilitated by guanine nucleotide exchange factors (GEF), and activation causes conformational changes.

[0055] The KRAS gene encodes two highly related protein isoforms, KRAS-4A and KRAS-4B, which comprise of 189 and 188 amino acids. KRAS generally refers to KRAS-4B, because of the high level of mRNA encoding KRAS-4B in cells. KRAS has two major domains, the catalytic G domain and a hypervariable region (HVR).

[0056] KRAS G domain is the basis of biological function of GTPase proteins. The G domain comprises 6 beta-strands of the protein core, surrounded by five alpha-helices, and comprises residues 1-166. The G domain also consists of other regions: switch I, switch II, and the P loop. KRAS-GTP binding alters the conformation of the switches I and II in the G domain. When activated, KRAS binds to its downstream molecules as monomers or dimers to mediate series of signaling cascades. KRAS also has a flexible C-terminal, the hypervariable region (HVR), which is important for localizing KRAS to the membrane.

[0057] The RAS family comprises three isoforms, but about 85% of RAS-related cancers are caused by mutations in the KRAS isoform. The mutations in KRAS isoform occurs most frequently in solid tumors such as colorectal carcinoma, lung adenocarcinoma, and pancreatic ductal carcinoma. Further, nearly 80% of KRAS mutant tumors are located within codon 12, with the most common mutations being p.G12D, p.G12V, and p.G12C.

[0058] KRAS protein functions as a molecular switch in growth factor signaling pathways by regulating proliferation by alternating between a GDP -bound inactive form and a GTP -bound active form. The GTP -bound active form is capable of engaging downstream effector proteins to trigger a pro-proliferative response. This regulation cycle is impaired by mutations in codon 12 which disrupts association of GTPase activating proteins, which impairs the inactivation of KRAS, which leads to accumulation of the pro-proliferative form. Many growth factors such as but not limited to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and fibroblast growth factors (FGF) can activate KRAS proteins through intermediary molecules after activating receptor tyrosine kinases. Upstream regulation can promote binding of GTP and KRAS, converting KRAS from an inactive to an active state. Molecules upstream of KRAS mainly mediate the activation or inactivation of KRAS by regulating guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386). Another molecule in KRAS activation is Src homology phosphatase 2 (SHP2) which plays a role in KRAS activation. SHP2 is a common signaling regulatory that mediates receptor tyrosine kinases signals to KRAS-ERK signaling, and dephosphorylation substrates of SHP2 have been shown to promote KRAS activation.

[0059] The RAF-MEK-ERK pathway is a downstream target of KRAS signaling. Another pathway KRAS is involved in is the PI3K-AKT-mTOR pathway (L. Huang et al., Signal Transduction and Targeted Therapy, 2021, 6, 386).

[0060] KRAS was previously considered to be an undruggable protein, but recently there have been advances in targeting codon 12, and specifically in G12C inhibitors. Many efforts have been focused on indirectly targeting KRAS, so there remains an unmet need of targeting KRAS, which the compounds provided herein fulfill. With the discovery of a new allosteric site of KRAS, G12C, several covalently binding inhibitors of KRAS have emerged and are under clinical investigation. However, KRAS inhibition is a complex issue with a lack of understanding of the underlying principles, and there still remains an unmet need for new inhibitors which target other KRAS mutations such as, but not limited to G12D and G12V.

[0061] KRAS mutations are frequently found in colorectal cancer, pancreatic cancer, and nonsmall cell lung cancer (M.H. Hofmann et al., Cancer Discov 2022; 12:924-37). The KRAS allelic distribution varies between the tumor types, with G12C mutations in 13.6% of lung adenocarcinomas, whereas the G12D and G12V mutations are most common in colorectal and pancreatic cancer. The G12D, G12V, and G12C mutations are the three most frequent allele mutations. KRAS mutations, especially at codon 12, is strongly associated with cellular KRAS dependency, indicating that KRAS acts as an oncogenic driver.

[0062] There have been advances for KRAS G12C inhibitors, such as sotorasib (AMG510) and adagrasib (MRTX849). Sotorasib is the first to be approved by the US Food and Drug Administration (FDA). Both inhibitors rely on the interaction with the nucleophilic cysteine 12 in the GDP state and occupy the switch II pocket.

[0063] NMR studies have shown that MRTX849 can engage mutant KRAS proteins lacking the nucleophilic mutant cysteine 12, but that the engagement is selected for inactive GDP -loaded state of KRAS protein. AMG510 exhibits weak binding and relies on irreversible reaction of the mutant cysteinel2 for KRAS (G12C) inhibitory activity (J.D. Vasta et al., Nature Chemical Biology, 2022, 18, 596-604).

[0064] AMG510 and additional KRAS inhibitors are described in Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors (B.A Lanman et al., J. Med. Chem. 2020, 63, 52-65).Novel Heterocyclic KRAS Inhibitor

[0065] One of the heterocyclic KRAS inhibitors described herein is compound 1, having the structure below, and the chemical name 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine. The synthesis andcharacterization of Compound 1 was presented in International Patent Application No.PCT / US2024 / 047282.Compound 1Cancer and Methods of Treatment

[0066] One embodiment provides a method of treating a cancer in a patient in need thereof, the method comprising administering to the patient 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

[0067] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

[0068] One embodiment provides a compound provided herein, or pharmaceutically acceptable salt or solvate thereof, for use in a method of treating cancer in a patient in need thereof.Another embodiment provides use of a compound provided herein, or pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of cancer.

[0069] One embodiment provides the method wherein the cancer is breast cancer. Another embodiment provides the method wherein the breast cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the breast cancer is a HER2+ breast cancer. Another embodiment provides the method wherein the breast cancer is a triple negative breast cancer (TNBC). Another embodiment provides the method wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.

[0070] One embodiment provides the method wherein the cancer is uterine cancer. Another embodiment provides the method wherein the cancer is uterine sarcoma.

[0071] One embodiment provides the method wherein the cancer is endometrial cancer. Another embodiment provides the method wherein the endometrial cancer is selected from endometrioidadenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

[0072] One embodiment provides the method wherein the cancer is cervical cancer. Another embodiment provides the method wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

[0073] One embodiment provides the method wherein the cancer is fallopian tube cancer (FTC). Another embodiment provides the method wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cell carcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

[0074] One embodiment provides the method wherein the cancer is prostate cancer. Another embodiment provides the method wherein the cancer is prostate adenocarcinoma. Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate squamous cell carcinoma. Another embodiment provides the method wherein the cancer is prostate small cell carcinoma. Another embodiment provides the method wherein the cancer is prostate lymphoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0075] One embodiment provides the method wherein the cancer is bladder cancer. Another embodiment provides the method wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non-urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma. Another embodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

[0076] One embodiment provides the method wherein the cancer is lung cancer.

[0077] One embodiment provides the method wherein the cancer is non-small cell lung cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, squamous cell cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenocarcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, large cell carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Anotherembodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is small cell lung cancer. Another embodiment provides the method wherein the cancer is combined small cell lung cancer.

[0078] One embodiment provides the method wherein the cancer is rectal cancer. Another embodiment provides the method wherein the rectal cancer is adenocarcinoma. Another embodiment provides the method wherein the rectal cancer is quamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the rectal cancer is gastrointestinal stromal. Another embodiment provides the method wherein the rectal cancer is lymphoma. One embodiment provides the method wherein the cancer is colon cancer (CRC). Another embodiment provides the method wherein the cancer is CRC, adenocarcinoma. Another embodiment provides the method wherein the cancer is CRC, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, colon cancer. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the cancer is CRC, gastrointestinal stromal. Another embodiment provides the method wherein the cancer is CRC lymphoma.

[0079] One embodiment provides the method wherein the cancer is anal cancer. Another embodiment provides the method wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

[0080] One embodiment provides the method wherein the cancer is biliary cancer. Another embodiment provides the method wherein the biliary cancer is cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra-hepatic cholangiocarcinoma.

[0081] One embodiment provides the method wherein the cancer is a meningioma.

[0082] One embodiment provides the method wherein the cancer is a glioma.

[0083] One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). Another embodiment provides the method wherein the cancer is PDAC, adenocarcinoma. Another embodiment provides the method wherein the cancer is PDAC, acinar cell carcinoma. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic cancer, squamous cell carcinoma. Another embodiment provides the methodwherein the cancer is pancreatic cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is pancreatoblastoma.

[0084] One embodiment provides the method wherein the cancer is thyroid cancer. Another embodiment provides the method wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

[0085] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0086] One embodiment provides the method wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

[0087] One embodiment provides the method wherein the cancer is stomach cancer or gastric cancer. Another embodiment provides the method wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

[0088] One embodiment provides the method wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

[0089] One embodiment provides the method wherein the cancer is skin cancer. Another embodiment provides the method wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma. Another embodiment provides the method wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

[0090] One embodiment provides the method wherein the cancer is melanoma. Another embodiment provides the method wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

[0091] One embodiment provides the method wherein the cancer is ovarian cancer. Another embodiment provides the method wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

[0092] One embodiment provides the method wherein the cancer is renal cell cancer.

[0093] One embodiment provides the method wherein the cancer is an appendiceal cancer. Another embodiment provides the method wherein the cancer is appendiceal carcinoid tumor. Another embodiment provides the method wherein the cancer is appendiceal mucinous neoplasm. Another embodiment provides the method wherein the cancer is appendix adenocarcinoma. Another embodiment provides the method wherein the cancer is appendicealadenocarcinoid or goblet cell appendiceal carcinoma. Another embodiment provides the method wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma, appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

[0094] One embodiment provides the method wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

[0095] One embodiment provides the method wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

[0096] One embodiment provides the method wherein the cancer is a sarcoma.

[0097] One embodiment provides the method wherein the cancer is a primary brain tumor. Another embodiment provides the method wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

[0098] One embodiment provides the method wherein the cancer is gallbladder cancer. Another embodiment provides the method wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

[0099] One embodiment provides the method wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

[0100] One embodiment provides the method wherein the cancer is germ cell tumor.Another embodiment provides the method wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

[0101] One embodiment provides the method wherein the cancer is plasma cell neoplasm. Another embodiment provides the method wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

[0102] One embodiment provides the method wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0103] One embodiment provides the method wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

[0104] One embodiment provides the method wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

[0105] One embodiment provides the method wherein the cancer is neuroendocrine carcinoma

[0106] One embodiment provides the method wherein the cancer is cancer of unknown primary (CUP).

[0107] One embodiment provides the method wherein the cancer is locally advanced.

[0108] One embodiment provides the method wherein the cancer is metastatic.

[0109] One embodiment provides the method wherein the method is adjuvant therapy following surgical resection.

[0110] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0111] One embodiment provides the method wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

[0112] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0113] One embodiment provides the method wherein the patient has acquired resistance to prior therapy.

[0114] One embodiment provides the method wherein the patient is refractory to therapy.

[0115] Another embodiment provides the method, wherein the oral administration occurs every other day, once per day, twice per day, or three times per day.

[0116] Oral doses typically range from about 1.0 mg to about 1500 mg, one to four times, or more, per day. In some embodiments, the oral daily dose of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine is about 15 mg, about 25 mg, about 35 mg, about 50 mg, about 75 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 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the oral daily dose of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, or about 200 mg.

[0117] Another embodiment provides the method, wherein the administration to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is correlated to plasma concentrations of DUSP6.

[0118] Another embodiment provides the method, wherein the frequency of administration to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is adjusted to maintain a DUSP6 plasma concentration of less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%, of the DUSP6 plasma concentration determined prior to starting therapy with 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

[0119] Another embodiment provides the method, wherein the dose administered to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is adjusted to maintain a DUSP6 plasma concentration of less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%, of the DUSP6 plasma concentration determined prior to starting therapy with 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

[0120] Another embodiment provides the method, wherein the administration to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is adjusted to maintain a pharmacokinetic area under the curve (AUCo-i2h,ss) of about 900 ng*h / mL, about 1000 ng*h / mL, about 1100 ng*h / mL, about 1200 ng*h / mL, about 1300 ng*h / mL, about 1400 ng*h / mL, about 1500 ng*h / mL, about 1600 ng*h / mL, about 1700 ng*h / mL, about 1800 ng*h / mL, about 1900 ng*h / mL, or about 2000 ng*h / mL.

[0121] One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12A mutation. One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12D mutation. One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12V mutation. One embodiment provides the method wherein the cancer is characterized by existence of KRAS G12C mutation.

[0122] In some embodiments, any method provided herein comprises administering a compound of Formula (I), or a pharmaceutically acceptable salt or solvate, thereof:wherein:X1is N;X2is C-H, C-F, C-CH3, or C-Cl;X3is N;Ar is an optionally substituted bicyclic aryl ring system;R1is L-G; wherein L is optionally substituted Cl alkylene; and G is an optionally substituted 5- to 10-membered heterocyclyl;-N(R2)R3form a heterocyclyl selected from:R4is H or O-CH3.

[0123] In some embodiments, X2is C-F. In some embodiments, X2is C-CH3. In some embodiments R4is H. In some embodiments R4is O-CH3.

[0124] In some embodiments, Ar is an optionally substituted 1-naphthyl.

[0125] In some embodiments, Ar is selected from the group consisting of:D D

[0126] In some embodiments, L is In some embodiments, L is

[0127] In some embodiments, G is selected from the group consisting of:

[0128] In some embodiments, -N(R2)R3form a heterocyclyl selected from the group consisting of:

[0129] In some embodiments, any method provided herein comprises administering a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate, thereof.

[0130] One embodiment provides a method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a compound selected from the group consisting of:5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lR,7S,8R)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octan- 6-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3- d]pyrimidin-7-yl)naphthalen-2-amine;6.7-difluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;(lS,7S,8S)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;6.7-difluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6.7-difluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lR,7S,8R)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;6-fluoro-4-(8-fluoro-4-((lR,7S,8R)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.E0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;(15.75.85)-2-(2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((S,E)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((S,Z)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;4-(2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-4-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;(lS,7S,8S)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-4-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;4-(4-((lS,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalen-2-amine;5 -ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 5 S, 7aS)-2-fluoro-5 -methyltetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6-chloro-5-ethynyl-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-amine;4-(8-chloro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;4-(4-((lR,7S,8R)-8-chloro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-methylnaphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,3R,7aS)-2-fluoro-3-methyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;4-(4-((lS,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,3R,7aS)-2-fluoro-3-methyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-amine;4-(4-((lS,7R,8S)-8-chloro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((R,E)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)- 2-(((R,Z)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((R,E)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octane;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((R,Z)-6'- (fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octane;(R,E)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.E0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6'-(fluoromethylene)hexahydrospiro[cyclopropane-l,l'-pyrrolizine];(R,Z)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.E0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6'-(fluoromethylene)hexahydrospiro[cyclopropane-l,l'-pyrrolizine];5-ethynyl-6-fluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((R,E)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2- (((R,Z)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,l'-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;(R)-6'-(difluoromethylene)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydrospiro[cyclopropane-l,l'-pyrrolizine];(R)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6'-methylenehexahydrospiro[cyclopropane-l,l'-pyrrolizine];5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,^-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;4-(4-((lS,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,^-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; and4-(4-((l S,7R,8S)-8-chloro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en-2-amine;or pharmaceutically acceptable salt or solvate thereof.

[0131] One embodiment provides a method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a compound selected from the group consisting of:5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lR,7S,8R)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6,7-difluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;(lS,7S,8S)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;6.7-difluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6.7-difluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lR,7S,8R)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;6-fluoro-4-(8-fluoro-4-((lR,7S,8R)-8-fluoro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(methoxy-d3)naphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;(lS,7S,8S)-2-(2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-(fluoromethoxy-d2)naphthalen-2-amine;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((S,E)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((S,Z)-2- (fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octane;4-(2-(((S)-2-(difluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;5-ethynyl-6,7-difluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-4-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-5-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,Z)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((S,E)-2-(fluoromethylene)tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octane;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octan-2-yl)-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]oct-4-en-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-5-methoxypyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;4-(4-((lS,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalen-2-amine;5 -ethynyl-6-fluoro-4-(8-fluoro-2-(((2R, 5 S, 7aS)-2-fluoro-5 -methyltetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;6-chloro-5-ethynyl-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin- 7-yl)naphthalen-2-amine;4-(8-chloro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;4-(4-((lR,7S,8R)-8-chloro-2-oxa-6-azabicyclo[5.1.0]octan-6-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-6-methylnaphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-2-(((2R,3R,7aS)-2-fluoro-3-methyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;4-(4-((lS,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.E0]octan-2-yl)-8-fluoro-2-(((2R,3R,7aS)-2-fluoro-3-methyltetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)- 5-ethynyl-6-fluoronaphthalen-2-amine;4-(4-((lS,7R,8S)-8-chloro-2-azabicyclo[5.1.0]octan-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl- 6-fluoronaphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((R,E)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((R,Z)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((R,E)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octane;(15.75.85)-2-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((R,Z)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-8-fluoro-5-oxa-2-azabicyclo[5.E0]octane;(R,E)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.E0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6'-(fluoromethylene)hexahydrospiro[cyclopropane-l,l'-pyrrolizine];(R,Z)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.E0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6'-(fluoromethylene)hexahydrospiro[cyclopropane-l,l'-pyrrolizine];5-ethynyl-6-fluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((R,E)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(8-fluoro-4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((R,Z)-6'-(fluoromethylene)tetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;(R)-6'-(difluoromethylene)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.E0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydrospiro[cyclopropane-l,l'-pyrrolizine];(R)-7a'-(((7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6'-methylenehexahydrospiro[cyclopropane-l,l'-pyrrolizine];5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2- (((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,^-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;4-(4-((lS,7S,8S)-8-chloro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((R)-6'-methylenetetrahydrospiro[cyclopropane-l,r-pyrrolizin]-7a'(5'H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-8-methyl-2-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(4-((l S,7R,8S)-8-fluoro-2-azabicyclo[5.1 ,0]octan-2-yl)-8-methyl-2- (((R)-6'-methylenetetrahydrospiro[cyclopropane-l,l'-pyrrolizin]-7a'(5'H)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol;5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine;5-ethynyl-6-fluoro-4-(4-((lS,7R,8S)-8-fluoro-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol; and4-(4-((l S,7R,8S)-8-chloro-2-azabicyclo[5.1 ,0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy-d2)-8-methylpyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthal en-2-amine;or pharmaceutically acceptable salt or solvate thereof.

[0132] One embodiment provides the method wherein the cancer is breast cancer. Another embodiment provides the method wherein the breast cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the breast cancer is a HER2+ breast cancer. Another embodiment provides the method wherein the breast cancer is a triple negative breast cancer (TNBC). Another embodiment provides the method wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.

[0133] One embodiment provides the method wherein the cancer is uterine cancer.Another embodiment provides the method wherein the cancer is uterine sarcoma.

[0134] One embodiment provides the method wherein the cancer is endometrial cancer. Another embodiment provides the method wherein the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

[0135] One embodiment provides the method wherein the cancer is cervical cancer.Another embodiment provides the method wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

[0136] One embodiment provides the method wherein the cancer is fallopian tube cancer (FTC). Another embodiment provides the method wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cellcarcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

[0137] One embodiment provides the method wherein the cancer is prostate cancer.Another embodiment provides the method wherein the cancer is prostate adenocarcinoma.Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate squamous cell carcinoma. Another embodiment provides the method wherein the cancer is prostate small cell carcinoma. Another embodiment provides the method wherein the cancer is prostate lymphoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0138] One embodiment provides the method wherein the cancer is bladder cancer.Another embodiment provides the method wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non-urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma. Another embodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

[0139] One embodiment provides the method wherein the cancer is lung cancer.

[0140] One embodiment provides the method wherein the cancer is non-small cell lung cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, squamous cell cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenocarcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, large cell carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is small cell lung cancer. Another embodiment provides the method wherein the cancer is combined small cell lung cancer.

[0141] One embodiment provides the method wherein the cancer is colon cancer (CRC). Another embodiment provides the method wherein the cancer is CRC, adenocarcinoma. Another embodiment provides the method wherein the cancer is CRC, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, colon cancer. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the cancer is CRC, gastrointestinal stromal. Another embodiment provides the method wherein the cancer is CRC lymphoma.

[0142] One embodiment provides the method wherein the cancer is anal cancer. Another embodiment provides the method wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

[0143] One embodiment provides the method wherein the cancer is biliary cancer. Another embodiment provides the method wherein the biliary cancer is cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra-hepatic cholangiocarcinoma.

[0144] One embodiment provides the method wherein the cancer is a meningioma.

[0145] One embodiment provides the method wherein the cancer is a glioma.

[0146] One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic ductal adenocarcinoma (PDAC). Another embodiment provides the method wherein the cancer is PDAC, adenocarcinoma. Another embodiment provides the method wherein the cancer is PDAC, acinar cell carcinoma. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic cancer, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is pancreatic cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is pancreatoblastoma.

