Methods for Treating Solid Tumors Using Heteroaromatic Macrocyclic Ether Compounds - Patent application

Abstract

Provided herein are methods of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, for treating, preventing, or managing solid tumors.

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Patent Application No. 63 / 251,536, filed October 1, 2021, and U.S. Patent Application No. 63 / 357,309, filed June 30, 2022, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive external signals, such as signals for growth and division, and transmit these signals in cells through kinase activity. Many RTKs are proto-oncogenes, and aberrant RTK activity can drive cell survival, growth, and proliferation leading to cancer and related disorders. This aberrant kinase activity can be caused by mutations, such as activating mutations in the kinase domain, gene rearrangements that result in fusion proteins containing intact kinase domains, amplification, and other means. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encoding TRKA), NTRK2 (encoding TRKB), and NTRK3 (encoding TRKC).

[0003] ROS1 is an RTK proto-oncogene with ROS1 rearrangements detected in non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and spitzoid melanoma. Oncogenic ROS1 gene fusions contain the kinase domain (3' region) of ROS1 fused to the 5' region of various partner genes. Examples of ROS1 fusion partner genes observed in NSCLC include SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC, GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17 (putative), SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, CLIP1 (putative), EEF1G, KIF21A (putative), KLC1, SART3, ST13 (putative), TRIM24 (putative), ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0004] NTRK1, NTRK2 and NTRK3 are RTK proto-oncogenes that encode TRK family kinases, and RTK proto-oncogenes have NTRK1, NTRK2 and NTRK3 chromosomal rearrangements that are detected in many cancers at low frequencies. However, for the treatment of ROS1-positive or ALK-positive patients, TRK inhibition, especially in the central nervous system (CNS), is associated with adverse reactions including dizziness / ataxia / gait disturbance, paresthesia, weight gain and cognitive changes.

[0005] Existing drugs used to treat oncogenic ROS1 and ALK have significant deficiencies that may manifest themselves as one or more of the following: associated TRK inhibition, limited CNS activity, and inadequate activity against resistant mutations. Treatment of ROS1-positive or ALK-positive patients with TRK inhibition is associated with adverse reactions, particularly in the CNS, including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes. In addition, there is a need for CNS-penetrant and TRK-sparing inhibitors of ROS1 with wild-type ROS1 kinase domain and acquired resistance mutations occurring either individually or in combination, including G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. Similarly, there is a need for CNS-penetrant and TRK-sparing inhibitors of ALK with acquired resistance mutations. A variety of ALK drug resistance mutations occurring either individually or in combination have been reported and include G1202R, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. Summary of the Invention

[0006] Provided herein are methods of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, for treating, preventing, or managing solid tumors.

[0007] In one embodiment, a method of treating a solid tumor comprises administering to a patient in need thereof a therapeutically effective amount of Compound 1: [ka] or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is Compound 1.

[0008] In one embodiment, the solid tumor is an aggressive ROS1-positive solid tumor. In one embodiment, the solid tumor is a locally aggressive ROS1-positive solid tumor. In one embodiment, the solid tumor is an aggressive ROS1-positive non-small cell lung cancer (NSCLC).

[0009] In one embodiment, the solid tumor is a metastatic ROS1-positive solid tumor. In one embodiment, the solid tumor is a central nervous system (CNS) (e.g., brain) metastatic ROS1-positive solid tumor. In one embodiment, the solid tumor is a metastatic ROS1-positive NSCLC. In one embodiment, the solid tumor is a CNS (e.g., brain) metastatic ROS1-positive NSCLC.

[0010] In one embodiment, the patient is tyrosine kinase inhibitor (TKI) therapy naive. In one embodiment, the patient has been treated with one or more previous TKI therapies. In one embodiment, the patient has been treated with one previous ROS1 TKI therapy (e.g., crizotinib or entrectinib). In one embodiment, the patient has been treated with two or more previous ROS1 TKI therapies. In one embodiment, the patient's tumor has no known oncogenic driver alterations other than ROS1.

[0011] In one embodiment, the compound is administered in an amount of about 5 mg to about 400 mg once (QD) or twice (BID) per day. In one embodiment, the compound is administered in an amount of about 5 mg to about 200 mg (by weight of Compound 1) once (QD) or twice (BID) per day. In one embodiment, the compound is administered to a patient who is fasting (e.g., at least 1 hour before and 2 hours or more after ingestion of food and / or beverages other than water). In one embodiment, the compound is administered to a patient after ingestion of food and / or beverages. In one embodiment, the patient is not taking any one of a strong inhibitor of CYP3A4, a strong inducer of CYP3A4, a sensitive substrate of CYP3A4, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of MATE1, or a gastric acid reducer. In one embodiment, the patient is taking any one of a strong inhibitor of CYP3A4, a strong inducer of CYP3A4, a sensitive substrate of CYP3A4, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of MATE1, or a gastric acid reducer. In one embodiment, the compound is administered in the absence of a strong inhibitor of CYP3A4, a strong inducer of CYP3A4, or a sensitive substrate of CYP3A4. In one embodiment, the compound is administered in the presence of a strong inhibitor of CYP3A4, a strong inducer of CYP3A4, or a sensitive substrate of CYP3A4. In one embodiment, the compound is administered in the absence of a strong inhibitor of CYP3A4. In one embodiment, the compound is administered in the absence of a strong inducer of CYP3A4. In one embodiment, the compound is administered in the absence of a sensitive substrate of CYP3A4. In one embodiment, the compound is administered in the absence of a P-gp / multidrug resistance protein 1 (MDR1) substrate, a BCRP / breast cancer resistance protein (ABCG2) substrate, or MATE 1. In one embodiment, the compound is administered in the presence of a P-gp / multidrug resistance protein 1 (MDR1) substrate, a BCRP / breast cancer resistance protein (ABCG2) substrate, or MATE 1. In one embodiment, the compound is administered in the absence of a gastric acid reducing agent (e.g., a proton pump inhibitor, e.g., lansoprazole).In one embodiment, the compound is administered in the presence of a gastric acid reducer (e.g., a proton pump inhibitor, e.g., lansoprazole). In one embodiment, the compound is administered in the absence of a strong inducer of CYP3A4. In one embodiment, the compound is administered in the presence of a strong inducer of CYP3A4.

[0012] In one embodiment, the compound is administered in the absence of a sensitive substrate of CYP3A4. In one embodiment, the compound and a sensitive substrate of CYP3A4 are not administered simultaneously. In one embodiment, the sensitive substrate of CYP3A4 includes one or more of buspirone, everolimus, lovastatin, midazolam, simvastatin, triazolam, maraviroc, conivaptan, and darifenacin. [Brief description of the drawings]

[0013] [Figure 1] The phase 1 and phase 2 study designs are shown.

[0014] [Diagram 2] A, B, and C show compound 1-induced regression in Lu01-0414, CTG-0848, and CTG-2532 patient-derived xenograft models (PDX), respectively. Compound 1 activity in various ROS1 PDX models subcutaneously implanted in Balb / c mice. Vehicle is 20% HP-beta-CD (hydroxypropyl-beta-cyclodextrin). Means ± SEM plotted. No significant changes in body weight were observed (data not shown). Compound 1 induced regression regardless of fusion partner (SDC4 or CD74).

[0015] [Diagram 3] 1 shows that ROS1 fusions signal through the PI3K and MAP kinase pathways, resulting in proliferation and other transcriptional changes.

[0016] [Figure 4A]Representative Western blots of Lu01-0414 PDX treated with Compound 1 (BID×5 PO) reveal suppression of ROS1-dependent cell signaling via reduced levels of pROS1, ROS1, pAKT, and pERK. Pharmacokinetic analysis showed dose-dependent differences in Compound 1 unbound plasma concentrations. In this model, 0.04 mg / kg achieved quiescence and 5 mg / kg achieved regression. [Figure 4B] Western blot quantification of three PDX models treated with Compound 1 (BIDx5 PO) confirmed reduced levels of ROS1, pROS1 and pERK. Y-axis shows fold change normalized to vehicle treatment, indicated by open black squares and grey horizontal lines. Mean ± SEM plotted. [Figure 4C] Western blot quantification of three PDX models treated with Compound 1 (BIDx5 PO) confirmed reduced levels of ROS1, pROS1 and pERK. Y-axis shows fold change normalized to vehicle treatment, indicated by open black squares and grey horizontal lines. Mean ± SEM plotted. [Figure 4D] Western blot quantification of three PDX models treated with Compound 1 (BIDx5 PO) confirmed reduced levels of ROS1, pROS1 and pERK. Y-axis shows fold change normalized to vehicle treatment, indicated by open black squares and grey horizontal lines. Mean ± SEM plotted.

[0017] [Diagram 5] A, B, and C show that Compound 1 inhibited ROS1 signaling in tumors by quantitative digital image analysis of immunohistochemical staining. Means ± SEM plotted. Effects on pERK, ERK, and pAKT were model dependent.

[0018] [Figure 6]A, B, and C show that Compound 1 reduced the expression levels of MAP kinase pathway genes in tumors. Gene expression profiling of tumor samples with NanoString 770 gene nCounter PanCancer Pathways panel. Expression levels of MAP kinase pathway genes DUSP6, FOS, IL1R1, and SPRY4 were dose-dependently reduced in tumors upon Compound 1 treatment. Y-axis shows relative expression normalized to vehicle treatment indicated by black dots and grey horizontal lines. Mean ± SEM plotted.

[0019] [Figure 7] Additional Phase 1 study designs are shown.

[0020] [Figure 8A] Representative computed tomography (CT) images are shown demonstrating a confirmed partial response (PR) to treatment with Compound 1 in a patient with CD74-ROS1 fusion-positive lung adenocarcinoma harboring a ROS1 G2032R resistance mutation following prior crizotinib, lorlatinib, and chemotherapy. The arrow indicates a left lung nodule that decreased in size over the course of treatment.

[0021] [Figure 8B] Representative CT (upper panel) and magnetic resonance imaging (lower panel) images are shown demonstrating a confirmed PR of treatment with compound 1 in a patient with EZR-ROS1 fusion-positive lung adenocarcinoma harboring a ROS1 G2032R resistance mutation following prior entrectinib, repotrectinib, and chemotherapy. The arrows in the upper panel indicate liver metastases in segments 5 / 6 and 3 with continued regression over the course of treatment. The arrows in the lower panel indicate right occipital lobe metastases that decreased in size at week 4 and were barely discernible at week 16.

[0022] [Figure 8C]Representative computed tomography images are shown demonstrating a confirmed partial response to Compound 1 in a patient with EZR-ROS1 fusion-positive lung adenocarcinoma without known ROS1 resistance mutations following prior crizotinib. The arrow indicates a left pleural-based lung nodule that decreased in size at week 4 and was barely discernible at week 24.

[0023] [Figure 9] We show that compound 1 inhibits signaling through the MAPK and PI3K / AKT pathways and induces apoptosis in SDC4-ROS1-harboring PDX tumors.

[0024] [Figure 10] A is a representative X-ray powder diffraction (XRPD) pattern of Form 1 of the free base of Compound 1. B is a representative differential scanning calorimetry (DSC) thermogram of Form 1 of the free base of Compound 1.

[0025] [Figure 11] 1 shows ctDNA data demonstrating that Compound 1 was active against both the ROS1 fusion and the ROS1 G2032R solvent front mutation at all dose levels tested.

[0026] [Figure 12] Radiographic tumor regressions are shown for patients receiving Compound 1. PD = progressive disease; PR = confirmed partial response; QD = once daily; SD = stable disease; TKI = tyrosine kinase inhibitor. a Unconfirmed single time point PR. b Ongoing partial response pending confirmation. c Best response PR due to residual non-target disease. d Additional prior ROS1 TKI was ceritinib or cabozantinib. e Includes immunotherapy, bevacizumab and investigational therapy.

[0027] [Figure 13] Figure 1 shows duration of treatment for response-evaluable patients with NSCLC who received Compound 1. PD = progressive disease; PR = partial response; TKI = tyrosine kinase inhibitor.

[0028] [Figure 14] Reduction in tumor burden in patients with ROS1 G2032R (left panel) and reduction in the ROS1 G2032R allele (right panel) by Compound 1. b Bars represent results at 2 weeks; results at 8 weeks are pending.

[0029] [Figure 15] 1 shows radiographic images demonstrating intracranial response in a 65-year-old female with CD74-ROS1 fusion NSCLC who had previously been treated with chemotherapy, crizotinib, and lorlatinib, and who had CNS progression and no known ROS1 resistance mutations.

[0030] [Figure 16] 1 shows radiographic images showing intracranial and extracranial activity in TKI-resistant ROS1 G2032R+ NSCLC in patients diagnosed with EZR-ROS1 fusion NSCLC.

[0031] [Figure 17] Figure 1 shows EZR-ROS1 (left y-axis) and ROS1 G2032R (right y-axis) variant allele frequencies in plasma from a 65-year-old patient with stage IV lung adenocarcinoma and multiple brain metastases, as determined by the Guardant 360 assay, who had EZR-ROS1 identified by plasma testing prior to treatment (C1D1) and during treatment (C1D15 and C3D1).

[0032] [Figure 18] A, B, and C show unbound plasma concentrations of Compound 1 over a 24-hour period for three patients on day 15 of treatment cycle 1 (see Results section of Example 5). The dashed line indicates the minimum effective concentration threshold of 5.3 ng / mL = 13 nM, based on the efficacy threshold in the murine CTG-2532 CD74-ROS1 G2032R PDX study.

[0033] [Figure 19]Compound 1 exposure in clinical trials has been shown to exceed target levels resulting in regression in preclinical models (see Example 5). Compound 1 has demonstrated low intra-cohort patient PK variability, increasing exposure with increasing dose levels, and favorable pharmacokinetics, including a half-life of approximately 20 hours, supporting QD dosing. Data as of September 13, 2022 for patients treated through September 1, 2022. Pharmacokinetic data for the 125 mg QD cohort is not shown due to incompleteness. QD = once daily. a, b Based on tumor regression in in vivo models with SDC4-ROS1 and CD74-ROS1 G2032R, respectively. c, d. Values ​​for a and b divided by predicted human CNS Kp, respectively.

[0034] [Figure 20] Data as of September 13, 2022 for patients treated by September 1, 2022 indicates that the Phase 1 population in Example 5 has heavily pretreated ROS1-positive solid tumors. All data shown as n (%) unless otherwise specified. CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small cell lung cancer; RECIST 1.1, Response Evaluation Criteria in Solid Tumours version 1.1; TKI, tyrosine kinase inhibitor. a Includes patients with untreated CNS disease. b Excludes therapy administered for early stage disease. c Categories are not mutually exclusive.

[0035] [Figure 21]Figure 1 shows treatment-related adverse events (TRAEs) in more than one patient in the Phase 1 study (Example 5) with data as of September 13, 2022 for patients treated through September 1, 2022. The safety profile of Compound 1 is favorable and consistent with the highly ROS1 selective TRK-sparing Compound 1. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DLT, dose-limiting toxicity; SAE, serious adverse event. a Includes edema and peripheral edema. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art of this disclosure. The following references provide those skilled in the art with general definitions of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the following meanings ascribed to them unless otherwise specified.

[0037] In some embodiments, chemical structures are disclosed with their corresponding chemical names. In case of conflict, the chemical structures, not the names, define the meaning.

[0038] As used herein, the terms "comprising" and "including" may be used without distinction. The terms "comprising" and "including" are interpreted as specifying the presence of a described feature or a referenced component, but do not exclude the presence or addition of one or more features or components, or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of". Thus, the term "consisting of" may be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0039] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components it comprises. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any succeeding recitation, except those that are not essential to the technical effect being achieved.

[0040] As used herein, unless specifically stated or clear from the context, the term "or" is understood to be inclusive. As used herein, unless specifically stated otherwise or clear from the context, the terms "a," "an," and "the" are understood to be singular or plural. For example, when a compound provided herein is administered to a "patient," this includes administering the compound to an individual patient or a population of patients.

[0041] As used herein, unless otherwise specified, "stereoisomer" refers to various stereoisomeric forms of a compound that contain one or more asymmetric centers or steric hindrance in the structure. In some embodiments, a stereoisomer is an enantiomer, a mixture of enantiomers, an atropisomer, or a tautomer. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers (e.g., atropisomers), or in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In some embodiments, the compounds provided herein may be atropisomers. In certain embodiments, atropisomers are stereoisomers that arise due to rotational hindrance around a single bond, and the energy difference due to steric strain or other contributors results in a sufficiently high rotational hindrance to allow the isolation of individual conformers. Stereoisomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) and Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention additionally encompasses compounds as individual isomers substantially free of other isomers, or alternatively, as mixtures of various isomers.

[0042] In certain embodiments, the compounds provided herein may be racemic. In certain embodiments, the compounds provided herein may be enriched in one enantiomer. For example, the compounds provided herein may have more than about 30% ee, more than about 40% ee, more than about 50% ee, more than about 60% ee, more than about 70% ee, more than about 80% ee, more than about 90% ee, or even more than about 95% ee. In certain embodiments, the compounds provided herein may have two or more stereocenters. In certain such embodiments, the compounds provided herein may be enriched in one or more diastereomers. For example, the compounds provided herein may have more than about 30% de, more than about 40% de, more than about 50% de, more than about 60% de, more than about 70% de, more than about 80% de, more than about 90% de, or even more than about 95% de.

[0043] In certain embodiments, the therapeutic preparation may be enriched to provide mainly one enantiomer of the compound. An enantiomerically enriched mixture may, for example, contain at least about 60 mole percent of one enantiomer, or more particularly at least about 75, about 90, about 95, or even about 99 mole percent. In certain embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question constitutes, for example, less than about 10% or less than about 5% or less than about 4% or less than about 3% or less than about 2% or less than about 1% compared to the amount of the other enantiomer in the composition or compound mixture. For example, if a composition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, the composition or compound mixture is said to contain about 98 mole percent of the first enantiomer and only about 2% of the second enantiomer.

[0044] In certain embodiments, therapeutic preparations can be enriched to provide predominantly one diastereomer of a compound. A diastereomerically enriched mixture can contain, for example, at least about 60 mole percent of one diastereomer, or more particularly, at least about 75, about 90, about 95, or even about 99 mole percent.

[0045] In some embodiments, moieties in a compound exist as a mixture of tautomers. A "tautomer" is a structural isomer of a moiety or compound that is readily interconverted with another structural isomer. For example, a pyrazole ring has two tautomers: [ka] The two tautomers differ in the location of the pi bonds and hydrogen atoms. Unless otherwise specified, a tautomer diagram of one of the moieties or compounds includes all possible tautomers.

[0046] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds, e.g., chickens, ducks, geese, quail, and / or turkeys. In certain embodiments, the subject is a human adult. In certain embodiments, the subject is a human adult at least 40 years of age. In certain embodiments, the subject is a human adult at least 50 years of age. In certain embodiments, the subject is a human adult at least 60 years of age. In certain embodiments, the subject is a human adult at least 70 years of age. In certain embodiments, the subject is a human adult at least 18 years of age or at least 12 years of age. As used herein, unless otherwise specified, a human subject to whom administration of a therapeutic agent (e.g., a compound described herein) is contemplated to treat, prevent, or manage a disease, disorder, or condition, or a symptom thereof, is also referred to as a "patient."

[0047] As used herein, a therapeutic agent that "prevents" a disorder or condition refers to a compound that reduces or delays the onset of a disorder or condition in a statistical sample relative to an untreated control sample, or reduces the severity of one or more symptoms of a disorder or condition relative to an untreated control sample. These effects are also referred to as "prophylactic" effects. Thus, as used herein, unless otherwise specified, the terms "prevention" and "preventing" refer to an approach for obtaining a beneficial or desired result, which includes, but is not limited to, a prophylactic benefit. For prophylactic benefit, a therapeutic agent may be administered to a patient at risk of developing a particular disease or who reports one or more of the physiological symptoms of a disease, even if a diagnosis of the disease may not have been made. In one embodiment, a therapeutic agent is administered prior to clinical signs of an undesired condition (e.g., the subject's disease or other undesired condition) for a prophylactic benefit (e.g., the therapeutic agent protects the subject from developing an undesired condition).

[0048] As used herein, unless otherwise specified, the terms "treatment" and "treating" refer to a curative or palliative procedure. Beneficial or desired clinical results include, but are not limited to, a total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, attenuation of the extent of the disease, a stabilized (i.e., not worsening) state of the disease, a delay or slowing of disease progression, remission or alleviation of a disease state (e.g., one or more symptoms of a disease), and remission (whether partial or complete). "Treatment" can also mean prolonging survival compared to the expected survival if not receiving treatment. In one embodiment, "treatment" includes administration of a therapeutic agent after the onset of an undesired condition (i.e., intended to attenuate, ameliorate, or stabilize an undesired condition or its side effects that exist).

[0049] As used herein, unless otherwise indicated, the term "managing" includes preventing the recurrence of a particular disease or disorder in a patient afflicted with the disease or disorder, extending the time that a patient afflicted with the disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity or avoidance of symptoms associated with the disease or condition being managed.

[0050] As used herein, "effective amount" refers to an amount that is sufficient to achieve a desired biological effect.As used herein, "therapeutically effective amount" refers to an amount that is sufficient to achieve a desired therapeutic effect.For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.

[0051] A "response" to a therapeutic method can include, among others, a decrease in or amelioration of negative symptoms, a decrease in the progression of the disease or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, stabilization of the disease, or a partial or complete cure of the disease.

[0052] As used herein, unless otherwise indicated, the term "recurrent" refers to a disorder, disease, or condition that has responded (e.g., achieved a complete response) to a previous treatment and has then had a progression. The previous treatment may include one or more lines of therapy.

[0053] As used herein, unless otherwise indicated, the term "resistant" refers to a disorder, disease or condition that has not responded to previous treatment, which may include one or more lines of therapy.

[0054] As used herein, unless otherwise specified, the terms "about" and "approximately" when used in connection with a dose, amount, or weight percentage of a component of a composition or dosage form means a dose, amount, or weight percentage that is recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specific dose, amount, or weight percentage. In certain embodiments, when used in this context, the terms "about" and "approximately" contemplate a dose, amount, or weight percentage that is within 30%, within 20%, within 15%, within 10%, or within 5% of the specific dose, amount, or weight percentage.

[0055] The term "between" includes the endpoint numbers at both ends of a range. For example, a range described by "from 3 to 5" includes the numbers "3" and "5."

[0056] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissue of a subject without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, alkyl, dialkyl, trialkyl, or tetraalkyl ammonium salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, L-arginine, benthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0057] Pharmaceutically acceptable acid addition salts may also exist as various solvates, for example with water, methanol, ethanol, dimethylformamide, etc. Also, mixtures of such solvates may be prepared. The source of such solvates may be from the solvent of crystallization, may be inherent in the solvent of preparation or crystallization, or may be exogenous to such solvent.

[0058] Pharmaceutically acceptable anionic salts include, but are not limited to, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate.

[0059] compound In one embodiment, the compound used in the methods provided herein is a compound of the following formula, also referred to as "Compound 1": [ka] or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. Compound 1 is (19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0 2 , 6 .0 8 , 12 .0 13 , 18 ], which has the chemical name pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine, and is described in International Patent Application No. PCT / US2021 / 030842, the entirety of which is incorporated herein by reference. As used herein, "Compound 1," "Compound 1 free base," "Compound 1 (free base)," and "free base Compound 1" are used interchangeably.

[0060] Unless otherwise specified, when the compounds described herein are provided as their pharma- ceutically acceptable salts, it is to be understood that the amounts by weight refer to the moiety exclusive of the salt moiety (i.e., as Compound 1 free base).

[0061] In one embodiment, Compound 1 (free base) is used in the methods provided herein. In one embodiment, a tautomer of Compound 1 is used in the methods provided herein. In one embodiment, Compound 1 substantially free of the (S)-enantiomer is used in the methods provided herein. As used herein, "substantially free" means that the (S)-enantiomer is present in less than about 10% by weight of Compound 1 (e.g., less than about 5% by weight or less than about 0.05% by weight of Compound 1). In one embodiment, Compound 1 is substantially pure and has an enantiomeric purity of at least about 98% (e.g., 99% or 99.5%). In one embodiment, a pharmaceutically acceptable salt of Compound 1 is used in the methods provided herein. In one embodiment, the pharmaceutically acceptable salt is a besylate salt. In one embodiment, the pharmaceutically acceptable salt is a phosphate salt.

[0062] In one embodiment, the compound used in the methods provided herein is a solid form of Compound 1. In one embodiment, the solid form is Form 1 of Compound 1. A representative XRPD pattern of Form 1 of Compound 1 is provided in Figure 10A.

[0063] In one embodiment, the solid form of Compound 1 is characterized by one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, or all of the XRPD peaks located at approximately the following positions (e.g., ±0.2 degrees 2θ): 10.7, 12.0, 12.2, 13.9, 15.0, 17.4, 18.4, 18.6, 20.8, 21.2, 21.3, 21.6, 21.7, 23.3, 23.5, 24.0, 25.2, 26.0, 26.2, 26.7, 27.7, 28.0, and 29.6 °2θ, as measured using Cu Kα radiation. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0064] In one embodiment, a solid form (e.g., a crystalline form) of Compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from the group consisting of approximately (e.g., ±0.2°) 10.7, 15.0, 17.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ when measured using Cu Kα radiation. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ±0.2°) 10.7, 15.0, 17.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks approximately (e.g., ±0.2°) selected from the group consisting of 10.7, 15.0, 17.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ.

[0065] In one embodiment, a solid form (e.g., a crystalline form) of Compound 1 is characterized by an XRPD pattern comprising at least three peaks selected from the group consisting of approximately (e.g., ±0.2°) 10.7, 12.0, 12.2, 13.9, 15.0, 17.4, 18.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ when measured using Cu Kα radiation. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ±0.2°) 10.7, 12.0, 12.2, 13.9, 15.0, 17.4, 18.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ±0.2°) 10.7, 12.0, 12.2, 13.9, 15.0, 17.4, 18.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ.

[0066] In one embodiment, a solid form (e.g., a crystalline form) of Compound 1 is characterized by an XRPD pattern that includes peaks at approximately (e.g., ±0.2°) 10.7, 15.0, and 21.2 °2θ. In one embodiment, the XRPD pattern further includes peaks at approximately (e.g., ±0.2°) 17.4 and 21.3 °2θ. In one embodiment, the XRPD pattern further includes peaks at approximately (e.g., ±0.2°) 12.0, 12.2, and 13.9 °2θ. In another embodiment, the XRPD pattern further includes peaks at approximately (e.g., ±0.2°) 21.6 and 24.0 °2θ. In one embodiment, the XRPD pattern includes peaks at approximately (e.g., ±0.2°) 10.7, 15.0, 17.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ. In one embodiment, the XRPD pattern includes peaks at approximately (e.g., ±0.2°) 10.7, 12.0, 12.2, 13.9, 15.0, 17.4, 18.4, 20.8, 21.2, 21.3, 21.6, 24.0, and 25.2 °2θ.

[0067] In one embodiment, the solid form is characterized by an XRPD pattern that matches the XRPD pattern shown in Figure 10A.

[0068] In one embodiment, the XRPD patterns described herein are obtained using Cu Kα radiation. In one embodiment, the XRPD patterns are measured by XRPD using Cu Kα radiation, including Kα1 radiation having a wavelength of 1.5406 Å and Kα2 radiation having a wavelength of 1.5444 Å, with a Kα1:Kα2 ratio of 0.5.

[0069] A representative DSC thermogram of Form 1 is provided in Figure 10B. In one embodiment, the solid form exhibits a thermal event (endotherm) as characterized by DSC with an onset temperature of about 265°C (e.g., ±2°). In one embodiment, the thermal event also has a peak temperature of about 267°C (e.g., ±2°). In one embodiment, without being bound by a particular theory, the thermal event corresponds to melting. In one embodiment, the solid form is characterized by a DSC thermogram consistent with the DSC thermogram shown in Figure 10B. In one embodiment, the DSC thermogram is as measured by DSC using a scan rate of about 10°C / min.

[0070] In another embodiment, the solid form has a melting point at about 270° C. (eg, ±2°).