[0147] One embodiment provides the method wherein the cancer is thyroid cancer.Another embodiment provides the method wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

[0148] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0149] One embodiment provides the method wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

[0150] One embodiment provides the method wherein the cancer is stomach cancer or gastric cancer. Another embodiment provides the method wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

[0151] One embodiment provides the method wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

[0152] One embodiment provides the method wherein the cancer is skin cancer. Another embodiment provides the method wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma. Another embodiment provides the method wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

[0153] One embodiment provides the method wherein the cancer is melanoma. Another embodiment provides the method wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

[0154] One embodiment provides the method wherein the cancer is ovarian cancer.Another embodiment provides the method wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

[0155] One embodiment provides the method wherein the cancer is renal cell cancer.

[0156] One embodiment provides the method wherein the cancer is an appendiceal cancer. Another embodiment provides the method wherein the cancer is appendiceal carcinoid tumor. Another embodiment provides the method wherein the cancer is appendiceal mucinous neoplasm. Another embodiment provides the method wherein the cancer is appendix adenocarcinoma. Another embodiment provides the method wherein the cancer is appendiceal adenocarcinoid or goblet cell appendiceal carcinoma. Another embodiment provides the method wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma, appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

[0157] One embodiment provides the method wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

[0158] One embodiment provides the method wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

[0159] One embodiment provides the method wherein the cancer is a sarcoma.

[0160] One embodiment provides the method wherein the cancer is a primary brain tumor. Another embodiment provides the method wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

[0161] One embodiment provides the method wherein the cancer is gallbladder cancer. Another embodiment provides the method wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

[0162] One embodiment provides the method wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

[0163] One embodiment provides the method wherein the cancer is germ cell tumor.Another embodiment provides the method wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

[0164] One embodiment provides the method wherein the cancer is plasma cell neoplasm. Another embodiment provides the method wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

[0165] One embodiment provides the method wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0166] One embodiment provides the method wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

[0167] One embodiment provides the method wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

[0168] One embodiment provides the method wherein the cancer is neuroendocrine carcinoma

[0169] One embodiment provides the method wherein the cancer is cancer of unknown primary (CUP).

[0170] One embodiment provides the method wherein the cancer is locally advanced.

[0171] One embodiment provides the method wherein the cancer is metastatic.

[0172] One embodiment provides the method wherein the method is adjuvant therapy following surgical resection.

[0173] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0174] One embodiment provides the method wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

[0175] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0176] One embodiment provides the method wherein the patient has acquired resistance to prior therapy.

[0177] One embodiment provides the method wherein the patient is refractory to therapy. Combination Therapy

[0178] One embodiment provides a method of treating a cancer in a patient in need thereof, comprising administering to the patient:(a) a composition comprising 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof; and(b) at least one oncology therapeutic selected from a rapidly accelerated fibrosarcoma (RAF) inhibitor, a BRAF inhibitor, a cyclin dependent kinase (CDK) inhibitor, a receptor tyrosine kinase (RTK) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor (VEGF) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a KRAS inhibitor, a methyl ethyl ketone (MEK) inhibitor, an immune checkpoint inhibitor, a phosphoinositide 3 -kinase (PI3K) inhibitor, an antibody drug conjugate (ADC), a mammalian target of rapamycin (mTOR) inhibitor, a radiopharmaceutical, a protein arginine methyltransferase 5 (PRMT5) inhibitor, a RAF / MEK dual inhibitor, a SHP2 inhibitor, a Son of Sevenless homolog 1 (S0S1) inhibitor, a focal adhesion kinase (FAK) inhibitor, a famesyltransferase inhibitor, a taxane, or a poly-ADP ribose polymerase (PARP) inhibitor.

[0179] One embodiment provides the method wherein at least one oncology therapeutic is a RAF inhibitor.

[0180] One embodiment provides the method wherein at least one oncology therapeutic is a BRAF inhibitor. Another embodiment provides the method wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, exarafenib, lifirafenib, naporafenib, sunitinib, TAK-580, orPLX8394.

[0181] One embodiment provides the method wherein at least one oncology therapeutic is a cyclin dependent kinase inhibitor. Another embodiment provides the method wherein the cyclin dependent kinase inhibitor is selected from palbociclib, abemaciclib, ribociclib, tagtociclib, atirmociclib, or AVZO-021.

[0182] One embodiment provides the method wherein at least one oncology therapeutic is an RTK inhibitor. Another embodiment provides the method wherein the RTK inhibitor is selected from dasatinib, imatinib, nilotinib, pazopanib, sorafenib, or sunitinib.

[0183] One embodiment provides the method wherein at least one oncology therapeutic is an EGFR inhibitor. Another embodiment provides the method wherein the EGFR inhibitor is selected from simotinib, icotinib, gefitinib, erlotinib, cetuximab, panitumumab, necitumumab, lazertinib, osimertinib, olmutinib, lapatinib, afatinib, neratinib, or dacomitinib.

[0184] One embodiment provides the method wherein the oncology therapeutic is a VEGF inhibitor. Another embodiment provides the method wherein the VEGF inhibitor is selected from bevacizumab, sunitibin, sorafenib, axitinib, cabozantinib, lenvatinib, pazopanib, pegaptanib, or ramucircumab.

[0185] One embodiment provides the method wherein at least one oncology therapeutic is an ERK inhibitor. Another embodiment provides the method wherein the ERK inhibitor is selected from temuterkib or ulixertinib.

[0186] One embodiment provides the method wherein the at least one oncology therapeutic is a RAS or KRAS inhibitor. One embodiment provides the method wherein at least one oncology therapeutic is a KRAS inhibitor. Another embodiment provides the method wherein the KRAS inhibitor is selected from daraxonrasib (RMC-6236), divarasib, elironrasib, adagrasib, JDQ44, LY3499446, D3S-001, BBO-8520, sotorasib, MRTX1133, TSN1611, HRS-4642, ERAS-0015, ERAS-4001, or RMC-9805. Another embodiment provides the method, wherein the KRAS inhibitor is selected from daraxonrasib (RMC-6236), divarasib, elironrasib, adagrasib, JDQ44, LY3499446, D3S-001, BBO-8520, sotorasib, MRTX1133, TSN1611, HRS-4642, ERAS-0015, ERAS-4001, RMC-9805, AN9205, GFH276, or BPI-572270. Another embodiment provides the method wherein the KRAS inhibitor is daraxonrasib (RMC-6236). Another embodiment provides the method wherein the KRAS inhibitor is AN9205. Another embodiment provides the method wherein the KRAS inhibitor is GFH276. Another embodiment provides the method wherein the KRAS inhibitor is BPI-572270.

[0187] One embodiment provides the method wherein at least one oncology therapeutic is a MEK inhibitor. Another embodiment provides the method wherein the MEK inhibitor is selected from binimetinib, cobimetinib, selumetinib, pimasertib, or trametinib.

[0188] One embodiment provides the method wherein at least one oncology therapeutic is an immune checkpoint inhibitor. Another embodiment provides the method wherein the immune checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a bi-specific PD-1 / CTLA4 inhibitor. Another embodiment provides the method wherein the CTLA-4 inhibitor is selected from ipilmumab or tremelimumab. Another embodiment provides the method wherein the PD-1 inhibitor is selected from spartalizumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab. Another embodiment provides the method wherein the bi-specific PD-1 / CTLA4 inhibitor is selected from AK104, MGD019, XmAb20717, or MEDI5752.

[0189] One embodiment provides the method wherein the oncology therapeutic is a phosphoinositide 3 -kinase inhibitor. Another embodiment provides the method wherein the phosphoinositide 3 -kinase inhibitor is selected from copanlisib, alpelisib, idelalisib, duvelisib, inavolisib, or umbralisib, or STX-478.

[0190] One embodiment provides the method wherein at least one oncology therapeutic is an ADC. Another embodiment provides the method wherein the ADC is selected from ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, sacituzumab govitecan , disitamabvedotin, tisotumab vedotin, raludotatug deruxtecan, ARX-788, datopotamab deruxtecan, patritumab deruxtecan, ladiratuzumab vedotin or HS-20089.

[0191] One embodiment provides the method wherein at least one oncology therapeutic is a mTOR inhibitor. Another embodiment provides the method wherein the mTOR inhibitor is deforolimus, everolimus, sirolimus, or temsirolimus.

[0192] One embodiment provides the method wherein at least one oncology therapeutic is a radiopharmaceutical. Another embodiment provides the method wherein the radiopharmaceutical is [lllIn] / [89Zr]-trastuzumab.

[0193] One embodiment provides the method wherein at least one oncology therapeutic is a PRMT5 inhibitor. Another embodiment provides the method wherein the PRMT5 inhibitor is selected from GSK3368715, TNG462, MRTX1719, or AMG193.

[0194] One embodiment provides the method wherein at least one oncology therapeutic is a RAF / MEK dual inhibitor. Another embodiment provides the method wherein the RAF / MEK inhibitor is selected from avutometinib (VS-6766).

[0195] One embodiment provides the method wherein at least one oncology therapeutic is a SHP2 inhibitor. Another embodiment provides the method wherein the SHP2 inhibitor is selected from RLY-1971, ERAS-601, TNO155, or RMC-4630.

[0196] One embodiment provides the method wherein at least one oncology therapeutic is a S0S1 inhibitor. Another embodiment provides the method wherein the S0S1 inhibitor is selected from BI 1701963 or MRTX0902.

[0197] One embodiment provides the method wherein at least one oncology therapeutic is a FAK inhibitor. Another embodiment provides the method wherein the FAK inhibitor is selected from defactinib, narmafotinib, or IN100189.

[0198] One embodiment provides the method wherein at least one oncology therapeutic is a famesyltransferase inhibitor. Another embodiment provides the method wherein the famesyltransferase inhibitor is selected from lonafamib, tipifamib, or KO-2806.

[0199] One embodiment provides the method wherein at least one oncology therapeutic is a taxane. Another embodiment provides the method wherein the taxane is selected from paclitaxel, docetaxel, cabazitaxel, or abraxane.

[0200] One embodiment provides the method wherein at least one oncology therapeutic is a PARP inhibitor. Another embodiment provides the method wherein the PARK inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, or veliparib.

[0201] One embodiment provides the method wherein the cancer is breast cancer. Another embodiment provides the method wherein the breast cancer is a hormone receptor positive (HR+) breast cancer. Another embodiment provides the method wherein the breast cancer is aHER2+ breast cancer. Another embodiment provides the method wherein the breast cancer is a triple negative breast cancer (TNBC). Another embodiment provides the method wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.

[0202] One embodiment provides the method wherein the cancer is uterine cancer. Another embodiment provides the method wherein the cancer is uterine sarcoma.

[0203] One embodiment provides the method wherein the cancer is endometrial cancer.Another embodiment provides the method wherein the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

[0204] One embodiment provides the method wherein the cancer is cervical cancer. Another embodiment provides the method wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

[0205] One embodiment provides the method wherein the cancer is fallopian tube cancer (FTC). Another embodiment provides the method wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cell carcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

[0206] One embodiment provides the method wherein the cancer is prostate cancer. Another embodiment provides the method wherein the cancer is prostate adenocarcinoma. Another embodiment provides the method wherein the cancer is prostate transitional cell carcinoma. Another embodiment provides the method wherein the cancer is prostate squamous cell carcinoma. Another embodiment provides the method wherein the cancer is prostate small cell carcinoma. Another embodiment provides the method wherein the cancer is prostate lymphoma. Another embodiment provides the method wherein the cancer is prostate sarcoma.

[0207] One embodiment provides the method wherein the cancer is bladder cancer. Another embodiment provides the method wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non-urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma. Another embodiment provides the method wherein the cancer is urothelial cancer. Another embodiment provides the method wherein the cancer is squamous cell cancer of the bladder. Another embodiment provides the method wherein the cancer is small cell cancer of the bladder. Another embodiment provides the method wherein the cancer is adenocarcinoma of the bladder.

[0208] One embodiment provides the method wherein the cancer is lung cancer.

[0209] One embodiment provides the method wherein the cancer is non-small cell lung cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, squamous cell cancer. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenocarcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, large cell carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is small cell lung cancer. Another embodiment provides the method wherein the cancer is combined small cell lung cancer.

[0210] One embodiment provides the method wherein the cancer is rectal cancer. Another embodiment provides the method wherein the rectal cancer is adenocarcinoma. Another embodiment provides the method wherein the rectal cancer is quamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the rectal cancer is gastrointestinal stromal. Another embodiment provides the method wherein the rectal cancer is lymphoma. One embodiment provides the method wherein the cancer is colon cancer (CRC). Another embodiment provides the method wherein the cancer is CRC, adenocarcinoma. Another embodiment provides the method wherein the cancer is CRC, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is CRC, colon cancer. Another embodiment provides the method wherein the cancer is CRC, carcinoid. Another embodiment provides the method wherein the cancer is CRC, gastrointestinal stromal. Another embodiment provides the method wherein the cancer is CRC lymphoma.

[0211] One embodiment provides the method wherein the cancer is anal cancer. Another embodiment provides the method wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

[0212] One embodiment provides the method wherein the cancer is biliary cancer. Another embodiment provides the method wherein the biliary cancer is cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra-hepatic cholangiocarcinoma.

[0213] One embodiment provides the method wherein the cancer is a meningioma.

[0214] One embodiment provides the method wherein the cancer is a glioma.

[0215] One embodiment provides the method wherein the cancer is pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic ductal adenocarcinoma(PDAC). Another embodiment provides the method wherein the cancer is PDAC, adenocarcinoma. Another embodiment provides the method wherein the cancer is PDAC, acinar cell carcinoma. Another embodiment provides the method wherein the cancer is exocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is neuroendocrine pancreatic cancer. Another embodiment provides the method wherein the cancer is pancreatic cancer, squamous cell carcinoma. Another embodiment provides the method wherein the cancer is pancreatic cancer, adenosquamous carcinoma. Another embodiment provides the method wherein the cancer is pancreatoblastoma.

[0216] One embodiment provides the method wherein the cancer is thyroid cancer. Another embodiment provides the method wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

[0217] One embodiment provides the method wherein the cancer is parotid gland cancer.

[0218] One embodiment provides the method wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

[0219] One embodiment provides the method wherein the cancer is stomach cancer or gastric cancer. Another embodiment provides the method wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

[0220] One embodiment provides the method wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

[0221] One embodiment provides the method wherein the cancer is skin cancer. Another embodiment provides the method wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma. Another embodiment provides the method wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

[0222] One embodiment provides the method wherein the cancer is melanoma. Another embodiment provides the method wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

[0223] One embodiment provides the method wherein the cancer is ovarian cancer. Another embodiment provides the method wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

[0224] One embodiment provides the method wherein the cancer is renal cell cancer.

[0225] One embodiment provides the method wherein the cancer is an appendiceal cancer. Another embodiment provides the method wherein the cancer is appendiceal carcinoid tumor. Another embodiment provides the method wherein the cancer is appendiceal mucinous neoplasm. Another embodiment provides the method wherein the cancer is appendix adenocarcinoma. Another embodiment provides the method wherein the cancer is appendiceal adenocarcinoid or goblet cell appendiceal carcinoma. Another embodiment provides the method wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma, appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

[0226] One embodiment provides the method wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

[0227] One embodiment provides the method wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

[0228] One embodiment provides the method wherein the cancer is a sarcoma.

[0229] One embodiment provides the method wherein the cancer is a primary brain tumor. Another embodiment provides the method wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

[0230] One embodiment provides the method wherein the cancer is gallbladder cancer. Another embodiment provides the method wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

[0231] One embodiment provides the method wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

[0232] One embodiment provides the method wherein the cancer is germ cell tumor. Another embodiment provides the method wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

[0233] One embodiment provides the method wherein the cancer is plasma cell neoplasm. Another embodiment provides the method wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

[0234] One embodiment provides the method wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

[0235] One embodiment provides the method wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

[0236] One embodiment provides the method wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

[0237] One embodiment provides the method wherein the cancer is neuroendocrine carcinoma.

[0238] One embodiment provides the method wherein the cancer is cancer of unknown primary (CUP).

[0239] One embodiment provides the method wherein the cancer is locally advanced.

[0240] One embodiment provides the method wherein the cancer is metastatic.

[0241] One embodiment provides the method wherein the method is adjuvant therapy following surgical resection.

[0242] One embodiment provides the method wherein the method is neo-adjuvant therapy.

[0243] One embodiment provides the method wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

[0244] One embodiment provides the method wherein the patient has relapsed after prior therapy.

[0245] One embodiment provides the method wherein the patient has acquired resistance to prior therapy.

[0246] One embodiment provides the method wherein the patient is refractory to therapy.

[0247] One embodiment provides the method wherein the cancer is characterized by existence of KRAS mutation. Another embodiment provides the method wherein the KRAS mutation is selected from G12A, G12C, G12D, G12V, G13D, or a combination thereof. One embodiment provides the method, wherein the cancer further comprises an additional mutation. Another embodiment provides the method, wherein the cancer comprises at least one mutation selected from the group consisting of G12C, RAF del, NRAS del, RAFl-amp. Another embodiment provides the method, wherein the cancer comprises at least one mutation selected from the group consisting of KRAS G12D, PIK3CA-H1047R, EGFR-HI. Another embodiment provides the method, wherein the cancer comprises at least one mutation selected from the group consisting of KRAS G13D and EGFR-HI. One embodiment provides the method, wherein the cancer is characterized by KRAS-WT-amp.Compounds

[0248] Another of the heterocyclic KRAS inhibitors described herein is Compound 2, having the structure below, and the chemical name 5-ethynyl-6-fluoro-4-(8-fluoro-4-((lS,7S,8S)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine. The synthesis and characterization of Compound 2 was presented in International Patent Application No. PCT / US2024 / 047282.NH2Compound 2Pharmaceutical Compositions

[0249] In certain embodiments, the heterocyclic KRAS inhibitor Compound 1, or pharmaceutically acceptable salt or solvate thereof, is administered as a pure chemical. In other embodiments, the heterocyclic KRAS inhibitor Compound 1, or pharmaceutically acceptable salt or solvate thereof, is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable or acceptable excipient, a physiologically suitable or acceptable excipient, or a physiologically suitable or acceptable carrier) selected based on a chosen route of administration and standard pharmaceutical practice.

[0250] Provided herein is the method wherein the pharmaceutical composition comprising the heterocyclic KRAS inhibitor Compound 1, or pharmaceutically acceptable salt or solvate thereof is administered orally. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methyl cellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0251] Provided herein is the method wherein the pharmaceutical composition is administered by injection. In some embodiments, the heterocyclic KRAS inhibitor Compound 1, or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0252] The dose of the composition comprising the heterocyclic KRAS inhibitor Compound 1, or pharmaceutically acceptable salt or solvate thereof, differs depending upon thesubject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors. Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0253] In certain embodiments, the heterocyclic KRAS inhibitor of Formula (I), or pharmaceutically acceptable salt or solvate thereof, is administered as a pure chemical. In other embodiments, the heterocyclic KRAS inhibitor of Formula (I), or pharmaceutically acceptable salt or solvate thereof, is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable or acceptable excipient, a physiologically suitable or acceptable excipient, or a physiologically suitable or acceptable carrier) selected based on a chosen route of administration and standard pharmaceutical practice.

[0254] Provided herein is the method wherein the pharmaceutical composition comprising the heterocyclic KRAS inhibitor of Formula (I), or pharmaceutically acceptable salt or solvate thereof is administered orally. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methyl cellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0255] Provided herein is the method wherein the pharmaceutical composition is administered by injection. In some embodiments, the heterocyclic KRAS inhibitor of Formula (I), or pharmaceutically acceptable salt or solvate thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0256] The dose of the composition comprising the heterocyclic KRAS inhibitor of Formula (I), or pharmaceutically acceptable salt or solvate thereof, differs depending upon thesubject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors. Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.EXAMPLES

[0257] The following illustrative examples are representative of embodiments of the software applications, systems, and methods described herein and are not meant to be limiting in any way.

[0258] “Ras” refers to a protein in the Ras superfamily of small GTPases, such as in the Ras subfamily. Ras proteins are small guanine nucleotide-binding proteins that act as molecular switches by cycling between active GTP -bound and inactive GDP -bound conformations. The Ras proteins play a critical role in the regulation of cell behaviors, including proliferation, differentiation, and survival. Mutation of any one of the three Ras isoforms (K-Ras, N-Ras, or H-Ras) has been shown to lead to oncogenic transformation, and in fact, K-Ras mutations are by far the most common in human cancers. KRAS G12V, G12D, and G12S variants are common in human cancers and Ras inhibitors binding in or near the Switch II pocket may provide mutant binding selectivity. RAS mutations are known to be often associated with pancreatic, colorectal and non-small-cell lung carcinomas (Lone, A. M. et al. J. Am. Chem. Soc. 2011, 133, 11665-74, which is entirely incorporated herein by reference; Dillon, M. B.; Bachovchin, D. A.; Brown, S. J.; Finn, M. G.; Rosen, H.; Cravatt, B. F.; Mowen, K. A. ACS Chem. Biol. 2012, 7, 1198-204, which is entirely incorporated herein by reference; Bachovchin, D. A.; Brown, S. J.; Rosen, EL; Cravatt, B. F. Nat. Biotechnol. 2009, 27, 387-94, Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K. M. Nature 2013, 503, 548-551. Ryan M.B. and Corcoran R.B, Nat. Rev Clin Onco. 2018, 11, 709-720.). Ras proteins are key members in the Ras / Raf / Mitogen-activated protein kinase (MAPK) signaling pathway. This pathway regulates a wide variety of cellular processes, including proliferation, differentiation, apoptosis, and stress responses. One way to measure the impact of an inhibitor of Ras proteins is to measure downstream phosphorylation of proteins in the MAPK pathway. The MAPK pathway includes extracellular signal-regulatedkinases named ERK1 and ERK2, which are serine-threonine kinases that regulate cellular signaling under both normal and oncogenic conditions. ERK expression and hyperactivation via phosphorylation plays a major role in cancer progression and are downstream of Ras proteins.Example 1: Biochemical Assay

[0259] Compound 1 was tested in biochemical assays to assess activity against GTPase family members in multiple independent experiments.TR-FRET Protein-Protein Interaction Assay

[0260] The effect of compound 1 on KRAS:CRAF protein: protein interaction (PPI) was measured via time-resolved fluorescence resonance energy transfer (TR FRET) assay, which uses a signal generated through fluorescent resonance energy transfer between a donor and an acceptor molecule when in close proximity to each other. For this assay, terbium cryptate (Tb)-tagged anti FLAG antibody was used as the donor (emission 620 nm) and XL665 labeled streptavidin (SA XL665) was used as the acceptor (emission 665 nm).