[0071] In one embodiment, a solid form (e.g., a crystalline form) of Compound 1 has unit cell dimensions of approximately a=8.4 Å, b=8.4 Å, c=14.9 Å, α=90°, β=106°, and γ=90°. In one embodiment, the solid form has unit cell dimensions of approximately a=8.43 Å, b=8.44 Å, c=14.91 Å, α=90°, β=105.6°, and γ=90°. In one embodiment, the solid form has unit cell dimensions of approximately a=8.431 Å, b=8.441 Å, c=14.914 Å, α=90°, β=105.55°, and γ=90°. In one embodiment, Form 1 has a unit cell of the P21 space group. In one embodiment, the solid form has a unit cell of approximately 1022.7 Å. 3 In one embodiment, Form 1 has a Z value of about 1.362 g / cm. 3 has a density of

[0072] In one embodiment, the (S)-enantiomer of Compound 1 is used in the methods provided herein. In one embodiment, the tautomer of the (S)-enantiomer of Compound 1 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of the (S)-enantiomer of Compound 1 is used in the methods provided herein.

[0073] In one embodiment, a racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a tautomer of a racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of a racemic mixture of Compound 1 is used in the methods provided herein.

[0074] How to use In one embodiment, provided herein is a method of treating cancer comprising administering a heteroaromatic macrocyclic ether compound, e.g., Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0075] In one embodiment, provided herein is a method of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, for treating, preventing, or managing solid tumors.

[0076] In one embodiment, a method of treating a patient having a solid tumor comprises administering to the patient a therapeutically effective amount of Compound 1: [ka] or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0077] In one embodiment, the cancer is anaplastic large cell lymphoma (ALCL), atypical meningioma, breast cancer, cholangiocarcinoma, gastric cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), inflammatory hepatocellular adenoma (HCA), melanoma, pancreatic cancer, papillary thyroid carcinoma, salivary gland carcinoma, serous ovarian carcinoma, or spitzoid tumor.

[0078] In one embodiment, the solid tumor is an advanced solid tumor. In one embodiment, the solid tumor is a locally advanced solid tumor. In one embodiment, the advanced solid tumor has relapsed after or is resistant or resistant to previous treatment with a tyrosine kinase inhibitor (TKI). In one embodiment, the solid tumor is a non-small cell lung cancer (NSCLC). In one embodiment, the solid tumor is a ROS1 positive (e.g., ROS1 fusion) NSCLC. In one embodiment, the solid tumor is an ALK positive (e.g., ALK fusion) NSCLC. In one embodiment, the solid tumor is an LTK positive (e.g., LTK fusion) NSCLC. In one embodiment, the solid tumor is an advanced NSCLC. In one embodiment, the solid tumor is a locally advanced NSCLC. In one embodiment, the solid tumor is metastatic. In one embodiment, the solid tumor is metastatic to the CNS (also referred to herein as "CNS metastatic" or "metastatic CNS"). In one embodiment, the solid tumor is a metastatic NSCLC. In one embodiment, the solid tumor is NSCLC metastatic to the CNS. As used herein, unless otherwise specified, "progressive tumor" refers to either locally advanced or metastatic tumors that cannot be cured or that grow beyond the initial site of origin.

[0079] In one embodiment, the solid tumor (or cancer) is ROS1 positive. In one embodiment, the solid tumor is ROS1 positive NSCLC. In one embodiment, the solid tumor is an progressive ROS1 positive solid tumor. In one embodiment, the solid tumor is a locally advanced ROS1 positive solid tumor. In one embodiment, the solid tumor is an advanced ROS1 positive NSCLC. In one embodiment, the solid tumor is a locally advanced ROS1 positive NSCLC. In one embodiment, the solid tumor is a metastatic ROS1 positive solid tumor. In one embodiment, the solid tumor is a CNS metastatic ROS1 positive solid tumor. In one embodiment, the solid tumor is a metastatic ROS1 positive NSCLC. In one embodiment, the solid tumor is a CNS metastatic ROS1 positive NSCLC. In one embodiment, the solid tumor (or cancer) has a ROS1 mutation. In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutations include G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N or G2101A. In one embodiment, the solid tumor (or cancer) harbors a ROS1 fusion.

[0080] In one embodiment, the solid tumor (or cancer) is ALK positive. As used herein, unless otherwise specified, "ALK positive" (ALK+) cancer, disease or disorder refers to a cancer, disease or disorder characterized by inappropriately high expression of the ALK gene and / or the presence of a mutation in the ALK gene and / or the presence of a partially deleted ALK protein. In one embodiment, the solid tumor is an ALK positive NSCLC. In one embodiment, the solid tumor is an advanced ALK positive solid tumor. In one embodiment, the solid tumor is a locally advanced ALK positive solid tumor. In one embodiment, the solid tumor is an advanced ALK positive NSCLC. In one embodiment, the solid tumor is a locally advanced ALK positive NSCLC. In one embodiment, the solid tumor is a metastatic ALK positive solid tumor. In one embodiment, the solid tumor is a CNS metastatic ALK positive solid tumor. In one embodiment, the solid tumor is a metastatic ALK positive NSCLC. In one embodiment, the solid tumor is a CNS metastatic ALK positive NSCLC. In one embodiment, the solid tumor (or cancer) has an ALK mutation.

[0081] In one embodiment, the ALK mutation comprises one or more ALK rearrangements (in one embodiment, one rearrangement). In one embodiment, the ALK mutation comprises one or more ALK fusions (in one embodiment, one fusion). In some embodiments, the cancer treated by the methods of the present disclosure comprises an ALK fusion. In one embodiment, the ALK fusion is with one of the fusion partners described in Ou et al., JTO Clinical and Research Reports, 1(1):1-10, the entirety of which is incorporated herein by reference. In one embodiment, the ALK fusion is EML4, TFG, KIF5B, KLC1, STRN, HIP1, TPR, BIRC6, DCTN1, SQSTM1, SOCS5, SEC31A, CLTC, PRKAR1A, PPM1B, EIF2AK3, CRIM1, CEBPZ, PICALM, CLIP1, BCL11A, GCC2, LMO7, PHACTR 1, CMTR1, VIT, DYSF, ITGAV, PLEKHA7, CUX1, VKORC1L1, FBXO36, SPTBN1, EML6, FBXO11, CLIP4, CA MKMT, NCOA1, MYT1L, SRBD1, SRD5A2, NYAP2, MPRIP, ADAM17, ALK, LPIN1, WDPCP, CEP55, ERC1, SLC1 and one of the fusion partners selected from the group consisting of 6A7, TNIP2, ATAD2B, SLMAP, FBN1, SWAP70, TCF12, TRIM66, WNK3, AKAP8L, SPECC1L, PRKCB, CDK15, LCLAT1, YAP1, PLEKHM2, DCHS1, PPFIBP1, ATP13A4, C12orf75, EPAS1, FAM179A, FUT8, LIMD1, LINC00327, LOC349160, LYPD1, RBM20, TACR1, TANC1, TTC27, TUBBB, SMPD4, SORCS1, LINC00211, SOS1, C9orf3, CYBRD1, MTA3, THADA, TSPYL6, WDR37 and PLEKHH2.In one embodiment, the ALK fusion is with one of the fusion partners selected from the group consisting of EML4, TMP1, WDCP, GTF2IRD1, TPM3, TPM4, CLTC, LMNA, PRKAR1A, RANBP2, TFG, FN1, KLC1, VCL, STRN, HIP1, NPM1, DCTN1, SQSTM1, TPR, CRIM1, PTPN3, FBXO36, ATIC, and KIF5B. In one embodiment, the ALK mutation is EML4-ALK, which is a fusion between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK tyrosine kinase domain. There are many variants of EML4-ALK that differ by breakpoint junctions, with variant 1 (v1) and variant 3 (v3) being the most frequent clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0082] In one embodiment, the solid tumor (or cancer) is leukocyte receptor tyrosine kinase (LTK) positive. As used herein, unless otherwise specified, "LTK positive" (LTK+) cancer, disease or disorder refers to a cancer, disease or disorder characterized by inappropriate high expression of the LTK gene and / or the presence of a mutation in the LTK gene, including LTK gene rearrangements resulting in LTK fusion proteins. In one embodiment, the solid tumor is LTK-positive invasive ductal breast carcinoma, prostate adenocarcinoma, pancreatic adenocarcinoma, adenocarcinoma of unknown primary or bladder urothelial carcinoma. In one embodiment, the cancer is LTK-positive leukemia. In one embodiment, the solid tumor is LTK-positive lung cancer. In one embodiment, the solid tumor is LTK-positive NSCLC. In one embodiment, the solid tumor (or cancer) has an LTK mutation. In one embodiment, the LTK mutation is G269A, F218I, N257T, A13fs or A214fs. In one embodiment, the solid tumor (or cancer) has an LTK fusion. In one embodiment, the LTK fusion is CLIP1-LTK. See Cooper AJ, Sequist LV, Johnson TW, Lin JJ. LTK fusions: A new target emerges in non-small cell lung cancer. Cancer Cell. 2022 Jan 10; 40(1): 23-25 ​​and Izumi, H., Matsumoto, S., Liu, J. et al. The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature 600, 319-323 (2021), each of which is incorporated herein by reference in its entirety.

[0083] In one embodiment, the patient has not been treated with prior therapy. In one embodiment, the patient is naive (i.e., not receiving) any tyrosine kinase inhibitor (TKI) therapy.

[0084] In one embodiment, the patient has been treated with one or more previous therapies. In one embodiment, the patient has been treated with at least one previous TKI therapy. In one embodiment, the patient has been treated with at least two previous TKI therapies. In one embodiment, the patient has been treated with one previous TKI therapy. In one embodiment, the patient has been treated with two previous TKI therapies. In one embodiment, the TKI is a ROS1 TKI (e.g., crizotinib or entrectinib). In one embodiment, the previous TKI therapy is one or more selected from the group consisting of crizotinib, entrectinib, repotrectinib, taretrectinib, and lorlatinib.

[0085] In one embodiment, the patient has not been treated with a previous platinum-based chemotherapy. In one embodiment, the patient has been treated with up to one previous platinum-based chemotherapy. In one embodiment, the patient has been treated with at least one previous platinum-based chemotherapy. In one embodiment, the patient has been treated with at least two previous platinum-based chemotherapy. In one embodiment, the patient has been treated with one previous platinum-based chemotherapy. In one embodiment, the patient has been treated with two previous platinum-based chemotherapy.

[0086] As used herein, "platinum-based chemotherapy" refers to a chemotherapeutic agent that is a coordination complex of platinum. Exemplary platinum-based chemotherapy agents include, but are not limited to, cisplatin, oxaliplatin, nedaplatin, or carboplatin.

[0087] In one embodiment, the patient has not been treated with immunotherapy. In one embodiment, the patient has been treated with immunotherapy. In one embodiment, the patient has been treated with at least one previous immunotherapy. In one embodiment, the patient has been treated with at least two previous immunotherapies. In one embodiment, the patient has been treated with one previous immunotherapy. In one embodiment, the patient has been treated with two immunotherapies.

[0088] As used herein, "immunotherapy" refers to the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to induce or amplify immune responses are classified as activating immunotherapies, while immunotherapies that reduce or suppress immune responses are classified as suppressing immunotherapies. Immunotherapies can act by modulating immune effector cells (e.g., lymphocytes, macrophages, dendritic cells, natural killer cells (NK cells), cytotoxic T lymphocytes (CTLs), etc.) to target abnormal antigens expressed on the surface of tumor cells together against cancer. Exemplary immunotherapies include, but are not limited to, checkpoint inhibitors (e.g., anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) antibodies). Exemplary PD-1 inhibitors include, but are not limited to, pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo). Exemplary PD-L1 inhibitors include, but are not limited to, atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi). Exemplary CTLA-4 inhibitors include, but are not limited to, ipilimumab (Yervoy).

[0089] In one embodiment, the patient has not been treated with chemotherapy. In one embodiment, the patient has been treated with at least one previous line of chemotherapy. In one embodiment, the patient has been treated with at least two previous lines of chemotherapy.

[0090] In one embodiment, the patient has been treated with at least three prior lines of anti-cancer therapy, hi one embodiment, the patient has been treated with at least two prior lines of anti-cancer therapy selected from the group consisting of ROS1 TKI (e.g., investigational ROS1 TKI, crizotinib, lorlatinib, entrectinib, taretrectinib, repotrectinib) and chemotherapy.

[0091] In one embodiment, the patient has been treated with at least one ROS1 TKI line and one chemotherapy line. In one embodiment, the patient has been treated with at least two ROS1 TKI lines and one chemotherapy line. In one embodiment, the patient has been treated with at least three ROS1 TKI lines and one chemotherapy line. In one embodiment, the patient has been treated with at least two chemotherapy lines. In one embodiment, the patient has been treated with at least one ROS1 TKI line and two chemotherapy lines. In one embodiment, the patient has been treated with at least two ROS1 TKI lines and two chemotherapy lines. In one embodiment, the patient has been treated with at least three ROS1 TKI lines and two chemotherapy lines.

[0092] In one embodiment, the ROS1 TKI is crizotinib. In one embodiment, the ROS1 TKI is entrectinib. In one embodiment, the ROS1 TKI is lorlatinib. In one embodiment, the ROS1 TKI is repotrectinib. In one embodiment, the patient is treated with lorlatinib and repotrectinib. In one embodiment, the ROS1 TKI is taretrectinib.

[0093] In one embodiment, the solid tumor is a metastatic ROS1-positive solid tumor and the patient has been treated with at least one prior ROS1 TKI therapy.

[0094] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC and the patient is TKI therapy naive and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy.

[0095] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC and the patient has been treated with one prior ROS1 TKI therapy and has not been treated with prior platinum-based chemotherapy or immunotherapy.

[0096] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC and the patient has been treated with one prior ROS1 TKI therapy and one prior platinum-based chemotherapy, with or without immunotherapy.

[0097] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC and the patient has been treated with at least two prior ROS1 TKI therapies and up to one prior platinum-based chemotherapy, with or without immunotherapy.

[0098] In one embodiment, the solid tumor is a metastatic ROS1-positive solid tumor and the patient has progressed on a previous therapy. In one embodiment, the previous therapy is a previous ROS1 TKI therapy. In one embodiment, the previous therapy is a previous chemotherapy (e.g., platinum-based chemotherapy). In one embodiment, the previous therapy is a previous immunotherapy.

[0099] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC and the patient is TKI therapy naïve and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy.

[0100] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC and the patient has been treated with one prior ROS1 TKI therapy and has not been treated with prior platinum-based chemotherapy or immunotherapy.

[0101] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC and the patient has been treated with one prior ROS1 TKI therapy and one prior platinum-based chemotherapy, with or without immunotherapy.

[0102] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC and the patient has been treated with at least two prior ROS1 TKI therapies and up to one prior platinum-based chemotherapy, with or without immunotherapy.

[0103] In one embodiment, the solid tumor is an advanced ROS1-positive solid tumor and the patient has progressed on a previous therapy. In one embodiment, the previous therapy is a previous ROS1 TKI therapy.

[0104] In one embodiment, the ROS1 TKI is crizotinib. In one embodiment, the ROS1 TKI is entrectinib.

[0105] In one embodiment, Compound 1 is administered to a patient for one or more days. In one embodiment, Compound 1 is administered to a patient for at least one treatment cycle. In one embodiment, one treatment cycle is at least 7 days. In one embodiment, one treatment cycle is at least 14 days. In one embodiment, one treatment cycle is at least 21 days. In one embodiment, one treatment cycle is at least 28 days.

[0106] In one embodiment, the patient does not experience a grade 4 adverse event after administration of Compound 1. In one embodiment, the patient does not experience a grade 3 adverse event after administration of Compound 1. In one embodiment, the patient does not experience a grade 2 adverse event after administration of Compound 1. In one embodiment, the patient does not experience a grade 1 adverse event after administration of Compound 1. As used herein, unless otherwise specified, the grade of adverse events is in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grades.

[0107] In one embodiment, the patient experiences only nausea after administration of Compound 1. In one embodiment, the patient does not experience a neurological adverse event after administration of Compound 1. In one embodiment, the patient does not experience one or more CNS adverse events selected from the group consisting of dizziness, ataxia, gait disturbance, paresthesia, weight gain, hyperphagia, paresthesia, abnormal movement, cognitive changes, seizures, hallucinations, speech effects (e.g., aphasia, dysarthria, slow speech or speech disorder), mood disorder (e.g., irritability, anxiety, depression, affective disorder, emotional lability, personality changes, mood swings, affective disorder, aggression, stress, agitation, mood changes, depressed mood, euphoric mood, suicidal ideation or mania), mental condition, sleep disorder and cognitive disorder (e.g., memory impairment, cognitive impairment, amnesia, confusion, attention disorder, delirium, mental impairment, attention deficit hyperactivity disorder, dementia, sleep disturbance, disorientation or dyslexia). In one embodiment, the neurological adverse event is one or more selected from the group consisting of cognitive impairment, mood disorder, sleep disorder, dizziness, and ataxia. In one embodiment, the patient does not experience weight gain and / or glucose metabolism disorder adverse events. In one embodiment, the glucose metabolism disorder is hyperglycemia (e.g., diabetes). In one embodiment, the glucose metabolism disorder is hypoglycemia. In one embodiment, the patient experiences a treatment-related adverse event of grade 1 after administration of Compound 1. In one embodiment, the patient experiences a treatment-related adverse event of up to grade 1 after administration of Compound 1. In one embodiment, the treatment-related adverse event of grade 1 is fatigue, myalgia, edema (e.g., edema and peripheral edema), increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), or nausea.

[0108] In one embodiment, the patient does not experience a treatment-related serious adverse event (SAE). In one embodiment, the patient does not experience a treatment-related CNS adverse event. In one embodiment, the patient does not experience treatment-related dizziness.

[0109] In one embodiment, less than about 40% of the patient population experiences a maximum grade 1 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 30% of the patient population experiences a maximum grade 1 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 20% of the patient population experiences a maximum grade 1 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 15% of the patient population experiences a maximum grade 1 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, the grade 1 adverse event (e.g., TRAE) is fatigue, myalgia, edema (e.g., edema and peripheral edema), increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), or nausea.

[0110] In one embodiment, less than about 30% of the patient population experiences a grade 2 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 20% of the patient population experiences a grade 2 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 15% of the patient population experiences a grade 2 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 10% of the patient population experiences a grade 2 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 5% of the patient population experiences a grade 2 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, the patient population does not experience a grade 2 adverse event (e.g., TRAE) after administration of Compound 1.

[0111] In one embodiment, less than about 20% of the patient population experiences a grade 3 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 15% of the patient population experiences a grade 3 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 10% of the patient population experiences a grade 3 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 5% of the patient population experiences a grade 3 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, the patient population does not experience a grade 3 adverse event (e.g., TRAE) after administration of Compound 1.

[0112] In one embodiment, less than about 10% of the patient population experiences a grade 4 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 5% of the patient population experiences a grade 4 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, less than about 1% of the patient population experiences a grade 4 adverse event (e.g., TRAE) after administration of Compound 1. In one embodiment, the patient population does not experience a grade 4 adverse event (e.g., TRAE) after administration of Compound 1.

[0113] In one embodiment, the patient has a complete response after one or more cycles of treatment. In one embodiment, the patient has a partial response after one or more cycles of treatment. In one embodiment, the patient achieves stable disease after one or more cycles of treatment. In one embodiment, the patient does not experience progressive disease after one or more cycles of treatment.

[0114] As used herein, unless otherwise specified, complete response (CR) refers to the disappearance of all target lesion(s). In some embodiments of CR, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to less than 10 mm. Partial response (PR) refers to at least a 30% decrease in the sum of the diameters of the target lesion(s). Progressive disease (PD) refers to at least a 20% increase in the sum of the diameters of the target lesion(s). In some embodiments of PD, in addition to a relative increase of 20%, the sum also demonstrates an increase of at least 5 mm. In some embodiments, the appearance of one or more new lesion(s) is also considered progression. Stable disease (SD) refers to neither a sufficient reduction in the minimum sum diameter during the study to qualify as PR, nor a sufficient increase to qualify as PD. Additional explanations of these terms according to RECIST 1.1 can be found in EUROPEAN JOURNAL OF CANCER 45(2009)228-247.

[0115] In one embodiment, the patient has brain metastases. In one embodiment, the patient has brain metastases and does not experience intracranial progression after at least one cycle of treatment.

[0116] In one embodiment, the patient has at least about 5% to about 100% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 35% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 45% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 55% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 65% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 75% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 85% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 100% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle.In one embodiment, the patient has undetectable ROS1 allele variant in circulating tumor DNA after at least one treatment cycle.In one embodiment, the ROS1 allele variant is G2032R.

[0117] In one embodiment, the previous therapy is a previous ROS1 TKI therapy. In one embodiment, the ROS1 TKI is crizotinib, entrectinib, lorlatinib, ceritinib, cabozantinib, taretrectinib, or repotrectinib.

[0118] In one embodiment, administration of Compound 1 is inducible by measuring the area under the curve (AUC 0~24In one embodiment, administration of Compound 1 provides a 0-24 hour area under the curve (AUC 0~24 In one embodiment, the area under the curve (AUC) of the compound from 0 to 24 hours is provided in the range of about 500 to about 30,000 ng*h / mL. 0~24 ) is in the range of about 1000 to about 13000 ng*h / mL after about half a treatment cycle (e.g., 15 days). In one embodiment, the area under the curve (AUC) of the compound from 0 to 24 hours 0~24 ) is in the range of about 1500 to about 10000 ng*h / mL after about half a treatment cycle (e.g., 15 days). In one embodiment, the area under the curve (AUC) of the compound from 0 to 24 hours 0~24 ) is in the range of about 2000 to about 8000 ng*h / mL after about half a treatment cycle (e.g., 15 days).

[0119] In one embodiment, such administration is based on the area under the curve (AUC) from 0 to 24 hours after administration of the compound. 0~24 ) in the range of (80%-125% of 20 ng*h / mL) to (80%-125% of 500 ng*h / mL) for every mg of compound administered. In one embodiment, such administration provides an area under the curve (AUC 0~24 ) in the range of about 20 to about 500 ng*h / mL for every mg of compound administered. In one embodiment, such administration provides an area under the curve (AUC 0~24 ) in the range of about 50 to about 200 ng*h / mL after about half a treatment cycle (e.g., 15 days).

[0120] In one embodiment, administration of Compound 1 is associated with an area under the curve of unbound Compound 1 (AUC last,unbound in the range of 80%-125% of 400 ng*h / mL to (80%-125% of 7000 ng*h / mL). In one embodiment, administration of Compound 1 provides an AUC last,unboundin the range of about 400 to about 7000 ng*h / mL. last,unbound In one embodiment, the AUC of the compound is in the range of about 1000 to about 6200 ng*h / mL. last,unbound teeth 、 After administration of about 25 mg of the compound, the AUC last,unbound teeth 、 After administration of about 50 mg of the compound, the AUC last,unbound teeth 、 After administration of about 75 mg of the compound, the AUC last,unbound teeth 、 After administration of about 100 mg of the compound, the AUC last,unbound teeth 、 After administration of about 125 mg of the compound, the AUC last,unbound teeth 、 After administration of about 150 mg of the compound, the AUC last,unbound is about 2850 ng*h / mL after administration of about 150 mg of the compound. In certain embodiments, the final measurable plasma concentration is at 24 hours.

[0121] In one embodiment, such administration involves the area under the curve (AUC last,unbound ) in the range of (80%-125% of 10 ng*h / mL) to (80%-125% of 80 ng*h / mL) for every mg of compound administered. In one embodiment, such administration 、 For every mg of compound administered, the AUC of the compound ranges from about 10 to about 80 ng*h / mL. last,unbound In one embodiment, such administration comprises 、For every mg of compound administered, the AUC of the compound ranges from about 30 to about 70 ng*h / mL. last,unbound In one embodiment, such administration comprises 、 For every mg of compound administered, the AUC of the compound ranges from about 35 to about 65 ng*h / mL. last,unbound In one embodiment, the AUC last,unbound is in the range of about 15 to about 25 ng*h / mL for every mg of compound administered. In one embodiment, the AUC last,unbound is about 19 ng*h / mL for every mg of Compound 1 administered. In certain embodiments, the final measurable plasma concentration is at 24 hours.

[0122] In one embodiment, administration of Compound 1 is performed using an area under the curve (AUC tau ) in the range of 2000hr*ng / mL to 10000hr*ng / mL. In one embodiment, administration of Compound 1 provides an AUC tau in the range of about 2000 to about 8000 ng*h / mL. In one embodiment, administration of Compound 1 provides an AUC tau in the range of about 2000 to about 8000 ng*h / mL after about half a treatment cycle (e.g., 15 days).

[0123] In one embodiment, administration of Compound 1 is performed using an area under the curve (AUC tau ) in the range of 30 hr*ng / mL to 200 hr*ng / mL for every mg of Compound 1 administered. In one embodiment, administration of Compound 1 provides an AUC tau in the range of about 50 to about 150 ng*h / mL for every mg of Compound 1 administered. In one embodiment, administration of Compound 1 provides an AUC tau in the range of about 50 to about 150 ng*h / mL after about half a treatment cycle (e.g., 15 days) for every mg of compound administered.

[0124] In one embodiment, administration of Compound 1 is inducible by increasing the area under the curve from 0 to infinity (AUC inf ) in the range of 3500 hr*ng / mL to 20000 hr*ng / mL. In one embodiment, administration of Compound 1 provides an AUC inf in the range of about 4000 to about 15000 ng*h / mL. In one embodiment, administration of Compound 1 provides an AUC inf in the range of about 4000 to about 15000 ng*h / mL after half a treatment cycle (e.g., 15 days).

[0125] In one embodiment, administration of Compound 1 is inducible by increasing the area under the curve from 0 to infinity (AUC inf ) in the range of 50 hr*ng / mL to 300 hr*ng / mL for every mg of Compound 1 administered. In one embodiment, administration of Compound 1 provides an AUC inf in the range of about 50 to about 250 ng*h / mL for every mg of Compound 1 administered. In one embodiment, administration of Compound 1 provides an AUC inf in the range of about 50 to about 250 ng*h / mL after about half a treatment cycle (e.g., 15 days) for every mg of compound administered.

[0126] In one embodiment, such administration results in a maximum plasma concentration of the compound (C max ) in the range of (80%-125% of 100 ng / mL) to (80%-125% of 1500 ng / mL). In one embodiment, such administration provides a maximum plasma concentration (C max ) in the range of about 100 to about 1500 ng / mL. In one embodiment, such administration provides a maximum plasma concentration (C max In one embodiment, administration of Compound 1 provides a C max in the range of about 200 to about 1000 ng*h / mL after about half a treatment cycle (e.g., 15 days).

[0127] In one embodiment, such administration results in a maximum plasma concentration of the compound (Cmax ) in the range of about 2 to about 50 ng / mL for every mg of compound administered. In one embodiment, such administration provides a maximum plasma concentration (C max ) in the range of about 5 to about 20 ng / mL for every mg of Compound 1 administered. In one embodiment, administration of Compound 1 provides a C max in the range of about 5 to about 20 ng / mL after about half a treatment cycle (e.g., 15 days) for every mg of compound administered.

[0128] In one embodiment, such administration is based on the minimum plasma concentration (C) achieved by Compound 1 during the time interval between administration of two doses. min ) in the range of about 50 to about 400 ng / mL. In one embodiment, such administration provides a minimum plasma concentration (C) achieved by Compound 1 during the time interval between administration of two doses. min ) in the range of about 50 to about 350 ng / mL. In one embodiment, such administration provides a minimum plasma concentration (C) achieved by Compound 1 during the time interval between administration of two doses. min ) in the range of about 50 to about 350 ng / mL after about half a treatment cycle (e.g., 15 days).

[0129] In one embodiment, such administration results in a maximum plasma concentration of the unbound compound (C max,unbound ) in the range of (80%-125% of 30 ng / mL) to (80%-125% of 400 ng / mL). In one embodiment, such administration provides a maximum unbound plasma concentration (C max,unbound ) in the range of about 30 ng / mL to about 400 ng / mL. In one embodiment, such administration provides a maximum unbound plasma concentration (C max,unbound ) in the range of about 50 ng / mL to about 350 ng / mL. In one embodiment, the C max,unbound is in the range of about 90 to about 140 ng / mL after administration of about 50 mg of the compound. max,unboundis in the range of about 200 to about 250 ng / mL after administration of about 75 mg of the compound. max,unbound is in the range of about 300 to about 400 ng / mL after administration of about 100 mg of the compound. max,unbound is in the range of about 200 to about 300 ng / mL after administration of about 150 mg of the compound. max,unbound is in the range of about 200 to about 300 ng / mL after administration of about 150 mg of the compound. max,unbound is about 258 ng / mL (about 0.62 μM) after administration of about 150 mg of the compound. max,unbound is in the range of about 150 to about 200 ng / mL after administration of about 100 mg of the compound. max,unbound is about 172 ng / mL (about 0.41 μM) after administration of about 100 mg of the compound. In one embodiment, such administration results in a C max,unbound in the range of about 1 to about 4 ng / mL for every mg of compound administered. max,unbound is approximately 1.7 ng / mL for every mg of Compound 1 administered.

[0130] In one embodiment, without being bound by any particular theory, the brain penetration (brain to plasma ratio) of Compound 1 is about 0.26 (about 26%).

[0131] In one embodiment, such administration reduces the T max In one embodiment, such administration provides a T of the compound after administration in the range of about 0.25 hours to about 5 hours. max In one embodiment, such administration provides a T of the compound after administration in the range of about 0.25 hours to about 4 hours. max In one embodiment, such administration provides a T of the compound after administration in the range of about 0.5 hours to about 5 hours. max In one embodiment, such administration provides a T of the compound after administration in the range of about 0.5 hours to about 2 hours. maxin the range of about 0.5 hours to about 1.0 hours. In one embodiment, such administration provides a T max In one embodiment, such administration provides a T of the compound of about 0.5 hours after administration. max to provide.

[0132] In one embodiment, such administration involves the t 1 / 2 In one embodiment, such administration provides a t 1 / 2 In one embodiment, such administration provides a t 1 / 2 In one embodiment, such administration provides a t 1 / 2 In one embodiment, such administration provides a t 1 / 2 In one embodiment, such administration provides a t of the compound of about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours after administration. 1 / 2 In one embodiment, such administration provides a t 1 / 2 to provide.

[0133] In one embodiment, administration provides an IC50 value of the compound against the ROS1 G2032R mutant for at least 70%, 80%, 90%, 95%, 97%, 98%, or 99% of the time immediately following administration for about 24 hours. 50 The dose provides a plasma concentration of the compound that is at least 10%, 20%, 30%, 40% or 50% higher than the dose provided by the method of the present invention.

[0134] 1. A method of reducing lesions in a subject having a ROS1-positive solid tumor (e.g., NSCLC), comprising: (i) obtaining a first radiological measurement of a size of the lesion; (ii) administering a pharma- tically effective amount of Compound 1 once daily for one or more days; (iii) obtaining a second radiological measurement of the size of the lesion; The method, wherein the second measurement is up to 100% of the first measurement.

[0135] In one embodiment, the second measurement is up to about 90% of the first measurement. In one embodiment, the second measurement is up to about 80% of the first measurement. In one embodiment, the second measurement is up to about 70% of the first measurement. In one embodiment, the second measurement is up to about 60% of the first measurement. In one embodiment, the second measurement is up to about 50% of the first measurement. In one embodiment, the second measurement is about 0.01% to about 90% of the first measurement. In one embodiment, the second measurement does not indicate a detectable lesion.

[0136] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered once a day (QD). In one embodiment, the compound is administered twice a day (BID). In a particular embodiment, the compound used herein is Compound 1.

[0137] In one embodiment, the compound is administered at a concentration of 0 to 24 hours following administration of the compound, preferably at a concentration of 0 to 24 hours following administration of the compound. 0~24 In one embodiment, the AUC 0~24 In one embodiment, the AUC 0~24 In one embodiment, the AUC 0~24 In one embodiment, AUC is in the range of about 1000 to about 13000 ng*h / mL. 0~24 In one embodiment, the AUC 0~24In one embodiment, the AUC 0~24 In one embodiment, AUC is in the range of about 1000 to about 3000 ng*h / mL. 0~24 In one embodiment, the AUC 0~24 In one embodiment, the AUC 0~24 In one embodiment, the AUC 0~24 In one embodiment, AUC is in the range of about 2000 to about 6000 ng*h / mL. 0~24 In one embodiment, AUC is in the range of about 3000 to about 5000 ng*h / mL. 0~24 In one embodiment, the AUC 0~24 In one embodiment, AUC is in the range of about 3000 to about 9000 ng*h / mL. 0~24 In one embodiment, the AUC 0~24 In one embodiment, the AUC 0~24 is in the range of about 6000 to about 10000 ng*h / mL.

[0138] In one embodiment, the compound is administered at a concentration of 100 mM NaCl, which is in the range of 100 mM to 150 mM NaCl. max In one embodiment, the amount of C is in the range of about 100 to about 1500 ng / mL. max In one embodiment, C is in the range of about 150 to about 1400 ng / mL. max In one embodiment, C is in the range of about 150 to about 350 ng / mL. max In one embodiment, C is in the range of about 300 to about 900 ng / mL. max In one embodiment, C is in the range of about 300 to about 700 ng / mL. max In one embodiment, C is in the range of about 450 to about 1050 ng / mL. maxis in the range of about 600 to about 1400 ng / mL.

[0139] In one embodiment, the compound is administered such that the plasma concentration of the compound is at a predetermined value (e.g., the IC 50 ) is administered in an amount that is higher (eg, at least 10%, 20%, 30%, 40% or 50% higher).

[0140] In one embodiment, the compound has a half-life in a patient of about 2 to about 50 hours. In one embodiment, the half-life is about 10 to about 20 hours. In one embodiment, the half-life is about 15 to about 25 hours. In one embodiment, the half-life is about 20 hours.

[0141] In one embodiment, the pharmacokinetic parameters provided herein (e.g., AUC 0~24 , AUC last,unbound , C max , T max and half-life) refer to the arithmetic mean of a patient population. In one embodiment, the pharmacokinetic parameters provided herein (e.g., AUC 0~24 , C max ) refers to the geometric mean of a patient population. In certain embodiments, t 1 / 2 refers to the arithmetic mean of a patient population. max refers to the median range for a patient population. In certain embodiments, AUC 0~24 , AUC last,unbound , AUC tau , AUC tau_DN , AUC inf , AUC inf_DN , C max , C max_DN , C max_unbound and C min Each of refers to the geometric mean of a patient population.

[0142] In one embodiment, the pharmacokinetic parameters provided herein (e.g., AUC0~24 , C max , T max and half-life) are measured after the compound is first administered to the patient in a treatment cycle (e.g., on day 1 of a treatment cycle, e.g., on day 1 of cycle 1 of a 28-day treatment cycle). In one embodiment, the pharmacokinetic parameters provided herein (e.g., AUC 0~24 , C max and half-life) are measured after the compound has been administered to the patient multiple times in a treatment cycle (e.g., after steady state in the patient may have been achieved for the compound) (e.g., on day 15 of cycle 1 of a 28 day treatment cycle).

[0143] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered in an amount of about 5 mg to about 500 mg (by weight of free base Compound 1) per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 250 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 200 mg per day. In one embodiment, the compound is administered in an amount of about 5 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 150 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount of about 25 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 125 mg per day. In one embodiment, the compound is administered in an amount of about 50 mg to about 100 mg per day. In one embodiment, the compound is administered in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, or about 200 mg per day. In one embodiment, the amount is about 5 mg per day. In one embodiment, the amount is about 10 mg per day. In one embodiment, the amount is about 15 mg per day. In one embodiment, the amount is about 20 mg per day. In one embodiment, the amount is about 25 mg per day. In one embodiment, the amount is about 30 mg per day. In one embodiment, the amount is about 35 mg per day. In one embodiment, the amount is about 40 mg per day. In one embodiment, the amount is about 45 mg per day. In one embodiment, the amount is about 50 mg per day. In one embodiment, the amount is about 75 mg per day.In one embodiment, the amount is about 100 mg per day. In one embodiment, the amount is about 125 mg per day. In one embodiment, the amount is about 150 mg per day. As used herein, weight amount refers to the weight amount of free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0144] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered once daily in an amount of about 5 mg to about 500 mg (by weight of free base Compound 1). In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 250 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 200 mg. In one embodiment, the compound is administered once daily in an amount of about 50 mg to about 200 mg. In one embodiment, the compound is administered once daily in an amount of about 5 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 150 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 125 mg. In one embodiment, the compound is administered once daily in an amount of about 25 mg to about 100 mg. In one embodiment, the compound is administered once a day in an amount of about 50 mg to about 125 mg. In one embodiment, the compound is administered once a day in an amount of about 50 mg to about 100 mg. In one embodiment, the compound is administered once a day in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, or about 200 mg. In one embodiment, the amount is about 5 mg once daily. In one embodiment, the amount is about 10 mg once daily. In one embodiment, the amount is about 15 mg once daily. In one embodiment, the amount is about 20 mg once daily. In one embodiment, the amount is about 25 mg once daily. In one embodiment, the amount is about 30 mg once daily. In one embodiment, the amount is about 35 mg once daily. In one embodiment, the amount is about 40 mg once daily. In one embodiment, the amount is about 45 mg once daily. In one embodiment, the amount is about 50 mg once daily. In one embodiment, the amount is about 75 mg once daily. In one embodiment, the amount is about 100 mg once daily.In one embodiment, the amount is about 125 mg once a day. In one embodiment, the amount is about 150 mg once a day. As used herein, weight amount refers to the weight amount of free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0145] In one embodiment, the compound used herein (Compound 1, or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof) is administered twice daily in an amount of about 5 mg to about 500 mg (by weight of free base Compound 1). In one embodiment, the compound is administered twice daily in an amount of about 5 mg to about 250 mg. In one embodiment, the compound is administered twice daily in an amount of about 25 mg to about 250 mg. In one embodiment, the compound is administered twice daily in an amount of about 25 mg to about 200 mg. In one embodiment, the compound is administered twice daily in an amount of about 5 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 50 mg. In one embodiment, the compound is administered twice daily in an amount of about 10 mg to about 100 mg. In one embodiment, the compound is administered twice daily in an amount of about 25 mg to about 100 mg. In one embodiment, the compound is administered in an amount of about 50 mg to about 100 mg twice daily. In one embodiment, the compound is administered in an amount of about 5 mg to about 150 mg twice daily. In one embodiment, the compound is administered in an amount of about 25 mg to about 150 mg twice daily. In one embodiment, the compound is administered twice daily in an amount of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195 or about 200 mg. In one embodiment, the amount is about 5 mg twice daily. In one embodiment, the amount is about 10 mg twice daily. In one embodiment, the amount is about 15 mg twice daily. In one embodiment, the amount is about 20 mg twice daily. In one embodiment, the amount is about 25 mg twice daily. In one embodiment, the amount is about 30 mg twice daily. In one embodiment, the amount is about 35 mg twice daily. In one embodiment, the amount is about 40 mg twice daily. In one embodiment, the amount is about 45 mg twice daily. In one embodiment, the amount is about 50 mg twice daily.In one embodiment, the amount is about 75 mg twice daily. In one embodiment, the amount is about 100 mg twice daily. In one embodiment, the amount is about 125 mg twice daily. In one embodiment, the amount is about 150 mg twice daily. As used herein, weight amount refers to the weight amount of free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0146] In one embodiment, the compound is administered orally.

[0147] In one embodiment, the compound is administered in the form of one or more tablets. In one embodiment, the tablet has a unit dose strength of about 5 mg by weight of free base Compound 1. In one embodiment, the tablet has a unit dose strength of about 25 mg by weight of free base Compound 1.

[0148] In one embodiment, the compound is administered to a subject having fasting. In one embodiment, the compound is administered to a subject in a fasting state. In one embodiment, the compound is administered to a subject without food. In one embodiment, the compound is administered to a subject at least 1 hour before and 2 hours or more after ingestion of food and / or beverages other than water. In one embodiment, the compound is administered to a subject having a sated stomach. In one embodiment, the compound is administered to a subject in a fed state. In one embodiment, the compound is administered to a subject with food. In one embodiment, the compound is administered with ingestion of food and / or beverages.

[0149] In one embodiment, the patient experiences an improvement in one or more symptoms selected from the group consisting of cognitive impairment, mood disorder, sleep disorder, dizziness, ataxia, and weight gain after administration of the compound. In one embodiment, the patient does not experience one or more symptoms selected from the group consisting of cognitive impairment, mood disorder, sleep disorder, dizziness, ataxia, and weight gain after administration of the compound. In one embodiment, the patient experiences reduced levels of one or more of pROS1, ROS1, pAKT, and pERK after administration of the compound. In one embodiment, the patient experiences reduced expression levels of one or more MAP kinase pathway genes in tumors after administration of the compound. In one embodiment, the patient experiences reduced expression levels of one or more MAP kinase pathway genes in solid tumors after administration of the compound. In one embodiment, the one or more MAP kinase pathway genes are selected from the group consisting of DUSP6, FOS, IL1R1, and SPRY4.

[0150] Cancer is a disease of uncontrolled cell proliferation resulting from alterations in certain genes. Some of these alterations occur in genes that code for receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth and proliferation. Abnormal RTK activation can lead to excessive cell growth and thus cancer. In general, RTKs contain an N-terminal domain that binds to extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0151] In some embodiments, the compounds of formula (I) are inhibitors of human ROS1. ROS1 is an RTK encoded by the ROS1 gene. Although the ligand and biological function of human ROS1 are unknown, its homologs in several other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is essential for male gamete maturation and reproduction. In humans, ROS1 chromosomal rearrangements are a well-documented cause of cancer, representing 1-2% of non-small cell lung cancer (NSCLC) and a subset of many other cancers. These rearrangements result in fusions of the C-terminus of ROS1 with the N-terminus of various partner proteins, the most common of which is CD74. ROS1 fusions have constitutive kinase activity that drives tumor growth via MAPK, PI3K and JAK / STAT signaling pathways. Small molecule tyrosine kinase inhibitors (TKIs) have been used to target ROS1 fusions in cancer, including crizotinib and entrectinib. Crizotinib was the first FDA-approved TKI for the treatment of ROS1-positive NSCLC. Despite initial response, most patients acquire resistance to crizotinib and relapse. The main mechanism of resistance is the G2032R mutation in the solvent front, which dramatically reduces crizotinib affinity. No inhibitors with activity against ROS1-G2032R fusions have been FDA-approved, indicating a need in the art.

[0152] In one embodiment, the compounds provided herein selectively inhibit ROS1. In one embodiment, the compounds selectively inhibit ROS1 over ALK. As non-limiting examples, the selectivity ratio can be greater than about 1.5-fold, greater than about 2-fold, greater than about 3-fold, greater than about 4-fold, greater than about 5-fold, greater than about 10-fold, greater than about 20-fold, greater than about 30-fold, greater than about 50-fold, or greater than about 100-fold, and selectivity can be measured, among other measures, by IC 50 In one embodiment, the selectivity of ROS1 over ALK can be measured by the ratio of IC 50 IC vs. ROS1 value 50 It is measured by the ratio of values.

[0153] In one embodiment, the compound selectively inhibits ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the selectivity ratio can be greater than about 5-fold, greater than about 10-fold, greater than about 50-fold, greater than about 100-fold, greater than about 200-fold, greater than about 400-fold, greater than about 600-fold, greater than about 800-fold, greater than about 1000-fold, greater than about 1500-fold, greater than about 2000-fold, greater than about 5000-fold, greater than about 10,000-fold, or greater than about 20,000-fold, and selectivity can be measured by, among other measures, IC 50 In one embodiment, the selectivity of ROS1 over TRK can be measured by the ratio of IC 50 IC vs. ROS1 value 50 It is measured by the ratio of values.

[0154] In one embodiment, provided herein is a method for selectively inhibiting ROS1 over ALK, where the inhibition occurs in a cell. In one embodiment, provided herein is a method for selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB and / or TRBC), where the inhibition occurs in a cell. In one embodiment, the method comprises contacting ROS1 with an effective amount of a compound provided herein. In one embodiment, such contacting occurs in a cell. In one embodiment, such contacting occurs in a cell in a mammal, e.g., a human. In one embodiment, such contacting occurs in a cell in a human patient with cancer provided herein.

[0155] In one embodiment, provided herein is a method for selectively inhibiting ROS1 over ALK, wherein the inhibition occurs in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein is a method for treating a subject suffering from a cancer associated with ROS1, the method comprising selectively inhibiting ROS1 over ALK by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount being sufficient to selectively inhibit ROS1 over ALK.

[0156] In one embodiment, provided herein is a method for selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC), wherein the inhibition occurs in a subject suffering from cancer, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In certain embodiments, provided herein is a method for treating a subject suffering from a cancer associated with ROS1, the method comprising selectively inhibiting ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering to the subject an amount of a compound or pharmaceutical composition provided herein, the amount being sufficient to selectively inhibit ROS1 over TRK (e.g., TRKA, TRKB, and / or TRBC).

[0157] As used herein, unless otherwise specified, inhibition of ROS1 includes inhibition of wild-type ROS1 or a mutation thereof, inhibition of ALK includes inhibition of wild-type ALK or a mutation thereof, and inhibition of TRK includes inhibition of wild-type TRK or a mutation thereof.

[0158] Cancers treated by the methods provided herein include, but are not limited to, lung cancer, e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovarian cancer, melanoma, e.g., spitzoid melanoma, glioblastoma, cholangiocarcinoma, e.g., cholangiocarcinoma, gastric cancer, colorectal cancer, angiosarcoma, anaplastic large cell lymphoma, diffuse large B cell lymphoma, large B cell lymphoma, esophageal cancer, e.g., esophageal squamous cell carcinoma, kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple negative breast cancer, thyroid cancer, e.g., papillary thyroid carcinoma, neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and spitzoid tumor.

[0159] Cancers treated by the methods provided herein include cancers originating from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by the methods provided herein include cancers that are drug resistant to treatments directed against one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC.

[0160] In one embodiment, the cancer in the methods provided herein is ROS1 positive (ROS1+). As used herein, unless otherwise specified, a "ROS1 positive" (ROS1+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriate high expression of the ROS1 gene and / or the presence of a mutation in the ROS1 gene. In one embodiment, the mutation alters the biological activity of a ROS1 nucleic acid molecule or polypeptide. As used herein, unless otherwise specified, a "mutation" or "mutant" of ROS1 includes one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequence of ROS1, or fragments thereof. As used herein, unless otherwise specified, a ROS1 "rearrangement" refers to a genetic translocation involving the ROS1 gene that may result in a ROS1 fusion gene and / or a ROS1 fusion protein. A ROS1 fusion may also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications, or fragments thereof, so long as the mutant retains kinase phosphorylation activity.

[0161] In one embodiment, the ROS1 mutation comprises one or more ROS1 point mutations. In some embodiments, the cancer treated by the methods provided herein comprises one or more mutations in ROS1 kinase. In one embodiment, the one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, 1981Tins, M2001T, and L2155. In one embodiment, the one or more ROS1 point mutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, and L2086F. In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutation is S1986F. In one embodiment, the ROS1 mutation is S1986Y. In one embodiment, the ROS1 mutation is L2026M. In one embodiment, the ROS1 mutation is D2033N. In one embodiment, the ROS1 mutation is L2086F. In one embodiment, the ROS1 mutation is F2004C. In one embodiment, the ROS1 mutation is F2004V. In one embodiment, the ROS1 mutation is G2101A. In one embodiment, the ROS1 mutation is L1982F. In one embodiment, the ROS1 mutation is G2032R and one or more of the co-mutations S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.

[0162] In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements (in one embodiment, one rearrangement). In one embodiment, the ROS1 mutation comprises one or more ROS1 fusions (in one embodiment, one fusion). In some embodiments, the cancer treated by the methods provided herein comprises a ROS1 fusion. In one embodiment, the ROS1 fusion is selected from the group consisting of SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., GOPC-S, GOPC-L), GPRC6A, LIMA1, LRIG3, MSN, MYO5C, OPRM1, SLC6A17, With one of the fusion partners selected from SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8, CCDC6, CAPRINI, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, ST13, TRIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is a CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is a SDC4-ROS1 fusion. In one embodiment, the ROS1 fusion is an EZR-ROS1 fusion. In one embodiment, the ROS1 fusion is a SLC34A2-ROS1 fusion. In one embodiment, the ROS1 fusion is a GOPC-ROS1 fusion (e.g., GOPC-ROS1-S, GOPC-ROS1-L). In one embodiment, the ROS1 fusion is a CEP85L-ROS1 fusion.

[0163] In one embodiment, the ROS1 mutation comprises one ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e.g., GOPC-ROS1-S, GOPC-ROS1-L) and CEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C, F2004V and G2032R. In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1 and SLC34A2-ROS1, and a ROS1 point mutation of G2101A.

[0164] In one embodiment, the ROS1 mutation is CD74-ROS1 F2004C. In one embodiment, the ROS1 mutation is CD74-ROS1 F2004V. In one embodiment, the ROS1 mutation is CD74-ROS1 G2101A. In one embodiment, the ROS1 mutation is CD74-ROS1 G2032R. In one embodiment, the ROS1 mutation is CD74-ROS1 S1986F. In one embodiment, the ROS1 mutation is CD74-ROS1 L2026M. In one embodiment, the ROS1 mutation is CD74-ROS1 D2033N. In one embodiment, the ROS1 mutation is EZR-ROS1 F2004C. In one embodiment, the ROS1 mutation is EZR-ROS1 F2004V. In one embodiment, the ROS1 mutation is EZR-ROS1 G2101A. In one embodiment, the ROS1 mutation is EZR-ROS1 G2032R. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004C. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004V. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 G2101A. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 G2032R. In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004C (e.g., GOPC-ROS1-S F2004C, GOPC-ROS1-L F2004C). In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In one embodiment, the ROS1 mutation is GOPC-ROS1 G2032R (e.g., GOPC-ROS1-S G2032R, GOPC-ROS1-L G2032R). In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004C. In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004V. In one embodiment, the ROS1 mutation is CEP85L-ROS1 G2032R.In one embodiment, the ROS1 mutation is GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). In one embodiment, the ROS1 mutation is CD74-ROS1 L1982F.

[0165] In some embodiments, provided herein is a method of treating a patient population having a ROS1-positive solid tumor, comprising administering to each of the patient population an effective amount of Compound 1 or a pharmaceutical composition provided herein, wherein the objective response rate (ORR) is at least about 10% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 20% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 30% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 40% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 50% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 60% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 70% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 80% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 90% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, at least about 20% of the patient population achieves a partial response. In one embodiment, at least about 30% of the patient population achieves a partial response. In one embodiment, at least about 40% of the patient population achieves a partial response. In one embodiment, at least about 50% of the patient population achieves a partial response. In one embodiment, at least about 60% of the patient population achieves a partial response. In one embodiment, at least about 70% of the patient population achieves a partial response. In one embodiment, at least about 80% of the patient population achieves a partial response. In one embodiment, at least about 10% of the patient population achieves stable disease. In one embodiment, at least about 20% of the patient population achieves stable disease. In one embodiment, at least about 30% of the patient population achieves stable disease. In one embodiment, at least about 40% of the patient population achieves stable disease.In one embodiment, at least about 50% of the patient population achieves stable disease. In one embodiment, at least about 60% of the patient population achieves stable disease. In one embodiment, at least about 70% of the patient population achieves stable disease.

[0166] In some embodiments, provided herein is a method of treating a patient population having a solid tumor with a ROS1 mutation (e.g., G2032R), comprising administering to each of the patient population an effective amount of Compound 1 or a pharmaceutical composition provided herein, wherein the ORR is at least about 30% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 40% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 50% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 60% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 70% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 80% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 90% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, at least about 20% of the patient population achieves a partial response. In one embodiment, at least about 30% of the patient population achieves a partial response. In one embodiment, at least about 40% of the patient population achieves a partial response. In one embodiment, at least about 50% of the patient population achieves a partial response. In one embodiment, at least about 60% of the patient population achieves a partial response. In one embodiment, at least about 70% of the patient population achieves a partial response. In one embodiment, at least about 80% of the patient population achieves a partial response. In one embodiment, at least about 90% of the patient population achieves a partial response. In one embodiment, at least about 5% of the patient population achieves stable disease. In one embodiment, at least about 10% of the patient population achieves stable disease. In one embodiment, at least about 15% of the patient population achieves stable disease. In one embodiment, at least about 20% of the patient population achieves stable disease. In one embodiment, at least about 30% of the patient population achieves stable disease.In one embodiment, at least about 40% of the patient population achieves stable disease. In one embodiment, at least about 50% of the patient population achieves stable disease. In one embodiment, at least about 60% of the patient population achieves stable disease.

[0167] In some embodiments, provided herein are methods of treating a patient population having ROS1-positive solid tumors and CNS disease at baseline, comprising administering to each of the patient population an effective amount of Compound 1 or a pharmaceutical composition provided herein, wherein the ORR is at least about 30% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 40% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 50% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 60% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 70% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 80% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 90% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, at least about 30% of the patient population achieves a partial response. In one embodiment, at least about 40% of the patient population achieves a partial response. In one embodiment, at least about 50% of the patient population achieves a partial response. In one embodiment, at least about 60% of the patient population achieves a partial response. In one embodiment, at least about 70% of the patient population achieves a partial response. In one embodiment, at least about 80% of the patient population achieves a partial response. In one embodiment, at least about 90% of the patient population achieves a partial response. In one embodiment, at least about 5% of the patient population achieves stable disease. In one embodiment, at least about 10% of the patient population achieves stable disease. In one embodiment, at least about 15% of the patient population achieves stable disease. In one embodiment, at least about 20% of the patient population achieves stable disease. In one embodiment, at least about 30% of the patient population achieves stable disease. In one embodiment, at least about 40% of the patient population achieves stable disease.In one embodiment, at least about 50% of the patient population achieves stable disease. In one embodiment, at least about 60% of the patient population achieves stable disease.

[0168] In some embodiments, provided herein is a method of treating a patient population having a ROS1-positive solid tumor after the patient population has received at least two prior ROS1 TKI therapies and at least one chemotherapy, comprising administering to each of the patient population an effective amount of compound 1 or a pharmaceutical composition provided herein, wherein the ORR is at least about 10% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 20% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 30% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 40% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 50% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 60% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 70% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 80% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 90% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, at least about 20% of the patient population achieves a partial response. In one embodiment, at least about 30% of the patient population achieves a partial response. In one embodiment, at least about 40% of the patient population achieves a partial response. In one embodiment, at least about 50% of the patient population achieves a partial response. In one embodiment, at least about 60% of the patient population achieves a partial response. In one embodiment, at least about 70% of the patient population achieves a partial response. In one embodiment, at least about 80% of the patient population achieves a partial response. In one embodiment, at least about 90% of the patient population achieves a partial response. In one embodiment, at least about 10% of the patient population achieves stable disease. Achieving stable disease In one embodiment, at least about 20% of the patient population achieves stable disease.In one embodiment, at least about 30% of the patient population achieves stable disease. In one embodiment, at least about 40% of the patient population achieves stable disease. In one embodiment, at least about 50% of the patient population achieves stable disease. In one embodiment, at least about 60% of the patient population achieves stable disease. In one embodiment, at least about 70% of the patient population achieves stable disease. In one embodiment, at least about 80% of the patient population achieves stable disease.

[0169] In some embodiments, provided herein is a method of treating a patient population having a ROS1-positive solid tumor after the patient population has received at least one prior ROS1 TKI therapy and at least one chemotherapy, comprising administering to each of the patient population an effective amount of compound 1 or a pharmaceutical composition provided herein, wherein the ORR is at least about 10% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 20% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 30% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 40% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 50% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 60% (RECIST 1.1) after a treatment cycle of compound 1. In one embodiment, the ORR is at least about 70% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 80% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 90% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, at least about 20% of the patient population achieves a partial response. In one embodiment, at least about 30% of the patient population achieves a partial response. In one embodiment, at least about 40% of the patient population achieves a partial response. In one embodiment, at least about 50% of the patient population achieves a partial response. In one embodiment, at least about 60% of the patient population achieves a partial response. In one embodiment, at least about 70% of the patient population achieves a partial response. In one embodiment, at least about 80% of the patient population achieves a partial response. In one embodiment, at least about 90% of the patient population achieves a partial response. In one embodiment, at least about 10% of the patient population achieves stable disease. Achieving stable disease In one embodiment, at least about 20% of the patient population achieves stable disease.In one embodiment, at least about 30% of the patient population achieves stable disease. In one embodiment, at least about 40% of the patient population achieves stable disease. In one embodiment, at least about 50% of the patient population achieves stable disease. In one embodiment, at least about 60% of the patient population achieves stable disease. In one embodiment, at least about 70% of the patient population achieves stable disease. In one embodiment, at least about 80% of the patient population achieves stable disease.