[0261] Compound 1 was dissolved in dimethyl sulfoxide (DMSO) to create a 0.3 mM or 1 mM stock solution. A 36 pL volume of compound 1 stock solution was transferred to a 384 well polypropylene compound source plate using the Tecan EV0200 liquid handler. A 3 fold, 10 point dilution was performed by transferring 12 pL of compound 1 solution into 24 pL of DMSO using the Apricot liquid handler. The compound source plate was centrifuged at 1000 rpm for 1 minute at room temperature before compound transfer.

[0262] Assay Buffer A was prepared with 25 mM HEPES (pH7.3), 0.002% polysorbate 20 (Tween 20), 0.1% bovine serum albumin, 100 mM sodium chloride, 5 mM magnesium chloride, and 10 pM GMP PNP. A 4X KRAS solution was prepared with 80 nM of biotin-tagged, GMP PNP loaded KRAS G12C, KRAS G12D, KRAS G12V, or KRAS WT protein in Assay Buffer A. A 4X CRAF RBD solution was prepared with 400 nM FLAG tagged CRAF RBD in Assay Buffer A. A 2X Detection Mixture was prepared with 2 nM Tb tagged anti FLAG antibody and 10 nM SA XL665 in Assay Buffer A. A 100 nL volume of lOOx compound 1 working solution or DMSO vehicle control was transferred from the compound source plate into each well (duplicate for each concentration) of a 384 well ProxiPlate Plus assay plate for a final 3 pM or 10 pM top concentration and 1% DMSO concentration. A 2.5 pL volume of 4X KRAS solution was added to each well of the assay plate for a final concentration of 20 nM biotin-tagged, GMP PNP loaded KRAS G12C / D / V or KRAS WT protein. For the low control, 2.5 pL of Assay Buffer A without KRAS protein was added. The assay plate was pre incubated for 30 minutes at room temperature.

[0263] Following pre incubation of compound 1 or DMSO with biotin-tagged, GMP PNP loaded KRAS G12C / D / V or KRAS WT protein, a 2.5 pL volume of 4X CRAF RBD solutionwas added to each well of the assay plate for a final concentration of 100 nM FLAG tagged CRAF RBD. The assay plate was centrifuged at 1000 rpm for 1 minute and then pre incubated for 150 minutes at room temperature. Following pre incubation with FLAG tagged CRAF RBD, a 5 pL volume of 2X Detection Mixture was added to each well of the assay plate for a final concentration of 1 nM Tb tagged anti FLAG antibody and 5 nM SA XL665. The assay plate was centrifuged at 1000 rpm for 1 minute and then incubated for 90 minutes at room temperature.

[0264] TR FRET signal was measured on a microplate reader set up for excitation at 340 nm and detection of fluorescence emission at 665 nm and 620 nm. TR FRET ratios were calculated by dividing the acceptor emission value (665 nm) by the donor emission value (620 nm) for each sample. Percent inhibition was calculated by multiplying the normalized TR FRET ratio by 100. IC50 values were calculated from normalized TR FRET ratios with the Levenberg-Marquardt 4 parameter fitting procedure and reported in Table 1.Table 1KRAS (G12D):CRAF TR-FRET PPI IC50Compound 1 9.9Example 2: Cellular AssayNanoBRET Assay

[0265] The effect of compound 1 on KRAS:CRAF protein: protein complexes in cellular contexts was measured via nano- bioluminescence resonance energy transfer (NanoBRET). The NanoBRET assay harnesses bioluminescence arising from aNanoLuc® Luciferase and HaloTag® protein interacting in distances permitting the production of bioluminescent signal. HEK293 cells were cultured in 90% DMEM with 10% fetal bovine serum. Cells were plated at appropriate densities for transfection with KRAS-mutant and CRAF RBD protein constructs. Transfection mixtures were created by mixing 3x plasmid constructs to 100 ng / pl. Lipid:DNA mixtures were prepared by combining 100 pL total of two plasmid mixtures containing the KRAS-mutant construct, CRAF, and luciferase enzyme with 30 pL FuGENE HD in OptiMEM. Mixtures were incubated for 10 minutes at room temperature before addition to cells.The next day, cells were dissociated and replated in assay medium containing 99% Opti-MEM® Reduced Serum Medium without phenol red and including 4% fetal bovine serum. Cells were plated on white, opaque 384-well plates and incubated overnight. On the final day of assay, compound was acoustically dispensed to the opaque 384-well plates. After compound incubation, 10 pL of NanoGLO Live Cell substrate was added and incubated for the given periods of time. Bioluminescent signal was read by a plate reader. Signals were normalized and IC50 values determined from normalized values and reported in Table 2.Table 2Compound 1 ECsoNanoBRET 2 hours 6 hours 8 hoursKRAS 2 2 4G12D:CRAFKRAS — 2 2G12V:CRAFKRAS 0.9 1.5 1.4G12GCRAFRAS Selectivity in Ba / F3 cells

[0266] An isogenic system using Ba / F3 cells, a murine interleukin 3 (IL-3) dependent pro B cell line, was used to study the effect of compound 1 on oncogene-driven cell proliferation in vitro. Ba / F3 cells were engineered to express various KRAS, HRAS, or NRAS alterations. A Ba / F3 cell line expressing an oncogenic valine-to-glutamate substitution in codon 600 of v-Raf murine sarcoma viral oncogene homolog B (BRAF V600E) was used to evaluate compound 1 effects on cell proliferation controlled by non-RAS oncogenic driver mutations, and a parental Ba / F3 cell line driven by exogenous IL-3 was used as a control.

[0267] The effects of compound 1 on cell proliferation were measured using the CellTiter-Glo® cell viability assay (CTG). CTG determines the number of viable cells by quantifying adenosine triphosphate (ATP), which indicates the presence of metabolically active cells. The light emitted by luciferase during ATP-dependent oxidation of luciferin is used to generate a luminescent signal proportional to the amount of ATP present.

[0268] Ba / F3 cells were harvested during the logarithmic growth period. Cells were counted, >90% cell viability was determined using a trypan blue assay, and cell concentrations were adjusted with culture medium. A 90 pL volume of cell suspension was added to each well of 96 well plates to obtain a final cell density of 3.0 x 103 cells / well. Plates were incubated in a humidified incubator at 37°C and 5% CO2.

[0269] Compound 1 was dissolved in DMSO to create a 10 mM stock solution. A 3.16-fold diluted 1000x solution of compound 1 was prepared using DMSO to generate intermediate solutions of 1.0 to 10000 pM compound 1 in 100% DMSO. These DMSO solutions were then diluted 100-fold with culture medium to 10x working solutions of 0.01 to 100 pM compound 1 in 1% DMSO. A 10x vehicle control solution of 1% DMSO in culture medium was also prepared.A volume of 10 pL of 10* compound 1 working solution or vehicle control solution was dispensed to each well (triplicate for each concentration) of the cell plates (each containing 90 pL of medium), yielding 9 concentrations of compound 1 from 1.0 nM to 10000 nM with a final DMSO concentration of 0.1%. Culture medium alone (no cells) was used as a blank control. Cell plates were cultured for 3 days.

[0270] On Day 3, CellTiter-Glo® reagent was thawed and cell plates were equilibrated at room temperature for approximately 30 minutes. A 100 pL volume of CellTiter-Glo® reagent was then added to each well, which was equal to the volume of cell culture medium present in each well. Contents were mixed for 5 minutes on an orbital shaker to induce cell lysis. Cell plates were allowed to incubate at room temperature for 20 minutes to stabilize the luminescent signal. Luminescence was then recorded using a CLARIOstar Plus microplate reader.

[0271] Percent cell viability was calculated by multiplying the normalized luminescence signal by 100. IC50 values were calculated from % cell death with the Levenberg-Marquardt 4 parameter fitting procedure and reported in Table 3.Table 3Ba / F3 Compound 1 EC50 (nM)Mutation NRAS HRAS KRASG12V 4722 3010 1.0G12D 4609 2499 2.9G12C 3077 1497 0.8G12A 2651 644 0.9Q61H 4415 2122 0.6BRAF V600E 6024p-ERK Cellular Assay

[0272] The effect of compound on target signaling was measured by assessing inhibition of the KRAS pathway biomarker, phosphorylated extracellular signal-regulated kinase (p-ERK), in human cancer cells. Phosphorylation of extracellular signal -regulated kinase (ERK) was measured using homogeneous time resolved fluorescence (HTRF), which uses a signal generated through fluorescent resonance energy transfer between a donor and an acceptor molecule. ERK phosphorylation occurs at threonine 202 and tyrosine 204 (T202 / Y204) residues in the ERK1 isoform and threonine 185 and tyrosine 187 (T185 / Y187) residues in the ERK2 isoform; in this format, p-ERK is used to refer to ERK1 phosphorylated at T202 / Y204 residues and ERK2 phosphorylated at T185 / Y187 residues, which were simultaneously measured by the assay.

[0273] Various cell lines containing different KRAS mutation or wildtype (WT) KRAS were diluted to the desired concentration per well based on a growth curve showing -75% confluence within 24 hours. A 24 pL volume of cell suspension was added into each well of poly-D-lysine coated 384 well plates or 384 well TC-treated plates and incubated at 37°C and 5% CO2 overnight for a minimum of 12 or 24 hours. The final seeding density was 8 * 103cells / well. Compound 1 was dissolved in DMSO to create a 10 mM stock solution. A 45 pL volume of stock solution was transferred to a 384-well polypropylene plate. A 3 -fold, 10-point dilution was performed by transferring 15 pL of compound 1 solution into 30 pL of DMSO. Cell plates were removed from the incubator, and 25 nL / well of the serial dilution of compound 1 was transferred to 24 pL of cells with a final DMSO concentration of 0.1% in all wells.

[0274] Plates were then removed from the incubator, and cells were lysed with 4X lysis buffer (lx phosphatase inhibitor cocktail included) from the kit reagents. An 8 pL volume of lysis buffer was dispensed to each well. Plate contents were mixed well on a plate shaker and incubated for 45 minutes for complete lysis. A 4 pL volume of Advanced Phospho-ERKl / 2 d2 fluorophore-conjugated antibody working solution and 4 pL of Advanced Phospho-ERKl / 2 Europium Cryptate antibody working solution (prepared in detection buffer) were added to each lysed well. The plates were incubated overnight at room temperature before reading. A 25 pL volume of the mix was transferred from the poly-D-lysine coated 384 well cell plate or 384 well black cell plate to a 384-well Optiplate reader plate and read using an EnVison plate reader.

[0275] HTRF ratios were calculated by dividing the acceptor-emission value by the donoremission value for each sample. Percent inhibition was calculated by multiplying the normalized HTRF ratio. The IC50 values were calculated from normalized HTRF ratios with the Levenberg-Marquardt 4 parameter fitting procedure. Table 4 provides pERK EC50 values for compound 1 with 1-hour incubation time across multiple cell lines. Table 5 provides pERK EC50 values for compound 1 at 2-, 8-, and 24-hour incubation time periods across multiple cell lines. Table 52 provides pERK IC50 values for compound 1 at 1 hour and / or 24-hour incubation time periods across multiple cell lines. Fig. 1 provides a time course of inhibition with compound 1 in various cell lines compared to BI-2493.Table 4KRAS Mutation Cell Line Compound 1ECso (nM)G12D HP AC* 0.5AsPCl* 1.6AGS 0.5KRAS Mutation Cell Line Compound 1ECso (nM) GP2d 0.2HPAF-II 0.7G12V NCI-H441* 0.6NCI-H727* 0.7Capan2 0.8SW403 0.9SW620 0.4G12C MiaPaCa2* 0.2NCI-H358* 0.4NCI-H2122 1.6G12A NCI-H2009* 0.2G12S A549 0.9G13D HCT-116 0.6Q61H NCI-H460 0.2Hs766T 0.8WT amplified MKN1 0.5BRAF CL I A375 10000 BRAF CL II NCI-H2405 10000 BRAF CL III WM3629 10000 EGFR exl9del HCC827 6459Note:* indicates selected for in vivo tumor xenograft model.Table 5Compound 1 ECso (nM)2 hours 8 hours 24 hours MiaPaCa-2 0.2 0.8 1NCI-H358 0.4 2.6 7.5AsPC-1 2.8 8.5 18.4 HPAC 0.8 2.2 9.5A549 0.6 1 2.5NCI-H441 0.7 2.3 7.3NCI-H727 1.8 4.5 4.5NCI-H2009 0.4 0.9 1.3Table 52KRAS 1 hr, IC50 24 hrs, IC50Cell LineMutation pERK pERKKRAS-G12C, SW837 0.73 1.51RAF del, NRASdelKRAS-G12C, SW1463 0.29 29.11RAFI -ampKRAS-G12D LS180 1.59 35.42KRAS-G12D, LS513 0.89 45.07PIK3CA- H1047RKRAS-G12V SW403 0.91 8.42KRAS-G12V SW620 0.41 1.49KRAS-G13D LoVo 0.17 3.91KRAS-G13D, NCI-H747 0.16 2.07EGFR-HIKRAS-G12D, GP2d - 1.69EGFR-HIKRAS-G12C NCI-H2122 - 1.42KRAS-G13D HCT-116 - 11.29KRAS-WT-amp MKN1 - 1.26amp = amplification mutation (i.e., increase in the number of copies of a gene)del = deletion mutation (i.e., removal of copies of a gene)EGFR-HI = elevated EGFR expressionExample 3: Evaluation of the Antitumor Activity of Compound 1 in Xenograft Mouse Models

[0276] Mice were subcutaneously inoculated unilaterally on the right flank with indicated cells in 0.1 mL of 1 : 1 medium / Matrigel for tumor development or with patient-derived xenograft fragments from stock mice once pre-study tumors reached 1000 - 1500 mm3. Animals were monitored daily throughout the study for any abnormalities of behavior and appearance including mobility, food and water consumption, body weight, eye appearance, hair matting, and any other abnormal observations. Any mortality and / or abnormal clinical signs were recorded. Body weights of all animals were measured and recorded 3x weekly or daily. Tumor size was measured by digital caliper and recorded 3x weekly. Treatment was started when the mean tumor volume (TV) reached approximately 150 to 250 mm3. Animals were dosed via oral gavage with vehicle or compound twice daily (BID) at concentrations and for durations as indicated. Doses were administered 12 hours apart.

[0277] Animals were humanely euthanized if they showed obvious signs of severe distress and / or pain. Any tumor-bearing animal had to be euthanized according to the Institutional Animal Care and Use Committee conditions of each institution. Conditions include: any animal with a single observation of >20% body weight loss (compared to first day of treatment); TV >10% of body weight (e.g., 2000 mm3for a 20 g mouse); the tumor became ulcerated or necrotic (animals with red tumors were to be recorded and monitored; animals with tumors that were ulcerated but had intact skin were to be recorded and monitored closely, i.e. twice daily; animals with tumors that were ulcerated and weeping and / or had holes were to be culled).Additional conditions include whether the animal’s ability to eat or drink was impaired; the animal’s ability to ambulate normally was impaired; the animal’s breathing was labored. If euthanasia criteria were not met, animals were euthanized after administration of the final dose and completion of final in vivo evaluations. Animals were humanely sacrificed by CO2 inhalation followed by cervical dislocation to ensure death.

[0278] Plasma samples for PK analysis were collected at 0.5, 1, 3, 7, 12, and 24 hours post dose (n=3 / group / time point), and tumor samples for PD analysis were collected at 3, 7, 12, and 24 hours post dose (n=3 / group / time point). Compound 1 plasma concentrations were measured using liquid chromatography with tandem mass spectrometry (LC-MS / MS), and free (unbound) compound 1 plasma concentrations were calculated.

[0279] Frozen tumor fragments were pulverized in a mortar with liquid nitrogen, and approximately 10 mg of pulverized tissue each was transferred into Eppendorf tubes containing 200 pL of pre chilled RIPA buffer with protease and phosphatase inhibitor. Another 300 pL of RIPA buffer with protease and phosphatase inhibitor was added, and tube contents were vortex mixed. The lysis buffer-tumor tissue mixture was kept on ice for 30 minutes with vortex mixing every 10 minutes; tubes were then placed in an -80°C freezer overnight. Samples were thawedon ice and then centrifuged at 13000 rpm for 20 minutes at 4°C. The supernatant was transferred into fresh Eppendorf tubes and kept on ice. Protein concentrations were determined with a bicinchoninic acid assay. Plates coated with capture antibody were blocked with blocking reagent at room temperature for 60 minutes. Plates were then washed 3 times with 150 pL of IX wash buffer. The samples were transferred to the plates and incubated at room temperature with shaking for 180 minutes. Plates were then washed 3 times with 150 pL of IX wash buffer. A 25 pL volume of detection antibody in antibody dilution buffer with blocker was added to each well, and plates were incubated at room temperature with shaking for 60 minutes. Plates were then washed 3 times with 150 pL of IX wash buffer. A 150 pL volume of IX MSD read buffer T was added to each well, and plates were read using a MSD MESO Scale Discovery Sector Imager 6000.10.6.2.

[0280] Ribonucleic acid (RNA) was purified from the tumor fragments in RNAlater® solution using the PureLink RNA Mini Kit. The RNA was reverse-transcribed into complementary deoxyribonucleic acid (cDNA) using the High Capacity RNA-to-cDNA Kit. To generate the RT Reaction Mix, a 2 pg amount of RNA was added to 10 pL of 2X RT Buffer Mix and 1 pL of 20X RT Buffer Mix, and sufficient nuclease free water was added to bring the total volume up to 20 pL. The lid of the thermocycler was brought to 110°C, and the RT Reaction Mix was placed into the thermocycler and incubated at 37°C for 1 hour. The reaction was then stopped by heating the mix to 95°C for 5 minutes. The RT Reaction Mix with cDNA was then held at 4°C until being stored at -20°C. For qPCR, all components of the PCR Reaction Mix were thawed in an ice-water bath and kept in the ice-water bath throughout preparation of the mix. A 10 pL volume of PCR Reaction Mix was prepared by combining 5 pL of 2X TaqMan Fast Advanced Master Mix, 0.5 pL of 20X GAPDH probe, 0.5 pL of 20X DUSP6 probe, 2 pL of sample cDNA template, and 2 pL of nuclease-free water. A 10 pL volume of PCR Reaction Mix containing sample cDNA template was added to each well of the PCR reaction plate. The lid of the qPCR system was brought to 105°C and the fluorescence gain was set to IX. The PCR reaction plate was placed in the qPCR system and incubated at 50°C for 2 minutes, held at 95°C for 20 seconds, and then run through 40 cycles of 1 second at 95 °C followed by 20 seconds at 60 °C.

[0281] Table 6 and Fig. 2 provide the results from the NCI-H2009 lung cancer xenograft.

[0282] Table 7 and Fig. 2 provide the results from the NCI-H358 lung cancer xenograft.

[0283] Table 8 and Fig. 2 provide the results from the MiaPaca-2 pancreatic cancer xenograft.

[0284] Table 9 and Fig. 3 provide the results from the HP AC pancreatic cancer xenograft.

[0285] Table 10 and Fig. 3 provide the results from the AsPC-1 pancreatic cancer xenograft.

[0286] Table 11 and Fig. 4 provide the results from the NCI-H441 lung cancer xenograft.