[0170] In some embodiments, provided herein are methods of treating a patient population having ROS1-positive solid tumors after the patient population has received a prior treatment of lorlatinib and / or repotrectinib, comprising administering to each of the patient population an effective amount of Compound 1 or a pharmaceutical composition provided herein, wherein the ORR is at least about 10% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 20% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 30% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 40% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 50% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 60% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 70% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 80% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, the ORR is at least about 90% (RECIST 1.1) after a treatment cycle of Compound 1. In one embodiment, at least about 20% of the patient population achieves a partial response. In one embodiment, at least about 30% of the patient population achieves a partial response. In one embodiment, at least about 40% of the patient population achieves a partial response. In one embodiment, at least about 50% of the patient population achieves a partial response. In one embodiment, at least about 60% of the patient population achieves a partial response. In one embodiment, at least about 70% of the patient population achieves a partial response. In one embodiment, at least about 80% of the patient population achieves a partial response. In one embodiment, at least about 90% of the patient population achieves a partial response. In one embodiment, at least about 10% of the patient population achieves stable disease. Achieving stable disease In one embodiment, at least about 10% of the patient population achieves stable disease.In one embodiment, at least about 20% of the patient population achieves stable disease. In one embodiment, at least about 30% of the patient population achieves stable disease. In one embodiment, at least about 40% of the patient population achieves stable disease. In one embodiment, at least about 50% of the patient population achieves stable disease. In one embodiment, at least about 60% of the patient population achieves stable disease. In one embodiment, at least about 70% of the patient population achieves stable disease. In one embodiment, at least about 80% of the patient population achieves stable disease.

[0171] In one embodiment, ROS1+ cancer is determined by FDA approved test or other test known in the art. Tests that can be used include, for example, Oncomine™ Dx Target Test by Thermo Fisher Scientific. (Qualitative in vitro diagnostic test using targeted high-throughput parallel sequencing technology to detect sequence variation in 23 genes in DNA and RNA isolated from formalin-fixed paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC) using Ion PGM Dx System system); Vysis ROS1 Break Apart FISH Probe Kit (Qualitative test to detect rearrangements, including ROS1 gene rearrangements at 6q22, in formalin-fixed paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens via fluorescent in situ hybridization (FISH)), or local diagnostic test via reverse transcription polymerase chain reaction (RT-PCR) or next generation sequencing (NGS).

[0172] Also provided herein is a method of treating a subject with cancer (e.g., a ROS1-positive cancer), comprising: determining whether cancer cells in a sample obtained from a subject with cancer and previously administered a first ROS1 inhibitor have one or more ROS1 inhibitor-resistant mutations; and administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt or solvate thereof, as a monotherapy or together with another anti-cancer agent, if the subject has cancer cells with one or more ROS1 inhibitor-resistant mutations. In some embodiments, the one or more ROS1 inhibitor-resistant mutations confer increased resistance to treatment with the first ROS1 inhibitor to the cancer cells or tumor. In some embodiments, the one or more ROS1 inhibitor-resistant mutations include one or more ROS1 inhibitor-resistant mutations. For example, the one or more ROS1 inhibitor resistance mutations can include substitutions at one or more of amino acid positions 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032, and 2086, e.g., G2032R, D ... 033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K and L2086F. In some embodiments, the other anti-cancer agent is any anti-cancer agent known in the art. For example, the other anti-cancer agent can be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).

[0173] In one embodiment, the compound provided herein is a CNS penetrating compound.In one embodiment, after effective amount of the compound provided herein is administered (for example, orally or intravenously), the compound can penetrate the CNS (for example, blood-brain barrier) and achieve a concentration in the CNS (for example, brain) that is still sufficient to inhibit (for example, selectively inhibit) ROS1.

[0174] In one embodiment, provided herein is a method for treating CNS metastasis of cancer, comprising administering to a subject in need thereof an effective amount of a compound provided herein, for example, a compound of formula (I), or its stereoisomer or mixture of stereoisomers, or its pharma- ceutically acceptable salt.In one embodiment, the CNS metastasis is brain metastasis.In one embodiment, the cancer is ROS1+ cancer.

[0175] In some embodiments, the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C. In certain embodiments, the IC of the compound for inhibition of mutated or non-mutated ROS1 or ALK is 50 is the IC of a compound for inhibition of wild-type tropomyosin receptor kinase A, B or C 50 TRK inhibition, particularly in the central nervous system (CNS), is associated with adverse reactions including dizziness / ataxia / gait disturbance, paresthesia, weight gain, and cognitive changes.

[0176] In some embodiments, provided herein is a method of minimizing treatment-related adverse events in a subject in need of treatment for cancer (e.g., a ROS1-positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, wherein the method minimizes treatment-related adverse events associated with a TRK inhibitor. In some embodiments, the cancer is a ROS1-associated cancer. In some embodiments, the adverse events are one or more of TRK-associated CNS adverse events.

[0177] As used herein, "minimizing" an adverse event refers to a reduction in the incidence of an adverse event in a subject or patient population compared to the paradigm incidence of the adverse event in a subject or patient population treated with a TRK inhibitor (e.g., entrectinib, repotrectinib, or lorlatinib). In some embodiments, the incidence of an adverse event refers to the frequency or percentage of a specific adverse event across a subject or patient population. In some embodiments, the incidence of an adverse event refers to the total number of adverse events experienced by an individual subject. In some embodiments, minimizing an adverse event refers to minimizing a TRK-related CNS adverse event. In some embodiments, minimizing a TRK-related CNS adverse event means that less than 40% of a patient population has a TRK-related CNS adverse event. In some embodiments, minimizing a TRK-related CNS adverse event means that less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, or less than 5% of a patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means that less than 12% of the patient population has two or more TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means that less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, or less than 3% of the patient population has two or more TRK-related CNS adverse events.

[0178] In some embodiments, a TRK-related CNS treatment-related adverse event refers to one or more of the following: dizziness, ataxia, gait disturbance, paresthesias, weight gain, hyperphagia, paresthesias, abnormal movements, cognitive changes, speech effects (e.g., dysarthria, slow speech or speech disorder), mood disorders (e.g., irritability, anxiety, depression, emotional lability, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoric mood or mania), and cognitive disorders (e.g., memory impairment, cognitive impairment, amnesia, confusion, attention disorder, delirium, mental impairment, attention deficit hyperactivity disorder, dementia, sleep disorder or dyslexia).

[0179] In one embodiment, provided herein is a method for preventing or limiting TRK-related treatment-related CNS side effects or adverse events in cancer treatment, comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the method prevents the occurrence of a TRK-related CNS adverse event. In one embodiment, the method limits the frequency of occurrence of a TRK-related CNS adverse event. In one embodiment, the method limits the severity of a TRK-related side effect. In one embodiment, provided herein is a method for treating CNS metastasis of cancer with reduced TRK-related side effects, comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the reduction / limitation / prevention in CNS side effects or adverse events is determined in a statistical sample compared to a standard of care, e.g., an approved ROS1 and / or ALK inhibitor for ROS1+ and / or ALK+ cancer (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib). In one embodiment, the TRK-related side effect is a TRKB-related CNS side effect. In one embodiment, the TRK-related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paresthesia, weight gain, cognitive impairment, mood disorder, or sleep disorder.

[0180] In one embodiment, provided herein is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, such as a compound of formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. In one embodiment, the cancer is a ROS1-associated cancer. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is identified as ROS1.

[0181] In one embodiment, provided herein is a method for treating a ROS1+ cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0182] In one embodiment, provided herein is a method for treating cancer in a subject, the method comprising: (i) identifying the cancer in the subject as ROS1+; and (ii) administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0183] In one embodiment, the cancer (or ROS1+ cancer) is a solid tumor. In one embodiment, the cancer (or ROS1+ cancer) is an aggressive solid tumor. In one embodiment, the cancer (or ROS1+ cancer) is a locally aggressive solid tumor. In one embodiment, the cancer (or ROS1+ cancer) is a lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchial carcinoma, glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, e.g., cholangiocarcinoma, ovarian cancer, e.g., serous ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, e.g., spitzoid melanoma, epithelioid hemangioendothelioma, esophageal cancer, e.g., esophageal squamous cell carcinoma (ESCC), kidney cancer, e.g., renal medullary carcinoma or renal cell carcinoma, breast cancer, e.g., triple-negative breast cancer, colon cancer, thyroid cancer, e.g., papillary thyroid carcinoma, spitzoid tumor, pancreatic cancer, inflammatory hepatocellular adenoma, or neuroblastoma.

[0184] In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In one embodiment, the cancer is recurrent or resistant non-small cell lung cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ROS1+ non-small cell lung cancer. In one embodiment, the cancer is bronchial carcinoma. In one embodiment, the cancer is ROS1+ bronchial carcinoma. In one embodiment, the cancer is recurrent or resistant bronchial carcinoma. In one embodiment, the cancer is recurrent or resistant ROS1+ bronchial carcinoma. In one embodiment, the cancer is newly diagnosed bronchial carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ bronchial carcinoma.

[0185] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is recurrent or resistant glioblastoma. In one embodiment, the cancer is recurrent or resistant ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma.

[0186] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ROS1+ IMT. In one embodiment, the cancer is recurrent or resistant IMT. In one embodiment, the cancer is recurrent or resistant ROS1+ IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ROS1+ IMT.

[0187] In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ROS1+ cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory cholangiocarcinoma. In one embodiment, the cancer is recurrent or refractory ROS1+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ cholangiocarcinoma.

[0188] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ROS1+ ovarian cancer. In one embodiment, the cancer is recurrent or resistant ovarian cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ROS1+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian cancer. In one embodiment, the ovarian cancer is high-grade serous ovarian cancer.

[0189] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ROS1+ gastric cancer. In one embodiment, the cancer is recurrent or resistant gastric cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ROS1+ gastric cancer.

[0190] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer is recurrent or resistant colorectal cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colorectal cancer.

[0191] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ROS1+ angiosarcoma. In one embodiment, the cancer is recurrent or refractory angiosarcoma. In one embodiment, the cancer is recurrent or refractory ROS1+ angiosarcoma. In one embodiment, the cancer is newly diagnosed angiosarcoma. In one embodiment, the cancer is newly diagnosed ROS1+ angiosarcoma.

[0192] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is a spitzoid tumor. In one embodiment, the cancer is spitzoid melanoma. In one embodiment, the cancer is ROS1+ spitzoid melanoma. In one embodiment, the cancer is recurrent or resistant spitzoid melanoma. In one embodiment, the cancer is recurrent or resistant ROS1+ spitzoid melanoma. In one embodiment, the cancer is newly diagnosed spitzoid melanoma. In one embodiment, the cancer is newly diagnosed ROS1+ spitzoid melanoma.

[0193] In one embodiment, the cancer is epithelioid hemangioendothelioma. In one embodiment, the cancer is ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is recurrent or refractory ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ROS1+ epithelioid hemangioendothelioma.

[0194] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ESCC. In one embodiment, the cancer is ROS1+ ESCC. In one embodiment, the cancer is recurrent or resistant ESCC. In one embodiment, the cancer is recurrent or resistant ROS1+ ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ROS1+ ESCC.

[0195] In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal medullary cancer. In one embodiment, the cancer is ROS1+ renal medullary cancer. In one embodiment, the cancer is recurrent or resistant renal medullary cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ renal medullary cancer. In one embodiment, the cancer is newly diagnosed renal medullary cancer. In one embodiment, the cancer is newly diagnosed ROS1+ renal medullary cancer. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ROS1+ renal cell carcinoma. In one embodiment, the cancer is recurrent or resistant renal cell carcinoma. In one embodiment, the cancer is recurrent or resistant ROS1+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal cell carcinoma.

[0196] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ROS1+ breast cancer. In one embodiment, the cancer is recurrent or resistant breast cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ROS1+ breast cancer. In one embodiment, the breast cancer is triple negative breast cancer.

[0197] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ROS1+ colon cancer. In one embodiment, the cancer is recurrent or resistant colon cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colon cancer.

[0198] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid cancer. In one embodiment, the cancer is ROS1+ papillary thyroid cancer. In one embodiment, the cancer is recurrent or refractory papillary thyroid cancer. In one embodiment, the cancer is recurrent or refractory ROS1+ papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed ROS1+ papillary thyroid cancer.

[0199] In one embodiment, the cancer is a ROS1+ glioma (e.g., grade 1, grade 2, grade 3, or grade 4). In one embodiment, the cancer is a recurrent or resistant glioma. In one embodiment, the cancer is a recurrent or resistant ROS1+ glioma. In one embodiment, the cancer is a newly diagnosed ROS1+ glioma. In one embodiment, the cancer is a ROS1+ glioblastoma. In one embodiment, the cancer is a newly diagnosed ROS1+ glioblastoma. In one embodiment, the cancer is a recurrent or resistant glioblastoma. In one embodiment, the cancer is a recurrent or resistant ROS1+ glioblastoma. In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is a ROS1+ neuroblastoma. In one embodiment, the cancer is a recurrent or resistant neuroblastoma. In one embodiment, the cancer is a recurrent or resistant ROS1+ neuroblastoma. In one embodiment, the cancer is a newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ neuroblastoma.

[0200] In one embodiment, the cancer is ROS1+ pancreatic cancer. In one embodiment, the cancer is recurrent or resistant pancreatic cancer. In one embodiment, the cancer is recurrent or resistant ROS1+ pancreatic cancer. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ pancreatic cancer.

[0201] In one embodiment, the cancer is ROS1+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is recurrent or resistant inflammatory hepatocellular adenoma. In one embodiment, the cancer is recurrent or resistant ROS1+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ inflammatory hepatocellular adenoma.

[0202] In one embodiment, the cancer (or ROS1+ cancer or ALK+ cancer) is a hematological cancer. In one embodiment, the cancer (or ROS1+ cancer or ALK+ cancer) is a lymphoma. In one embodiment, the lymphoma is a non-Hodgkin's lymphoma. In one embodiment, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL) or large B-cell lymphoma. Also provided herein are methods for treating other hematological disorders or hematological malignancies that are ROS1+ or ALK+, in addition to hematological cancers.

[0203] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ROS1+ ALCL. In one embodiment, the cancer is ALK+ ALCL. In one embodiment, the cancer is recurrent or resistant ALCL. In one embodiment, the cancer is recurrent or resistant ROS1+ ALCL. In one embodiment, the cancer is recurrent or resistant ALK+ ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ROS1+ ALCL. In one embodiment, the cancer is newly diagnosed ALK+ ALCL.

[0204] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ROS1+ DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In one embodiment, the cancer is recurrent or resistant DLBCL. In one embodiment, the cancer is recurrent or resistant ROS1+ DLBCL. In one embodiment, the cancer is recurrent or resistant ALK+ DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ROS1+ DLBCL. In one embodiment, the cancer is newly diagnosed ALK+ DLBCL.

[0205] In one embodiment, the cancer is large B cell lymphoma. In one embodiment, the cancer is ROS1+ large B cell lymphoma. In one embodiment, the cancer is ALK+ large B cell lymphoma. In one embodiment, the cancer is relapsed or refractory large B cell lymphoma. In one embodiment, the cancer is relapsed or refractory ROS1+ large B cell lymphoma. In one embodiment, the cancer is relapsed or refractory ALK+ large B cell lymphoma. In one embodiment, the cancer is newly diagnosed large B cell lymphoma. In one embodiment, the cancer is newly diagnosed ROS1+ large B cell lymphoma. In one embodiment, the cancer is newly diagnosed ALK+ large B cell lymphoma. In one embodiment, the cancer (or ROS1+ cancer) is newly diagnosed. In one embodiment, the cancer (or ROS1+ cancer) has not been previously treated.

[0206] In one embodiment, the cancer (or ROS1+ cancer) is recurrent or resistant. In one embodiment, the cancer is recurrent. In one embodiment, the cancer (or ROS1+ cancer) is resistant.

[0207] In one embodiment, the subject is not previously treated. In one embodiment, the subject is naïve with tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received one or more prior lines of therapy. In one embodiment, the subject has received two or more prior lines of therapy. In one embodiment, the subject has developed resistance to one or more of the prior lines of therapy. In one embodiment, the prior therapy comprises a tyrosine kinase inhibitor (TKI). In one embodiment, the prior TKI therapy comprises treatment with one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taretrectinib, merestinib, masitinib, and ensartinib. In one embodiment, the prior therapy comprises one or more chemotherapy. In one embodiment, the one or more chemotherapy regimens is in addition to a TKI therapy.

[0208] In one embodiment, the cancer is an aggressive cancer, for example an aggressive cancer that has relapsed after prior treatment with a TKI or is resistant or refractory thereto.

[0209] In one embodiment, the cancer (or ROS1+ cancer) is resistant to a tyrosine kinase inhibitor (TKI).

[0210] In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is resistant bronchial carcinoma. In one embodiment, the cancer is resistant non-small cell lung cancer. In one embodiment, the cancer is non-small cell lung cancer that is resistant to TKI. In one embodiment, the cancer is ROS1+ non-small cell lung cancer that is resistant to TKI.

[0211] In one embodiment, the cancer is lung cancer (e.g., NSCLC, bronchial carcinoma). In one embodiment, the cancer is advanced lung cancer, for example, advanced lung cancer that has relapsed after or is resistant to previous treatment with a TKI.

[0212] In one embodiment, the compound provided herein is administered as a first line of therapy. In one embodiment, the compound provided herein is administered as a second line of therapy. In one embodiment, the compound provided herein is administered as a third or fourth line of therapy.

[0213] In one embodiment, the cancer (or ROS1+ cancer) is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (NSCLC). In one embodiment, the cancer is metastatic ROS1+ NSCLC.

[0214] In one embodiment, provided herein is a method for treating a patient having metastatic ROS1+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0215] In one embodiment, the patient is an adult patient, hi one embodiment, the patient is a pediatric patient.

[0216] In one embodiment, provided herein is a method for treating an adult patient having metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof.

[0217] In one embodiment, provided herein is a method for treating an adult patient having metastatic ROS1+ NSCLC, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant to at least one prior TKI therapy.

[0218] In one embodiment, provided herein is a method for treating an adult patient with metastatic NSCLC that is ROS1+ with the solvent front mutation G2032R, the method comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant to at least one prior TKI therapy.

[0219] In one embodiment, provided herein is a method of treating a ROS1-associated (or ROS1+) cancer in a subject in need thereof, where the cancer has become resistant to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0220] In one embodiment, provided herein is a method of treating a ROS1-associated (or ROS1+) cancer in a subject in need thereof, the cancer being resistant to a tyrosine kinase inhibitor (TKI), the cancer being identified as having one or more ROS1 inhibitor-resistant mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, for example, a compound of formula (I), or a stereoisomer or mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof. In one embodiment, the one or more ROS1 inhibitor-resistant mutations comprise one or more amino acid substitutions at amino acid positions selected from 1986, 2004, 2026, 2032, and 2033. In one embodiment, the one or more ROS1 inhibitor-resistant mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In one embodiment, the one or more ROS1 inhibitor-resistant mutations are G2032R. In one embodiment, the one or more ROS1 inhibitor-resistant mutations include G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitor-resistant mutation is L2086F.

[0221] In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigutinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taretrectinib, masitinib or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib. In one embodiment, the TKI is lorlatinib. In one embodiment, the TKI is repotrectinib.

[0222] In certain embodiments, the subject has relapsed after a first line of treatment for cancer, hi other embodiments, the subject has relapsed after a second line of treatment for cancer.

[0223] In certain embodiments, methods for treating or preventing cancer may be demonstrated by one or more responses, such as increased apoptosis, inhibition of tumor growth, reduction in tumor metastasis, inhibition of tumor metastasis, reduction in microvascular density, decreased neovascularization, inhibition of tumor migration, tumor regression, and increased survival of the subject.

[0224] Combination treatment In some embodiments, the methods of treating or preventing cancer may include administering a compound of formula (I) in combination with one or more other chemotherapeutic agent(s).

[0225] As used herein, unless otherwise specified, "concomitantly" or "in combination with" is not intended to imply that the other agent and the compound of formula (I) must be administered at the same time and / or formulated together for delivery, although these delivery methods are within the scope of this disclosure. The compounds provided herein may be administered simultaneously with, prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks), or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks). In general, each therapeutic agent is administered at a dose and / or time schedule determined for that particular agent. The other therapeutic agents may be administered in a single composition together with the compounds provided herein or separately in different compositions. Triple therapy is also contemplated herein.Chemotherapeutic agents that may be administered in conjunction with the compounds provided herein include 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino] ... Oxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, ABT-263, afatinib maleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (BCG), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, camptothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridine, dexamethasone , dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide,Letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porf These include: dimers, PPADS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be administered in conjunction with the compounds provided herein include ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be administered in conjunction with the compounds provided herein include 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate,These include 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline 2,4-dinitrobenzenesulfonate sodium, sumarin, and tonapophilin. In some embodiments, the chemotherapeutic agent is a biologic, e.g., an ADC or a MET antibody. In some embodiments, the chemotherapeutic agent is a MET inhibitor, a MEK inhibitor, a RET inhibitor, another ALK inhibitor, or a ROS1 inhibitor. In some embodiments, the compounds described herein are used in conjunction with one or more platinum-based chemotherapy and / or immunotherapy (e.g., checkpoint inhibitors).

[0226] Many combination therapies have been developed for the treatment of cancer.In certain embodiments, the compounds provided herein (e.g., compounds of formula (I)) can be administered in combination with one or more combination therapies.Examples of combination therapies that the compounds provided herein can be administered in combination with are included in Table 1. [Table 1] TIFF2024537794000007.tif236165TIFF2024537794000008.tif232165TIFF20245377940 00009.tif227165TIFF2024537794000010.tif227165TIFF2024537794000011.tif150165

[0227] In certain embodiments, the conjugation therapy provided herein includes the conjugation with other types of chemotherapeutic agents, such as immuno-oncology agents. Cancer cells often have specific cell surface antigens that can be recognized by the immune system. Thus, immuno-oncology agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and cause cell death. Other immuno-oncology agents can suppress tumor-mediated inhibition of innate immune response or can otherwise activate immune response, thus facilitating tumor recognition by the immune system. Exemplary antibody immuno-oncology agents include, but are not limited to, abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intetumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immuno-oncology agent is selected from an anti-CD73 monoclonal antibody (mAb), an anti-CD39 mAb, an anti-PD-1 mAb, and an anti-CTLA4 mAb. Thus, in some embodiments, the methods provided herein include the co-administration of one or more immuno-oncology agents, such as those listed above.

[0228] In some embodiments, the combination therapy includes co-administration of a compound provided herein, e.g., a compound of Formula (I), with an SH2 inhibitor, e.g., CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056.

[0229] In some embodiments, the combination therapy includes co-administration of a solid form or pharmaceutical composition provided herein, e.g., a compound of Formula (I), with an ERK1 / 2 inhibitor, e.g., ASN007, GDC-0994, KO-947, LTT462, LY3214996, MK-8353, ulixertinib.

[0230] In some embodiments, the combination therapy includes co-administration of a compound provided herein, e.g., a compound of Formula (I), with a MEK inhibitor, e.g., trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733.

[0231] In some embodiments, the combination therapy includes co-administration of a compound provided herein, e.g., a compound of Formula (I), with a MET inhibitor selected from JNJ-38877605, PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.

[0232] In some embodiments, the combination therapy involves the co-administration of a compound of the disclosure, such as Formula (I), with an SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[0233] In some embodiments, the combination therapy includes co-administration of a compound provided herein, e.g., a compound of Formula (I), with a RAS inhibitor selected from aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[0234] In some embodiments, the combination therapy includes administering a compound provided herein, for example, a compound of formula (I), in combination with a TKI. In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigutinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taretrectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigutinib. In one embodiment, the TKI is lorlatinib.

[0235] In some embodiments, the combination therapy comprises the co-administration of a compound provided herein, e.g., a compound of Formula (I), and an anti-PD-1 therapy. In certain embodiments, the combination therapy comprises the co-administration of a compound provided herein, e.g., a compound of Formula (I), and oxaliplatin. In other embodiments, the combination therapy comprises the co-administration of a compound provided herein, e.g., a compound of Formula (I), and doxorubicin.

[0236] In certain embodiments, the compounds provided herein can be administered in conjunction with non-chemical methods of cancer treatment.In certain embodiments, the compounds provided herein can be administered in conjunction with radiation therapy.In certain embodiments, the compounds provided herein can be administered in conjunction with surgery, thermal ablation, focused ultrasound therapy, cryotherapy or any combination thereof.

[0237] In certain embodiments, the compounds provided herein can be administered in combination with one or more other compounds provided herein.Such combinations can also be administered in combination with other therapeutic agents, such as other agents suitable for treating cancer, immunological or neurological diseases, such as the agents identified above.In certain embodiments, administering one or more additional chemotherapeutic agents in combination with the compounds provided herein provides a synergistic effect.In certain embodiments, administering one or more additional chemotherapeutic agents in combination provides an additive effect.

[0238] Pharmaceutical Compositions In certain embodiments, provided herein is a pharmaceutical preparation suitable for use in a human patient, the pharmaceutical preparation including a compound provided herein (e.g., a compound of Formula (I)) and one or more pharma- ceutically acceptable excipients. In certain embodiments, the pharmaceutical preparation can be for use in the treatment or prevention of a condition or disease described herein. The compounds provided herein can be used in the manufacture of a medicament for the treatment of any disease or condition disclosed herein.

[0239] In one embodiment, the pharmaceutical composition comprises a compound of formula (I): [ka] or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof, a diluent, a binder, a disintegrant, and a lubricant. In one embodiment, Compound 1, or a stereoisomer or a mixture of stereoisomers thereof, or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is the free base of Compound 1. In one embodiment, the free base of Compound 1 is amorphous. In one embodiment, the free base of Compound 1 is one of the solid forms of the free base of Compound 1 provided herein. In one embodiment, the free base of Compound 1 is Form 1 of the free base of Compound 1.

[0240] In one embodiment, the diluent is mannitol. In one embodiment, the diluent is Pearlitol 100SD, Pearlitol 110 C, Pearlitol 160 C, Pearlitol 25 C, Pearlitol 300 DC, Pearlitol 400 DC, Pearlitol 500 DC, Pearlitol SW-F 200, Parteck M 100, Parteck M 200 or lactose monohydrate. In one embodiment, the diluent is mannitol Pearlitol 50C. In one embodiment, the diluent is mannitol Pearlitol 200SD.

[0241] In one embodiment, the binder is hydroxypropyl cellulose (HPC), silicified microcrystalline cellulose (SMCC), or a mixture thereof. In one embodiment, the binder is HPC. In one embodiment, the binder is SMCC. In one embodiment, the binder is a mixture of HPC and SMCC. In certain embodiments, the binder is carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia, or a mixture thereof.

[0242] In one embodiment, the disintegrant is sodium starch glycolate (SSG).In one embodiment, the disintegrant is cross-linked sodium carboxymethylcellulose.

[0243] In one embodiment, the lubricant is magnesium stearate, hi another embodiment, the lubricant is sodium lauryl sulfate.

[0244] In one embodiment, the diluent is mannitol, the binder is a mixture of HPC and SMCC, the disintegrant is sodium starch glycolate (SSG), and the lubricant is magnesium stearate.

[0245] In one embodiment, the tablet is coated with a non-functional film coating (eg, Opadry II Pink).

[0246] In one embodiment, the pharmaceutical composition provided herein is an oral dosage form. In one embodiment, the oral dosage form is a tablet. In one embodiment, the oral dosage form is an immediate release tablet.

[0247] The compositions and methods provided herein may be used to treat a subject in need thereof. In certain embodiments, the subject is a mammal, e.g., a human or a non-human mammal. When administered to a subject, e.g., a human, the composition or compound is preferably administered as a pharmaceutical composition, e.g., a pharmaceutical composition comprising a compound provided herein and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, e.g., aqueous solutions, e.g., water or buffered saline, or other solvents or vehicles, e.g., glycols, glycerol, oils, e.g., olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients may be selected, e.g., to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in unit dosage form, such as tablets, capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized powders for reconstitution, solutions, syrups, suppositories, or injections. The composition can also be in a transdermal delivery system, such as a skin patch. The composition can also be in a solution suitable for topical administration, such as eye drops.