[0287] Table 12 and Fig. 4 provide the results from the NCI-H727 lung cancer xenograft.Table 6Antitumor Activity and PK / PD Relationship of Compound 1 in NCI-H2009 Human Lung Cancer Xenograft Model in NOD SCID MiceTreatment Tumor Tumor DT / DCb(%) TGIb(%) PcP Value SizeaSizea(mm3) (mm3)at PG-D0 at PG- D21G1 Vehicle, 20% 167±9 2660±144dPEG400, 10% solutolin pH 4.0 citrate buffer,PO, BIDG2 Compound 1 168±9 338±30 7 93 **** <0.0001 10 mg / kg, PO, BIDG3 Compound 1 168±10 125±16 -2 102 **** <0.0001 30 mg / kg, PO, BIDG4 Compound 1 167±8 35±2 -5 105 **** <0.0001 100 mg / kg, PO, BIDG5 Compound 1 167±8 32±2 -5 105 **** <0.0001 200 mg / kg, PO, BIDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. The tumor volume for vehicle group was measured on PG-D19. According to the termination criteria, the mice of Gl-46# was humanely euthanized on PG-D17.Table 7Antitumor Activity of Compound 1 in NCI-H358 Human Lung Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(% TGIb(% P p SizeaSizea) ) Valuec(mm3) (mm3)at PG- at PG- D0 D28dG1 Vehicle, 20% PEG400, 201±l 1356±3110% solutol in pH 4.0 8 0citrate buffer, PO, BIDG2 Compound 1 201±l 248±76 4 96 *** 0.0002 10 mg / kg, PO, BID 6G3 Compound 1 201±l 46±9 -13 113 *** <0.0001 30 mg / kg, PO, BID 7 *G4 Compound 1 201±l 20±3 -16 116 *** <0.0001 100 mg / kg, PO, BID 8 *G5 Compound 1 201±l 11±2 -16 116 *** <0.0001 200 mg / kg, PO, BID 8 *Note:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. The mice of G1 and G6 taken down on PG-D21 per protocol. According to the termination criteria, the mouse of Gl-82# with tumor volume more than 10% body weight was euthanized on PG-D12Table 8Antitumor Activity of Compound 1 in MiaPaca-2 Human Pancreatic Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(%) TGIb’e(%) P P Value SizeaSizea(mm3) (mm3)atPG- atPG- D0 D53dG1 Vehicle, 20% 202±l 2112±169ePEG400, 10% solutol in 1pH4.0 citrate buffer, PO,BIDG2 Compound 1 203±l 89±34 -6 106 **** <0.0001 30 mg / kg, PO, BID 0G3 Compound 1 203±9 10±5 -10 110 **** <0.0001 100 mg / kg, PO, BIDG4 Compound 1 203±l 0±0 -11 111 **** <0.0001 200 mg / kg, PO, BID 1Note:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. G1 were taken down on PG-D38. According to the termination criteria, the mice of Gl-33#, Gl-74# and Gl-63# were humanely euthanized on PG-D27, PG-D28 and PG-D30, respectively. Gl-35# and Gl-79# were humanely euthanized on PG-D35, Gl-12#, Gl-20# and Gl-62# on PG-D38. G4-82# were taken down on PG-D46 due to the hypothermia.e. G1 mean tumor size calculated using the Vehicle TV final of all G1 animals.Table 9Antitumor Activity of Compound 1 in HPAC Human Pancreatic Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(%) TGIb(%) Pcp SizeaSizeaValue (mm3) (mm3)at PG- at PG- D0 D21G1 Vehicle, 20% PEG400, 211±1 1580±1010% solutol in pH4.0 3 5citrate buffer, PO, BIDG2 Compound 1 212±1 707±67 36 64 *** <0.000 10 mg / kg, PO, BID 4 * 1 G3 Compound 1 212±1 322±42 8 92 *** <0.000 30 mg / kg, PO, BID 6 * 1 G4 Compound 1 212±1 70±8 -10 110 *** <0.000 100 mg / kg, PO, BID 4 * 1 G5 Compound 1 212±1 52±8 -12 112 *** <0.000 200 mg / kg, PO, BID 5 * 1 Note:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.Table 10Antitumor Activity of Compound 1 in AsPC-1 Human Pancreatic Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(%) TGIb(%) P P SizeaSizeaValue (mm3) (mm3)at PG- at PG- D0 D23G1 Vehicle, 20% PEG400, 201±14 893±6210% solutol in pH4.0 citratebuffer, PO, BIDG2 Compound 1 201±15 572±103 54 46 * 0.0118 10 mg / kg, PO, BIDG3 Compound 1 201±13 541±66 49 51 ** 0.0032 30 mg / kg, PO, BIDG4 Compound 1 201±15 245±31 6 94 **** <0.0001 100 mg / kg, PO, BIDG5 Compound 1 201±14 65±3 -20 120 **** <0.0001 200 mg / kg, PO, BIDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. The mice of G1 and G5 taken down on PG-D21 per protocol.Table 11Antitumor Activity of Compound 1 vs BI-2493 in NCI-H441 Human Lung Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(% TGIb(% Pcp SizeaSizea) ) Value (mm3) (mm3)at PG- at PG- D0 D28dG1 Vehicle, 20% PEG400, 202±2 3022±2010% solutol in pH4.0 3 9citrate buffer, PO, BIDG2 Compound 1 202±l 898±103 25 75 *** <0.000 10 mg / kg, PO, BID 8 * 1 G3 Compound 1 202±l 324±55 4 96 *** <0.000 30 mg / kg, PO, BID 8 * 1G4 Compound 1 202±l 41±5 -6 106 *** <0.000 100 mg / kg, PO, BID 8 * 1 G5 Compound 1 203±l 15±2 -7 107 *** <0.000 200 mg / kg, PO, BID 9 * 1 G6 B 1-2493 203±l 688±79 17 83 *** <0.000 90 mg / kg, PO, BID 7 * 1 Note:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated final-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. According to the termination criteria, the tumor volume of Gl-84# was more than 10% body weight, the mouse was humanely euthanized on PG-D25, and the last tumor volume was measured on PG- D25.Table 12Antitumor Activity of Compound 1 vs BI-2493 in NCI-H727 Human Lung Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(%) TGIb(%) PcP SizeaSizeaValue (mm3) (mm3)at PG- at PG- D0 D28G1 Vehicle, 20% 199±14 2123±388dPEG400, 10% solutol inpH4.0 citrate buffer, PO,BIDG2 Compound 1 200±10 1357±63 60 40 *** 0.0001 10 mg / kg, PO, BIDG3 Compound 1 200±10 343±61 7 93 **** <0.0001 30 mg / kg, PO, BIDG4 Compound 1 200±10 12±2 -10 110 **** <0.0001 100 mg / kg, PO, BIDG5 Compound 1 201±9 1±1 -10 110 **** <0.0001 200 mg / kg, PO, BIDG6 B 1-2493 200±10 1142±94 49 51 **** <0.0001 90 mg / kg, PO, BIDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. According to the termination criteria, the tumor volume of Gl-54# was more than 10% body weight, the mouse was humanely euthanized on PG-D21. G1 were taken down on PG-D24 and the last tumor volume was measured on PG-D23.

[0288] Table 13 and Fig. 5 provide the results from the long duration NCI-H441 lung cancer xenograft. These results support the conclusion that compound 1 provides durable regressions.Table 13Antitumor Activity of Compound 1 in NCI-H441 Human Lung Cancer Xenograft Model in BALB / c Nude MiceTreatment Tumor Tumor DT / DCb(%) TGIb(%) P p SizeaSizeaValuec(mm3) (mm3)at PG-D0 at PG- D61dG1 Vehicle, 20% 202±17 2469±341PEG400, 10% solutolin pH4.0 citrate buffer,PO, BIDG2 Compound 1 202±18 2094±253 83 17 ** 0.0081 10 mg / kg, PO, BIDG3 Compound 1 202±18 1017±203 36 64 **** <0.0001 30 mg / kg, PO, BIDG4 Compound 1 202±16 61±23 -6 106 **** <0.0001100 mg / kg, PO, BIDG5 Compound 1 203±16 13±1 -8 108 **** <0.0001 200 mg / kg, PO, BIDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant. Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. G1 and G2 were taken down on PG-D20, PG-D41 and PG-21, the last tumor measurement day was PG-D19, PG-D40 and PG-D21, respectively.

[0289] Table 14, Table 23, Figure 10A, and Figure 10B provide the results from SW403 colorectal cancer.

[0290] Table 15, Table 24, Figure 11 A, and Figure 1 IB provide the results from SW620 colorectal cancer.

[0291] Table 16, Table 25, Figure 12A, and Figure 12B provide the results from GP2d colorectal cancer.

[0292] Table 17, Table 26, Figure 13 A, and Figure 13B provide the results from NCI-H727 non-small cell lung cancer.

[0293] Table 18, Table 27, Figure 14A, and Figure 14B provide the results from LoVo colorectal cancer.

[0294] Table 19, Table 28, Figure 15 A, and Figure 15B provide the results from LSI 80 colorectal cancer.Table 14. Provides the results from the SW403 Human Colon Adenocarcinoma xenograftAntitumor Activity of Compound 1 and RMC-6236 in SW403 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor Size3Tumor Size3p Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) PValuecat PG-D0 at PG-D28G1 Vehicle, 20%PEG400,10% solutol HS-15 in citrate 163±15 1237±141 - - - - buffer pH4.0, PO, BID****G2 Compound 1, 163±15 739±84 54 46 <0.000130 mg / kg, PO, BIDG3 Compound 1,163±17 164±36 0 100 **** <0.0001 100 mg / kg, PO, BIDG4 Compound 1,164±14 54±10 -10 110 **** <0.0001 200 mg / kg, PO, BIDG5 RMC-6236,163±13 131±28 -3 103 **** <0.0001 5 mg / kg, PO, QDG6 RMC-6236,163±14 39±3 -12 112 **** <0.0001 25 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significantTwo-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.Table 15. Provides the results from the SW620 Human Colon Adenocarcinoma xenograftAntitumor Activity and PKPD Relationship of Compound 1 in SW620 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) pc P Value at PG-D0 at PG-D21G1 Vehicle, 20%PEG400, 10%solutol in pH4.0 citrate buffer, PO, 159±12 2598±216d- - - - BIDG2 Compound 1, 30 mg / kg. PO,159±12 887±117 30 70 **** <0.0001 BIDG3 Compound 1, 100 mg / kg. PO,159±13 530±45 15 85 **** <0.0001 BIDG4 Compound 1, 200 mg / kg. PO,159±13 406±40 10 90 **** <0.0001 BIDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.d. The tumor volume for G1 was measured on PG-D19. According to the termination criteria 3.3.3,the mice of Gl-12# and Gl-45# were humanely euthanized on PG-D18.Table 16. Provides the results from the GP2d Human Colon Adenocarcinoma xenograftAntitumor Activity of Compound 1 and RMC-6236 in GP2d Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) P P ValuecatPG- at PG-D28D0G1 Vehicle, 20% PEG400, 10% solutol HS- 179±15 1592±184 - - - - 15 in citrate buffer pH4.0, PO, BIDG2 Compound 1,181±17 307±47 9 91 **** <0.0001 30 mg / kg, PO, BIDG3 Compound 1,180±16 139±22 -3 103 **** <0.0001 100 mg / kg, PO, BIDG4 Compound 1,181±15 64±5 -8 108 **** <0.0001 200 mg / kg, PO, BIDG5 RMC-6236,180±16 419±89 17 83 **** <0.0001 5 mg / kg, PO, QDG6 RMC-6236,181±18 77±18 -7 107 **** <0.0001 25 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle fmal-TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significantTwo-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.Table 17. Provides the results from the NCI-H727 Human Lung Cancer xenograft Antitumor Activity of Compound 1 and RMC-6236 NCI-H727 Human Lung Cancer Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3TGITreatment (mm3) (mm3) DT / DCb(%)bpc P Valuee(%)atPG- atPG- D0 D28dG1 Vehicle, 20% PEG400, 10% solutol in171±13 2145±186 - - - - pH4.0 citrate buffer, PO, BIDG2 Compound 1, 30 mg / kg, PO, BID 170±14 380±60 11 89 **** <0.0001 G3 Compound 1, 100 mg / kg. PO, BID 171±13 22±3 -8 108 **** <0.0001 G6 RMC-6236, 3 mg / kg, PO, QD 171±15 1017±140 43 57 **** <0.0001 G7 RMC-6236, 5 mg / kg, PO, QD 170±13 714±162 28 72 **** <0.0001 G8 RMC-6236, 25 mg / kg, PO, QD 170±12 10±2 -8 108 **** <0.0001Note:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. G1 was taken down on PG-D25, G4 and G5 were taken down on PG-D21;e. Gl, G4 and G5 mean tumor size calculated using the Vehicle TV final of animals.Table 18. Provides the results from the LoVo Human Colon Adenocarcinoma xenograftAntitumor Activity of Compound 1 and RMC-6236 in LoVo Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3p Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) pc Value at PG- at PG- D0 D28dGl Vehicle, 20% PEG400, 10% solutol in194±15 1872±203 - - - - pH4.0 citrate buffer, PO, BIDG2 Compound 1,193±17 80±10 -7 107 **** <0.0001 60 mg / kg, PO, BIDG3 Compound 1,193±16 51±8 -8 108 **** <0.0001 100 mg / kg, PO, BIDG4 Compound 1,193±15 41±4 -9 109 **** <0.0001 200 mg / kg, PO, BIDG5 RMC-6236,194±16 1095±163 54 46 **** <0.0001 10 mg / kg, PO, QDG6 RMC-6236,194±15 508±38 19 81 **** <0.0001 25 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. The mice of G10 taken down on PG-D23 per protocol.Table 19. Provides the results from the LSI 80 Human Colon Adenocarcinoma xenograftAntitumor Activity of Compound 1 in LS180 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) pc p Value atPG- atPG- D0 D21dG1 Vehicle, 20% PEG400, 10% solutol in150±8 2757±143 - - - - pH4.0 citrate buffer, PO, BIDG2 Compound 1,151±7 2093±109 74 26 *** 0.0003 30 mg / kg, PO, BIDG3 Compound 1,150±7 2378±230 85 15 **** <0.0001 60 mg / kg, PO, BIDG4 Compound 1,151±7 2068±159 74 26 **** <0.0001 100 mg / kg, PO, BIDG5 Compound 1,150±7 1524±73 53 47 **** <0.0001 200 mg / kg, PO, BIDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. The mice of G1 taken down on PG-D11, G2 and G6 on PG-D13, G3 on PG-D16, G4 on PG-D18 perprotocol.

[0295] Results from the patient-derived xenograft of NSCLC CTG-1358 (G12V) and NSCLC CTG-2803 (G12D) are provided in Table 20 and Table 21, respectively, and Fig. 6. In the CTG-1358 xenograft, administration of compound 1 was stopped after day 60 and the animals monitored until day 149. At the highest dose levels, the lack of tumor growth during the drug holiday support the conclusion that compound 1 provides a durable response.Table 20CTG-1358 Tumor Volume - MeanTreatment Vehicle Compound 1 Compound 1 Compound 1 Compound 1 Day Control (10 mg / kg) (30 mg / kg) (100 mg / kg) (200 mg / kg)0 190 190 190 190 19058 1231 421 75 14 8CTG-1358 Tumor Volume - SEMTreatment Vehicle Compound 1 Compound 1 Compound 1 Compound 1 Day Control (10 mg / kg) (30 mg / kg) (100 mg / kg) (200 mg / kg)0 18 23 23 21 2458 148 122 22 4 5 CTG-1358 Tumor Growth Inhibition (%)Treatment Vehicle Compound 1 Compound 1 Compound 1 Compound 1 Day Control (lO mg / kg) (30 mg / kg) (100 mg / kg) (200 mg / kg) 0 0 0 0 0 058 0 78 112 117 118Table 21CTG-2803 Tumor Volume - MeanTreatment Vehicl Compound 1 Compound 1 Compound 1 Compound 1 Day e (10 mg / kg) (30 mg / kg) (100 mg / kg) (200 mg / kg) Control0 187 186 186 186 18648 493 1786 454 53 22CTG-2803 Tumor Vo ume - SEMTreatment Vehicl Compound 1 Compound 1 Compound 1 Compound 1 Day e (10 mg / kg) (30 mg / kg) (100 mg / kg) (200 mg / kg) Control0 10 9 10 9 1048 292 307 134 9 7CTG-2803 Tumor Growth Inhibition (%)Treatment Vehicl Compound 1 Compound 1 Compound 1 Compound 1 Day e (10 mg / kg) (30 mg / kg) (100 mg / kg) (200 mg / kg) Control0 0 0 0 0 048 0 -422 13 144 154Single Dose PK-PD and DUSP6 Biomarker Analysis