[0248] A pharma- ceutically acceptable carrier can contain, for example, a physiologically acceptable agent that acts to stabilize, increase the solubility or increase the absorption of a compound, for example, a compound provided herein. Such physiologically acceptable agents include, for example, carbohydrates, for example, glucose, sucrose or dextran, antioxidants, for example, ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of a pharma- ceutical acceptable carrier that includes a physiologically acceptable agent depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, for example, a compound provided herein can be incorporated within the liposome or other polymer matrix. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, metabolizable carriers that are relatively simple to prepare and administer.

[0249] The phrase "pharmacologically acceptable" is used herein to indicate that these compounds, materials, compositions and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0250] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the subject. Some examples of materials that can function as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer solution, and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0251] Pharmaceutical compositions (preparations) can be administered to a subject by any of several routes of administration, including, for example, oral (e.g., as drenches, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue, as aqueous or non-aqueous solutions or suspensions); absorption through the oral mucosa (e.g., sublingual); anal, rectal, or vaginal (e.g., as pessaries, creams, or foams); parenteral (e.g., as sterile solutions or suspensions, including intramuscular, intravenous, subcutaneous, or intrathecal); nasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin); and topical (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds can also be formulated for inhalation. In certain embodiments, the compounds can be simply dissolved or suspended in sterile water. Details of suitable administration routes and compositions suitable therefor can be found, for example, in U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, and patents cited therein.

[0252] The formulations can be conveniently presented in unit dosage form and can be prepared by any method well known in the art of pharmacy. In certain embodiments, the unit dosage form is a tablet. In certain embodiments, the unit dosage form is a tablet of 5 mg dosage strength (by weight of free base Compound 1). In certain embodiments, the unit dosage form is a tablet of 25 mg dosage strength (by weight of free base Compound 1). The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form is generally that amount of compound that produces a therapeutic effect. Generally, out of 100 percent, this amount ranges from about 1 percent to about 99 percent of active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0253] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, e.g., a compound provided herein, with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound provided herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0254] Formulations provided herein suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia, or tragacanth), lyophilized, powdered, granulated; or as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; or as a pastille (using an inert base, e.g., gelatin and glycerin, or sucrose and acacia); and / or as a mouthwash, each containing a predetermined amount of a compound provided herein as an active ingredient. The composition or compound may also be administered as a bolus, electuary, or paste.

[0255] To prepare solid dosage forms for oral administration (such as capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, and granules), the active ingredient is mixed with one or more pharma- ceutically acceptable carriers, for example, sodium citrate or dicalcium phosphate, and / or with one or more of the following: (1) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, for example, glycerol; (4) disintegrants, for example, agar-agar; The pharmaceutical composition may be mixed with any of the following: calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (5) solution retarders such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof, (10) complexing agents such as modified and unmodified cyclodextrins, and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical composition may also include buffering agents. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0256] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets can be made by molding a mixture of powdered compound moistened with an inert liquid diluent in a suitable machine.

[0257] Tablets, as well as other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills, and granules, may be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres in various proportions to provide a desired release profile. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that may be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0258] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilized agents for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, groundnut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0259] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0260] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0261] Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as suppositories, which may be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate; suppositories are solid at room temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compounds.

[0262] Formulations of the pharmaceutical composition for administration to the buccal cavity may be presented as a mouthwash or a mouth spray or an oral ointment.

[0263] Alternatively or additionally, the compositions may be formulated for delivery via a catheter, stent, wire or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0264] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0265] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0266] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0267] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0268] Transdermal patch has the additional advantage of providing controlled delivery of the compound provided herein to the body.Such dosage forms can be prepared by dissolving or dispersing active compound in suitable medium.Also, absorption enhancers can be used to increase the flux of compound across skin.The rate of such flux can be controlled by either providing a rate-controlling membrane or dispersing compound in a polymer matrix or gel.

[0269] Also contemplated within the scope of the present disclosure are eye drop formulations, eye ointments, powders, solutions, and the like.Exemplary eye drop formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, and U.S. Patent No. 6,583,124, the contents of which are incorporated herein by reference.If desired, the liquid eye drop formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids.The preferred route of administration is topical administration (e.g., external administration, e.g., eye drops, or administration via implants).

[0270] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0271] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or in combination with sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0272] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0273] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0274] In some cases, it is desirable to slow down the absorption of drugs from subcutaneous or intramuscular injections in order to prolong the effect of drugs.This can be achieved by using liquid suspensions of crystalline or amorphous materials with poor water solubility.The rate of absorption of the drug then depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.As an alternative, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0275] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0276] For use in the methods provided herein, the active compounds may be administered per se or as pharmaceutical compositions containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharma- ceutically acceptable carrier.

[0277] Also, the method of introduction can be provided by rechargeable or biodegradable devices. Recently, various sustained release polymeric devices have been developed and tested in vivo for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. Various biocompatible polymers, including both biodegradable and non-degradable polymers (including hydrogels), can be used to form implants for sustained release of compounds at specific target sites.

[0278] Actual dosage levels of the active ingredients in pharmaceutical compositions may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0279] The selected dosage level will depend on a variety of factors, including the activity of the particular compound or combination of compounds, or esters, salts or amides thereof, being used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) being used, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and similar factors well known in the medical arts.

[0280] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start with a dose of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and the dosage can be gradually increased until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound that is sufficient to induce the desired therapeutic effect. In general, it is understood that the effective amount of the compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount may include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered together with the compound provided herein. A larger total dose may be delivered by multiple administrations of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0281] If desired, the effective daily dose of active compound can be administered as 1, 2, 3, 4, 5, 6 or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In certain embodiments provided herein, active compound can be administered 2 or 3 times a day.In a preferred embodiment, active compound is administered once a day.

[0282] In certain embodiments, the compounds provided herein may be used alone or may be administered in combination with another type of therapeutic agent. As used herein, the phrase "co-administration" refers to any administration form of two or more different therapeutic compounds, in which the previously administered therapeutic compound is still effective in the body while the second compound is administered (e.g., the two compounds are effective in the subject at the same time, which may include the synergistic effect of the two compounds). For example, the different therapeutic compounds can be administered either simultaneously or sequentially, either in the same formulation or in separate formulations. In certain embodiments, the different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, the subject receiving such treatment can benefit from the combined effect of the different therapeutic compounds.

[0283] In certain embodiments, the co-administration of a compound provided herein with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy over separate administration of the compound provided herein or each of the one or more additional therapeutic agent(s). In certain such embodiments, the co-administration provides an additive effect, where additive effect refers to the sum of the effects of separate administration of a compound provided herein and one or more additional therapeutic agent(s).

[0284] Wetting agents, emulsifying agents, and lubricating agents, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0285] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha tocopherol; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0286] The disclosure, having now been generally described, will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the disclosure and are not intended to limit the disclosure. EXAMPLES

[0287] Example 1. Generation of Ba / F3 stable expressing cell lines. Genes encoding CD74-ROS1 wild type (wt) and CD74-ROS1 G2032R were synthesized (GeneRay), cloned into the retroviral construct pMSCV-puro (Biovector) and packaged into retroviral particles. Viruses were used to infect Ba / F3 cells (RIKEN) at a multiplicity of infection = 1 for 1 day. Infected cells were rescued for 2 days in medium (RPMI-1640 with 10% fetal bovine serum, 1% streptomycin and penicillin) supplemented with mouse IL-3 (10 ng / mL), and stable expressing cell lines were selected by IL-3 withdrawal and puromycin (0.8 μg / mL) for 7 days. Monoclones were selected by single cell dilution in IL-3-free medium containing puromycin (0.8 μg / mL). Transformation of the desired gene was confirmed by Sanger sequencing and Western blot using ROS1 antibody (CST #3287).

[0288] Cell proliferation assay. Stable expressing cells were plated at 1,000 cells / well (40 μL) in 384-well plates for one day. Test compounds (40 nL) were then added in 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 h. Plates were equilibrated at room temperature for 15 min, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0289] The results for Compound 1 and several ROS1 inhibitors are shown below. [Table 2]

[0290] Example 2. In vivo evaluation of Compound 1 Model 2A: Female Balb / c nude mice were treated with tumor sections (approximately 30 mm 3 ) was implanted subcutaneously in the right flank. Model LU-01-0414 was derived from a 51-year-old female with NSCLC and unknown smoking history. The tumor was G3 and tumor stage was T2N2M0. The tumor harbored SDC4-ROS1. In the efficacy study, tumors were 160 mm 3 After tumors had grown to a mean tumor volume of 100 μg / mL, mice (n=5-8 / group) were randomized and administered vehicle or Compound 1 by oral gavage twice daily (BID; 12 h apart) for 28 days. The results are shown in Figure 2A.

[0291] Model 2B: Female athymic nude-Foxn1 nu Mice were implanted subcutaneously in the left flank with tumor fragments from model CTG-0848. Model CTG-0848 was derived from a 41-year-old Asian male with stage II NSCLC. Tumors harbored the CD74-ROS1 fusion. Tumors were approximately 240 mm 3After growing to adulthood, mice (n=5-5 / group) were randomized and administered vehicle or Compound 1 by oral gavage twice daily (BID, 12 h apart) for 21 days (BID x 21 days). The results are shown in Figure 2B.

[0292] Model 2C: Female athymic nude-Foxn1 nu Mice were subcutaneously implanted with tumor fragments from model CTG-2532 in the left flank, which was derived from a female Asian non-smoker with stage IV NSCLC whose disease responded to TKI crizotinib and then progressed. The tumors carried CD74-ROS1 G2032R. After tumors grew to approximately 215 mm, mice (n=5 mice / group) were randomized and administered vehicle or 1, 5 or 15 mg / kg of Compound 1 by oral gavage twice daily (BID, 12 hours apart) for 21 days (BID×21 days). The results are shown in FIG. 2C.

[0293] Example 3. In vivo evaluation of Compound 1 Model 1 (LU-01-0414 PDX SDC4-ROS1): Female Balb / c nude mice were treated with tumor sections (approximately 30 mm 3 ) was implanted subcutaneously in the right flank. Model LU-01-0414 was derived from a 51-year-old female with NSCLC and unknown smoking history. The tumor was G3 and tumor stage was T2N2M0. The tumor harbored SDC4-ROS1. The tumor was 492 mm 3After growing to a mean tumor volume of 1000 mg / kg, mice received a single dose or BID x 5 days of vehicle or Compound 1, and tumors and blood were collected 1 and 12 hours (treatment only) after the final dose. Tumors were split, snap frozen, and processed for Western blot (Figure 4A and Figure 4B, described below) or fixed in formalin for 24-48 hours, followed by preparation of FFPE blocks and processing for immunohistochemistry (Figure 5A, described below) or gene expression analysis by NanoString assay (Figure 6A, described below). Blood samples were collected in tubes containing EDTA-K2, centrifuged, and the resulting plasma was analyzed by LC / MS / MS to determine the total concentration of Compound 1 in plasma. The free concentration of Compound 1 (Figure 4A) was calculated by multiplying the unbound fraction for Compound 1 in female Balb / c mouse plasma determined by equilibrium dialysis.

[0294] Model 2 (CTG-0848 PDX CD74-ROS1): Female Athymic Nude-Foxn1 nu Mice were implanted subcutaneously in the left flank with tumor fragments from model CTG-0848, derived from a 41-year-old Asian male with stage II NSCLC. Tumors harbored the CD74-ROS1 fusion. Tumors were 350-500 mm 3 After growth to maturity, mice received a single dose or BID x 5 days of vehicle or Compound 1, and tumors were harvested 1 and 12 hours (treatment only) after the final dose and processed for Western blot analysis (Figure 4C), immunohistochemistry (Figure 5B), or gene expression analysis (Figure 6B) as described for Model 1.

[0295] Model 3 (CTG-2532 PDX CD74-ROS1 G2032R): Female Athymic Nude-Foxn1 nuMice were implanted subcutaneously in the left flank with tumor fragments from model CTG-2532, derived from a female Asian non-smoker with stage IV NSCLC whose disease responded to the TKI crizotinib and then progressed. Tumors harbored CD74-ROS1 G2032R. Tumors were 350-500 mm 3 After growth to maturity, mice received vehicle or Compound 1 either single or BID x 5 days (total of 11 doses) and tumors were harvested 1 and 12 hours (treatment only) after the final dose and processed for Western blot analysis (Figure 4D), immunohistochemistry analysis (Figure 5C) or gene expression analysis (Figure 6C) as described for Model 1.

[0296] The following preparations were used to evaluate the inhibitory activity of Compound 1 on ROS1 signaling in tumors in these three models.

[0297] For Western blot analysis, flash frozen tumors were sectioned, lysed in RIPA buffer (containing protease and phosphatase inhibitor cocktail), ground and centrifuged. Supernatants were collected, proteins were quantified, and supernatant samples of similar concentration were separated by electrophoresis and transferred to nitrocellulose membranes. Membranes were cut, blotted, treated with HRP substrate, and chemiluminescence was detected by Amersham Imager 680. Intensity of individual bands was quantified using 1D quant (GE) densitometry software. The following antibodies were used: phospho-ROS1 (Tyr2274), Cell Signaling Technology (CST) 3078; ROS1 (D4D6) CST 3287; phospho-AKT (Ser473) (D9E), CST 4060; AKT, CST 9272; phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204), CST 9101; p44 / 42 MAPK (Erk1 / 2), CST 9102; β2 microglobulin (β2m), CST 12851; GAPDH (D4C6R), CST 97166; goat anti-rabbit IgG H&L (HRP), Abcam ab6721; and goat anti-mouse IgG H&L (HRP), Abcam ab97023.

[0298] For immunohistochemistry analysis, FFPE blocks were sectioned, stained automatically on a Leica Bond RX system, and imaged on a Leica Aperio Versa8. Tumor areas were manually selected in HALO (Indica Labs) and the percentage of positive cells was automatically recorded. The following antibodies were used: ROS1, CST 63452; rabbit IgG, Abcam 172730; ERK, CST 4695; phospho-ERK, CST 4376; and Ki-67, CST 9027.

[0299] For gene expression analysis by NanoString assay, RNA was extracted from FFPE sections by RNAstorm FFPE RNA Extraction Kit, quantified by NanoDrop, Qubit and Agilent BioAnalyzer 2100, and analyzed by NanoString nCounter PanCancer Human Pathways Panel according to the manufacturer's instructions. NanoString data was analyzed by Excel and packages from R / Biocondutor, including experimental quality control, background correlation and linearity by negative and positive spike-ins, normalization based on housekeeping genes by the Median of Ratio method, and differential gene expression analysis by Walt test, and p-values ​​were corrected for multiple testing by the Benjamini-Hochberg method.

[0300] Example 4: Phase 1 / 2 Clinical Study An FIH Phase 1 / 2 multicenter, open-label, dose escalation and expansion study will be conducted to evaluate the safety and tolerability of Compound 1, determine the RP2D, and evaluate antitumor activity in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors.

[0301] Phase 1 objectives:

[0302] Primary objective: To determine the RP2D and / or maximum tolerated dose (MTD) of compound 1 in patients with advanced ROS1-positive solid tumors.

[0303] Secondary objectives: to assess the overall safety and tolerability of Compound 1; to characterize the PK profile of Compound 1; to evaluate the preliminary antitumor activity of Compound 1 in patients with advanced ROS1-positive solid tumors.

[0304] Phase 2 objectives:

[0305] Primary objective: To evaluate the ORR of compound 1 at RP2D in patients with advanced ROS1-positive NSCLC and other solid tumors.

[0306] Secondary objectives: to evaluate additional measures of clinical efficacy in patients with ROS1-positive NSCLC and other solid tumors; to evaluate the intracranial antitumor activity of Compound 1 at the RP2D in patients with advanced ROS1-positive NSCLC and other solid tumors; to characterize the safety and tolerability of Compound 1 at the RP2D; to determine the PK profile of Compound 1 at the RP2D.

[0307] Phase 1 Endpoints:

[0308] Primary endpoint: incidence of dose-limiting toxicities (DLTs) during cycle 1

[0309] Secondary Endpoints: Incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters Pharmacokinetic parameters of compound 1: Maximum plasma concentration (C max );C max - Dose normalization; plasma concentration at the end of the dosing interval (C tau ); Time of maximum concentration (T max ); area under the curve at the end of the dosing interval (AUC tau );AUC tau - Dose normalized; area under the curve (AUC 0~24 );AUC 0~24 - Dose normalized; area under the curve from time 0 to infinity (AUC inf );AUC inf -Dose normalized; oral clearance (CL / F); volume of distribution (V z / F); and half-life (t 1 / 2 ) Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - defined as the percentage of patients with a complete response (CR) or partial response (PR) according to RECIST 1.1 Duration of response (DOR) by RECIST 1.1 - defined as the time from first response by RECIST 1.1 to radiographic disease progression or death in responders - Intracranial ORR (IC-ORR) by RECIST 1.1 - In patients with measurable metastatic CNS disease, up to five intracranial target lesions will be assessed for response per RECIST 1.1 Intracranial DOR by RECIST 1.1 (IC-DOR) - defined as the time from first IC response by RECIST 1.1 to radiographic IC disease progression or death in responders with metastatic CNS disease Clinical benefit rate (CBR) by RECIST 1.1 - defined as the percentage of patients with confirmed CR or PR or stable disease (SD) lasting at least 24 weeks according to RECIST 1.1 Time to response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic response per RECIST 1.1 Progression-free survival (PFS) by RECIST 1.1 - defined as the time from first dose to radiographic disease progression by RECIST 1.1 or death

[0310] Exploratory Endpoints: Pharmacodynamic markers associated with efficacy of Compound 1 Extracranial ORR (EC-ORR) by RECIST 1.1 In patients with extracranial metastatic disease, defined as the percentage of patients with extracranial response per investigator-assessed RECIST 1.1 Evaluate the metabolic profile of compound 1

[0311] Phase 2 Endpoints:

[0312] Primary Endpoint: ORR by RECIST 1.1 - defined as the proportion of patients with confirmed CR or PR according to RECIST 1.1 by BICR among patients with measurable disease at baseline by Blinded Independent Central Review (BICR).

[0313] Secondary Endpoints - DOR-responders by RECIST 1.1, defined as the time from first confirmed BICR response by RECIST 1.1 to radiographic disease progression or death - IC-ORR by RECIST 1.1 - In patients with measurable metastatic CNS disease, up to five intracranial target lesions will be assessed for response according to RECIST 1.1 by BICR in patients with confirmed measurable intracranial disease at baseline by BICR IC-DOR by RECIST 1.1 – defined as the time from first BICR-assessed confirmed response by RECIST 1.1 to radiographic disease progression or death in responders with metastatic CNS disease. -CBR-BICR by RECIST 1.1 -Defined as the percentage of patients with confirmed CR or PR or SD according to RECIST 1.1 lasting at least 24 weeks Time to response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic response according to RECIST 1.1 by BICR Time to IC response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic IC response per RECIST 1.1 by BICR in patients with metastatic CNS disease Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters Pharmacokinetic parameters of compound 1-C max , C max -Dose normalization, C tau , T max , AUCtau , AUC tau -Dose normalization, AUC 0~24 , AUC 0~24 -Dose normalization, AUC inf , AUC inf -Dose normalization, CL / F, V z / F,t 1 / 2 PFS by RECIST 1.1 - defined as the time from first dose to radiographic disease progression or death by RECIST 1.1 based on BICR assessment Intracranial PFS by RECIST 1.1 (IC-PFS) - defined as the time from first dose to radiographic disease progression or death by RECIST 1.1 based on BICR assessment in patients with metastatic CNS disease Overall Survival (OS) – defined as the time from first dose to death from any cause

[0314] Study Design: The study will be conducted in two phases (Figure 1). ● Phase 1 will use a Bayesian Optimal Interval Design (BOIN) with dose escalation with a 3+3 lead-in period. Patients with advanced / metastatic ROS1-positive solid tumors treated with at least one prior ROS1 TKI therapy. ●Phase 2 includes five cohorts. Cohort 2a: Patients with advanced / metastatic ROS1-positive NSCLC naïve with TKI therapy. Up to one prior platinum-based chemotherapy with or without immunotherapy is allowed. Cohort 2b: Patients with advanced / metastatic ROS1-positive NSCLC who have been treated with one prior ROS1 TKI (either crizotinib or entrectinib) and are not amenable to prior platinum-based chemotherapy or immunotherapy. Cohort 2c: Patients with advanced / metastatic ROS1-positive NSCLC who had been treated with one prior ROS1 TKI (either crizotinib or entrectinib) and one prior platinum-based chemotherapy with or without immunotherapy. Cohort 2d: Patients with advanced / metastatic ROS1-positive NSCLC who had been treated with two or more prior ROS1 TKIs and up to one prior platinum-based chemotherapy with or without immunotherapy. Cohort 2e (exploratory): Patients with any advanced / metastatic ROS1-positive solid tumor (including patients with ROS1-positive NSCLC who are otherwise ineligible for any other cohort) who have progressed on any prior therapy (including but not limited to patients who have progressed on a prior ROS1 TKI).

[0315] The Phase 1 portion of the study will evaluate dose escalation using a BOIN design with a 3+3 lead-in period. The primary objective of the Phase 1 portion of the study is to determine the RP2D and evaluate the safety of Compound 1 in patients with solid tumors. The safety profile will be assessed based on physical examination; ECOG PS; changes from baseline in laboratory parameters, ECG, vital signs, and ophthalmologic examination (baseline only and if clinically indicated); and reporting of AEs. The DLT observation period is defined as the first dose on Day 1 of Cycle 1 (C1D1) to the end of the first cycle (28-day cycle duration).

[0316] After patients have been treated at a given dose level and monitored for 28 days, all available safety data will be reviewed. Initiation of the next dose arm will depend on the outcome of the BOIN analysis.

[0317] The selection of the RP2D will occur after a sufficient number of patients have been enrolled, completed the first imaging / efficacy assessments, and the data have been reviewed.

[0318] Phase 1 Dose Levels: Phase 1 will evaluate escalating doses of Compound 1 monotherapy administered orally once daily (QD) continuously until disease progression, unacceptable toxicity, or voluntary withdrawal of consent. Each treatment cycle will be 28 days. Under the BOIN design, up to approximately 53 patients will be enrolled and treated at the dose levels presented in the table below. [Table 3]

[0319] Intermediate dose levels may be explored during dose escalation; lower dose levels (e.g., 10 mg QD and 5 mg QD) may be explored as additional dose levels based on the results of BOIN.

[0320] Recommended Phase 2 Dose: The recommended phase 2 dose (RP2D) is the dose level that is expected to be the MTD or lower optimal biological dose, or maximum feasible dose, and is considered suitable for testing in the phase 2 portion of the study. The RP2D is expected to achieve sufficient target coverage of the G2032R ROS1 mutation in the periphery and CNS based on PK modeling simulations; the RP2D also demonstrates preliminary antitumor activity along with a tolerable safety profile. The selection of the RP2D was made using the totality of data obtained from phase 1, including evaluation of clinical PK, pharmacodynamics, safety, and antitumor activity.

[0321] Duration of Treatment: Across both phases, patients will receive study drug continuously from the first dose until independent radiological confirmation of disease progression, unacceptable toxicity, patient withdrawal, study termination, or commercial availability. Patients may continue to receive Compound 1 following progression in the body or brain suitable for local ablation.

[0322] Definition of End of Study: End of study is defined as the date of the last visit of the last patient in the study or the end date of the study.

[0323] Participation Criteria: Patients must meet all of the following criteria to be eligible for enrollment in the study. 1. Age 18 years or older. (Phase 2 cohort 2e only: age 12 years or older and weight >40 kg.) 2. Disease Criteria a. Phase 1: Histologically or cytologically confirmed metastatic solid tumors with documented ROS1 rearrangements as determined by testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the United States or a comparably accredited diagnostic laboratory outside the United States (US) using a local diagnostic test or a commercially available test, or by regulatory agency approved fluorescent in situ hybridization (FISH) or next generation sequencing (NGS) or reverse transcription polymerase chain reaction (RT-PCR). b. Cohorts 2a, 2b, 2c, and 2d: Histologically or cytologically confirmed metastatic NSCLC with ROS1 rearrangements as determined by testing in a CLIA or equivalent certified diagnostic laboratory using a local diagnostic test or a commercially available test, or by regulatory agency approved FISH or NGS or RT-PCR. c. Cohort 2e: Histologically or cytologically confirmed metastatic solid tumors (other than NSCLC) with ROS1 rearrangements as determined by testing in a CLIA or equivalent certified diagnostic laboratory using a local diagnostic test or a commercially available test, or by regulatory agency approved FISH or NGS or RT-PCR. 3. Previous anti-cancer treatment a. Phase 1: Patients must have received at least one prior ROS1 TKI therapy; any number of prior platinum-based chemotherapy with or without immunotherapy is permitted. b. Cohort 2a: Must be treatment-naive with TKI therapy and up to one prior platinum-based chemotherapy (with or without immunotherapy). c. Cohort 2b: Must have received one prior ROS1 TKI therapy (either crizotinib or entrectinib) and must not have received any prior platinum-based chemotherapy or immunotherapy. d. Cohort 2c: Must have received one prior ROS1 TKI therapy (either crizotinib or entrectinib) and one prior platinum-based chemotherapy (with or without immunotherapy). e. Cohort 2d: Must have received at least two prior ROS1 TKI therapies and up to one prior platinum-based chemotherapy (with or without immunotherapy). f. Cohort 2e: Must have progressed on any prior therapy (including but not limited to patients who have progressed on a prior ROS1 TKI). 4. Phase 1: Must have evaluable disease (target or non-target) according to RECIST 1.1. Phase 2: Must have measurable disease defined as one or more radiologically measurable target lesions according to RECIST 1.1 (Oken et al., Am. J. Clin. Oncol. 1982, 5(6):649-655). In all study parts, patients are eligible if they have asymptomatic CNS-only measurable disease of 10 mm or greater as defined by RECIST 1.1. 5. Patient agrees to provide tumor tissue (archived or fresh biopsy, if applicable) for confirmation of ROS1 status and is willing to consider intra-treatment tumor biopsy if deemed safe and medically feasible. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 (Eisenhauer et al., Eur. J. Cancer 2009, 45(2):228-247). 7. Adequate organ function and bone marrow reserve as demonstrated by the following laboratory evaluations performed prior to the first dose of study drug: Bone marrow function: absolute neutrophil count (ANC) ≥ 1500 / μL; platelet count > 75,000 / μL; hemoglobin ≥ 8 g / dL. b. Renal function: Estimated creatinine clearance of 60 mL / min or more by Cockroft-Gault formula. c. Liver function: Bilirubin less than 1.5 x ULN unless there is evidence of Gilbert's syndrome in which patients should have total bilirubin less than 3.0 mg / dL; aspartate aminotransferase and alanine aminotransferase less than 3.0 x ULN (less than 5.0 x ULN if liver metastases are present). 8. All clinically relevant toxicities associated with prior anticancer therapy must be ≤ Grade 1 or have resolved to baseline (except for alopecia or ototoxicity). 9. Women of childbearing potential (WOCBP) and male patients must be willing to abstain from sexual activity, use effective contraception, or be surgically sterilized from the time they sign the Informed Consent Form (ICF), for the duration of the study, and for 30 days for women and 90 days for men after the last dose of study drug. Effective contraception for WOCBP includes one "highly effective" method or two "effective" methods based on World Health Organization (WHO) criteria. 10. Willing and able to provide written informed consent and comply with the requirements of the study protocol. For patients under 18 years of age (Phase 2 Cohort 2e only), assent must be obtained and a parent / guardian must provide written consent.

[0324] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. 1. The patient's cancer has a known primary driver alteration other than ROS1, e.g., NSCLC with targetable mutations in EGFR, ALK, MET, RET or BRAF; colorectal with oncogenic KRAS, NRAS or BRAF mutations. 2. Known allergy / hypersensitivity to any of the Compound 1 excipients. 3. Major surgery within 4 weeks of study entry. Minor surgical procedures (e.g., port insertion) will be permitted, but with sufficient time for wound healing as deemed clinically appropriate. 4. Ongoing or recent anticancer therapy within the following time frames prior to the first dose of study drug (Compound 1 may be initiated within the limits for prior TKI or chemotherapy if deemed safe and in the patient's best interest and with prior approval): a. TKIs or other non-chemotherapy / non-immunotherapy anticancer drugs with less than 5 half-lives or less than 7 days, whichever is longer. b. Chemotherapy for less than 21 days c. Immunotherapy or cell therapy for less than 28 days 5. Ongoing or recent radiation therapy within the following time frames prior to the first dose of study drug: Radiation therapy for less than 14 days (excluding palliative radiation to relieve bone pain) b. Palliative radiation to relieve bone pain for less than 48 hours c. Stereotactic or small-field brain irradiation for less than 7 days d. Whole brain radiation for less than 14 days 6. Previous high-dose chemotherapy requiring stem cell rescue. 7. Uncontrolled clinically relevant bacterial or fungal infection requiring systemic therapy. 8. Have known active tuberculosis or active hepatitis B or C. Active hepatitis B is defined by a known positive HBsAg result. Active hepatitis C is defined by a known positive hepatitis C Ab result and a known quantitative HCV RNA result above the lower limit of detection of the assay. 9. The patient has a consistent QTcF of >450 ms. The patient has a history of Long QT Syndrome or Torsades de Pointes. 10. Patients with clinically significant cardiovascular disease, including: Within 3 months of enrollment: cerebrovascular accident / stroke; myocardial infarction; unstable angina; uncontrolled atrial fibrillation of any grade b. History of congestive heart failure (New York Heart Association Classification Class II or greater); second- or third-degree AV block (unless paced), or any AV block with a consistent PR of >220 ms; or ongoing arrhythmia of NCI-CTCAE Grade 2 or greater. 11. The patient has a primary central nervous system (CNS) tumor associated with CNS metastases or progressive neurological symptoms, or requires an increased dose of corticosteroids to control CNS disease. If the patient requires corticosteroids for management of CNS disease, the dose must be stable for 2 weeks prior to C1D1. 12. Symptomatic spinal cord compression. 13. Patients with moderate to severe cognitive or psychiatric impairment that impairs the patient's ability to comply with study requirements. 14. Evidence of active malignancy (other than a current ROS1-positive solid malignancy) within the past 2 years requiring systemic therapy. Exceptions: nonmelanoma skin cancer, melanoma in situ, cervical cancer in situ, papillary thyroid cancer, intraductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer. Patients on long-term antihormonal therapy for a previous malignancy are permitted as long as the malignancy has not been active within the past 2 years. 15. Concurrent use of a strong CYP3A4 inducer or a strong CYP3A4 inhibitor (within 12 days of enrollment). 16. Evidence of malabsorption due to previous gastrointestinal surgery, disease or other illnesses that may affect the oral absorption, distribution, metabolism or excretion of the study drug. 17. The patient is pregnant or breastfeeding. WOCBP must have a negative serum pregnancy test at screening and a negative urine test prior to the first dose of study drug. 18. Actively receiving systemic treatment or direct medical intervention in another therapeutic clinical study. 19. Any medical condition or laboratory abnormality that poses risk to the study patient or confounds the ability to interpret the study results.

[0325] Study Drug, Dose and Route of Administration: Compound 1 is supplied as tablets for oral administration in two strengths, 5 mg and 25 mg, and the tablets are provided in 32-count high-density polyethylene bottles with induction seal / child-resistant cap oral administration. Compound 1 should be taken on an empty stomach, at least 1 hour before and not less than 2 hours after ingestion of food and / or beverages other than water.

[0326] Previous and Concomitant Medications and Therapies:

[0327] Compound 1 was not considered a substrate for CYP2B6, CYP2C9, CYP2C19, or CYP2D6. Compound 1 is a substrate for CYP3A4 with potential for contributions from CYP1A2 and CYP2C8.

[0328] Compound 1 is an inhibitor of CYP1A2, CYP2B6, or CYP2D6 (IC >100 μM). 50 ) and CYP2C8 (IC 50 = 70 μM), CYP2C9 (IC 50 =70.3μM), CYP3A4 (testosterone IC 50 = 62.7 μM), CYP2C19 (IC 50 = 38.4 μM) and CYP3A4 (midazolam IC 50 Compound 1 was a weak inhibitor of CYP3A4 (testosterone) and CYP3A4 (midazolam). Compound 1 was a potent inducer of CYP3A4.

[0329] In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is prohibited. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is permitted. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is used with caution.

[0330] In certain embodiments, the concomitant use (within 12 days of registration) of a drug that is a substrate or inducer of CYP3A4, an inhibitor of CYP3A4 or CYP2C8, a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or MATE1 transporter, or a substrate of CYP2C19 with a narrow therapeutic index is used with caution. In certain embodiments, the concomitant use (within 12 days of registration) or coadministration of Compound 1 with any one or more drugs that are substrates or inducers of CYP3A4, inhibitors of CYP3A4 or CYP2C8, substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or MATE1 transporter, or a substrate of CYP2C19 with a narrow therapeutic index is permitted. In certain embodiments, concurrent use (within 12 days of enrollment) or coadministration of drugs that are substrates or inducers of CYP3A4, inhibitors of CYP3A4 or CYP2C8, substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or the MATE1 transporter, or substrates of CYP2C19 with narrow therapeutic indexes is prohibited.

[0331] In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be avoided. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be used with caution. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 is permitted.

[0332] Exemplary agents provided herein include, but are not limited to, the following: ●CYP3A4 inducers: phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort CYP3A4 inhibitors: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, grapefruit (including juice) - CYP3A4 substrates (sensitive): buspirone, everolimus, lovastatin, midazolam, simvastatin, triazolam, maraviroc, conivaptan, darifenacin P-gp substrates: digoxin, fexofenadine, loperamide, quinidine, talinolol, vinblastine ●BCRP substrates: daidzein, dantrolene, estrone-3-sulfate, prazosin, sulfasalazine MATE1 substrates: metformin, tetraethylammonium (TEA), cimetidine, procainamide

[0333] Example 5: Phase 1 / 2 Clinical Study An FIH Phase 1 / 2 multicenter, open-label, dose escalation and expansion study will be conducted to evaluate the safety and tolerability of Compound 1, determine the RP2D, and, if applicable, the MTD, and evaluate antitumor activity in patients with advanced ROS1-positive NSCLC and other advanced ROS1-positive solid tumors.

[0334] Phase 1 objectives:

[0335] Primary objective: To determine the RP2D and / or maximum tolerated dose (MTD) of compound 1 in patients with advanced ROS1-positive solid tumors.

[0336] Secondary objectives: to assess the overall safety and tolerability of Compound 1; to characterize the PK profile of Compound 1; to evaluate the preliminary antitumor activity of Compound 1 in patients with advanced ROS1-positive solid tumors.

[0337] Phase 2 objectives:

[0338] Primary objective: To evaluate the ORR of compound 1 at RP2D in patients with advanced ROS1-positive NSCLC and other solid tumors.

[0339] Secondary objectives: to evaluate additional measures of clinical efficacy in patients with ROS1-positive NSCLC and other solid tumors; to evaluate the intracranial antitumor activity of Compound 1 at the RP2D in patients with advanced ROS1-positive NSCLC and other solid tumors; to characterize the safety and tolerability of Compound 1 at the RP2D; to determine the PK profile of Compound 1 at the RP2D.

[0340] Phase 1 Endpoints:

[0341] Primary endpoints: incidence of DLTs during cycle 1, overall safety profile, RP2D determined by PK, PD and preliminary efficacy, and MTD, if applicable.

[0342] Secondary Endpoints: Incidence and severity of treatment-emergent adverse events (TEAEs) and changes in clinically relevant laboratory parameters Pharmacokinetic parameters of compound 1: Maximum plasma concentration (C max );C max_DN (C max -dose normalized), plasma concentration at the end of the dosing interval (C tau ); Time of maximum concentration (T max ); area under the curve at the end of the dosing interval (AUCtau );AUC tau_DN (AUC tau -dose normalized), area under the curve (AUC 0~24 );AUC 0~24_DN (AUC 0~24 -dose normalized), area under the curve from time 0 to infinity (AUC inf );AUC inf_DN (AUC inf -dose normalized; oral clearance (CL / F); volume of distribution (V z / F); and half-life (t 1 / 2 ) Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - defined as the percentage of patients with a complete response (CR) or partial response (PR) according to RECIST 1.1 Duration of response (DOR) by RECIST 1.1 - defined as the time from first response by RECIST 1.1 to radiographic disease progression or death in responders Intracranial ORR by RECIST 1.1 (IC-ORR) - defined as the proportion of patients with measurable metastatic CNS disease at baseline who have a confirmed intracranial response (IC-CR or IC-PR) based on the assessment of up to five intracranial target lesions according to RECIST 1.1 principles by investigator assessment Intracranial DOR by RECIST 1.1 (IC-DOR) - in patients with an intracranial response, defined as the time from first investigator-assessed IC response by RECIST 1.1 principles to radiographic IC disease progression or death Clinical benefit rate (CBR) by RECIST 1.1 - defined as the percentage of patients with confirmed CR or PR or stable disease (SD) lasting at least 24 weeks according to RECIST 1.1 Time to response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic response per RECIST 1.1 Progression-free survival (PFS) by RECIST 1.1 - defined as the time from first dose to radiographic disease progression by RECIST 1.1 or death

[0343] Exploratory Endpoints: Pharmacodynamic markers associated with efficacy of Compound 1 Extracranial ORR (EC-ORR) by RECIST 1.1 In patients with extracranial metastatic disease, defined as the percentage of patients with extracranial response per investigator-assessed RECIST 1.1 Evaluate the metabolic profile of compound 1

[0344] Phase 2 Endpoints:

[0345] Primary Endpoint: ORR by RECIST 1.1 - defined as the proportion of patients with confirmed CR or PR according to RECIST 1.1 by BICR among patients with measurable disease at baseline by Blinded Independent Central Review (BICR).

[0346] Secondary Endpoints - DOR-responders by RECIST 1.1, defined as the time from first confirmed BICR response by RECIST 1.1 to radiographic disease progression or death IC-ORR by RECIST 1.1 - defined as the proportion of patients with measurable metastatic CNS disease at baseline who have a confirmed intracranial response (IC-CR or IC-PR) based on assessment of up to five intracranial target lesions according to RECIST 1.1 principles by BICR In patients with an intracranial IC-DOR by RECIST 1.1 - defined as the time from first BICR-assessed confirmed IC response by RECIST 1.1 principles to radiographic IC disease progression or death -CBR-BICR by RECIST 1.1, defined as the percentage of patients with confirmed CR or PR or SD lasting at least 24 weeks according to RECIST 1.1 Time to response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic IC response according to RECIST 1.1 principles by BICR in patients with measurable metastatic CNS disease Time to IC response by RECIST 1.1 - defined as the time from first dose to first confirmed radiographic IC response per RECIST 1.1 by BICR in patients with metastatic CNS disease Incidence and severity of TEAEs and changes in clinically relevant laboratory parameters Pharmacokinetic parameters of compound 1-C max , C max_DN (C max dose normalization), C tau , T max , AUC tau , AUC tau_DN (AUC tau -dose normalized), AUC 0~24 , AUC 0~24_CN (AUC 0~24 dose normalized), AUC inf , AUC inf_DN (AUC inf -dose normalization), CL / F, V z / F,t 1 / 2 PFS by RECIST 1.1 - defined as the time from first dose to radiographic disease progression or death by RECIST 1.1 based on BICR assessment Intracranial PFS by RECIST 1.1 (IC-PFS) - defined as the time from first dose to radiographic disease progression or death by RECIST 1.1 principles based on BICR assessment in patients with measurable metastatic CNS disease Overall Survival (OS) – defined as the time from first dose to death from any cause

[0347] Study Design: The study will be conducted in two phases (except for Figure 1, n=54 for Phase 1). ● Phase 1 will use a Bayesian Optimal Interval Design (BOIN) with dose escalation with a 3+3 lead-in period.Patients with advanced / metastatic ROS1-positive NSCLC treated with at least one prior ROS1 TKI therapy, or patients with other ROS1-positive solid tumors who have progressed on any prior therapy (including but not limited to patients who have progressed on a prior ROS1 TKI). ●Phase 2 includes five cohorts. Cohort 2a: Patients with advanced / metastatic ROS1-positive NSCLC naïve with TKI therapy. Up to one prior platinum-based chemotherapy with or without immunotherapy is allowed. Cohort 2b: Patients with advanced / metastatic ROS1-positive NSCLC who have been treated with one prior ROS1 TKI (either crizotinib or entrectinib) and are not amenable to prior platinum-based chemotherapy or immunotherapy. Cohort 2c: Patients with advanced / metastatic ROS1-positive NSCLC who had been treated with one prior ROS1 TKI (either crizotinib or entrectinib) and one prior platinum-based chemotherapy with or without immunotherapy. Cohort 2d: Patients with advanced / metastatic ROS1-positive NSCLC who had been treated with two or more prior ROS1 TKIs and up to one prior platinum-based chemotherapy with or without immunotherapy. Cohort 2e (exploratory): Patients with any advanced / metastatic ROS1-positive solid tumor (including patients with ROS1-positive NSCLC who are otherwise ineligible for any other cohort) who have progressed on any prior therapy (including but not limited to patients who have progressed on a prior ROS1 TKI).

[0348] The Phase 1 portion of the study will evaluate dose escalation using a BOIN design with a 3+3 lead-in period. The primary objectives of the Phase 1 portion of the study are to determine the RP2D, if applicable, the MTD, and evaluate the safety of Compound 1 in patients with solid tumors. The safety profile will be assessed based on physical examination; ECOG PS; changes from baseline in laboratory parameters, ECG, vital signs, and ophthalmologic examination (baseline only and if clinically indicated); and reporting of AEs. The DLT observation period is defined as the first dose on Day 1 of Cycle 1 (C1D1) to the end of the first cycle (28-day cycle duration).

[0349] After patients are treated at a given dose level and monitored for 28 days, available safety data (including but not limited to incidence of DLTs / other AEs and preliminary PK) are reviewed. Initiation of the next dose arm will depend on the occurrence of DLTs and the outcome of the BOIN analysis, taking into account the overall safety profile. During dose escalation, when available data support the safety, PK, and clinical activity of a given dose level, additional patients (up to a total of 12 patients, including those already included in the BOIN dose escalation) may be enrolled at this dose level.

[0350] The BOIN dose escalation is declared complete when the number of evaluable patients treated at the current dose reaches 9 and a decision is made to remain at the current dose, or when the maximum sample size is reached. However, if the optimal biological dose or maximum feasible dose is reached prior to the completion of the BOIN dose escalation, the RP2D may be declared. The selection of the RP2D occurs after a sufficient number of patients have been enrolled and completed the first imaging / efficacy assessments and the data have been reviewed.

[0351] To further evaluate safety and efficacy, and to confirm the RP2D, up to 20 additional patients may be treated with the RP2D or one or more candidate RP2Ds prior to the start of the Phase 2 portion of the study.

[0352] Phase 1 Dose Levels: Phase 1 will evaluate escalating doses of Compound 1 monotherapy administered orally once daily (QD) continuously until disease progression, unacceptable toxicity, or voluntary withdrawal of consent. Each treatment cycle will be 28 days. Under the BOIN design, up to approximately 53 patients will be enrolled and treated at the dose levels presented in the table below. [Table 4]

[0353] Intermediate dose levels may be explored during dose escalation; lower dose levels (e.g., 10 mg QD and 5 mg QD) may be explored as additional dose levels based on the results of BOIN. For example, the following dose reduction levels are provided herein: [Table 5]

[0354] Recommended Phase 2 Dose: The recommended phase 2 dose (RP2D) is the dose level that is expected to be the MTD or lower optimal biological dose, or maximum feasible dose, and is considered suitable for testing in the phase 2 portion of the study. The RP2D is expected to achieve sufficient target coverage of the G2032R ROS1 mutation in the periphery and CNS based on PK modeling simulations; the RP2D also demonstrates preliminary antitumor activity along with a tolerable safety profile. The selection of the RP2D was made using the totality of data obtained from phase 1, including evaluation of clinical PK, pharmacodynamics, safety, and antitumor activity.

[0355] Duration of treatment: Across both phases, patients will receive study drug continuously from the first dose until disease progression, unacceptable toxicity, patient withdrawal, end study or commercial availability. Patients may continue to receive Compound 1 following progression in the body or brain suitable for local ablation.

[0356] Definition of End of Study: End of study is defined as the date of the last visit of the last patient in the study or the end date of the study.

[0357] Participation Criteria: Patients must meet all of the following criteria to be eligible for enrollment in the study. 1. Age 18 or older. Phase 2 Cohort 2e only: Age 12 years or older and weight >40 kg. (Patients aged 12-17 years will be enrolled only in countries and centers where regulations permit.) 2. Disease Criteria a. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumors with a documented ROS1 rearrangement as determined by testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the United States or a comparably accredited diagnostic laboratory outside the United States (US) using a local diagnostic test or a commercially available test, or by a regulatory agency approved test, such as fluorescent in situ hybridization (FISH) or next generation sequencing (NGS) or reverse transcription polymerase chain reaction (RT-PCR). b. Cohorts 2a, 2b, 2c, and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement as determined by testing in a CLIA or equivalent certified diagnostic laboratory using a local diagnostic test or a commercially available test, or by a regulatory agency approved test, e.g., FISH or NGS or RT-PCR. c. Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumors with ROS1 rearrangements as determined by testing in a CLIA or equivalent certified diagnostic laboratory using a local diagnostic test or a commercially available test, or by a regulatory agency approved test, e.g., FISH or NGS or RT-PCR (including NSCLC not eligible for Cohorts 2a-2d). 3. Previous anti-cancer treatment a. Phase 1: Patients with ROS1 fusion-positive NSCLC must have previously received at least one prior ROS1 TKI, and patients with other ROS1-positive solid tumors must have progressed on any prior therapy (including but not limited to patients who have progressed on a prior ROS1 TKI); any number of prior platinum-based chemotherapy with or without immunotherapy is permitted. b. Cohort 2a: Must be treatment-naive with TKI therapy and up to one prior platinum-based chemotherapy (with or without immunotherapy). c. Cohort 2b: Must have received one prior ROS1 TKI therapy (either crizotinib or entrectinib) and must not have received any prior platinum-based chemotherapy or immunotherapy. d. Cohort 2c: Must have received one prior ROS1 TKI therapy (either crizotinib or entrectinib) and one prior platinum-based chemotherapy (with or without immunotherapy). e. Cohort 2d: Must have received at least two prior ROS1 TKI therapies and up to one prior platinum-based chemotherapy (with or without immunotherapy). f. Cohort 2e: Must have progressed on any prior therapy (including but not limited to patients who have progressed on a prior ROS1 TKI). 4. Phase 1: Must have evaluable disease (target or non-target) according to RECIST 1.1. Phase 2: Must have measurable disease defined as one or more radiologically measurable target lesions according to RECIST 1.1 (Eisenhauer et al., Eur. J. Cancer 2009, 45(2):228-247). Patients with CNS-only disease are eligible, provided that their disease is evaluable (phase 1) or measurable (phase 2) and does not meet exclusion criterion #11. 5. Patients agree to provide tumor tissue (archived or fresh biopsy, if applicable) for central analysis. Submitted tumor tissue is preferably obtained during or after the most recent disease progression. If suitable tissue is not available and a biopsy is not considered safe and medically feasible, patients may be approved for enrollment after consultation with medical monitors. 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2 (Oken et al., Am. J. Clin. Oncol. 1982,5(6):649-655). 7. Adequate organ function and bone marrow reserve as demonstrated by the following laboratory values ​​at the last evaluation prior to the first dose of study drug: Bone marrow function: absolute neutrophil count (ANC) ≥ 1500 / μL; platelet count > 75,000 / μL; hemoglobin ≥ 8 g / dL (without transfusions). b. Renal function: Estimated creatinine clearance of 60 mL / min or greater by Cockroft-Gault or modified Cockroft-Gault formula, or 24-hour creatinine clearance. c. Liver function: Bilirubin less than 1.5 x ULN unless there is evidence of Gilbert's syndrome in which patients should have total bilirubin less than 3.0 mg / dL; aspartate aminotransferase and alanine aminotransferase less than 3.0 x ULN (less than 5.0 x ULN if liver metastases are present). 8. All clinically relevant toxicities associated with prior anticancer therapy must be ≤ Grade 1 or have resolved to baseline (except for alopecia or ototoxicity). 9. Women of childbearing potential (WOCBP) and male patients must be surgically sterilized or willing to abstain from sexual activity or use effective contraception from the time they sign the Informed Consent Form (ICF) and for at least 30 days after the last dose of study drug for women and at least 90 days after the last dose of study drug for men (or for such longer period as may be required by law or regulation). Effective contraception for WOCBP includes one "highly effective" method or two "effective" methods based on World Health Organization (WHO) criteria. 10. Willing and able to provide written informed consent and comply with the requirements of the study protocol. For patients under 18 years of age (or for minors below the age of consent as defined by local regulations), assent must be obtained and a parent / guardian must provide written consent.

[0358] Exclusion Criteria: Patients who meet any of the following criteria will be excluded from the study. 1. The patient's cancer has a known oncogenic driver alteration other than ROS1, e.g., NSCLC with targetable mutations in EGFR, ALK, MET, RET or BRAF; colorectal with oncogenic KRAS, NRAS or BRAF mutations. 2. Known allergy / hypersensitivity to any of the Compound 1 excipients. 3. Major surgery within 4 weeks of the first dose of study drug. Minor surgical procedures (e.g., port insertion) are permitted, but with sufficient time for wound healing as deemed clinically appropriate. 4. Ongoing or recent anticancer therapy within the following time frames prior to the first dose of study drug (Compound 1 may be initiated within the limits for prior TKI or chemotherapy if deemed safe and in the patient's best interest and with prior approval): a. TKIs or other anticancer drugs (excluding chemotherapy, immunotherapy or cell therapy for which guidance is provided below) that are less than 5 half-lives or less than 7 days, whichever is longer b. Chemotherapy for less than 21 days c. Immunotherapy or cell therapy for less than 28 days 5. Ongoing or recent radiation therapy within the following time frames prior to the first dose of study drug: Radiation therapy for less than 14 days (excluding palliative radiation to relieve bone pain) b. Palliative radiation to relieve bone pain for less than 48 hours c. Stereotactic or small-field brain irradiation for less than 7 days d. Whole brain radiation for less than 14 days 6. Previous high-dose chemotherapy requiring stem cell rescue. 7. Uncontrolled clinically relevant bacterial or fungal infection requiring systemic therapy. 8. Have known active tuberculosis or active hepatitis B or C. Active hepatitis B is defined by a known positive HBsAg result and a known quantitative HBV DNA result above the lower limit of detection of the assay. Active hepatitis C is defined by a known positive hepatitis C Ab result and a known quantitative HCV RNA result above the lower limit of detection of the assay. 9. The patient has a QTcF of >450 ms (repeatedly demonstrated in 2 or more assessments). The patient has a history of long QT syndrome or torsades de pointes. 10. Patients with clinically significant cardiovascular disease, including: Within 3 months of enrollment: cerebrovascular accident / stroke; myocardial infarction; unstable angina; uncontrolled atrial fibrillation of any grade b. History of congestive heart failure (New York Heart Association Classification Class II or greater); second- or third-degree AV block (unless paced), or any AV block with a consistent PR of >220 ms; or ongoing arrhythmia of NCI-CTCAE Grade 2 or greater. 11. Patients have primary central nervous system (CNS) tumors associated with CNS metastases or progressive neurological symptoms, or require increased doses of corticosteroids to control CNS disease. If patients require corticosteroids for management of CNS disease, the dose must be stable for 2 weeks prior to C1D1. Asymptomatic leptomeningeal carcinomatosis is permitted. 12. Symptomatic spinal cord compression. 13. Patients with moderate to severe cognitive or psychiatric impairment that impairs the patient's ability to comply with study requirements. 14. Evidence of active malignancy (other than a current ROS1-positive solid malignancy) within the past 2 years requiring systemic therapy. Exceptions: nonmelanoma skin cancer, melanoma in situ, cervical cancer in situ, papillary thyroid cancer, intraductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer. Patients on long-term antihormonal therapy for a previous malignancy are permitted as long as the malignancy has not been active within the past 2 years. 15. Concurrent use of a strong CYP3A4 inducer or a strong CYP3A4 inhibitor (within 12 days of the first dose of study drug). 16. Evidence of malabsorption due to previous gastrointestinal surgery, disease or other illnesses that may affect the oral absorption, distribution, metabolism or excretion of the study drug. 17. The patient is pregnant or breastfeeding. WOCBP must have a negative serum pregnancy test at screening and a negative serum or urine test prior to the first dose of study drug. 18. Actively receiving systemic treatment or direct medical intervention in another therapeutic clinical study. 19. Any medical condition or laboratory abnormality that poses risk to the study patient or confounds the ability to interpret the study results.

[0359] Study Drug, Dose and Route of Administration: Compound 1 will be supplied as film-coated tablets for oral administration in two strengths, 5 mg and 25 mg, and the tablets will be provided in 32-count high-density polyethylene bottles with induction seal / child-resistant caps. Compound 1 should be taken on an empty stomach, at least 1 hour before and not less than 2 hours after ingestion of food and / or beverages other than water.

[0360] Previous and Concomitant Medications and Therapies:

[0361] Compound 1 was not considered a substrate for CYP2B6, CYP2C9, CYP2C19, or CYP2D6. Compound 1 is a substrate for CYP3A4 with potential for contributions from CYP1A2 and CYP2C8.

[0362] Compound 1 is an inhibitor of CYP1A2, CYP2B6, or CYP2D6 (IC >100 μM). 50 ) and CYP2C8 (IC 50 = 70 μM), CYP2C9 (IC 50 =70.3μM), CYP3A4 (testosterone IC 50 = 62.7 μM), CYP2C19 (IC 50 = 38.4 μM) and CYP3A4 (midazolam IC 50 Compound 1 was a weak inhibitor of CYP3A4 (testosterone) and CYP3A4 (midazolam). Compound 1 was a potent inducer of CYP3A4.

[0363] In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is prohibited. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is permitted. In certain embodiments, the concurrent use (within 12 days of enrollment) of drugs that are known strong CYP3A4 inducers (e.g., phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort) is used with caution.

[0364] In certain embodiments, the concomitant use (within 12 days of registration) of a drug that is a substrate or inducer of CYP3A4, an inhibitor of CYP3A4 or CYP2C8, a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or MATE1 transporter, or a substrate of CYP2C19 with a narrow therapeutic index is used with caution. In certain embodiments, the concomitant use (within 12 days of registration) or coadministration of Compound 1 with any one or more drugs that are substrates or inducers of CYP3A4, inhibitors of CYP3A4 or CYP2C8, substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or MATE1 transporter, or a substrate of CYP2C19 with a narrow therapeutic index is permitted. In certain embodiments, concurrent use (within 12 days of enrollment) or coadministration of drugs that are substrates or inducers of CYP3A4, inhibitors of CYP3A4 or CYP2C8, substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or the MATE1 transporter, or substrates of CYP2C19 with narrow therapeutic indexes is prohibited.

[0365] In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be avoided. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 should be used with caution. In certain embodiments, the simultaneous use (within 12 days of registration) or co-administration of gastric acid reducers with Compound 1 is permitted.

[0366] Exemplary agents provided herein include, but are not limited to, the following: ●CYP3A4 inducers: phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's wort CYP3A4 inhibitors: clarithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, goldenseal, grapefruit (including juice) - CYP3A4 substrates (sensitive): buspirone, everolimus, lovastatin, midazolam, simvastatin, triazolam, maraviroc, conivaptan, darifenacin P-gp substrates: digoxin, fexofenadine, loperamide, quinidine, talinolol, vinblastine ●BCRP substrates: daidzein, dantrolene, estrone-3-sulfate, prazosin, sulfasalazine MATE1 substrates: metformin, tetraethylammonium (TEA), cimetidine, procainamide

[0367] Results: Twenty patients (19 with NSCLC and 1 with pancreatic cancer) received compound 1 orally once daily at dose levels ranging from 25 to 100 mg. Patients received a median of 3 (range: 1-9) prior anticancer therapies, including any ROS1 TKI (100%), investigational ROS1 TKI (85%, including lorlatinib in 55% and repotrectinib in 40%), 2 or more ROS1 TKIs (75%), any chemotherapy (80%), or 2 or more chemotherapy (50%). At baseline, 55% had CNS metastases and 45% had ROS1 G2032R. No DLTs, dose reductions, or drug-related treatment discontinuations were reported. All treatment-related adverse events (TRAEs) were grade 1. The only TRAE in more than one patient was nausea (n=2). PK analysis of compound 1 demonstrated dose-dependent exposure. Of 12 efficacy-evaluable patients with ROS1+ NSCLC treated with 25-75 mg QD, 6 confirmed partial responses (PRs) were achieved. Shrinkage or resolution of intracranial metastases was observed, and no patients had intracranial progression. PRs were achieved in most (n=5 / 7) ROS1 G2032R mutant cancers, including tumors pretreated with lorlatinib or repotrectinib. Circulating tumor DNA analysis shows reduced ROS1 variant allele frequency. The RP2D has not been identified and dose escalation is ongoing.