[0296] Table 22 and Fig. 7 provide the results from a single dose PK-PD study at three dose levels. In Fig. 7, the dashed line represents the IC90 of compound 1 in the various G12D and G12V models. Free drug concentrations are provided as mean ± SEM of xenograft models. DUSP6 biomarker levels were determined by qPCR and the values are provided as geomean ± SD Geomean of xenograft models. DUSP6 levels show a clear inverse correlation with free drugconcentration and support the conclusion that DUSP6 levels can be used as a biomarker to aid patient dosing decisions.Table 22Dose Time (h) Free Drug pERK / ERK DUSP6 (mg / kg) (nM) (%Veh) (%Veh) HPAC 30 0.5 268.1 ___ ___HPAC 30 1 135.91 ___ ___HPAC 30 3 72.12 ___ 1.456667 HPAC 30 7 4.86 ___ 8.806667 HPAC 30 12 0.85 ___ 29.89333 HPAC 30 24 0.07 ___ 160.8NCI- 100 0.5 178.76 — —H2009NCI- 100 1 360.99 — —H2009NCI- 100 3 98.1 46.09188 3.696667 H2009NCI- 100 7 34.66 45.40492 2.1H2009NCI- 100 12 5.29 12.42465 3.703333 H2009NCI- 100 24 0.18 73.89483 51.20667 H2009NCI-H358 100 0.5 247.9187 ___ ___NCI-H358 100 1 233.3942 ___ ___NCI-H358 100 3 63.60743 34.73 ___NCI-H358 100 7 7.512688 29.59667 ___NCI-H358 100 12 16.77834 27.41333 ___NCI-H358 100 24 0.14224 92.05667 ___ MiaPaca-2 100 0.5 811.96 ___ ___ MiaPaca-2 100 1 705.52 ___ ___ MiaPaca-2 100 3 168.97 53.25397 5.018675 MiaPaca-2 100 7 25.68 54.41715 4.352379 MiaPaca-2 100 12 52.78 11.55499 4.592471Dose Time (h) Free Drug pERK / ERK DUSP6 (mg / kg) (nM) (%Veh) (%Veh) MiaPaca-2 100 24 0.28 116.3419 172.2763 HPAC 100 0.5 136.61 ___ ___ HPAC 100 1 159.96 ___ ___ HPAC 100 3 47.38 30.52 ___ HPAC 100 7 38.59 37.15333 ___ HPAC 100 12 18.68 25.58667 ___ HPAC 100 24 0.43 40.10333 ___ AsPC-1 100 0.5 135.2284 ___ ___ AsPC-1 100 1 256.4331 ___ ___ AsPC-1 100 3 27.69678 11.30333 ___ AsPC-1 100 7 7.462604 16.47667 ___ AsPC-1 100 12 10.81827 20.71667 ___ AsPC-1 100 24 4.51763 34.08333 ___ NCI-H441 100 0.5 181.81 ___ ___ NCI-H441 100 1 215.27 ___ ___ NCI-H441 100 3 63.93 33.87667 29.14 NCI-H441 100 7 3.58 18.76333 24.04333 NCI-H441 100 12 6.69 40.52667 29.89333 NCI-H441 100 24 0.93 41.74333 61.36 NCI-H727 100 0.5 208.28 ___ ___ NCI-H727 100 1 127.87 ___ ___ NCI-H727 100 3 86.91 25.70333 16.52667 NCI-H727 100 7 6.99 30.34667 7.903333 NCI-H727 100 12 8.64 9.136667 6.683333 NCI-H727 100 24 0.85 78.03 85.80667 NCI- 200 0.5 618.84 — — H2009NCI- 200 1 634.2 — — H2009NCI- 200 3 362.09 38.67333 3.3 H2009Dose Time (h) Free Drug pERK / ERK DUSP6 (mg / kg) (nM) (%Veh) (%Veh) NCI- 200 7 102.46 31.95667 2.656667 H2009NCI- 200 12 47.89 49.01333 3.366667 H2009NCI- 200 24 0.39 48.86667 18.89 H2009NCI-H358 200 0.5 305.516 ___ ___ NCI-H358 200 1 324.5481 ___ ___ NCI-H358 200 3 52.58882 53.45667 ___ NCI-H358 200 7 38.86564 22.06333 ___ NCI-H358 200 12 58.59897 44.16 ___ NCI-H358 200 24 6.66125 58.02333 ___ MiaPaca-2 200 0.5 944.72 ___ ___ MiaPaca-2 200 1 1108.21 ___ ___ MiaPaca-2 200 3 205.18 46.09188 5.185914 MiaPaca-2 200 7 110.82 45.40492 5.118317 MiaPaca-2 200 12 36.21 12.42465 21.93421 MiaPaca-2 200 24 15.47 73.89483 38.34554 HPAC 200 0.5 729.66 ___ ___ HPAC 200 1 510.22 ___ ___ HPAC 200 3 174.4 25.69 ___ HPAC 200 7 6.26 27.83667 ___ HPAC 200 12 53.34 23.59 ___ HPAC 200 24 35.68 26.54 ___ AsPC-1 200 0.5 308.5211 ___ ___ AsPC-1 200 1 485.3197 ___ ___ AsPC-1 200 3 46.82909 14.46333 ___ AsPC-1 200 7 5.108628 15.73333 ___ AsPC-1 200 12 6.961758 20.35667 ___ AsPC-1 200 24 43.8741 13.22667 ___ NCI-H441 200 0.5 230.26 ___ ___ NCI-H441 200 1 199.79 ___ ___Dose Time (h) Free Drug pERK / ERK DUSP6 (mg / kg) (nM) (%Veh) (%Veh) NCI-H441 200 3 103.89 39.98667 43.89NCI-H441 200 7 10.49 24.89 19.15667 NCI-H441 200 12 30.62 38.84 22.35667 NCI-H441 200 24 21.48 34.10667 29.92667 NCI-H727 200 0.5 437.54 ___ ___NCI-H727 200 1 318.17 ___ ___NCI-H727 200 3 155.84 23.53 15.06333 NCI-H727 200 7 18.73 20.93333 12.33333 NCI-H727 200 12 12.99 10.00333 6.983333 NCI-H727 200 24 8.79 69.09333 59.76Table 23. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in SW403 Human Colon Adenocarcinoma XenograftsPK Confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in SW403 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Free Group Compound Dose (mg / kg) Timepoint (Hr) Drug (nM) G2 - Compound 1 Compound 1 30 0.5 52.25 G2 - Compound 1 Compound 1 30 1 50.07 G2 - Compound 1 Compound 1 30 3 22.67 G2 - Compound 1 Compound 1 30 7 3.07 G2 - Compound 1 Compound 1 30 12 0.32 G2 - Compound 1 Compound 1 30 24 0.06 G3 - Compound 1 Compound 1 100 0.5 178.03 G3 - Compound 1 Compound 1 100 1 366.48 G3 - Compound 1 Compound 1 100 3 133.70 G3 - Compound 1 Compound 1 100 7 48.69 G3 - Compound 1 Compound 1 100 12 6.53 G3 - Compound 1 Compound 1 100 24 0.53 G4 - Compound 1 Compound 1 200 0.5 542.03 G4 - Compound 1 Compound 1 200 1 526.67 G4 - Compound 1 Compound 1 200 3 649.56 G4 - Compound 1 Compound 1 200 7 121.35 G4 - Compound 1 Compound 1 200 12 6.66 G4 - Compound 1 Compound 1 200 24 0.91 G6 - RMC-6236 RMC-6236 25 0.5 1.40 G6 - RMC-6236 RMC-6236 25 1 2.93 G6 - RMC-6236 RMC-6236 25 3 1.68 G6 - RMC-6236 RMC-6236 25 7 0.21 G6 - RMC-6236 RMC-6236 25 12 0.02G6 - RMC-6236 RMC-6236 25 24 0.00Table 24. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 in SW620 Human Colon Adenocarcinoma XenograftsPK Confirmation of Compound 1 in Study of Compound 1 in SW620 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Free Group Compound Dose (mg / kg) Timepoint (Hr) Drug (nM)G2 - Compound 1 Compound 1 30 0.5 61.66 G2 - Compound 1 Compound 1 30 1 47.98 G2 - Compound 1 Compound 1 30 3 13.79 G2 - Compound 1 Compound 1 30 7 3.34 G2 - Compound 1 Compound 1 30 12 0.39 G2 - Compound 1 Compound 1 30 24 0.10 G3 - Compound 1 Compound 1 100 0.5 222.35 G3 - Compound 1 Compound 1 100 1 376.77 G3 - Compound 1 Compound 1 100 3 81.59 G3 - Compound 1 Compound 1 100 7 30.36 G3 - Compound 1 Compound 1 100 12 7.11 G3 - Compound 1 Compound 1 100 24 1.19 G4 - Compound 1 Compound 1 200 0.5 427.76 G4 - Compound 1 Compound 1 200 1 554.19 G4 - Compound 1 Compound 1 200 3 373.53 G4 - Compound 1 Compound 1 200 7 131.22 G4 - Compound 1 Compound 1 200 12 38.79G4 - Compound 1 Compound 1 200 24 1.15Table 25. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in GP2d Human Colon Adenocarcinoma Xenografts PK Confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in GP2d Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Free Group Compound Dose (mg / kg) Timepoint (Hr) Drug (nM) G2 - Compound 1 Compound 1 30 0.5 39.82 G2 - Compound 1 Compound 1 30 1 46.14 G2 - Compound 1 Compound 1 30 3 14.02 G2 - Compound 1 Compound 1 30 7 1.76 G2 - Compound 1 Compound 1 30 12 0.57 G2 - Compound 1 Compound 1 30 24 0.06 G3 - Compound 1 Compound 1 100 0.5 148.24 G3 - Compound 1 Compound 1 100 1 215.09 G3 - Compound 1 Compound 1 100 3 92.29 G3 - Compound 1 Compound 1 100 7 28.99 G3 - Compound 1 Compound 1 100 12 2.65 G3 - Compound 1 Compound 1 100 24 0.49 G4 - Compound 1 Compound 1 200 0.5 461.94G4 - Compound 1 Compound 1 200 1 590.31G4 - Compound 1 Compound 1 200 3 498.15 G4 - Compound 1 Compound 1 200 7 141.70 G4 - Compound 1 Compound 1 200 12 11.12 G4 - Compound 1 Compound 1 200 24 1.10 G6 - RMC-6236 RMC-6236 25 0.5 1.02 G6 - RMC-6236 RMC-6236 25 1 3.43 G6 - RMC-6236 RMC-6236 25 3 1.67 G6 - RMC-6236 RMC-6236 25 7 0.15 G6 - RMC-6236 RMC-6236 25 12 0.04G6 - RMC-6236 RMC-6236 25 24 0.01Table 26. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in NCI-H727 Human Lung Cancer Xenografts PK Confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in NCI-H727Human Lung Cancer Xenograft Model in BALB / c Nude MicePlasma Free Group Compound Dose (mg / kg) Timepoint (Hr) Drug (nM)G2 - Compound 1 Compound 1 30 0.5 74.85 G2 - Compound 1 Compound 1 30 1 78.48 G2 - Compound 1 Compound 1 30 3 55.88 G2 - Compound 1 Compound 1 30 7 19.04 G2 - Compound 1 Compound 1 30 12 6.01 G2 - Compound 1 Compound 1 30 24 1.63 G3 - Compound 1 Compound 1 100 0.5 87.20 G3 - Compound 1 Compound 1 100 1 156.96 G3 - Compound 1 Compound 1 100 3 479.49 G3 - Compound 1 Compound 1 100 7 91.56 G3 - Compound 1 Compound 1 100 12 10.75 G3 - Compound 1 Compound 1 100 24 0.75 G8 - RMC-6236 RMC-6236 25 0.5 1.42 G8 - RMC-6236 RMC-6236 25 1 3.12 G8 - RMC-6236 RMC-6236 25 3 2.47 G8 - RMC-6236 RMC-6236 25 7 0.29 G8 - RMC-6236 RMC-6236 25 12 0.06G8 - RMC-6236 RMC-6236 25 24 0.01Table 27. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in LoVo Human Colon Adenocarcinoma Xenografts PK Confirmation of Compound 1 in Study of Compound 1 or RMC-6236 in LoVo Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Free Group Compound Dose (mg / kg) Timepoint (Hr) Drug (nM) G2 - Compound 1 Compound 1 60 0.5 60.89 G2 - Compound 1 Compound 1 60 1 88.65 G2 - Compound 1 Compound 1 60 3 47.96 G2 - Compound 1 Compound 1 60 7 10.90 G2 - Compound 1 Compound 1 60 12 1.41 G2 - Compound 1 Compound 1 60 24 0.55G3 - Compound 1 Compound 1 100 0.5 156.96G3 - Compound 1 Compound 1 100 1 195.47 G3 - Compound 1 Compound 1 100 3 148.24 G3 - Compound 1 Compound 1 100 7 28.85 G3 - Compound 1 Compound 1 100 12 2.79 G3 - Compound 1 Compound 1 100 24 0.20 G4 - Compound 1 Compound 1 200 0.5 657.24 G4 - Compound 1 Compound 1 200 1 809.76 G4 - Compound 1 Compound 1 200 3 547.52 G4 - Compound 1 Compound 1 200 7 116.99 G4 - Compound 1 Compound 1 200 12 24.20G4 - Compound 1 Compound 1 200 24 1.71Table 28. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 in LSI 80 Human Colon Adenocarcinoma Xenografts PK Confirmation of Compound 1 in Study of Compound 1 in LS180 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Free Group Compound Dose (mg / kg) Timepoint (Hr) Drug (nM) G2 - Compound 1 Compound 1 30 0.5 27.54 G2 - Compound 1 Compound 1 30 1 32.63 G2 - Compound 1 Compound 1 30 3 7.78 G2 - Compound 1 Compound 1 30 7 2.89 G2 - Compound 1 Compound 1 30 12 0.29 G2 - Compound 1 Compound 1 30 24 0.08 G3 - Compound 1 Compound 1 60 0.5 33.35 G3 - Compound 1 Compound 1 60 1 60.17 G3 - Compound 1 Compound 1 60 3 29.14 G3 - Compound 1 Compound 1 60 7 5.01 G3 - Compound 1 Compound 1 60 12 1.88 G3 - Compound 1 Compound 1 60 24 0.49 G4 - Compound 1 Compound 1 100 0.5 111.91 G4 - Compound 1 Compound 1 100 1 152.60 G4 - Compound 1 Compound 1 100 3 72.52 G4 - Compound 1 Compound 1 100 7 21.51 G4 - Compound 1 Compound 1 100 12 5.59 G4 - Compound 1 Compound 1 100 24 1.62 G5 - Compound 1 Compound 1 200 0.5 466.33 G5 - Compound 1 Compound 1 200 1 479.49 G5 - Compound 1 Compound 1 200 3 212.91 G5 - Compound 1 Compound 1 200 7 52.25 G5 - Compound 1 Compound 1 200 12 18.38G5 - Compound 1 Compound 1 200 24 5.94Pharmacokinetic evaluation

[0297] Pharmacokinetic profile for compound 1 was measured by single dosing in male Sprague-Dawley rats or beagle dogs. The animals were allowed to acclimate to their new environment for at least 3 days prior to the initiation of any studies. Rats were dosed orally with compound 1 at 30, 100, 300, 600 and 1000 mg / kg in 20% PEG400, 10% HS-15 Solutol, 70% 50mM citrate buffer (pH 4.0). Dogs were dosed orally with compound 1 at 10, 30, 100, and 300 mg / kg in 20% PEG400, 10% HS-15 Solutol, 70% 50 mM citrate buffer (pH 4.0). Time of blood sampling was 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours following PO dosing. Blood samples (~0.2 mL / sample) were collected via jugular vein and placed in tubes containing Heparin-Na. The blood samples in tubes were mixed well and then placed on wet ice prior to centrifugation for plasma. The blood samples were centrifuged at 4000xg for 5 minutes at 4°C to obtain plasma. The obtained plasma was separated and stored frozen at approximately -80°C.

[0298] All plasma samples were analyzed using a Shimadzu (DGU-405) HPLC with an API 6500+ MS / MS system, following the manufacture instructions. All the analytes were detected with positive-mode electrospray ionization (ES+). A standard curve for compound 1 was generated and used to measure the compound 1 concentrations in the rat or dog plasma samples. Based on the time course sampling, an area under the curve (AUC) was calculated.

[0299] Pharmacokinetic evaluation in rat and dog demonstrated that compound 1 exhibits dose-proportional exposure as illustrated in Tables 29 and 30, and Fig. 8. From these experiments, a predicted human efficacious exposure (AUCo-i2h,ss) was calculated to be about 1320 ng*h / mL.Table 29Rat PK dataDoseAUCiast (ng*h / mL) %F(mg / kg)30 3666100 14185 28.7300 27878 42.1600 560691000 92488 18.7Table 30Dog PK dataDoseAUCiast (ng*h / mL) %F(mg / kg)10 110430 5132100 31990 48.0300 161679 80.9

[0300] Fig. 9 provides the results of pharmacokinetic modeling of compound 1 which predicts an efficacious human dose. The model predicts >90% target coverage of EC$>o to achieve regressions in humans with a predicted dose of compound 1 of 25 mg twice daily to inhibit G12C and G12A signal, 50 mg twice daily to inhibit G12D signal, and 100 mg twice daily to inhibit G12V signal.Example 4: Synergy Metrics of Compound 1 and Combination Partners

[0301] Compound 2 was used for Example 4. Compound 2 is a Compound 1 analog without deuterium replacement. Indicated cell lines were seeded at 1,000 - 2,000 cells / well in 96-well ultra low cluster plates (Corning 7007) to achieve suspensions in media containing 2% Matrigel. Plates were allowed to equilibrate for 30 minutes at room temperature. Cells were treated with compounds serially diluted in dimethyl sulfoxide (DMSO) to achieve the indicated final concentrations after a working dilution of 15 pL was added to cell cultures for a final concentration of 150 pL. After compound addition, cells were incubated for 5 days at 37°C with 5% CO2. At the end of treatment, plates were removed from the incubator and equilibrated at room temperature for 15 minutes. Cultures were then treated with 3D CellTiter-Glo reagent (Promega G9682) at room temperature for 5 minutes using a plate shaker to ensure complete lysing. Luminescent signal was stabilized by allowing plates to incubate at room temperature for an additional 25 minutes. Mixtures were then transferred to 96-well flat bottom plates (PE 6055680). Flat bottom plates were used to measure the resulting luminescent measure of viability, with normalized signal fit to a dose-response regression curve utilizing a 4-parameter analytical method. Combinatorial benefit was determined by evaluating shifts in maximum viability; shifts in potency of the pan-KRAS inhibitor; and the sum of synergy and antagonism as determined by Loewe, BLISS, and HSA synergy models. The combination of a pan-KRAS molecule with MEK inhibitor, binimenetib; or RAF / MEK dual inhibitor, VS-6766, resulted in enhanced depletion of maximum viability and / or potentiation of Compound 2 in a dosedependent manner. The combination of a pan-KRAS and a pan-RAS inhibitor resulted in significant depletion of maximum viability and Compound 2 potency in a dose-dependent manner (see Tables 31-37 and Figures 16-22, Compound 2, a Compound 1 analog without deuterium, was used to acquire data in Tables 31-37 and Figures 16-22).Table 31. Combination of pan-KRAS and MEK inhibitor in KRAS G12D cell line.AsPC-1 Max Viability Compound 2 Combination Partner (% DayO) IC50 (nM)Binimetinib (200 nM) 7.113 10.81Binimetinib (50 nM) 21.51 8.651 Binimetinib (12.5 nM) 57.44 8.18 Binimetinib (3.13 nM) 82.84 11.84 Binimetinib (0.78 nM) 76.38 12.41 DMSO 89.87 13.82Sum of Synergy & Antagonism (Model)45.7 (Loewe) -7.4 (BLISS) 65.2 (HSA)Table 32. Combination of pan-KRAS and RAF / MEK inhibitor in KRAS G12D cell line.AsPC-1 Max Viability Compound 2 Combination Partner (% DayO) ICso (nM)VS-6766 (500 nM) -15.82 26.31 VS-6766 (100 nM) -3.674 17.85 VS-6766 (20 nM) 32.67 11.93 VS-6766 (4 nM) 80.93 10.25 VS-6766 (0.8 nM) 84.24 11.5 DMSO 103.3 10.32Sum of Synergy & Antagonism (Model)49.8 (Loewe) 11.2 (BLISS) 71.3 (HSA)Table 33. Combination of pan-KRAS and MEK inhibitor in KRAS G12V cell line.NCI-H727 Max Viability Compound 2 Combination Partner (% DayO) ICso (nM) Binimetinib (200 nM) -64.06 28.68 Binimetinib (50 nM) -43.68 18.29 Binimetinib (12.5 nM) -10.22 16.34 Binimetinib (3.13 nM) 42.84 18.65 Binimetinib (0.78 nM) 96.6 15.71 DMSO 131.3 15.64Sum of Synergy & Antagonism (Model)24.0 (Loewe) 5.5 (BLISS) 43.1 (HSA)Table 34. Combination of pan-KRAS and RAF / MEK inhibitor in KRAS G12V cell line.NCI-H727 Max Viability Compound 2 Combination Partner (% DayO) ICso (nM)VS-6766 (500 nM) -58.12 26.41 VS-6766 (100 nM) -38.8 18.03VS-6766 (20 nM) -6.639 22.52VS-6766 (4 nM) 45.71 18.26VS-6766 (0.8 nM) 75.98 18.22 DMSO 108 13.72Sum of Synergy & Antagonism (Model)19.7 (Loewe) -24.4 (BLISS) 40.0 (HSA)Table 35. Combination of pan-KRAS and pan-RAS inhibitors in KRAS G12D cell line.HPAC Max Viability Compound 2 Combination Partner (% DayO) ICso (nM)RMC- 6236 (37.04 nM) -85.86 5.357 RMC- 6236 (12.35 nM) -59.78 1.801 RMC-6236 (4.12 nM) 13.65 6.038 RMC-6236 (1.37 nM) 73.8 16.77 RMC-6236 (0.46 nM) 95.88 28.93 RMC-6236 (0.15 nM) 108.2 244.4 RMC-6236 (0.05 nM) 102.8 36.52Sum of Synergy & Antagonism (Model)68.1 (Loewe) 37.0 (BLISS) 88.0 (HSA)Table 36. Combination of pan-KRAS and pan-RAS inhibitors in KRAS G12V cell line.NCI-H727 Max Viability Compound 2 Combination Partner (% DayO) ICso (nM) RMC- 6236 (12.35 nM) -85.91 3.273 RMC-6236 (4.12 nM) -72.72 1.589 RMC-6236 (1.37 nM) -52.96 5.112 RMC-6236 (0.46 nM) -2.78 8.502 RMC-6236 (0.15 nM) 60.17 9.075 RMC-6236 (0.05 nM) 86.27 8.94Sum of Synergy & Antagonism (Model)14.0 (Loewe) -28.0 (BLISS) 25.8 (HSA)Table 37. Combination of pan-KRAS and pan-RAS inhibitors in KRAS G12R cell line.PSN-1 Max Viability Compound 2 Combination Partner (% DayO) ICso (nM)RMC-6236 (100 nM) -48.32 UnstableRMC-6236 (25 nM) -42.32 21RMC-6236 (6.25 nM) -22.89 12.04RMC-6236 (1.56 nM) 50.13 5.692 RMC-6236 (0.39 nM) 111.5 25.45 DMSO 137.1 259.4Sum of Synergy & Antagonism (Model)59.8 (Loewe) 20.4 (BLISS) 73.4 (HS A)Example 5: Evaluation of the Antitumor Activity of Compound 1 and Combination Partners in Xenograft Mouse Models

[0302] Mice were subcutaneously inoculated unilaterally on the right flank with indicated cells in 0.1 mL of 1:1 medium / Matrigel for tumor development. Animals were monitored daily throughout the study for any abnormalities of behavior and appearance including mobility, food and water consumption, body weight, eye appearance, hair matting, and any other abnormal observations. Any mortality and / or abnormal clinical signs were recorded. Body weights of all animals were measured and recorded 3x weekly or daily. Tumor size was measured by digital caliper and recorded 3x weekly. Treatment was started when the mean tumor volume (TV) reached approximately 150 to 250 mm3. Animals were dosed via oral gavage with vehicle or indicated treatment article twice daily (BID), once daily (QD), or via intraperitoneal injection once every three days (IP Q3D) at concentrations and for durations as indicated. Doses were administered 12 hours apart when delivered twice daily.

[0303] Animals were humanely euthanized if they showed obvious signs of severe distress and / or pain. Any tumor-bearing animal had to be euthanized according to the Institutional Animal Care and Use Committee conditions of each institution. Conditions include: any animal with a single observation of >20% body weight loss (compared to first day of treatment); TV >10% of body weight (e.g., 2000 mm3for a 20 g mouse); the tumor became ulcerated or necrotic (animals with red tumors were to be recorded and monitored; animals with tumors that were ulcerated but had intact skin were to be recorded and monitored closely, i.e. twice daily; animals with tumors that were ulcerated and weeping and / or had holes were to be culled).Additional conditions include whether the animal’s ability to eat or drink was impaired; the animal’s ability to ambulate normally was impaired; the animal’s breathing was labored. If euthanasia criteria were not met, animals were euthanized after administration of the final dose and completion of final in vivo evaluations. Animals were humanely sacrificed by CO2 inhalation followed by cervical dislocation to ensure death.