[0368] Based on data as of September 13, 2022 for patients treated through September 1, 2022, the Phase 1 patient population has heavily pretreated ROS1-positive solid tumors (Figure 20). The safety profile was favorable and consistent with the highly ROS1-selective, TRK-sparing compound 1. No DLTs were observed, no treatment-related SAEs, no AEs leading to dose reduction or discontinuation, and no treatment-related dizziness (Figure 21).

[0369] Based on data as of September 13, 2022 for patients treated through September 1, 2022, Compound 1 exposure in clinical trials exceeded target levels that resulted in regression in preclinical models (Figure 19). Compound 1 demonstrated low within-cohort patient PK variability, increasing exposure with increasing dose levels, and favorable pharmacokinetics, including a half-life of approximately 20 hours, supporting QD dosing.

[0370] As an example, a 54-year-old patient with metastatic lung adenocarcinoma who responded to two cycles of carboplatin, paclitaxel, bevacizumab, and atezolizumab resulted in a positive test for ROS1 fusions by fluorescent in situ hybridization in tumor tissue. The patient received crizotinib for two months, developed pneumonitis, and then received lorlatinib with an initial partial response (PR). Intrathoracic disease progression followed 32 months later. The patient then received two cycles of carboplatin and pemetrexed, continued lorlatinib, and had stable disease. Next-generation sequencing of a lorlatinib-resistant lung nodule revealed a CD74-ROS1 fusion with ROS1 G2032R. The patient began treatment with compound 1 at a minimum dose level of 25 mg daily. Clinical response was achieved within 2 weeks of therapy, and the patient achieved a significant improvement in dyspnea. Imaging after 4 weeks showed PR with a reduction in multiple bilateral pulmonary metastases (-31% by RECIST 1.1). The patient's compound 1 dose was titrated to 75 mg daily, as permitted by protocol. The patient continues therapy for over 5 months, with an ongoing confirmed PR without neurological toxicity (-60% by RECIST 1.1, Figure 8A). The unbound plasma concentration of compound 1 over a 24-hour period on day 15 of cycle 1 is shown in Figure 18A.

[0371] In addition to the extracranial antitumor activity, intracranial activity was observed in another patient with metastatic NSCLC harboring EZR-ROS1 G2032R. A 65-year-old patient with stage IV lung adenocarcinoma and multiple brain metastases had EZR-ROS1 identified by ctDNA testing. Entrectinib was initiated with an initial response, but the patient's disease progressed 9 months later. A biopsy of the growing liver lesion confirmed the known EZR-ROS1 fusion and identified the ROS1 G2032R mutation. The patient was transitioned to a clinical trial of repotrectinib. Due to progressive disease, the patient quickly required a change in systemic therapy and was initiated on a combination of carboplatin, pemetrexed, bevacizumab, and entrectinib. Unfortunately, a mixed response, growing brain metastases, and new liver metastases were observed. ctDNA testing was repeated again, detecting ROS1 G2032R. Treatment with Compound 1 was initiated at 50 mg daily. At week 4, regression of the right occipital lobe metastasis was observed in addition to a reduction in some metastases in the liver and lung (-38% by RECIST 1.1). The patient continued therapy and had a confirmed PR at approximately 5 months, with further disease regression in the brain and liver (-58% by RECIST 1.1, FIG. 8B). No neurological toxicity was reported. The corresponding ctDNA analysis is shown in FIG. 17, and the unbound plasma concentration of Compound 1 over a 24-hour period on day 15 of cycle 1 is shown in FIG. 18B.

[0372] The antitumor activity of Compound 1 extended to cases without known ROS1 resistance mutations. A 75-year-old patient with metastatic EZR-ROS1 fusion-positive lung adenocarcinoma was initially treated with alectinib by the referring physician. Primary progression was observed as expected, and treatment was transitioned to crizotinib. Clinical and radiological responses were maintained through 39 months, at which time growing bilateral pulmonary nodules were noted on imaging. ctDNA analysis did not reveal any ROS1 kinase domain mutations. Treatment with Compound 1 was initiated at 25 mg daily. Treatment was well tolerated with no evidence of dizziness, orthostatic effect, or paresthesia. A PR (-33% by RECIST 1.1) was observed at week 4, which was confirmed and maintained with ongoing treatment for over 7 months (-48% by RECIST 1.1, Figure 8C). The unbound plasma concentrations of Compound 1 over a 24 hour period on day 15 of cycle 1 are shown in Figure 18C.

[0373] Compound 1 is well tolerated at doses up to 125 mg daily and has good pharmacokinetics. Activity has been demonstrated in heavily pretreated patients (70% of patients had received two or more prior ROS1 TKIs plus chemotherapy), including patients with brain metastases and G2032R mutations.

[0374] Whole blood samples were collected at the clinical investigational site into STRECK Cell-Free DNA BCT® tubes and shipped at ambient temperature to a central laboratory for plasma generation and storage at −80° C. Plasma samples were then analyzed to determine genomic alterations in circulating tumor DNA (ctDNA) via a hybrid capture-based next-generation sequencing method.

[0375] ctDNA analysis demonstrated that Compound 1 potently suppressed ROS1 variant allele frequency (VAF) compared to baseline at all dose levels tested (Cycle 1, Day 1, "C1D1"). At 25 mg, treatment with Compound 1 resulted in complete clearance of both EZR-ROS1 and ROS1 G2032R variants in ctDNA. Complete clearance of ROS1 fusions and G2032R was also observed at higher dose levels. Taken together, the ctDNA data suggest that Compound 1 was active against both ROS1 fusions and ROS1 G2032R solvent front mutations at all dose levels tested, supporting the on-target activity of the compound in patients (Figure 11). As used in Figure 11, C1D15 represents cycle 1, day 15, and C3D1 represents cycle 3, day 1.

[0376] As of data cutoff September 19, 2022, preliminary clinical pharmacokinetic analyses are summarized in the table below. [Table 6]

[0377] As used herein, C max means maximum plasma concentration; max_DN means dose-normalized Cmax; AUC last AUC refers to the area under the plasma concentration-time curve from time 0 to the last measurable concentration. last_DN is the dose-normalized AUC last AUC 0~24 AUC refers to the area under the curve from 0 to 24 hours. tau refers to the area under the curve over the dosing interval; AUC tau_DN is the dose-normalized AUC tau AUC inf AUC is the area under the curve from time 0 to infinity. inf_DN is the dose-normalized AUC inf Refers to ; CL / F refers to oral clearance; V z / F is the volume of distribution (Vz / F) refers to;t 1 / 2 refers to half-life; min refers to the minimum plasma concentration achieved by a drug over a dosing interval.

[0378] In addition, based on a data cutoff date of September 8, 2022 for patients treated by September 1, 2022, a preliminary efficacy analysis based on radiographic measurements showed that Compound 1 induced tumor responses across a heavily pretreated patient population (see table below). As used herein, CNS refers to the central nervous system, PD refers to progressive disease, PR refers to confirmed partial response, SD refers to stable disease, and TKI refers to tyrosine kinase inhibitors. [Table 7]

[0379] Based on a data cutoff date of September 13, 2022 for patients treated through September 1, 2022, a preliminary efficacy analysis showed radiographic tumor regression across all dose levels of Compound 1 (see Figure 12). Two patients (25 mg QD and 125 mg QD dose cohorts, both with prior therapy consisting of crizotinib, lorlatinib, and chemotherapy) are not represented due to incomplete or missing post-baseline tumor assessments in the setting of PD and symptomatic progression.

[0380] Based on data as of September 13, 2022 for response-evaluable patients with NSCLC treated by September 1, Compound 1 provided sustained duration of treatment. Median (range) duration of treatment was approximately 3.6 (1.0, 8.3+) months. No treatment was discontinued due to toxicity. 76% (16 / 21) of response-evaluable patients remain on treatment. Median time to response was approximately 3.6 (range 3.1, 4.6) weeks (see Figure 13).

[0381] Based on data as of September 13, 2022 for response-evaluable patients with NSCLC treated by September 1, 2022, Compound 1 was observed to induce rapid responses in TKI-resistant patients (see Figure 14). For the patient subgroup with known ROS1 G2032R resistance mutation, the ORR was 78% (7 / 9), with 100% (9 / 9) found to have tumor shrinkage. Complete clearance of the G2032R allele in all 7 patients with G2032R detected in central ctDNA analysis. One patient with ROS1 D2033N with ongoing PR (-40%) is pending.

[0382] Based on data as of September 13, 2022 for patients treated through September 1, 2022, Compound 1 was found to induce responses in intracranial disease. Intracranial PR in 3 / 3 patients with measurable (>10 mm) CNS metastases (one patient with ongoing intracranial PR is pending). An ORR of 73% (8 / 11) was observed in response-evaluable patients with any CNS disease. CNS progression was not observed in any of the 35 treated patients.

[0383] An intracranial response was observed in a 65-year-old woman with CD74-ROS1 fusion NSCLC who had previously been treated with chemotherapy, crizotinib, and lorlatinib, had CNS progression, and had no known ROS1 resistance mutations (see FIG. 15). The patient continues treatment with Compound 1 (100 mg QD) with an ongoing response at 3.2 months.

[0384] Another case study of treatment with Compound 1 provided intracranial and extracranial activity in TKI-resistant ROS1 G2032R+ NSCLC in a patient diagnosed with EZR-ROS1 fusion NSCLC. The patient had been previously treated with entrectinib (disease progression with ROS1 G2032R was identified) and repotrectinib (rapid disease progression was observed). The patient had also been previously treated with platinum-based chemotherapy + bevacizumab + entrectinib (disease progression was observed). Based on data as of September 13, 2022, Compound 1 (50 mg) was observed to result in a PR (-38% by RECIST 1.1) after 4 weeks, including shrinkage of the right occipital lobe metastasis and reduction in several liver / lung metastases. Further disease regression (-58%) was observed at 16 weeks, including near-complete resolution of brain lesions. Treatment was well tolerated with no evidence of dizziness, orthostatic effects, or paresthesias. The patient continues to receive Compound 1 with an ongoing response at 5.3 months. Radiographic images are shown in FIG.

[0385] Example 6: Phase 1 Clinical Study A Phase 1 study is conducted to investigate the food effect, potential effects of pH adjustment, and potential drug-drug interactions of Compound 1 in healthy subjects. 28 healthy subjects are planned (14 subjects in Part A and 14 subjects in Part B).

[0386] Primary Objectives: Part A: To determine the effect of food on single oral dose PK of Compound 1 in healthy subjects;To determine the effect of multiple oral doses of the PPI lansoprazole (offender molecule) on single oral dose PK of Compound 1 (offender molecule) in healthy subjects. Part B: To determine the effect of multiple oral doses of Compound 1 (offender molecule) on single oral dose PK of midazolam (offender molecule) in healthy subjects.

[0387] Secondary Objectives: Parts A and B: To further evaluate the safety and tolerability of Compound 1 in healthy subjects.

[0388] Primary Endpoint: Part A: Pharmacokinetic parameters of Compound 1 determined using non-compartmental analysis (C max , T max , AUC 0~24 , AUC last , AUC inf , t 1 / 2 Part B: Pharmacokinetic parameters of midazolam determined using noncompartmental analysis (C max , AUC 0~24 , AUC inf ).

[0389] Secondary Endpoints: Parts A and B: Incidence and severity of TEAEs, changes in ECG parameters, and changes in clinically relevant laboratory parameters.

[0390] Study design: The study was conducted in two parts (Figure 7).

[0391] This is a Phase 1 open-label study. Part A and Part B will be conducted in parallel.

[0392] Part A - Food Effects, Proton Pump Inhibitor (PPI) Drug Interactions: Part A uses a randomized balanced crossover study design. Fourteen healthy subjects are studied in a single cohort as follows. ●Subjects will reside in the CRU from Day -1 to Day 19. ● In the food effect portion of the study, each subject will receive a single oral dose (25 mg) of Compound 1 in either a fed (high fat breakfast) or fasted state on days 1 and 6. Half of the subjects (n=7) will be randomized to receive Compound 1 under fed conditions on day 1, then crossed over to receive Compound 1 under fasted conditions on day 6, and half (n=7) will be randomized to receive Compound 1 under fasted conditions on day 1, then crossed over to receive Compound 1 under fed conditions on day 6. In the PPI drug interaction portion of this study, subjects will receive lansoprazole (30 mg QD) on days 11-17 followed by a third dose of Compound 1 (25 mg) under fasting conditions on day 17. Post-dose PK sampling will continue until 48 hours (morning of day 19). All subjects will have a follow-up (clinic visit or phone call) 5-7 days after the final compound dose to re-examine safety.

[0393] Part B - Compound 1 Pernicious Drug-Drug Interactions: Part B uses a fixed-sequence multiple oral Compound 1 dose study design. Fourteen healthy subjects are studied as a single group. ●The subject will remain in the CRU from day -1 to the morning of day 10. Midazolam (2 mg) is administered on days 1 and 9 and PK time points are collected over 24 hours. Compound 1 (25 mg QD) is administered under fasting conditions on days 2-9. All subjects will have a follow-up (clinic visit or phone call) 5-7 days after the final compound dose to re-examine safety.

[0394] Duration of Treatment: Subjects in Part A will receive treatment for 17 days, receiving three single daily doses of Compound 1 (Study Days 1, 6, and 17), and lansoprazole on days 11 through 17. Subjects in Part B will receive treatment for 9 days, receiving daily dosing of Compound 1 (Study Days 2 through 9), and receiving midazolam on days 1 and 9.

[0395] Participation Criteria: Subjects must meet all of the following criteria to be eligible for enrollment in the study. 1. Healthy males and females. 2. Ages 18 to 55, including 18 and 55. 3. BMI between 18 and 32 kg / m2, including 18 and 32 kg / m2. 4. Any ethnic origin. 5. Non-smoker. 6. Females and male patients of childbearing potential must be surgically sterilized or must be willing to abstain from sexual activity or use effective contraception from the time of signing the ICF until 30 days after the last dose of study drug for females and 90 days after the last dose of study drug for males. 7. Male subjects must agree to not donate sperm throughout the study and for 90 days after the final dose of Compound 1. 8. Be willing and able to provide written informed consent and comply with the requirements of the study protocol, including, but not limited to, the study restrictions outlined regarding food intake, alcohol, caffeine, tobacco / nicotine, recreational drug use, exercise, and (for male subjects) sperm and / or blood, plasma or platelet donation.

[0396] Exclusion Criteria: Subjects meeting any of the following criteria will be excluded from the study. 1. History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, or any contraindication to lansoprazole (Part A) or midazolam (Part B), unless approved by the Investigator (or designee). 2. Hospital admission within 2 months prior to admission to the CRU, or any type of major surgical procedure within 6 months. 3. History of chronic or recurrent infection considered by the investigator to be a risk; serious or life-threatening infection within 6 months prior to admission to the CRU; or any suspected current active bacterial or viral infection requiring antibiotics, antivirals or other active treatment or considered by the investigator to be a risk to study participation. 4. Have known active TB, positive HIV test, positive Hepatitis B panel and / or Hepatitis C antibody. Subjects with Hepatitis B results compatible with previous vaccination may be included. 5. The subject has a QTcF consistently greater than 450 ms (in men) or greater than 470 ms (in women). In cases of out-of-range values, the ECG can be repeated twice and the average of the three results can be used to determine whether the subject is excluded. The subject has a history of long QT syndrome or torsades de pointes. 6. Subject with moderate to severe cognitive or psychiatric impairment that impairs the subject's ability to comply with the requirements of the study. 7. Subjects who are receptive to the following: Herbal medicines (e.g. St. John's Wort) or vaccines (including COVID vaccine and / or booster) within 30 days prior to admission to the CRU. b. OTC medicines, multivitamins or homeopathic preparations within 7 days prior to admission to the CRU. c. Any other medicines (including prescription medicines, oral contraceptives or other hormonal contraceptive treatments) within 14 days prior to admission to the CRU. d. Note: Allowed exceptions include a maximum of 2 grams of acetaminophen per day for more than 3 consecutive days and the occasional use (upon approval by the investigator) of other medications where more than 5 half-lives have elapsed since the last dose. 8. Self-reported drug or alcohol abuse and / or dependence within 1 year prior to admission to the CRU; includes subjects attending a drug or alcohol rehabilitation program within 1 year prior to admission to the CRU. 9. Active alcohol consumption of more than 14 units per week or consumption of alcohol within 48 hours prior to admission to the CRU. 10. Use of any tobacco or nicotine-containing substances from at least 3 months prior to admission to the CRU until final discharge from the CRU. 11. Positive test result for drugs of abuse, alcohol or cotinine upon screening or admission to the CRU. 12. Consumption of caffeine within 48 hours prior to admission to the CRU. 13. Consumption of food and beverages containing grapefruit within 7 days prior to admission to the CRU. 14. Donation or loss of more than 500 mL of whole blood within 30 days prior to admission to the CRU; donation of plasma within 2 weeks prior to admission to the CRU; or donation of platelets within 6 weeks prior to admission to the CRU. 15. Participate in any strenuous exercise within 72 hours prior to admission to the CRU; and agree not to start any new exercise program or participate in any unusually strenuous exertion throughout study participation. 16. The subject is pregnant or breastfeeding. Female subjects must have a negative serum pregnancy test at screening and admission to the CRU. A positive BHcG test is an exclusion unless determined to be consistent with postmenopausal status upon quantitative testing. 17. Active enrollment in another clinical study involving an investigational drug. 18. Any of the following laboratory abnormalities at screening or admission to the CRU (repeat testing may be performed for confirmation): Total bilirubin greater than 1.5 x ULN (Note: Subjects with known or suspected Gilbert's syndrome are excluded.) b. AST, ALT, or alkaline phosphatase >2×ULN 19. Previous gastrointestinal surgery (excluding uncomplicated appendectomy, uncomplicated cholecystectomy or hernia repair, or cosmetic surgery, e.g., abdominoplasty), disease or other illness that could potentially affect the oral absorption, distribution, metabolism, or excretion of the study drug as determined by the investigator. 20. Any other medical condition or laboratory abnormality or other reason which, in the investigator's opinion, poses a risk to the study subject or confounds the ability to interpret the study results.

[0397] Study Drug, Dose and Route of Administration: Compound 1 will be supplied as tablets (oval shaped) for oral administration in one strength of 25 mg, with the tablets provided in 32 count high density polyethylene bottles with induction seal / child resistant caps.

[0398] Study Drug, Dose, and Route of Administration: Subjects should refrain from taking any medications during the course of the study. Any medications deemed necessary for the subject's safety and health may be given at the investigator's discretion, taking into account the following guidance: Administration of all medications (including investigational products) must be listed on the appropriate CRF page.

[0399] Medications to Avoid or Take with Caution: The following medicines, supplements and foods should be avoided or taken with caution (exemplary agents are provided in Example 4). •Medicines that are strong inhibitors of CYP3A4. ●Herbal supplements and foods that are strong inhibitors of CYP3A4; including, but not limited to, grapefruit and grapefruit juice. •Medicines that are known substrates of CYP3A4. •Medicines that are CYP2C19 substrates with a narrow therapeutic index. •Medicines that are known substrates of P-gp / MDR1 and BCRP / ABCG2. •Medicines that are known substrates of the MATE1 transporter (including but not limited to metformin, cimetidine, procainamide, etc.). Gastric acid reducers, e.g., PPIs. Co-administration of gastric acid reducers with Compound 1 should be avoided as there is potential for drug-drug interactions between Compound 1 and gastric acid reducers. • Warfarin and low molecular weight heparins.

[0400] Prohibited Medications and Therapies: The following medications and therapies should be excluded during the study: Any other investigational therapy -Medicines that are strong inducers of CYP3A4

[0401] Statistical methods:

[0402] Analysis Sets: The PK analysis set is defined as all subjects receiving study treatment and with at least one evaluable plasma PK sample. PK will be investigated in the following subsets of subjects: Part A: Compound 1 PK in fed subjects (n=14); Compound 1 PK in fasted subjects (n=14); Compound 1 PK in subjects receiving lansoprazole (PPI) to steady state (n=14). Part B: Midazolam PK (n=14); Midazolam PK in subjects receiving Compound 1 to steady state (n=14). The safety analysis set consists of subjects receiving at least one dose of Compound 1.

[0403] Pharmacokinetic analysis: PK parameters are determined using Phoenix 64 (Certara, version 8.2) and non-compartmental methods. All PK concentration and parameter analyses are performed in the PK analysis set. Terminal phase elimination half-life is C max is estimated using a minimum of at least three time points after the time point at which PK was established. For plots and derivations of PK parameters, the lower limit of quantification values ​​occurring before the first measurable concentration are set to zero. Missing values ​​occurring after the first measurable concentration are set to missing. Use actual sample collection times. Actual post-dose sample collection times are expressed in hours and rounded to three significant figures.

[0404] Derived PK parameters: C max : Maximum observed plasma concentration. T max : C max Time to reach AUC 0~24 AUC: Area under the plasma concentration-time curve from the time of administration to 24 hours after administration last : Area under the plasma concentration-time curve from the time of administration to the last measurable non-zero concentration. AUC inf : Area under the plasma concentration-time curve from the time of administration to infinity. t 1 / 2 : Terminal phase elimination half-life. CL / F: Apparent total clearance of drug from plasma after oral administration.

[0405] Summary of PK parameters: Derived PK parameters will be summarized using the number of observations (n) and the following statistics: mean, median, standard deviation, coefficient of variation, minimum, maximum, geometric mean.

[0406] Comparison of PK parameters:

[0407] Part A: Food effect: C for Compound 1 in subjects in fed and fasted states max , AUC last and AUC inf The geometric mean (%CV) is calculated. Data are presented as the ratio of fed vs. fasted geometric means.

[0408] Part A: PPI drug interactions: C for Compound 1 in fasted subjects and in fasted subjects receiving lansoprazole (PPI) at steady state max , AUC last and AUC inf The geometric mean (% CV) is calculated. Data are presented as the geometric mean ratio of Compound 1 alone to Compound 1 + lansoprazole.

[0409] Part B: Compound 1-inflicted DDIL: C for midazolam in subjects before receiving Compound 1 and after administration of Compound 1 at steady state max , AUC 0~24 , AUC inf The geometric mean (% CV) is calculated. Data are presented as the geometric mean ratio of midazolam alone to midazolam + Compound 1.

[0410] Other derived PK parameters can be evaluated and included in the data set, as needed or deemed useful in the analysis.

[0411] Preliminary analysis of Part A study:

[0412] Preliminary analysis of data as of September 21, 2022 showed that AUC 0~inf The geometric mean ratio of 0~48 The geometric mean ratio of is about 1.08, and Cmax The geometric mean ratio of the C-values ​​for subjects in the fed state versus the fasted state was found to be about 0.84. max , AUC 0~48 and AUC inf ) Preliminary results suggest that Compound 1 can be taken with or without food.

[0413] Preliminary analysis of data as of September 21, 2022 showed that AUC 0~inf The geometric mean ratio of is about 0.92, and the AUC 0~48 The geometric mean ratio of is about 0.92, and C max The geometric mean ratio of C was found to be about 0.73. The geometric mean ratio was calculated by multiplying the values ​​for subjects receiving both Compound 1 and lansoprazole versus those receiving Compound 1 alone (e.g., C max , AUC 0~48 and AUC inf ) Preliminary results suggest that Compound 1 can be taken concomitantly with a PPI.

[0414] Preliminary analysis of Part B study:

[0415] Preliminary analysis of data as of September 21, 2022 showed that AUC 0~inf The geometric mean ratio of 0~24 The geometric mean ratio of is about 1.11, and C max The geometric mean ratio of C was found to be about 1.20. The geometric mean ratio was calculated based on the values ​​for subjects receiving midazolam alone versus those receiving both midazolam and Compound 1 (e.g., C max , AUC 0~48 and AUC inf Preliminary results suggest that Compound 1 cannot be coadministered with sensitive CYP3A4 substrates.

[0416] Example 7: Cell viability assay Cell culture: All cells were maintained at 37°C with 5% CO2. Ba / F3 cells were provided by RIKEN BRC through the National Bio-Resource Project of MEXT, Japan. Ba / F3 cells were maintained in RPMI-1640 + 10% FBS. Genes encoding human CD74-ROS1 (wild-type kinase domain or with G2032R, D2033N, L2026M or S1986F mutations), TPM3-TRKA, ETV6-TRKB, ETV6-TRKC or TRKB (full length) were synthesized, cloned into retroviral vectors with puromycin resistance markers and packaged into retroviral particles. Viruses were used to infect Ba / F3 cells. Stable expressing cell lines were selected by interleukin (IL)-3 withdrawal and puromycin for at least 7 days. Polyclonal cultures were used directly in the assay or monoclonal cultures were established via limiting dilution and then used in the assay. Successful transformants were confirmed by Sanger sequencing and Western blot. All cells were confirmed to express the complete desired protein. Ba / F3 CD74-ROS1 contained a small C-terminal truncation and Ba / F3 ETV6-TRKC contained a small C-terminal frameshift. Both were confirmed by orthogonal assays to have no discernible effect on inhibitor activity. HCC78 and A549 were obtained at Pharmaron and cultured in 1640 medium + 10% FBS or F12K medium + 10% FBS, respectively.

[0417] Alternatively, Ba / F3 cells expressing the following genes were generated separately: ROS1 fusion mutants were generated using site-directed mutagenesis (Agilent, New England Biolabs). Platinum E cells (Cell Biolabs, Inc) were transfected with pBABE CD74-ROS1, pMIG CEP85L-ROS1, pCX4 EZR-ROS1, pBABE GOPC(S)-ROS1, pCX4 GOPC(S)-ROS1, pBABE GOPC(L)-ROS1, pCX4 GOPC(L)-ROS1 or pMIG SLC34A2-ROS1 wild-type or mutant constructs using Biotool DNA transfection reagent to generate replication-deficient ecotropic retroviruses. Ba / F3 parental cells were infected with the retroviruses. Cells were treated with puromycin to select for cells stably expressing the respective fusions. Cells that survived after IL-3 withdrawal were used for in vitro assays. All transformed cell lines were sequenced to verify the presence of the desired mutations. Cells were harvested and pelleted, and DNA was extracted using QuickExtract™ DNA Extraction Solution (Lucigen). ROS1 kinase and C-terminal domains were PCR amplified. Chromatographic alignment was performed using Benchling software to confirm the presence of the desired mutations and to verify that no undesired mutations were introduced during viral transduction.

[0418] Cell viability assay: A549 or stable Ba / F3 cells were seeded in 384-well plates and test compounds were added in 3-fold serial dilutions in complete culture medium containing 10% FBS. After 72 h of incubation with inhibitors, cell viability was measured using CellTiter-Glo reagent (Promega). Untreated wells served as negative controls (no inhibition of proliferation) and wells treated with a high concentration of the nonspecific kinase inhibitor staurosporine served as positive controls (complete inhibition of proliferation). IC 50 was calculated from percent inhibition and log(inhibitor concentration) using four-parameter logistic regression.

[0419] Alternatively, all inhibitors were prepared as 1 mM stocks in DMSO. Plates were pre-seeded with 25 μL of complete medium per well using a Multidrop Combi reagent dispenser (Thermo Scientific). Inhibitors were dispensed onto 384-well plates at 2x the indicated concentrations in 25 μL of complete medium per well using a D300 Digital Dispenser (Hewlett-Packard). Ba / F3 cell lines expressing wild-type or mutant ROS1 fusions were seeded at 1,000 cells per well in a volume of 25 μL using a Multidrop Combi reagent dispenser (Thermo Scientific). Plates were incubated for 72 hours. Viability was measured using a WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium monosodium salt] based assay (Bimake) and read on a Biotek Synergy 2 plate reader. Each condition was assayed in triplicate. Data were normalized using Microsoft Excel and IC 50 Values ​​were calculated using nonlinear regression analysis in GraphPad Prism.

[0420] Results: Six ROS1 TKIs (crizotinib, entrectinib, lorlatinib, taretrectinib, repotrectinib, and compound 1) were profiled in cell viability assays against one human cancer cell line and 18 engineered Ba / F3 cell lines, which encompassed six ROS1 fusion partners (SLC34A2, EZR, CD74, GOPC(L), GOPC(S), and CEP85L) and eight ROS1 mutant variants (wild type, G2032R, S1986F, F2004C, F2004V, L2026M, D2033N, and G2101A).