[0304] Plasma samples for PK analysis were collected at 0.5, 1, 3, 7, 12, and 24 hours post dose (n=3 / group / time point), and tumor samples for PD analysis were collected at 3, 7, 12, and24 hours post dose (n=3 / group / time point). Compound 1 plasma concentrations were measured using liquid chromatography with tandem mass spectrometry (LC-MS / MS), and free (unbound) compound 1 plasma concentrations were calculated (see Tables 38-51 and Figures 23A-29B).Table 38. Provides the results from treatment of Compound 1 and RMC-6236 in SW403 Human Colon Adenocarcinoma Xenograft Model.Antitumor Activity of Compound 1 and RMC-6236 in SW403 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSizeaSizeap Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) PValuecat PG- at PG- D0 D28G1 Vehicle, 20% PEG400, 10% solutol163±15 1237±141 - - - - HS-15 in citrate buffer pH4.0, PO, BIDG2 Compound 1,163±15 739±84 54 46 * * * * <0.0001 30 mg / kg, PO, BIDG3 Compound 1,163±17 164±36 0 100 * * * * <0.0001 100 mg / kg, PO, BIDG5 RMC-6236, 163±13 131±28 -3 103 * * * * <0.0001 5 mg / kg, PO, QDG7 Compound 1,30 mg / kg, PO, BID164±16 67±13 -9 109 * * * * <0.0001 & RMC-6236,5 mg / kg, PO, QDG8 Compound 1,100 mg / kg, PO, BID164±14 40±5 -12 112 * * * * <0.0001 & RMC-6236,5 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significantTwo-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.Table 39. Provides the results from treatment of Compound 1 and RMC-6236 in GP2d Human Colon Adenocarcinoma Xenograft Model.Antitumor Activity of Compound 1 and RMC-6236 in GP2d Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSizeaSizeap Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) PValuecat PG- at PG- D0 D28G1 Vehicle, 20% PEG400, 10% solutol179±15 1592±184 - - - - HS-15 in citrate buffer pH4.0, PO, BIDG2 Compound 1,181±17 307±47 9 91 * * * * <0.0001 30 mg / kg, PO, BIDG3 Compound 1,180±16 139±22 -3 103 * * * * <0.0001 100 mg / kg, PO, BIDG5 RMC-6236,180±16 419±89 17 83 * * * * <0.0001 5 mg / kg, PO, QDG7 Compound 1,30 mg / kg, PO, BID180±17 122±19 -4 104 * * * * <0.0001 & RMC-6236,5 mg / kg, PO, QDG8 Compound 1,100 mg / kg, PO, BID181±14 64±12 -8 108 * * * * <0.0001 & RMC-6236,5 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** =p<0.01 *** =p<0.001 **** = p<0.0001 ns = not significantTwo-way RM ANOVA followed by Tukey’s post hoc comparisons of the means.Table 40. Provides the results from treatment of Compound 1 and RMC-6236 in NCI-H727Human Lung Cancer Xenograft Model.Antitumor Activity of Compound 1 and RMC-6236 in NCI-H727 Human Lung Cancer Xenograft Model in BALB / c Nude MiceTumor TumorSizeaSizeaTGIbTreatment (mm3) (mm3) DT / DCb(%) pc P Valuee(%)at PG- at PG- D0 D28dG1 Vehicle, 20% PEG400, 10% solutol in171±13 2145±186 - - - - pH4.0 citrate buffer, PO, BIDG2 Compound 1, 30 mg / kg, PO, BID 170±14 380±60 11 89 * * * * <0.0001 G6 RMC-6236, 3 mg / kg, PO, QD 171±15 1017±140 43 57 * * * * <0.0001 G7 RMC-6236, 5 mg / kg, PO, QD 170±13 714±162 28 72 * * * * <0.0001* * * *G9 Compound 1, 30 mg / kg, PO BID & 171±12 8±2 -8 108 <0.0001RMC-6236,3 mg / kg, PO, QDGIO Compound 1, 30 mg / kg, PO BID &RMC-6236, 171±13 4±1 -8 108 * * * * <0.0001 5 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. G1 was taken down on PG-D25, G4 and G5 were taken down on PG-D21.e. Gl, G4 and G5 mean tumor size calculated using the Vehicle TV final of animals.Table 41. Provides the results from treatment of Compound 1 and RMC-6236 in LoVo Human Colon Adenocarcinoma Xenograft Model.Antitumor Activity of Compound 1 and RMC-6236 in LoVo Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSizeaSizeaTreatment (mm3) (mm3) DT / DCb(%) TGIb(%) pc P Value at PG- at PG- D0 D28dGl Vehicle, 20% PEG400, 10% solutol194±15 1872±203 - - - - in pH4.0 citrate buffer, PO, BIDG2 Compound 1,193±17 80±10 -7 107 * * * * <0.0001 60 mg / kg, PO, BIDG5 RMC-6236,194±16 1095±163 54 46 * * * * <0.0001 10 mg / kg, PO, QDG10 Compound 1,60 mg / kg, PO, BID &RMC-6236, 193±17 109±19 -5 105 * * * * <0.000110 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. The mice of GIO taken down on PG-D23 per protocol.Table 42. Provides the results from treatment of Compound 1 and Cetuximab in SW620 Human Colon Adenocarcinoma Xenograft Model.Antitumor Activity and PKPD Relationship of Compound 1 and Cetuximab in SW620 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3p Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) pcValue at PG- atPG- D0 D21G1 Vehicle, 20%PEG400, 10% solutol159±12 2598±216d- - - - in pH4.0 citrate buffer, PO, BIDG2 Compound 1, 30 mg / kg, PO, BID 159±12 887±117 30 70 **** <0.0001G3 Compound 1, 100 mg / kg, PO, BID 159±13 530±45 15 85 **** <0.0001 G5 Cetuximab, 0.25 mg / dose, lOOpL / 159±12 2499±152d96 4 ns 0.7612 mouse, IP, Q3DG6 Compound 1, 30 mg / kg, PO, BID &Cetuximab, 0.25 mg / dose lOOpL / 159±13 663±47 21 79 **** <0.0001 mouse, IP, Q3DG7 Compound 1, 100 mg / kg, PO, BID &Cetuximab, 0.25 mg / dose lOOpL / 159±11 478±34 13 87 **** <0.0001 mouse, IP, Q3DNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle fmal- TV Vehicle initial);c. Significance levels: * = p<0.05 ** = p<0.01 *** = p<0.001 **** = p<0.0001 ns = notsignificantTwo-way RM ANOVA followed by Tukeys post hoc comparisons of the means.d. The tumor volume for G1 was measured on PG-D19. According to the termination criteria 3.3.3,the mice of Gl-12# and Gl-45# were humanely euthanized on PG-D18.Table 43. Provides the results from treatment of Compound 1 and Cetuximab in LoVo Human Colon Adenocarcinoma Xenograft Model.Antitumor Activity of Compound 1 and Cetuximab in LoVo Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorSize3Size3(mm3) (mm t e t3)Trea m n DT / DCb(%) TGIb(%) pc p Value atPG- at PG- D0 D28dG1 Vehicle, 20%PEG400, 10% solutol194±15 1872±203 - - - - in pH4.0 citrate buffer, PO, BIDG2 Compound 1,193±17 80±10 -7 107 **** <0.0001 60 mg / kg, PO, BIDG3 Compound 1,193±16 51±8 -8 108 **** <0.0001 100 mg / kg, PO, BIDG7 Cetuximab,193±17 735±100 32 68 **** <0.0001 0.75 mg / dose, 200 pL / mouse, IP, Q3DG8 Compound 1,60 mg / kg, PO, BID & Cetuximab, 0.75 193±16 42±5 -9 109 **** <0.0001 mg / dose 200 pL / mouse, IP, Q3DG9 Compound 1,100 mg / kg, PO, BID & Cetuximab, 0.75 193±17 23±4 -10 110 **** <0.0001 mg / dose 200 pL / mouse, IP, Q3DNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** =p<0.01 *** =p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. The mice of G10 taken down on PG-D23 per protocol.Table 44. Provides the results from treatment of Compound 1 and Cetuximab in LSI 80 Human Colon Adenocarcinoma Xenograft Model.Antitumor Activity of Compound 1 and Cetuximab in LS180 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceTumor TumorTreatment Size3Size3DT / DCb(%) TGIb(%) pc P Value (mm3) (mm3)atPG- atPG- D0 D21dG1 Vehicle, 20%PEG400, 10% solutol150±8 2757±143 - - - - in pH4.0 citrate buffer, PO, BIDG2 Compound 1,151±7 2093±109 74 26 *** 0.0003 30 mg / kg, PO, BIDG3 Compound 1,150±7 2378±230 85 15 **** <0.0001 60 mg / kg, PO, BIDG4 Compound 1,151±7 2068±159 74 26 **** <0.0001 100 mg / kg, PO, BIDG6 Cetuximab,151±8 2044±295 73 27 *** 0.0002 0.75 mg / dose, 200 pL / mouse, IP, Q3DG7 Compound 1,30 mg / kg, PO, BID & Cetuximab, 0.75 150±7 1492±191 51 49 **** <0.0001 mg / dose 200 pL / mouse, IP, Q3DG8 Compound 1,60 mg / kg, PO, BID & Cetuximab, 0.75 151±7 809±101 25 75 **** <0.0001 mg / dose 200 pL / mouse, IP, Q3DG9 Compound 1,100 mg / kg, PO, BID & Cetuximab, 0.75 150±7 457±45 12 88 **** <0.0001 mg / dose 200 pL / mouse, IP, Q3DNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** =p<0.01 *** =p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the means;d. The mice of G1 taken down on PG-D11, G2 and G6 on PG-D13, G3 on PG-D16, G4 on PG-D18 perprotocol.End of Study PK Confirmation of Compound 1 Levels

[0305] Tables 45, 46, 47, 48, 49, 50, 51 provide the results from treatment of Compound 1 at various dose levels. Free drug concentrations are provided as mean ± SEM of xenograft models.Table 45. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in SW403 Human Colon Adenocarcinoma Xenografts. PK Confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in SW403 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasmaDose Free Drug Group Compound (mg / kg) Timepoint (Hr) (nM)G2 - Compound 1 Compound 1 30 0.5 52.25 G2 - Compound 1 Compound 1 30 1 50.07 G2 - Compound 1 Compound 1 30 3 22.67 G2 - Compound 1 Compound 1 30 7 3.07 G2 - Compound 1 Compound 1 30 12 0.32 G2 - Compound 1 Compound 1 30 24 0.06 G3 - Compound 1 Compound 1 100 0.5 178.03 G3 - Compound 1 Compound 1 100 1 366.48 G3 - Compound 1 Compound 1 100 3 133.70 G3 - Compound 1 Compound 1 100 7 48.69 G3 - Compound 1 Compound 1 100 12 6.53 G3 - Compound 1 Compound 1 100 24 0.53 G7 - RMC Combo Compound 1 30 + 5 0.5 69.83 G7 - RMC Combo Compound 1 30 + 5 1 52.03 G7 - RMC Combo Compound 1 30 + 5 3 15.70 G7 - RMC Combo Compound 1 30 + 5 7 2.47 G7 - RMC Combo Compound 1 30 + 5 12 0.45 G7 - RMC Combo Compound 1 30 + 5 24 0.05 G8 - RMC Combo Compound 1 100 + 5 0.5 217.27 G8 - RMC Combo Compound 1 100 + 5 1 414.76 G8 - RMC Combo Compound 1 100 + 5 3 141.70 G8 - RMC Combo Compound 1 100 + 5 7 29.43 G8 - RMC Combo Compound 1 100 + 5 12 8.14G8 - RMC Combo Compound 1 100 + 5 24 2.65Table 46. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in GP2d Human Colon Adenocarcinoma Xenografts. PK Confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in GP2d Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Dose Free Drug Group Compound (mg / kg) Timepoint (Hr) (nM)G2 - Compound 1 Compound 1 30 0.5 39.82 G2 - Compound 1 Compound 1 30 1 46.14 G2 - Compound 1 Compound 1 30 3 14.02 G2 - Compound 1 Compound 1 30 7 1.76 G2 - Compound 1 Compound 1 30 12 0.57 G2 - Compound 1 Compound 1 30 24 0.06 G3 - Compound 1 Compound 1 100 0.5 148.24 G3 - Compound 1 Compound 1 100 1 215.09 G3 - Compound 1 Compound 1 100 3 92.29 G3 - Compound 1 Compound 1 100 7 28.99 G3 - Compound 1 Compound 1 100 12 2.65 G3 - Compound 1 Compound 1 100 24 0.49 G7 - RMC Combo Compound 1 30 + 5 0.5 52.03G7 - RMC Combo Compound 1 30 + 5 1 73.39G7 - RMC Combo Compound 1 30 + 5 3 26.52 G7 - RMC Combo Compound 1 30 + 5 7 3.12 G7 - RMC Combo Compound 1 30 + 5 12 0.45 G7 - RMC Combo Compound 1 30 + 5 24 0.06 G8 - RMC Combo Compound 1 100 + 5 0.5 341.24 G8 - RMC Combo Compound 1 100 + 5 1 375.25 G8 - RMC Combo Compound 1 100 + 5 3 167.86 G8 - RMC Combo Compound 1 100 + 5 7 44.33 G8 - RMC Combo Compound 1 100 + 5 12 6.12G8 - RMC Combo Compound 1 100 + 5 24 0.85Table 47. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in NCI-H727 Human Lung Cancer Xenografts. PK Confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in NCI-H727Human Lung Cancer Xenograft Model in BALB / c Nude MicePlasma Dose Free Drug Group Compound (mg / kg) Timepoint (Hr) (nM)G2 - Compound 1 Compound 1 30 0.5 74.85 G2 - Compound 1 Compound 1 30 1 78.48 G2 - Compound 1 Compound 1 30 3 55.88 G2 - Compound 1 Compound 1 30 7 19.04 G2 - Compound 1 Compound 1 30 12 6.01 G2 - Compound 1 Compound 1 30 24 1.63 G9 - RMC Combo Compound 1 30 + 3 0.5 138.79 G9 - RMC Combo Compound 1 30 + 3 1 137.34 G9 - RMC Combo Compound 1 30 + 3 3 89.38 G9 - RMC Combo Compound 1 30 + 3 7 3.89 G9 - RMC Combo Compound 1 30 + 3 12 0.56 G9 - RMC Combo Compound 1 30 + 3 24 0.09 G10 - RMC Combo Compound 1 30 + 5 0.5 92.29 G10 - RMC Combo Compound 1 30 + 5 1 121.35 G10 - RMC Combo Compound 1 30 + 5 3 45.63 G10 - RMC Combo Compound 1 30 + 5 7 4.51 G10 - RMC Combo Compound 1 30 + 5 12 0.59G10 - RMC Combo Compound 1 30 + 5 24 0.07Table 48. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in LoVo Human Colon Adenocarcinoma Xenografts. PK Confirmation of Compound 1 in Study of Compound 1 and RMC-6236 in LoVo Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceDose Plasma Free Group Compound (mg / kg) Timepoint (Hr) Drug (nM) G2 - Compound 1 Compound 1 60 0.5 60.89G2 - Compound 1 Compound 1 60 1 88.65G2 - Compound 1 Compound 1 60 3 47.96 G2 - Compound 1 Compound 1 60 7 10.90 G2 - Compound 1 Compound 1 60 12 1.41 G2 - Compound 1 Compound 1 60 24 0.55 GIO - RMC Combo Compound 1 60 + 10 0.5 110.45 GIO - RMC Combo Compound 1 60 + 10 1 137.34 GIO - RMC Combo Compound 1 60 + 10 3 103.19 GIO - RMC Combo Compound 1 60 + 10 7 24.85 GIO - RMC Combo Compound 1 60 + 10 12 5.44GIO - RMC Combo Compound 1 60 + 10 24 1.16Table 49. Provides the results from End of Study PK confirmation of Compound 1 in Study of Compound 1 and Cetuximab in SW620 Human Colon Adenocarcinoma Xenografts. PK Confirmation of Compound 1 in Study of Compound 1 and Cetuximab in SW620 Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MiceDose(mg / kg + Timepoint Plasma Free Group Compound mg / dose) (Hr) Drug (nM) G2 - Compound 1 Compound 1 30 0.5 61.66 G2 - Compound 1 Compound 1 30 1 47.98 G2 - Compound 1 Compound 1 30 3 13.79 G2 - Compound 1 Compound 1 30 7 3.34 G2 - Compound 1 Compound 1 30 12 0.39 G2 - Compound 1 Compound 1 30 24 0.10 G3 - Compound 1 Compound 1 100 0.5 222.35 G3 - Compound 1 Compound 1 100 1 376.77 G3 - Compound 1 Compound 1 100 3 81.59 G3 - Compound 1 Compound 1 100 7 30.36 G3 - Compound 1 Compound 1 100 12 7.11 G3 - Compound 1 Compound 1 100 24 1.19 G6 - Cetux Combo Compound 1 30 + 0.25 0.5 71.55 G6 - Cetux Combo Compound 1 30 + 0.25 1 60.62 G6 - Cetux Combo Compound 1 30 + 0.25 3 16.21 G6 - Cetux Combo Compound 1 30 + 0.25 7 3.09 G6 - Cetux Combo Compound 1 30 + 0.25 12 0.54 G6 - Cetux Combo Compound 1 30 + 0.25 24 0.27 G7 - Cetux Combo Compound 1 100 + 0.25 0.5 348.95 G7 - Cetux Combo Compound 1 100 + 0.25 1 416.70 G7 - Cetux Combo Compound 1 100 + 0.25 3 138.20 G7 - Cetux Combo Compound 1 100 + 0.25 7 64.80 G7 - Cetux Combo Compound 1 100 + 0.25 12 9.48G7 - Cetux Combo Compound 1 100 + 0.25 24 0.32Table 50. Provides the results from End of Study PK confirmation of Compound 1 in study of Compound 1 and Cetuximab in LoVo Human Colon Adenocarcinoma Xenografts. PK Confirmation of Compound 1 in Study of Compound 1 and Cetuximab in LoVo Human Colon Adenocarcinoma Xenograft Model in BALB / c Nude MicePlasma Free Dose Timepoint Drug Group Compound (mg / kg + mg / dose) (Hr) (nM)G2 - Compound 1 Compound 1 60 0.5 60.89 G2 - Compound 1 Compound 1 60 1 88.65 G2 - Compound 1 Compound 1 60 3 47.96 G2 - Compound 1 Compound 1 60 7 10.90 G2 - Compound 1 Compound 1 60 12 1.41 G2 - Compound 1 Compound 1 60 24 0.55 G3 - Compound 1 Compound 1 100 0.5 156.96 G3 - Compound 1 Compound 1 100 1 195.47 G3 - Compound 1 Compound 1 100 3 148.24 G3 - Compound 1 Compound 1 100 7 28.85 G3 - Compound 1 Compound 1 100 12 2.79 G3 - Compound 1 Compound 1 100 24 0.20 G8 - Cetuximab Combo Compound 1 60 + 0.75 0.5 85.02 G8 - Cetuximab Combo Compound 1 60 + 0.75 1 121.35 G8 - Cetuximab Combo Compound 1 60 + 0.75 3 48.40 G8 - Cetuximab Combo Compound 1 60 + 0.75 7 11.05 G8 - Cetuximab Combo Compound 1 60 + 0.75 12 1.43 G8 - Cetuximab Combo Compound 1 60 + 0.75 24 0.28 G9 - Cetuximab Combo Compound 1 100 + 0.75 0.5 396.10 G9 - Cetuximab Combo Compound 1 100 + 0.75 1 489.37 G9 - Cetuximab Combo Compound 1 100 + 0.75 3 441.09 G9 - Cetuximab Combo Compound 1 100 + 0.75 7 53.55 G9 - Cetuximab Combo Compound 1 100 + 0.75 12 10.90G9 - Cetuximab Combo Compound 1 100 + 0.75 24 0.37Table 51. Provides the results from End of Study PK confirmation study of Compound 1 in study of Compound 1 and Cetuximab in LSI 80 Human Colon Adenocarcinoma Xenografts.PK Confirmation of Compound 1 in Study of Compound 1 and Cetuximab in LS180 Human Co on Adenocarcinoma Xenografts in BALB / c Nude MiceDose Timepoint Plasma Free Group Compound (mg / kg + mg / dose) (Hr) Drug (nM) G2 - Compound 1 Compound 1 30 0.5 27.54 G2 - Compound 1 Compound 1 30 1 32.63 G2 - Compound 1 Compound 1 30 3 7.78 G2 - Compound 1 Compound 1 30 7 2.89 G2 - Compound 1 Compound 1 30 12 0.29 G2 - Compound 1 Compound 1 30 24 0.08 G3 - Compound 1 Compound 1 60 0.5 33.35G3 - Compound 1 Compound 1 60 1 60.17G3 - Compound 1 Compound 1 60 3 29.14 G3 - Compound 1 Compound 1 60 7 5.01 G3 - Compound 1 Compound 1 60 12 1.88 G3 - Compound 1 Compound 1 60 24 0.49 G4 - Compound 1 Compound 1 100 0.5 111.91 G4 - Compound 1 Compound 1 100 1 152.60 G4 - Compound 1 Compound 1 100 3 72.52 G4 - Compound 1 Compound 1 100 7 21.51 G4 - Compound 1 Compound 1 100 12 5.59 G4 - Compound 1 Compound 1 100 24 1.62 G7 - Cetux Combo Compound 1 30 + 0.75 0.5 33.72 G7 - Cetux Combo Compound 1 30 + 0.75 1 53.34 G7 - Cetux Combo Compound 1 30 + 0.75 3 19.11 G7 - Cetux Combo Compound 1 30 + 0.75 7 2.72 G7 - Cetux Combo Compound 1 30 + 0.75 12 0.58 G7 - Cetux Combo Compound 1 30 + 0.75 24 0.45 G8 - Cetux Combo Compound 1 60 + 0.75 0.5 99.55 G8 - Cetux Combo Compound 1 60 + 0.75 1 116.99 G8 - Cetux Combo Compound 1 60 + 0.75 3 61.26 G8 - Cetux Combo Compound 1 60 + 0.75 7 5.37 G8 - Cetux Combo Compound 1 60 + 0.75 12 1.16 G8 - Cetux Combo Compound 1 60 + 0.75 24 0.47 G9 - Cetux Combo Compound 1 100 + 0.75 0.5 144.60 G9 - Cetux Combo Compound 1 100 + 0.75 1 146.06 G9 - Cetux Combo Compound 1 100 + 0.75 3 101.73 G9 - Cetux Combo Compound 1 100 + 0.75 7 24.34 G9 - Cetux Combo Compound 1 100 + 0.75 12 4.72G9 - Cetux Combo Compound 1 100 + 0.75 24 1.36Example 6: Evaluation of the Antitumor Activity of Compound 1 and Combination Partners in Xenograft Mouse Models

[0306] Compound 1 in Murine Colorectal Syngeneic Cancer Cell line-derived xenograft model

[0307] Compound 1 was dosed orally twice per day (BID) and anti-mPDl (clone RMP1-14) was dosed by intraperitoneal injection twice per week (BIW) as either monotherapy or in combination in mice bearing murine colorectal syngeneic cancer (KRAS G12D) tumors. The study design with study groups and number of animals per group are in Table 53. Groups and treatments were started when the mean tumor volume reached 125 mm3as indicated in Table 54. Mice were assigned to respective groups based on their starting tumor volume and body weight such that the average values were the same for each treatment group. On Day 11, the termination time point for the vehicle + isotype antibody group, Compound 1 monotherapy induced tumor growth inhibition (TGI) of 62.2%, 80.0%, 89.0%, or 106.0% after treatment with 30, 60, 100, or 200 mg / kg BID, respectively, and anti-mPDl 10 mg / kg BIW monotherapy induced tumor growth inhibition (TGI) of 47.9%. Combination treatment with Compound 1 on Day 11 induced tumor growth inhibition (TGI) of 74.6%, 84.8%, 90.8%, and 104.2% in the groups receiving 10mg / kg anti-mPDl BIW in combination with 30, 60, 100, or 200 mg / kg Compound 1 BID, respectively. Fig. 30a shows tumor volume and Fig. 30b shows body weight for the treatment groups between day 0 and treatment day 11.

[0308] Kaplan-Meier survival analysis was performed using the time to reach the criterion TV threshold of >1400 mm3, at which point the animal was considered to have met animal welfare termination criteria for the study. Median survival in the vehicle + isotype antibody group was 11 days. Animals receiving anti-mouse programmed cell death protein 1 monoclonal antibody (anti-mPDl) alone experienced an increased median survival of 16 days (Logrank p=0.0015 compared to vehicle). Treatment with Compound 1 as a single agent was associated with significant, dose-dependent increases in median survival, with animals receiving 30, 60, 100, or 200 mg / kg Compound 1 twice daily (BID) exhibiting median survival of 18, 25, 27.5, or 41 days, respectively (all Logrank p=0.0015 compared to vehicle). Combination treatment with Compound 1 and anti-mPDl resulted in further increases in median survival compared to the matched single Compound 1 dose or single agent anti-mPDl. Animals treated with anti-mPDl 10 mg / kg twice weekly (BIW) in combination with Compound 1 at 30, 60, or 100 mg / kg BID achieved median survival of 24, 33.5, or 36.5 days, respectively (Logrank p=0.0029 to 0.0310 compared to matched single agent Compound group and Logrank p=0.0054 to <0.001 compared to single agent anti-mPDl). Six of 10 animals treated with 10 mg / kg anti-mPDl BIW +200 mg / kg Compound 1 BID did not reach the defined tumor burden criterion for termination during the study period, with TV ranging from 441 to 991 mm3after 43 days of dosing, and were thus censored from analysis. By the end of the study, only 4 of 10 animals in this group reached the criterion TV for termination. As a result, median survival of the 200 mg / kg Compound 1 BID + anti-mPDl combination was not reached.

[0309] Kaplan-Meier survival plots for the different treatment groups are shown in Fig. 31 A, Fig. 3 IB, Fig. 31C, and Fig. 3 ID. Survival plots for the vehicle + isotype antibody group and the single agent anti-mPDl (10 mg / kg) compared to the groups treated with: single agent 30 mg / kg Compound 1 BID vs. 30 mg / kg Compound 1 BID + 10 mg / kg anti-mPDl BIW (Fig. 31 A), single agent 60 mg / kg Compound 1 BID vs. 60 mg / kg Compound 1 BID + 10 mg / kg anti-mPDl BIW (Fig. 3 IB), single agent 100 mg / kg Compound 1 BID vs. 100 mg / kg Compound 1 BID + 10 mg / kg anti-mPDl BIW (Fig. 31C), and single agent 200 mg / kg Compound 1 BID vs. 200 mg / kg Compound 1 BID + 10 mg / kg anti-mPDl BIW (Fig. 3 ID). The median survival comparisons are summarized in Table 55.Table 53Group Drug No. Dose Volume Route Regimen Duration No. Animals (mg / kg) (mL / kg)1 Vehicle 10 — 5 PO BID 11 Isotype antibody 10 10 IP BIW2 Anti-mPDl (clone RMP1- 10 10 10 IP BIW 2414)3 Compound 1 10 30 5 PO BID 23 4 Compound 1 10 60 5 PO BID 35 5 Compound 1 10 100 5 PO BID 37 6 Compound 1 10 200 5 PO BID 43 7 Compound 1 10 30 5 PO BID 43Anti-mPDl (clone RMP1- 10 10 IP BIW14)Compound 1 60 5 PO BID8 Anti-mPDl (clone RMP1- 10 10 10 IP BIW 4214)Compound 1 100 5 PO BID9 Anti-mPDl (clone RMP1- 10 10 10 IP BIW 4314)Compound 1 200 5 PO BID10 Anti-mPDl (clone RMP1- 10 10 10 IP BIW 4314)Table 54Antitumor Activity of Compound 1 and anti-mPDl in CT26 Murine Colorectal Syngeneic Cancer Xenograft Model in BALB / c Nude MiceTumor TumorSizeaSizeaTreatment (mm3) (mm3) DT / DCb(%) TGIb(%) pc P Value at PG- at PG- D0 Dll1617.18G1 Vehicle, 20% PEG400, 10% solutol 124.38± - - - - in pH4.0 citrate buffer, PO, BID ± 4.81110.57G2 Anti-mPDl (clone RMP1-14) 907.30125.38± 56.1 47.6 ** 0.0051 10 mg / kg, IP, BIW ± 4.75101.83G3 Compound 1, 125.40 688.6642.6 62.2 * * * 0.0001 30 mg / kg, PO, BID ± 4.73 ±76.34G4 Compound 1, 125.46 423.9126.2 80.0 * * * * <0.000160 mg / kg, PO, BID ± 4.76 ± 51.07G5 Compound 1, 125.36 288.7417.9 89.0 * * * * <0.0001 100 mg / kg, PO, BID ± 4.68 ± 30.41G6 Compound 1, 125.32 36.53 ±2.3 106.0 * * * * <0.0001 200 mg / kg, PO, BID ± 4.73 5.97G7 Compound 1,30 mg / kg, PO, BID125.38 504.3031.2 74.6 * * * * <0.0001 ± 4.61 ± 65.70Anti-mPDl (clone RMP1-14)10 mg / kg, IP, BIWG8 Compound 1,60 mg / kg, PO, BID125.36 352.1021.8 84.8 * * * * <0.0001 ± 4.75 ± 90.22Anti-mPDl (clone RMP1-14)10 mg / kg, IP, BIWG9 Compound 1,100 mg / kg, PO, BID125.38 262.3916.2 90.8 * * * * <0.0001 ± 4.61 ± 49.81Anti-mPDl (clone RMP1-14)10 mg / kg, IP, BIWG10 Compound 1,200 mg / kg, PO, BID125.40 62.26 ±3.9 104.2 * * * * <0.0001 ± 4.74 10.16Anti-mPDl (clone RMP1-14)10 mg / kg, IP, BIWNote:a. a. Mean ± SEM.b. Tumor Growth Inhibition is calculated by dividing the group average tumor volume for the treated group by the group average tumor volume for the control group (T / C).c. TGI (%) = [l-(Tn-To) / (Vn-Vo)]x100; Tn is the average tumor volume of atreatment group on PG-D11, To is the average tumor volume of the treatment group on the day of treatment starts, Vn is the average tumor volume of Group 1 on the same day with Tn, and Vo is the average tumor volume of Group 1 on the day of treatment starts.d. Significance levels: * = p<0.05 ** =p<0.01 *** =p<0.001 **** =p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the meansTable 55Treatment Median Lower Upper Logrank Logrank Logrank Survival 95% 95% CI P-value P-value vs. P-value vs. (days) CI vs. vehicle matched single agent + isotype single agent anti-mPDl3antibody3Compound I3Vehicle, PO, BID + 11 9 +infmity — — — 10 mg / kg Isotype Antibody, IP,BIW10 mg / kg Anti-mPDl, IP, BIW 16 14 21 0.0015 — — Compound 1, 30 mg / kg, PO, 18 16 21 0.0015 — — BIDCompound 1, 60 mg / kg, PO, 25 18 28 0.0015 — — BIDCompound 1, 100 mg / kg, PO, 27.5 21 35 0.0015 — — BIDCompound 1, 200 mg / kg, PO, 41 32 +infmity 0.0015 — — BID10 mg / kg Anti-mPDl, IP, BIW 24 16 35 0.0015 0.0068 0.0054 + Compound 1, 30 mg / kg, PO,BID10 mg / kg Anti-mPDl, IP, BIW 33.5 18 +infmity 0.0015 0.0029 <0.0001 + Compound 1, 60 mg / kg, PO,BID10 mg / kg Anti-mPDl, IP, BIW 36.5 25 +infmity 0.0015 0.0310 <0.0001 + Compound 1, 100 mg / kg, PO,BID10 mg / kg Anti-mPDl, IP, BIW NC NC NC 0.0015 0.2655 <0.0001 + Compound 1, 200 mg / kg, PO,BID- = not applicable; anti-mPDl = anti-mouse programmed cell death protein 1 monoclonal antibody; BID = twice daily; BIW = twice weekly; CI = confidence interval; D = aspartate; G12 = glycine 12; IP = intraperitoneal;KRAS = Kirsten rat sarcoma virus; NC = not calculable; PO = oral.aP-values were determined using the Kaplan-Meier test.Compound 1 in human gastric cancer (KRAS WT amplified) patient-derived xenograft model in BALB / c Nude MiceCompound 1 was dosed orally twice per day and RMC-6236 was dosed orally once per day.Compound 1 and RMC-6236 were dosed as either monotherapy or combination in mice bearing patient derived gastric cancer (KRAS WT amplified) tumor fragments. The study design with study groups and number of animals per group are in Table 56. Groups and treatments were started when the mean tumor volume reached 183 mm3as indicated in Table 57. Mice were assigned to respective groups based on their starting tumor volume and body weight such thatthe average values were the same for each treatment group. Compound 1 monotherapy dosed at 30, 60, 100, and 200 mg / kg BID induced tumor growth inhibition (TGI) of 141%, 143%, 145%, and 144% respectively. RMC-6236 monotherapy dosed at 10 and 25 mg / kg QD induced tumor growth inhibition (TGI) of 29% and 60% respectively. 30 mg / kg BID of Compound 1 was dosed in combination with RMC-6236 at 10 mg / kg QD, inducing tumor growth inhibition (TGI) of 143%. Fig. 32a shows tumor volume and Fig. 32b shows body weight for the treatment groups between day 0 and treatment day 21.Table 56Group Drug No. Dose Volume Route Regimen Duration No. Animals (mg / kg) (mL / kg)1 Vehicle 8 0 10 PO BID 212 Compound 1 8 30 10 PO BID 213 Compound 1 8 60 10 PO BID 214 Compound 1 8 100 10 PO BID 215 Compound 1 8 200 10 PO BID 216 RMC-6236 8 10 10 PO QD 217 RMC-6236 8 25 10 PO QD 21Compound 1 30 10 PO BID8 8 21RMC-6236 10 10 PO QDTable 57Antitumor Activity of Compound 1 and RMC-6236 in Human Gastric Cancer Patient Derived Xenograft Model in BALB / c Nude MiceTumor TumorSizeaSizeap Treatment (mm3) (mm3) DT / DCb(%) TGIb(%) pc Value at PG- at PG- D0 D21577.42G1 Vehicle, 20% PEG400, 10% solutol 183.01 ±± - - - - in pH4.0 citrate buffer, PO, BID 10.5930.02G2 Compound 1, 183.39 ± 22.30-41 141 * * * * <0.0001 30 mg / kg, PO, BID 11.07 ± 5.49G3 Compound 1, 182.63 ± 12.19-43 143 * * * * <0.0001 60 mg / kg, PO, BID 9.21 ± 3.96G4 Compound 1, 182.91 ± 5.85 ±-45 145 * * * * <0.0001100 mg / kg, PO, BID 10.12 4.14G5 Compound 1, 182.64 ± 7.97 ±-44 144 * * * * <0.0001 200 mg / kg, PO, BID 12.28 4.23G6 RMC-6236, 183.07 ± 464.6071 29 ns 0.2225 10 mg / kg, PO, QD 11.86 ± 30.6341.16G7 RMC-6236, 182.79 ±± 40 60 ** 0.0014 25 mg / kg, PO, QD 9.8530.23G8 Compound 1,30 mg / kg, PO, BID & 182.93 ± 12.37-43 143 * * * * <0.0001 RMC-6236, 11.62 ± 6.4410 mg / kg, PO, QDNote:a. Mean ± SEM;b. TGI = (1-T / C) x 100%, T / C = 100% x (TV treated fmal-TV treated initial) / (TV Vehicle final- TV Vehicle initial);c. Significance levels: * = p<0.05 ** =p<0.01 *** =p<0.001 **** = p<0.0001 ns = not significant Two-way RM ANOVA followed by Tukey’s post hoc comparisons of the meansCONCLUSION

[0310] Compound 1 achieves KRAS active (ON-state) inhibition targeting common mutations, including G12V and G12D. Compound 1 exhibits isoform selectivity and shows minimal inhibition of NRAS and HRAS with sub-nanomolar cellular potency towards KRAS and mutants via a non-covalent mechanism of action. The pharmacokinetic profile of compound 1 affords complete target coverage resulting in durable regressions in multiple KRAS-mutant xenograft models.

[0311] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure.

Claims

1. CLAIMS2.We claim:

1. A method of treating a cancer in a patient in need thereof, comprising administering to the patient 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

2. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

3. The method of claim 1 or 2, wherein the cancer is breast cancer.

4. The method of claim 3, wherein the breast cancer is a hormone receptor positive (HR+) breast cancer.

5. The method of claim 3, wherein the breast cancer is a HER2+ breast cancer.

6. The method of claim 3, wherein the breast cancer is a triple negative breast cancer (TNBC).

7. The method of claim 3, wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.

8. The method of claim 1 or 2, wherein the cancer is uterine cancer.

9. The method of claim 8, wherein the cancer is uterine sarcoma.

10. The method of claim 1 or 2, wherein the cancer is endometrial cancer.

11. The method of claim 10, wherein the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

12. The method of claim 1 or 2, wherein the cancer is cervical cancer.

13. The method of claim 12, wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

14. The method of claim 1 or 2, wherein the cancer is fallopian tube cancer (FTC).

15. The method of claim 14, wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cell carcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

16. The method of claim 1 or 2, wherein the cancer is prostate cancer.

17. The method of claim 16, wherein the cancer is prostate adenocarcinoma.

18. The method of claim 16, wherein the cancer is prostate transitional cell carcinoma.

19. The method of claim 16, wherein the cancer is prostate squamous cell carcinoma.

20. The method of claim 16, wherein the cancer is prostate small cell carcinoma.

21. The method of claim 16, wherein the cancer is prostate lymphoma.

22. The method of claim 16, wherein the cancer is prostate sarcoma.

23. The method of claim 1 or 2, wherein the cancer is bladder cancer.

24. The method of claim 23, wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non-urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma.

25. The method of claim 23, wherein the cancer is urothelial cancer.

26. The method of claim 23, wherein the cancer is squamous cell cancer of the bladder.

27. The method of claim 23, wherein the cancer is small cell cancer of the bladder.

28. The method of claim 23, wherein the cancer is adenocarcinoma of the bladder.

29. The method of claim 1 or 2, wherein the cancer is lung cancer.

30. The method of claim 1 or 2, wherein the cancer is non-small cell lung cancer.

31. The method of claim 29, wherein the cancer is non-small cell lung cancer, squamous cell cancer.

32. The method of claim 29, wherein the cancer is non-small cell lung cancer, adenocarcinoma.

33. The method of claim 29, wherein the cancer is non-small cell lung cancer, large cell carcinoma.

34. The method of claim 29, wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma.

35. The method of claim 29, wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma.

36. The method of claim 29, wherein the cancer is small cell lung cancer.

37. The method of claim 29, wherein the cancer is combined small cell lung cancer.

38. The method of claim 1 or 2, wherein the cancer is colon cancer (CRC).

39. The method of claim 38, wherein the cancer is CRC, adenocarcinoma.

40. The method of claim 38, wherein the cancer is CRC, squamous cell carcinoma.

41. The method of claim 38, wherein the cancer is CRC, colon cancer.

42. The method of claim 38, wherein the cancer is CRC, carcinoid.

43. The method of claim 38, wherein the cancer is CRC, gastrointestinal stromal.

44. The method of claim 38, wherein the cancer is CRC lymphoma.

45. The method of claim 1 or 2, wherein the cancer is anal cancer.

46. The method of claim 45, wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

47. The method of claim 1 or 2, wherein the cancer is biliary cancer.

48. The method of claim 47, wherein the biliary cancer is cholangiocarcinoma, extra-hepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra-hepatic cholangiocarcinoma.

49. The method of claim 1 or 2, wherein the cancer is a meningioma.

50. The method of claim 1 or 2, wherein the cancer is a glioma.

51. The method of claim 1 or 2, wherein the cancer is pancreatic cancer.

52. The method of claim 51, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

53. The method of claim 51, wherein the cancer is PDAC, adenocarcinoma.

54. The method of claim 51, wherein the cancer is PDAC, acinar cell carcinoma.

55. The method of claim 51, wherein the cancer is exocrine pancreatic cancer.

56. The method of claim 51, wherein the cancer is neuroendocrine pancreatic cancer.

57. The method of claim 51, wherein the cancer is pancreatic cancer, squamous cell carcinoma.

58. The method of claim 51, wherein the cancer is pancreatic cancer, adenosquamous carcinoma.

59. The method of claim 51, wherein the cancer is pancreatoblastoma.

60. The method of claim 1 or 2, wherein the cancer is thyroid cancer.

61. The method of claim 60, wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

62. The method of claim 1 or 2, wherein the cancer is parotid gland cancer.

63. The method of claim 1 or 2, wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

64. The method of claim 1 or 2, wherein the cancer is stomach cancer or gastric cancer.

65. The method of claim 64, wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

66. The method of claim 1 or 2, wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

67. The method of claim 1 or 2, wherein the cancer is skin cancer.

68. The method of claim 67, wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma.

69. The method of claim 67, wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

70. The method of claim 1 or 2, wherein the cancer is melanoma.

71. The method of claim 70, wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

72. The method of claim 1 or 2, wherein the cancer is ovarian cancer.

73. The method of claim 72, wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

74. The method of claim 1 or 2, wherein the cancer is renal cell cancer.

75. The method of claim 1 or 2, wherein the cancer is an appendiceal cancer.

76. The method of claim 75, wherein the cancer is appendiceal carcinoid tumor.

77. The method of claim 75, wherein the cancer is appendiceal mucinous neoplasm.

78. The method of claim 75, wherein the cancer is appendix adenocarcinoma.

79. The method of claim 75, wherein the cancer is appendiceal adenocarcinoid or goblet cell appendiceal carcinoma.

80. The method of claim 75, wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma, appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

81. The method of claim 1 or 2, wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

82. The method of claim 1 or 2, wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

83. The method of claim 1 or 2, wherein the cancer is a sarcoma.

84. The method of claim 1 or 2, wherein the cancer is a primary brain tumor.

85. The method of claim 84, wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

86. The method of claim 1 or 2, wherein the cancer is gallbladder cancer.

87. The method of claim 86, wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

88. The method of claim 1 or 2, wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

89. The method of claim 1 or 2, wherein the cancer is germ cell tumor.

90. The method of claim 89, wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

91. The method of claim 1 or 2, wherein the cancer is plasma cell neoplasm.

92. The method of claim 91, wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

93. The method of claim 1 or 2, wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

94. The method of claim 1 or 2, wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

95. The method of claim 1 or 2, wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

96. The method of claim 1 or 2, wherein the cancer is neuroendocrine carcinoma.

97. The method of claim 1 or 2, wherein the cancer is cancer of unknown primary (CUP).

98. A method of treating a cancer in a patient in need thereof, comprising administering to the patient:95.a) a composition comprising 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro- 5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh- pyrrolizin-7a(5h)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2- amine, or pharmaceutically acceptable salt or solvate thereof; and b) at least one oncology therapeutic selected from a rapidly accelerated fibrosarcoma (RAF) inhibitor, a BRAF inhibitor, a cyclin dependent kinase (CDK) inhibitor, a receptor tyrosine kinase (RTK) inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a vascular endothelial growth factor (VEGF) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a KRAS inhibitor, a methyl ethyl ketone (MEK) inhibitor, an immune checkpoint inhibitor, a phosphoinositide 3 -kinase (PI3K) inhibitor, an antibody drug conjugate (ADC), a mammalian target of rapamycin (mTOR) inhibitor, a radiopharmaceutical, a protein arginine methyltransferase 5 (PRMT5) inhibitor, a RAF / MEK dual inhibitor, a SHP2 inhibitor, a Son of Sevenless homolog 1 (S0S1) inhibitor, a focal adhesion kinase (FAK) inhibitor, a famesyltransferase inhibitor, a taxane, or a poly-ADP ribose polymerase (PARP) inhibitor.