[0421] In seven cell lines expressing wild-type ROS1 fusions, all six TKIs had significant growth inhibitory activity, albeit with different levels of potency. Compound 1 and lorlatinib were the most potent (mean IC 50 = 0.4 nM and 0.5 nM) and were 7-fold more potent than repotrectinib (IC 50 =3.3 nM), and was 19-fold higher than that of crizotinib, entrectinib, or taretrectinib (IC 50 =9.7~30nM).

[0422] In six cell lines harboring a ROS1 fusion with the G2032R mutation, compound 1 exhibited single-digit nanomolar potency (mean IC 50 = 1.6 nM), and its efficacy was more than 10-fold higher (IC 50 =18-44 nM), and more than 60-fold higher than lorlatinib (IC 50 = 98 nM), and crizotinib and entrectinib were more than 500-fold more potent (IC 50 =846nM~916nM).

[0423] IC of compound 1 and several ROS1 inhibitors 50 (nM) Results are shown below. [Table 8]

[0424] To measure the effect of the G2032R substitution on TKI sensitivity, IC 50 The shift was analyzed for six TKIs in three matched fusion pairs (CD74-ROS1, EZR-ROS1 and GOPC(L)-ROS1 cell lines, wt and G2032R positive). The analysis revealed two distinct groups of ROS1 TKIs based on their tolerance to G2032R. For the first group, including crizotinib, entrectinib and lorlatinib, G2032R was deleterious, with a mean IC of 60-220-fold compared to wild-type ROS1. 50The second group, which included taretrectinib, repotrectinib and compound 1, showed that G2032R was well tolerated and had a modest IC of 3-4 fold compared to wild-type ROS1. 50 However, in contrast to repotrectinib and taretrectinib, compound 1 contained a four-fold shift for ROS1 G2032R and still maintained single-digit nanomolar potency due to its sub-nanomolar potency against wild-type ROS1.

[0425] In addition to G2032R, other substitutions observed after disease progression on crizotinib and / or entrectinib include S1986F, F2004C, F2004V, L2026M, D2033N, and G2101A. CD74-ROS1 or EZR-ROS1 fusion proteins carrying these mutations were expressed in Ba / F3 cells and tested in cell viability assays against six TKIs. Compound 1 potently inhibited non-G2032R ROS1 mutants, with an IC of 1.5 nM or less. 50 I.C. 50 SHIFT analysis demonstrated that most non-G2032R mutations cause ROS1 to become more resistant to crizotinib and entrectinib, but only moderately resistant (IC 50 shift = 0.7-5.7 times) and is smaller in magnitude (IC 50 Conversely, non-G2032R mutations did not confer resistance to lorlatinib, taretrectinib, repotrectinib, or compound 1 (IC 50 shift = 0.01 to 1.3 times).

[0426] IC of compound 1 and several ROS1 inhibitors 50 (nM) Results are shown below. [Table 9]

[0427] Given the diversity of upstream ROS1 fusion partners, ROS1 TKIs were investigated in Ba / F3 cells expressing CD74-, EZR-, GOPC(L)-, GOPC(S)-, CEP85L-, or SLC34A2-ROS1 fusions carrying the wild-type kinase domain or the G2032R mutation. Compound 1 showed potent activity across all ROS1 fusions evaluated (IC<10 nM). 50 ).

[0428] Example 8: Anchorage-independent growth Abstract: Anoikis evasion is a hallmark of cancer and potentially indicates migratory or metastatic tendencies. To study the effect of ROS1 inhibition on anoikis, we performed anchorage-independent colony formation assays in NIH3T3 cells expressing CD74-ROS1 or EZR-ROS1 fusions.

[0429] Colony formation assay: Plates were pre-seeded with 0.8% agarose in complete medium with either DMSO or inhibitors (crizotinib, entrectinib, lorlatinib or compound 1 at 10, 100 or 1000 nM). Each inhibitor was paired with its own DMSO condition to serve as an accurate control. NIH3T3 cells expressing CD74-ROS1 or EZR-ROS1 wild-type or mutant fusions were plated at a density of 2,000 cells per 0.5 mL of agarose in 0.4% agarose in complete medium with DMSO or inhibitors at the same concentration as the bottom layer. Plates were incubated for 4 weeks, feeding each well with 75 μL of complete medium with or without inhibitors three times per week to adapt each well to the respective plate conditions and to prevent drying of the agarose. After 3 and 4 weeks, plates were read using a GelCount™ (Oxford Optronix). Colony counts were averaged by condition and normalized to colony counts from the paired DMSO condition. Data analysis and visualization were performed using Microsoft Excel and GraphPad Prism.

[0430] Results: ROS1-transformed NIH3T3 cells lost contact inhibition and formed colonies on soft agar. For NIH3T3 cells expressing wild-type ROS1 fusions, all ROS1 TKIs assessed suppressed colony formation by more than 80% at less than 100 nM, with compound 1 and lorlatinib having the highest potency, followed by crizotinib and then entrectinib. This potency trend correlated with the degree of target binding and signaling modulation measured by Western blotting. In contrast, for NIH3T3 cells expressing ROS1 fusions with G2032R, only compound 1 was able to inhibit colony formation by more than 90% at 100 nM, with the other TKIs (crizotinib, entrectinib, and lorlatinib) having weaker effects at the same concentrations. This potency trend was confirmed by pathway analysis. Although taretrectinib was not evaluated in the colony formation assay, Western blot analysis showed that compound 1 was more potent than taretrectinib in ROS1-driven NIH3T3 cells, consistent with the observations in Example 7.

[0431] Example 9: Cellular phosphorylation assay Summary: The relative potency of Compound 1 and other ROS1 inhibitors between TRK and ROS1 was evaluated.

[0432] Methods: For Ba / F3 TRKB cell phosphorylation assay, cells were seeded in 384-well plates and test compounds were added in 3-fold serial dilutions in complete culture medium + 10% FBS. Cells were stimulated with 100ng / mL BDNF for 20 minutes. TRK phosphorylation was measured using phospho-TRKA (Tyr674 / 675) / phospho-TRKB (Tyr706 / Tyr707) AlphaLISA reagent (PerkinElmer #ALSU-PTRKAB). Untreated wells served as negative controls (no inhibition) and wells treated with a high concentration of the non-specific kinase inhibitor staurosporine served as positive controls (complete inhibition). IC 50 was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0433] NIH3T3 cells expressing EZR-ROS1 wild-type or mutant fusions were treated with the indicated concentrations of inhibitors for 3 hours before harvesting. Cells were washed with PBS and harvested with cell lysis buffer supplemented with 0.25% deoxycholate, 0.05% SDS, and protease and phosphatase inhibitors. Protein concentrations were determined using the Pierce™ BCA Protein Assay (ThermoFisher Scientific). Lysates were extracted with Laemelli sample buffer supplemented with beta-mercaptoethanol for 10 minutes at 75°C, and lysates were run on 4-20% precast gradient Bis-Tris gels (Invitrogen; ThermoFisher Scientific). Proteins were transferred to nitrocellulose membranes (Prometheus) and stained with phospho-ROS1 Y2274 (3078; 1:1000; Cell Signaling Technology), DYKDDDDK[Flag] (8H8L17; 1:1000; Invitrogen), phospho-SHP2 (A5278; 1:1000; Bimake), phospho-ERK1 / 2 (9101; 1:1000; Cell Signaling Technology), ERK2 (sc-1647; 1:1000; Santa Cruz), phospho-S6 (4858; 1:1000; Cell Signaling Technology), S6 (2216; 1:1000, Cell Signaling Technology), phospho-Akt (4060; 1:1000, Cell Signaling Technology), Akt (9272; 1:1000, Cell Signaling Technology), and phospho-S6 (2216; 1:1000, Cell Signaling Technology). Cells were probed with actin (JLA-20; 1:5000; Developmental Studies Hybridoma Bank) or actin (JLA-20; 1:5000; Developmental Studies Hybridoma Bank). Signals were detected using HRP-conjugated or IRDye secondary antibodies on a BioRad ChemiDoc imaging station or a LI-COR Odyssey imaging station, respectively.

[0434] Results: TRK-associated neurological toxicity is most consistent with known functions of the TRKB signaling pathway. Therefore, an assay was developed using Ba / F3 cells stably expressing full-length TRKB. Stimulation of this cell line with brain-derived neurotrophic factor (BDNF) promotes TRKB autophosphorylation (pTRKB). Consistent with our biochemical and cell viability assays, compound 1 only weakly inhibited cellular TRKB phosphorylation (IC 50 =850 nM), providing a wide selectivity window for both wild-type ROS1 and ROS1 G2032R (670-fold and 240-fold) over pTRKB that was not achieved with any other ROS1 TKI tested.

[0435] IC of compound 1 and several ROS1 inhibitors 50 The measured values ​​(nM) are shown below. [Table 10]

[0436] Example 10: Preclinical intracranial activity METHODS: All procedures relating to the handling, care, and treatment of animals in these studies were performed in accordance with guidelines approved by Pharmaron's IACUC, which follows AAALAC guidance.

[0437] Compound 1 was formulated as a 1 mg / mL suspension in 20% hydroxypropyl-β-cyclodextrin (HP-β-CD) in deionized water. Compounds were orally administered to male Wistar Han rats (n=3 each). After 1 hour, brain samples and plasma were collected and brain samples were homogenized in phosphate buffered saline (PBS). Brain and plasma samples were precipitated with acetonitrile and centrifugation (4700 rpm, 15 min). Drug concentrations in the supernatant were quantified by LC / MS / MS. Unbound fractions were determined using rapid equilibrium dialysis. K p,uu was calculated as the ratio between the unbound drug concentration in the brain and the unbound drug concentration in the plasma.

[0438] Ba / F3 CD74-ROS1 G2032R cells were transduced with viral particles containing the firefly luciferase gene and a neomycin resistance marker. Infected cells were selected in neomycin and monoclonal cultures were established via limiting dilution. Successful transformants were confirmed by Sanger sequencing and bioluminescence. For in vivo studies, 1 × 10 5 Ba / F3 CD74-ROS1 G2032R luciferase cells were stereotactically implanted into the right forebrain of 6-8 week old female Balb / c nude mice. Five days later, mice were randomized into three groups of n=7-10 mice each based on the mean bioluminescence signal, and mice received 2 mg / kg vehicle or Compound 1 PO, BID. Bioluminescence and body weight were measured at regular intervals until the end of the study (61 days after treatment initiation) or until the animals met criteria for euthanasia.

[0439] Results: Compound 1 showed favorable K values ​​of 0.16 measured 1 hour after a single oral dose of 10 mg / kg in Wistar-Han rats. p,uu (unbound brain-plasma distribution). To evaluate intracranial antitumor activity, a Ba / F3 CD74-ROS1 G2032R luciferase model was generated, which allows monitoring of brain tumor burden via live animal bioluminescence imaging. Ba / F3 CD74-ROS1 G2032R luciferase cells were injected intracranially into mice, and rapid tumor growth was observed. All vehicle-treated mice lost weight and succumbed to disease by day 19, with a median overall survival (mOS) of 16.5 days. In contrast, compound 1 at 2 mg / kg suppressed intracranial tumor growth without significant changes in body weight, and all mice survived to the end of the study (mOS of >61 days), corresponding to a >4-fold increase in survival versus vehicle treatment. These results indicated that compound 1 has potent intracranial antitumor activity.

[0440] Example 11: In vivo pharmacology Methods: Mice bearing PDX tumors carrying SDC4-ROS1 were treated with a single dose (PO) of vehicle (20% HP-β-CD) or compound 1, followed by harvesting tumors at the indicated time points (n=3) and Western blots. Anti-β2 microglobulin (β2m) is a loading control that does not recognize mouse β2 microglobulin. pERK, pAKT and cleaved PARP are markers of MAPK signaling, PI3K signaling and apoptosis, respectively.

[0441] Results: The results of this study are shown in Figure 9. Direct inhibition of ROS1 fusions by Compound 1 in vivo was supported by downstream inhibition of the signaling pathways MAPK and PI3K, as measured by reductions in the levels of phospho-p44 / 42 MAPK ERK1 / 2 (pERK) and phospho-AKT (pAKT), respectively. These results indicate that Compound 1 inhibits signaling through the MAPK and PI3K / AKT pathways and induces apoptosis in PDX tumors harboring SDC4-ROS1.

[0442] Example 12: Cell viability assay for LTK cell lines Generation of Ba / F3 stable expressing cell line: The gene encoding CLIP1-LTK was synthesized, cloned into retroviral construct pMSCV-puro (Biovector) and packaged into retroviral particles. The virus was used to infect Ba / F3 cells (RIKEN) at a multiplicity of infection of 1 or 10 for 1 day. Infected cells were rescued for 2 days in medium (RPMI-1640 with 10% fetal bovine serum, 1% streptomycin and penicillin) supplemented with mouse IL-3 (10 ng / mL), and stable expressing cell lines were selected by IL-3 withdrawal and puromycin (0.8 μg / mL) for 7 days. Transformation of the desired gene was confirmed by Sanger sequencing and Western blot.

[0443] Cell proliferation assay: Stable cells were plated at 1,000 cells / well (40 μL) in 384-well plates for one day. Test compounds (40 nL) were then added in 3-fold dilution series using a TECAN EVO200 liquid handler and incubated for 72 h. Plates were equilibrated at room temperature for 15 min, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression.

[0444] Results: IC for compound 1 against Ba / F3 CLIP1-LTK cell line 50 was determined to be 9.57 nM.

[0445] Example 13: Ba / F3 stable expression cell line carrying the L2086F mutation Biochemical kinase assays ROS1 L2086F (amino acids 1881-2347) was custom ordered at SignalChem (catalog no. NP72-092G / Y4232-2). Kinase reactions were initiated by mixing ATP (1 mM) with fluorogenic phosphorylation substrate AQT0101 (15 μM, AssayQuant) and ROS1 L2086F (0.5 nM, SignalChem) in buffer (54 mM HEPES pH 7.5, 0.012% Brij-35, 0.52 mM EGTA, 1.2 mM DTT, 1% glycerol, 0.2 mg / mL BSA, 10 mM MgCl2). Plates were sealed and read on a SpectraMax Paradigm at λ=485 nm every 2 min for 120 min at 30°C. The initial velocity of the reaction (v) was calculated from the change in fluorescence intensity over time during the initial linear part of the reaction. Finally, the apparent inhibition constant (K i app ) was determined from the regression of v and I (inhibitor concentration) to the Morrison equation (E=enzyme concentration).

number

[0446] Generation of Ba / F3 stable cell line The gene encoding CD74-ROS1 L2086F was synthesized in GeneRay, cloned into the retroviral construct pMSCV-puro (Biovector) and packaged into retroviral particles. The virus was used to infect Ba / F3 cells (RIKEN) at a multiplicity of infection of 1 for 1 day. Infected cells were rescued for 2 days in medium (RPMI-1640 with 10% fetal bovine serum, 1% streptomycin and penicillin) supplemented with mouse IL-3 (10 ng / mL), and stable expressing cell lines were selected by IL-3 withdrawal and puromycin (0.8 μg / mL) for 7 days. Transformation of the desired gene was confirmed by Sanger sequencing and Western blot using ROS1 antibody (CST #3287).

[0447] Cell proliferation assay Stable cells were plated at 1,000 cells / well (40 μL) in 384-well plates for one day. Test compounds (40 nL) were then added in 3-fold serial dilutions using a TECAN EVO200 liquid handler and incubated for 72 h. Plates were equilibrated at room temperature for 15 min, followed by the addition of 40 μL of CellTiter-Glo reagent (Promega). Luminescence was measured in a plate reader. Half-maximal inhibitory concentrations (IC 50 ) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression. The cell proliferation assay data are summarized in the table below. [Table 11]

[0448] Several references have been cited, the disclosures of which are incorporated herein by reference in their entireties.

[0449] The above embodiments are intended to be merely illustrative, and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials and procedures, all of which are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims

1. 1. A pharmaceutical composition for treating a patient with a solid tumor, comprising Compound 1: 【Chemical 1】 or a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the solid tumor is an advanced solid tumor.

3. 3. The pharmaceutical composition of claim 2, wherein the advanced solid tumor is recurrent after, refractory to, or resistant to prior treatment with a tyrosine kinase inhibitor (TKI).

4. 2. The pharmaceutical composition of claim 1, wherein the solid tumor is non-small cell lung cancer (NSCLC).

5. 2. The pharmaceutical composition of claim 1, wherein the solid tumor is inflammatory myofibroblastic tumor (IMT), pancreatic adenocarcinoma, glioma, ovarian cancer, cholangiocarcinoma, gastric cancer, or thyroid cancer.

6. The pharmaceutical composition of claim 1 , wherein the solid tumor is metastatic.

7. The pharmaceutical composition of claim 6 , wherein the solid tumor is CNS metastatic.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the solid tumor is ROS1 positive.

9. The pharmaceutical composition of any one of claims 1 to 7, wherein the solid tumor comprises a ROS1 mutation.

10. 10. The pharmaceutical composition of claim 9, wherein the ROS1 mutation is one or more mutations selected from G2032R, S1986F, L1951R, L1982F, S1986F, F2004C, F2004V, L2026M, D2033N, and G2101A.

11. 10. The pharmaceutical composition of claim 9, wherein the solid tumor comprises a ROS1 fusion.

12. The pharmaceutical composition of any one of claims 1 to 7, wherein the solid tumor is ALK-positive (eg, ALK fusion) or LTK-positive.

13. (a) the patient is tyrosine kinase inhibitor (TKI) therapy naive; (b) whether the patient has been treated with one prior TKI therapy; (c) the patient has been treated with at least one prior TKI therapy; or (d) the patient has been treated with at least two prior TKI therapies; Optionally, the TKI is a ROS1 TKI; or 8. The pharmaceutical composition of any one of claims 1-7, optionally wherein the prior TKI therapy is one or more selected from the group consisting of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib, masitinib, or ensartinib.

14. (a) the patient has not been treated with prior platinum-based chemotherapy; (b) the patient has been treated with up to one prior platinum-based chemotherapy; (c) whether the patient has been treated with one prior platinum-based chemotherapy; (d) the patient has not been treated with immunotherapy; (e) whether the patient is being treated with immunotherapy; (f) whether the patient has been treated with chemotherapy; (g) whether the patient has been treated with at least one prior line of chemotherapy; (h) whether the patient has been treated with at least two prior lines of chemotherapy; (i) the patient has been treated with at least three prior lines of anti-cancer therapy; or (j) The pharmaceutical composition of any one of claims 1 to 7, wherein the patient has been treated with at least two prior lines of anticancer therapy selected from the group consisting of a ROS1 TKI (e.g., an investigational ROS1 TKI, crizotinib, lorlatinib, entrectinib, repotrectinib, and taretrectinib) and chemotherapy.

15. (a) whether the patient has been treated with at least one line of ROS1 TKI and one line of chemotherapy; (b) the patient has been treated with at least two lines of ROS1 TKI and one line of chemotherapy; (c) the patient has been treated with at least three lines of ROS1 TKI and one line of chemotherapy; (d) the patient has been treated with at least two lines of chemotherapy; (e) whether the patient has been treated with at least one line of ROS1 TKI and two lines of chemotherapy; (f) the patient has been treated with at least two lines of ROS1 TKI and two lines of chemotherapy; or (g) whether the patient has been treated with at least three lines of ROS1 TKI and two lines of chemotherapy; Optionally, the ROS1 TKI is crizotinib, entrectinib, lorlatinib, or repotrectinib; or 8. The pharmaceutical composition of any one of claims 1 to 7, wherein optionally the patient is being treated with lorlatinib and repotrectinib.

16. a. the solid tumor is an advanced or metastatic ROS1-positive solid tumor and the patient has been treated with at least one prior ROS1 TKI therapy; b. the solid tumor is advanced or metastatic ROS1-positive NSCLC and the patient is TKI therapy-naive and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy; c. the solid tumor is advanced or metastatic ROS1-positive NSCLC and the patient has been treated with one prior ROS1 TKI therapy and no prior platinum-based chemotherapy or immunotherapy; d. the solid tumor is advanced or metastatic ROS1-positive NSCLC and the patient has been treated with one prior ROS1 TKI therapy and one prior platinum-based chemotherapy, with or without immunotherapy; e. the solid tumor is advanced or metastatic ROS1-positive NSCLC and the patient has been treated with at least two prior ROS1 TKI therapies and up to one prior platinum-based chemotherapy, with or without immunotherapy; or f. the solid tumor is an advanced or metastatic ROS1-positive solid tumor and the patient has progressed on prior therapy; 8. The pharmaceutical composition of any one of claims 1 to 7, optionally wherein the previous ROS1 TKI is an investigational ROS1 TKI, crizotinib, lorlatinib, entrectinib, repotrectinib, or taretrectinib.

17. 8. The pharmaceutical composition of any one of claims 1-7, wherein the pharmaceutical composition is formulated so that Compound 1 is administered to the patient for at least one treatment cycle, optionally, a treatment cycle of at least 7 days, at least 14 days, at least 21 days, or at least 28 days.

18. a. the patient does not experience a Grade 4 adverse event (e.g., a TRAE) after administration of Compound 1; b. the patient does not experience a Grade 3 adverse event (e.g., a TRAE) after administration of Compound 1; c. the patient does not experience a Grade 2 adverse event (e.g., a TRAE) after administration of Compound 1; d. the patient does not experience a Grade 1 adverse event (e.g., a TRAE) after administration of Compound 1; and / or e. the patient experienced a maximum Grade 1 adverse event (e.g., a TRAE) following administration of Compound 1; 8. The pharmaceutical composition of any one of claims 1 to 7, wherein optionally, the grade 1 adverse event is fatigue, muscle pain, or nausea.

19. the patient does not experience a CNS adverse event after administration of Compound 1; 8. The pharmaceutical composition of any one of claims 1 to 7, wherein optionally the CNS adverse event is one or more selected from the group consisting of dizziness, ataxia, gait disturbance, paresthesia, weight gain, hyperphagia, paresthesia, abnormal movement, cognitive changes, speech effects (e.g., dysarthria, slow speech or speech disorder), mood disorders (e.g., irritability, anxiety, depression, emotional lability, personality changes, mood swings, affective disorders, aggression, agitation, mood changes, depressed mood, euphoric mood or mania) and cognitive disorders (e.g., memory impairment, cognitive impairment, amnesia, confusion, attention disorder, delirium, mental impairment, attention deficit hyperactivity disorder, dementia, sleep disorder or dyslexia).

20. the patient is a patient population; and a. Less than 30% of the patient population experiences a Grade 1 TRAE following administration of Compound 1; b. Less than 20% of the patient population experiences a Grade 2 TRAE after administration of Compound 1; or c) The pharmaceutical composition of any one of claims 1 to 7, wherein the patient population does not experience a grade 3 or grade 4 TRAE after administration of Compound 1.

21. a. the patient has a partial or complete response after one or more cycles of treatment; or b) The pharmaceutical composition of any one of claims 1 to 7, wherein the patient has achieved stable disease after one or more treatment cycles.

22. The pharmaceutical composition of any one of claims 1 to 7, wherein the patient has brain metastases and, optionally, does not experience intracranial progression after at least one treatment cycle.

23. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the patient has at least about a 5% to about a 100% reduction in ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle, or has undetectable ROS1 allelic variants in circulating tumor DNA after at least one treatment cycle.

24. The pharmaceutical composition comprises: a. Administration of the compound results in an area under the curve (AUC) from 0 to 24 hours after administration of the compound. ０～２４ ) in the range of (80%-125% of 20 ng*h / mL) to (80%-125% of 500 ng*h / mL) for every mg of Compound 1 administered; b. Administration of the compound ｌａｓｔ，ｕｎｂｏｕｎｄ in the range of about 10 to about 80 ng*h / mL for every mg of Compound 1 administered; c. Administration of the compound ｔａｕ in the range of about 50 to about 150 ng*h / mL for every mg of Compound 1 administered; d. Administration of the compound ｉｎｆ in the range of about 50 to about 250 ng*h / mL for every mg of Compound 1 administered; e. administration results in a maximum plasma concentration (C ｍａｘ ) in the range of about 2 to about 50 ng / mL for every mg of Compound administered; f. The minimum plasma concentration (C) achieved by Compound 1 during the time interval between administration of two doses. ｍｉｎ ) in the range of about 50 to about 350 ng / mL; g. Administration results in a maximum unbound plasma concentration (C ｍａｘ，ｕｎｂｏｕｎｄ ) in the range of about 30 ng / mL to about 400 ng / mL; h. administration of the compound after administration ｍａｘ for a period ranging from about 0.25 hours to about 5 hours or from about 0.7 hours to about 1.3 hours; i. administration of the compound after administration １／２ for a period ranging from about 2 hours to about 50 hours or from about 10 hours to about 24 hours; and / or j. administration results in an IC50 of the compound against the ROS1 G2032R mutant for at least 70%, 80%, 90%, 95%, 97%, 98%, or 99% of the time immediately following administration for about 24 hours. ５０ 8. The pharmaceutical composition of any one of claims 1 to 7, formulated to provide a plasma concentration of the compound at a dose that is at least 10%, 20%, 30%, 40% or 50% greater than

25. 1. A pharmaceutical composition for reducing lesions in a subject with a ROS1-positive solid tumor, comprising: the pharmaceutical composition is formulated so that Compound 1 is administered once daily for one or more days after obtaining a first radiological measurement of the size of the lesion; and a second radiological measurement of the size of the lesion is obtained after administering Compound 1; and The pharmaceutical composition, wherein the second measurement is up to 100%, up to 90%, up to 80%, up to 70%, up to 60%, or up to 50% of the first measurement.

26. the pharmaceutical composition is formulated so that the compound is administered once or twice daily (BID) in an amount of about 5 mg to about 500 mg (by weight of Compound 1 free base); 8. The pharmaceutical composition of any one of claims 1-7, optionally formulated so that the compound is administered once daily or twice daily (BID) in an amount of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg (by weight of free base Compound 1).

27. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition is formulated so that the compound is administered to a patient with or without food, optionally in a fasted or fed state.

28. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition is formulated such that the compound is administered to the patient when the patient is not taking any one of a strong inhibitor of CYP3A4, a strong inducer of CYP3A4, a sensitive substrate of CYP3A4, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of MATE1, or a gastric acid-reducing agent.

29. 29. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is formulated such that the compound is administered when the patient is not taking a strong inhibitor of CYP3A4.

30. 29. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is formulated such that the compound is administered when the patient is not taking a strong inducer of CYP3A4.

31. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition is formulated so that the compound is administered to the patient while the patient is taking any one of a strong inhibitor of CYP3A4, a strong inducer of CYP3A4, a sensitive substrate of CYP3A4, a substrate of P-gp / multidrug resistance protein (MDR1), a substrate of BCRP / breast cancer resistance protein (ABCG2), a substrate of MATE1, or a gastric acid reducer.

32. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition is formulated such that the compound is administered in the absence of sensitive substrates of CYP3A4, optionally wherein the sensitive substrates of CYP3A4 include one or more of buspirone, everolimus, lovastatin, midazolam, simvastatin, triazolam, maraviroc, conivaptan, and darifenacin.

33. The patient: a. experiences reduced levels of one or more of pROS1, ROS1, pAKT, and pERK after administration of the compound; b. experience reduced expression levels of one or more MAP kinase pathway genes in the tumor after administration of the compound; and / or c. experiencing a reduced expression level of one or more MAP kinase pathway genes in a solid tumor after administration of the compound; 8. The pharmaceutical composition of any one of claims 1 to 7, optionally wherein the one or more MAP kinase pathway genes are selected from the group consisting of DUSP6, FOS, IL1R1 and SPRY4.

34. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the compound is Compound 1 free base, and optionally, the compound is a solid form of Compound 1 characterized by an XRPD pattern comprising peaks at approximately 10.7, 15.0, and 21.2 degrees two-theta (±0.2 degrees).

35. the pharmaceutical composition comprises Compound 1, or a stereoisomer or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, a diluent, a binder, a disintegrant, and a lubricant; 8. The pharmaceutical composition of any one of claims 1 to 7, optionally wherein the diluent is mannitol, the binder is a mixture of HPC and SMCC, the disintegrant is sodium starch glycolate (SSG), and the lubricant is magnesium stearate.

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