99. The method of claim 98, wherein at least one oncology therapeutic is a RAF inhibitor.

100. The method of claim 98, wherein at least one oncology therapeutic is a BRAF inhibitor.

101. The method of claim 100, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib, encorafenib, exarafenib, lifirafenib, naporafenib, sunitinib, TAK-580, or PLX8394.

102. The method of claim 98, wherein at least one oncology therapeutic is a cyclin dependent kinase inhibitor.

103. The method of claim 102, wherein the cyclin dependent kinase inhibitor is selected from palbociclib, abemaciclib, riboci clib, tagtociclib, atirmociclib, or AVZO-021.

104. The method of claim 98, wherein at least one oncology therapeutic is an RTK inhibitor.

105. The method of claim 104, wherein the RTK inhibitor is selected from dasatinib, imatinib, nilotinib, pazopanib, sorafenib, or sunitinib.

106. The method of claim 98, wherein at least one oncology therapeutic is an EGFR inhibitor.

107. The method of claim 106, wherein the EGFR inhibitor is selected from simotinib, icotinib, gefitinib, erlotinib, cetuximab, panitumumab, necitumumab, lazertinib, osimertinib, olmutinib, lapatinib, afatinib, neratinib, or dacomitinib.

108. The method of claim 98, wherein the oncology therapeutic is a VEGF inhibitor.

109. The method of claim 108, wherein the VEGF inhibitor is selected from bevacizumab, sunitibin, sorafenib, axitinib, cabozantinib, lenvatinib, pazopanib, pegaptanib, or ramucircumab.

110. The method of claim 98, wherein at least one oncology therapeutic is an ERK inhibitor.

111. The method of claim 110, wherein the ERK inhibitor is selected from temuterkib or ulixertinib.

112. The method of claim 98, wherein at least one oncology therapeutic is a KRAS inhibitor.

113. The method of claim 112, wherein the KRAS inhibitor is selected from daraxonrasib (RMC-6236), divarasib, elironrasib, adagrasib, JDQ44, LY3499446, D3S-001, BBO- 8520, sotorasib, MRTX1133, TSN1611, HRS-4642, ERAS-0015, ERAS-4001, orRMC- 9805.

114. The method of claim 112, wherein the KRAS inhibitor is selected from daraxonrasib (RMC-6236), divarasib, elironrasib, adagrasib, JDQ44, LY3499446, D3S-001, BBO- 8520, sotorasib, MRTX1133, TSN1611, HRS-4642, ERAS-0015, ERAS-4001, RMC- 9805, AN9205, GFH276, or BPI-572270.

115. The method of claim 98, wherein at least one oncology therapeutic is a MEK inhibitor.

116. The method of claim 115, wherein the MEK inhibitor is selected from binimetinib, cobimetinib, selumetinib, pimasertib, or trametinib.

117. The method of claim 98, wherein at least one oncology therapeutic is an immune checkpoint inhibitor.

118. The method of claim 117, wherein the immune checkpoint inhibitor is selected from a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, or a bi-specific PD-1 / CTLA4 inhibitor.

119. The method of claim 118, wherein the CTLA-4 inhibitor is selected from ipilmumab or tremelimumab.

120. The method of claim 118, wherein the PD-1 inhibitor is selected from spartalizumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, durvalumab, dostarlimab, retifanlimab, or toripalimab.

121. The method of claim 118, wherein the bi-specific PD-1 / CTLA4 inhibitor is selected from AK104, MGD019, XmAb20717, or MEDI5752.

122. The method of claim 98, wherein the oncology therapeutic is a phosphoinositide 3- kinase inhibitor.

123. The method of claim 122, wherein the phosphoinositide 3-kinase inhibitor is selected from copanlisib, alpelisib, idelalisib, duvelisib, inavolisib, or umbralisib, or STX-478.

124. The method of claim 98, wherein at least one oncology therapeutic is an ADC.

125. The method of claim 124, wherein the ADC is selected from ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, sacituzumab govitecan , disitamab vedotin, tisotumab vedotin, raludotatug deruxtecan, ARX-788, datopotamab deruxtecan, patritumab deruxtecan, ladiratuzumab vedotin or HS-20089.

126. The method of claim 98, wherein at least one oncology therapeutic is a mTOR inhibitor.

127. The method of claim 126, wherein the mTOR inhibitor is deforolimus, everolimus, sirolimus, or temsirolimus.

128. The method of claim 98, wherein at least one oncology therapeutic is a radiopharmaceutical.

129. The method of claim 128, wherein the radiopharmaceutical is [11 Hn] / [89Zr]- trastuzumab.

130. The method of claim 98, wherein at least one oncology therapeutic is a PRMT5 inhibitor.

131. The method of claim 130, wherein the PRMT5 inhibitor is selected from GSK3368715, TNG462, MRTX1719, or AMG193.

132. The method of claim 98, wherein at least one oncology therapeutic is a RAF / MEK dual inhibitor.

133. The method of claim 132, wherein the RAF / MEK inhibitor is selected from avutometinib (VS-6766).

134. The method of claim 98, wherein at least one oncology therapeutic is a SHP2 inhibitor.

135. The method of claim 134, wherein the SHP2 inhibitor is selected from RLY-1971, ERAS-601, TNO155, or RMC-4630.

136. The method of claim 98, wherein at least one oncology therapeutic is a S0S1 inhibitor.

137. The method of claim 136, wherein the S0S1 inhibitor is selected from BI 1701963 or MRTX0902.

138. The method of claim 98, wherein at least one oncology therapeutic is a FAK inhibitor.

139. The method of claim 138, wherein the FAK inhibitor is selected from defactinib, narmafotinib, orIN100189.

140. The method of claim 98, wherein at least one oncology therapeutic is a famesyltransferase inhibitor.

141. The method of claim 140, wherein the famesyltransferase inhibitor is selected from lonafamib, tipifamib, or KO-2806.

142. The method of claim 98, wherein at least one oncology therapeutic is a taxane.

143. The method of claim 142, wherein the taxane is selected from paclitaxel, docetaxel, cabazitaxel, or abraxane.

144. The method of claim 98, wherein at least one oncology therapeutic is a PARP inhibitor.

145. The method of claim 144, wherein the PARK inhibitor is selected from olaparib, rucaparib, niraparib, talazoparib, orveliparib.

146. The method of claim 98, wherein the cancer is breast cancer.

147. The method of claim 146, wherein the breast cancer is a hormone receptor positive (HR+) breast cancer.

148. The method of claim 146, wherein the breast cancer is a HER2+ breast cancer.

149. The method of claim 146, wherein the breast cancer is a triple negative breast cancer (TNBC).

150. The method of claim 146, wherein the breast cancer is ductal carcinoma, lobular carcinoma, or inflammatory breast cancer.

151. The method of claim 98, wherein the cancer is uterine cancer.

152. The method of claim 151, wherein the cancer is uterine sarcoma.

153. The method of claim 98, wherein the cancer is endometrial cancer.

154. The method of claim 153, wherein the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma (uterine papillary serous carcinoma), uterine carcinosarcoma, uterus sarcoma, endometrial undifferentiated carcinoma, endometrial squamous cell carcinoma, endometrial small cell carcinoma, endometrial transitional carcinoma, endometrial mucinous adenocarcinoma, or endometrial clear cell adenocarcinoma.

155. The method of claim 98, wherein the cancer is cervical cancer.

156. The method of claim 155, wherein the cervical cancer is a cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, cervical clear cell carcinoma, or cervical small cell carcinoma.

157. The method of claim 98, wherein the cancer is fallopian tube cancer (FTC).

158. The method of claim 157, wherein the fallopian tube cancer (FTC) cancer is FTC papillary serous adenocarcinoma, FTC endometrioid carcinoma, FTC clear cell carcinoma, FTC mucinous carcinoma, FTC transitional cell carcinoma, FTC sarcoma, or primary fallopian tube cancer.

159. The method of claim 98, wherein the cancer is prostate cancer.

160. The method of claim 159, wherein the cancer is prostate adenocarcinoma.

161. The method of claim 159, wherein the cancer is prostate transitional cell carcinoma.

162. The method of claim 159, wherein the cancer is prostate squamous cell carcinoma.

163. The method of claim 159, wherein the cancer is prostate small cell carcinoma.

164. The method of claim 159, wherein the cancer is prostate lymphoma.

165. The method of claim 159, wherein the cancer is prostate sarcoma.

166. The method of claim 98, wherein the cancer is bladder cancer.

167. The method of claim 166, wherein the bladder cancer is urothelial carcinoma (transitional cell carcinoma), bladder squamous cell carcinoma, urachal adenocarcinoma, non-urachal adenocarcinoma, bladder small cell carcinoma, or bladder sarcoma.

168. The method of claim 167, wherein the cancer is urothelial cancer.

169. The method of claim 167, wherein the cancer is squamous cell cancer of the bladder.

170. The method of claim 167, wherein the cancer is small cell cancer of the bladder.

171. The method of claim 167, wherein the cancer is adenocarcinoma of the bladder.

172. The method of claim 98, wherein the cancer is lung cancer.

173. The method of claim 98, wherein the cancer is non-small cell lung cancer.

174. The method of claim 173, wherein the cancer is non-small cell lung cancer, squamous cell cancer.

175. The method of claim 173, wherein the cancer is non-small cell lung cancer, adenocarcinoma.

176. The method of claim 173, wherein the cancer is non-small cell lung cancer, large cell carcinoma.

177. The method of claim 173, wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma.

178. The method of claim 173, wherein the cancer is non-small cell lung cancer, adenosquamous carcinoma.

179. The method of claim 173, wherein the cancer is small cell lung cancer.

180. The method of claim 173, wherein the cancer is combined small cell lung cancer.

181. The method of claim 98, wherein the cancer is colon cancer (CRC).

182. The method of claim 98, wherein the cancer is rectal cancer.

183. The method of claim 181 or 182, wherein the cancer is adenocarcinoma.

184. The method of claim 181 or 182, wherein the cancer is squamous cell carcinoma.

185. The method of claim 181, wherein the cancer is colon cancer.

186. The method of claim 181 or 182, wherein the cancer is carcinoid.

187. The method of claim 181 or 182, wherein the cancer is gastrointestinal stromal.

188. The method of claim 181 or 182, wherein the cancer is lymphoma.

189. The method of claim 98, wherein the cancer is anal cancer.

190. The method of claim 189, wherein the anal cancer is selected from squamous cell carcinoma anal cancer, or adenocarcinoma anal cancer.

191. The method of claim 98, wherein the cancer is biliary cancer.

192. The method of claim 191, wherein the biliary cancer is cholangiocarcinoma, extrahepatic cholangiocarcinoma, perihilar bile duct cancer (Klatskin tumor), distal bile duct cancer, or intra-hepatic cholangiocarcinoma.

193. The method of claim 98, wherein the cancer is a meningioma.

194. The method of claim 98, wherein the cancer is a glioma.

195. The method of claim 98, wherein the cancer is pancreatic cancer.

196. The method of claim 195, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

197. The method of claim 195, wherein the cancer is PDAC, adenocarcinoma.

198. The method of claim 195, wherein the cancer is PDAC, acinar cell carcinoma.

199. The method of claim 195, wherein the cancer is exocrine pancreatic cancer.

200. The method of claim 195, wherein the cancer is neuroendocrine pancreatic cancer.

201. The method of claim 195, wherein the cancer is pancreatic cancer, squamous cell carcinoma.

202. The method of claim 195, wherein the cancer is pancreatic cancer, adenosquamous carcinoma.

203. The method of claim 195, wherein the cancer is pancreatoblastoma.

204. The method of claim 98, wherein the cancer is thyroid cancer.

205. The method of claim 204, wherein the thyroid cancer is selected from papillary thyroid cancer, follicular thyroid cancer, medullary thyroid cancer, or anaplastic thyroid cancer.

206. The method of claim 98, wherein the cancer is parotid gland cancer.

207. The method of claim 98, wherein the cancer is esophageal cancer, esophageal adenocarcinoma, or esophageal squamous cell carcinoma.

208. The method of claim 98, wherein the cancer is stomach cancer or gastric cancer.

209. The method of claim 208, wherein the stomach cancer or gastric cancer is selected from gastric adenocarcinoma, intestinal type gastric adenocarcinoma, diffuse type gastric adenocarcinoma, adenocarcinoma of the stomach, gastroesophageal junction adenocarcinoma (GEJ), gastrointestinal neuroendocrine tumor (GNET), gastrointestinal stromal tumor (GIST), gastric adenosquamous carcinoma, gastric carcinoid tumor, or primary gastric lymphoma.

210. The method of claim 98, wherein the cancer is small bowel adenocarcinoma, small bowel sarcoma, small bowel lymphoma, small bowel neuroendocrine tumor, or small bowel carcinoid tumor.

211. The method of claim 98, wherein the cancer is skin cancer.

212. The method of claim 211, wherein the skin cancer is basal cell carcinoma, or squamous cell carcinoma.

213. The method of claim 211, wherein the cancer is non-melanoma skin cancer, squamous non-melanoma skin cancer, or non-squamous non-melanoma skin cancer.

214. The method of claim 98, wherein the cancer is melanoma.

215. The method of claim 214, wherein the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, or desmoplastic melanoma.

216. The method of claim 98, wherein the cancer is ovarian cancer.

217. The method of claim 216, wherein the ovarian cancer is epithelial ovarian cancer, ovarian fibrosarcoma, ovarian mucinous carcinoma, neuroendocrine cancer of ovary.

218. The method of claim 98, wherein the cancer is renal cell cancer.

219. The method of claim 98, wherein the cancer is an appendiceal cancer.

220. The method of claim 219, wherein the cancer is appendiceal carcinoid tumor.

221. The method of claim 219, wherein the cancer is appendiceal mucinous neoplasm.

222. The method of claim 219, wherein the cancer is appendix adenocarcinoma.

223. The method of claim 219, wherein the cancer is appendiceal adenocarcinoid or goblet cell appendiceal carcinoma.

224. The method of claim 219, wherein the cancer is signet ring cell appendiceal carcinoma, colonic-type appendiceal adenocarcinoma, appendiceal paraganglioma, epithelial appendiceal cancer, or neuroendocrine appendiceal cancer.

225. The method of claim 98, wherein the cancer is a peritoneal cancer or primary peritoneal carcinoma.

226. The method of claim 98, wherein the cancer is a bone cancer, osteosarcoma, chondrosarcoma, or chordoma.

227. The method of claim 98, wherein the cancer is a sarcoma.

228. The method of claim 98, wherein the cancer is a primary brain tumor.

229. The method of claim 228, wherein the brain cancer is glioblastoma, astrocytoma, anaplastic astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma.

230. The method of claim 98, wherein the cancer is gallbladder cancer.

231. The method of claim 230, wherein the gallbladder cancer is gallbladder adenocarcinoma, nonpapillary adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, gallbladder squamous cell carcinoma, gallbladder adenosquamous carcinoma, or gallbladder carcinosarcoma.

232. The method of claim 98, wherein the cancer is soft tissue sarcoma, or undifferentiated pleomorphic sarcoma.

233. The method of claim 98, wherein the cancer is germ cell tumor.

234. The method of claim 233, wherein the germ cell tumor is testicular germ cell cancer, ovarian germ cell tumor, brain germ cell tumor, or endodermal sinus tumor.

235. The method of claim 98, wherein the cancer is plasma cell neoplasm.

236. The method of claim 235, wherein the plasma cell neoplasm is selected from isolated plasmacytoma of bone, extramedullary plasmacytoma, multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS).

237. The method of claim 98, wherein the cancer is myelodysplastic / myeloproliferative neoplasms (MDS / MPN).

238. The method of claim 98, wherein the cancer is myelodysplastic neoplasm, myeloproliferative neoplasm, chronic myelomonocytic leukemia, atypical chronic myeloid leukemia, or juvenile myelomonocytic leukemia.

239. The method of claim 98, wherein the cancer is acute leukemia, acute lymphocytic leukemia, or acute myelogenous leukemia.

240. The method of claim 98, wherein the cancer is neuroendocrine carcinoma.

241. The method of claim 98, wherein the cancer is cancer of unknown primary (CUP).

242. The method of any one of the preceding claims, wherein the cancer is locally advanced.

243. The method of any one of the preceding claims, wherein the cancer is metastatic.

244. The method of any one of the preceding claims, wherein the method is adjuvant therapy following surgical resection.

245. The method of any one of the preceding claims, wherein the method is neo-adjuvant therapy.

246. The method of any one of the preceding claims, wherein the method is first-line systemic therapy for locally advanced or metastatic disease.

247. The method of any one of the preceding claims, wherein the patient has relapsed after prior therapy.

248. The method of any one of the preceding claims, wherein the patient has acquired resistance to prior therapy.

249. The method of any one of the preceding claims, wherein the patient is refractory to therapy.

250. The method of any one of the preceding claims, wherein the cancer is characterized by existence of KRAS mutation.

251. The method of claim 250, wherein the KRAS mutation is selected from G12A, G12C, G12D, G12V, G13D, or a combination thereof.

252. The method of claim 251, wherein the cancer further comprises an additional mutation.

253. The method of claim 251, wherein the cancer comprises at least one mutation selected from the group consisting of G12C, RAF del, NRAS del, RAFl-amp.

254. The method of claim 251, wherein the cancer comprises at least one mutation selected from the group consisting of KRAS G12D, PIK3CA-H1047R, EGFR-HI.

255. The method of claim 251, wherein the cancer comprises at least one mutation selected from the group consisting of KRAS G13D and EGFR-HI.

256. The method of claim 251, wherein the cancer is characterized by KRAS-WT-amp.

257. The method of any one of the preceding claims, wherein the 5-ethynyl-6-fluoro-4-(8- fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2-azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2- fluorotetrahydro-lh-pyrrolizin-7a(5h)-yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7- yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is administered orally.

258. The method of claim 257, wherein oral administration occurs once per day, twice per day, three times per day, every other day, or one to six days per week.

259. The method of claim 258, wherein an oral daily dose is about 15 mg, about 25 mg, about 35 mg, about 50 mg, about 75 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 350 mg, about 400 mg, about 450 mg, or about 500 mg.

260. The method of any one of the preceding claims, wherein the administration to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is correlated to plasma concentrations of DUSP6.

261. The method of any one of the preceding claims, wherein frequency of administration to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is adjusted to maintain a DUSP6 plasma concentration of less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%, of the DUSP6 plasma concentration determined prior to starting therapy with 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2-- Ill - azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

262. The method of any one of the preceding claims, whereina dose administered to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is adjusted to maintain a DUSP6 plasma concentration of less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, less than 10%, less than 15%, less than 20%, less than 25%, or less than 30%, of the DUSP6 plasma concentration determined prior to starting therapy with 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof.

263. The method of any one of the preceding claims, wherein the administration to the patient of 5-ethynyl-6-fluoro-4-(8-fluoro-4-((ls,7s,8s)-8-fluoro-5-oxa-2- azabicyclo[5.1.0]octan-2-yl)-2-(((2r,7as)-2-fluorotetrahydro-lh-pyrrolizin-7a(5h)- yl)methoxy-d2)pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-amine, or pharmaceutically acceptable salt or solvate thereof, is adjusted to maintain a pharmacokinetic area under the curve (AUCo-i2h,ss) of about 900 ng*h / mL, about 1000 ng*h / mL, about 1100 ng*h / mL, about 1200 ng*h / mL, about 1300 ng*h / mL, about 1400 ng*h / mL, about 1500 ng*h / mL, about 1600 ng*h / mL, about 1700 ng*h / mL, about 1800 ng*h / mL, about 1900 ng*h / mL, or about 2000 ng*h / mL.

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