Heteroaromatic macrocyclic ether compounds

Abstract

Provided herein are certain heteroaromatic macrocyclic ether compounds of formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and methods of treating, preventing or managing cancers using the compounds.

Description

HETERO AROMATIC MACROCYCLIC ETHER COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Serial No. 63 / 585,054, filedSeptember 25, 2023, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Receptor tyrosine kinases (RTKs) are cell surface enzymes that receive outside signals, such as whether to grow and divide, and transmit those signals in the cell through kinase activity. Many RTKs are proto-oncogenes; 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 the intact kinase domain, amplification and other means. RTK proto-oncogenes include ROS1, anaplastic lymphoma kinase (ALK), NTRK1 (encodes TRKA), NTRK2 (encodes TRKB), and NTRK3 (encodes TRKC).

[0003] ROS1 is an RTK proto-oncogene, with ROS1 rearrangements detected in nonsmall cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and spitzoid melanoma. Oncogenic ROS I gene fusions contain the kinase domain of ROS I (3’ region) fused to the 5’ region of a variety of 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, MY05C, 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, MY05A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0004] NTRKL NTRK2 and NTRK3 are RTK proto-oncogenes that encode TRK-family kinases, with NTRK1, NTRK2 and NTRK3 chromosomal rearrangements detected at low frequency in many cancers. For treatment of RO SI -positive or ALK-positive patients, however, TRK inhibition, particularly in the central nervous system (CNS), has been associated withadverse reactions, including dizziness / ataxia / gait disturbance, paraesthesia, weight gain and cognitive changes.

[0005] Existing agents used to treat oncogenic ROS1 and ALK have substantial deficiencies. These deficiencies may represent one or more of the following: associated TRK inhibition, limited CNS activity, and inadequate activity against resistance mutations. Treatment of RO SI -positive or ALK-positive patients accompanied by TRK inhibition is associated with adverse reactions, particularly in the CNS, including dizziness / ataxia / gait disturbance, paraesthesia, weight gain and cognitive changes. Additionally, there is a need for CNS-penetrant and TRK-sparing inhibitors of the wild type ROS1 kinase domain and ROS1 with 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, G2101 A, D2113N, D2113G, L2155S, L2032K, and L2086F. Likewise, 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, including G1202R, LI 196M, G1269A, Cl 156Y, Il 171T, Il 171N, Il 171 S, Fl 174L, VI 180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, LI 152R, LI 196Q, LI 198P, L1198F, R1275Q, L1152P, C1156T, and F1245V.

[0006] Certain heteroaromatic macrocyclic ether compounds, including compounds that are CNS-penetrant, TRK-sparing, ROS1 and / or ALK inhibitors, have been described in International Patent Application Publication No. WO 2021 / 226208, the entirety of which is incorporated herein by reference.SUMMARY

[0007] Provided herein are certain heteroaromatic macrocyclic ether compounds, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0008] In one embodiment, provided herein is a compound of Formula (I):(I), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein Ri, R2, and L are as defined herein or elsewhere.

[0009] Also provided herein is a compound which is an oxidized form of a compound ofFormula (II):(II), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; andR2 is H or methyl.

[0010] Also provided herein are pharmaceutical compositions, comprising a compound provided herein and a pharmaceutically acceptable carrier or excipient.

[0011] Also provided herein are methods of treating cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound provided herein or a pharmaceutical composition provided herein.

[0012] Also provided herein are methods for selectively inhibiting ROS1 over TRK, wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering to the subject an effective amount of a compound provided herein or a pharmaceutical composition provided herein. Also provided herein are methods for selectively inhibiting ALK over TRK, wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering to the subject an effective amount of a compound provided herein or a pharmaceutical composition provided herein.

[0013] Also provided herein are methods of decreasing a level of ROS1 or ALK in a cell, comprising contacting the cell with a compound provided herein or a pharmaceutical composition provided herein.DETAILED DESCRIPTIONDEFINITIONS

[0014] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. The following references provide one of skill with a general definition 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 meanings ascribed to them below, unless specified otherwise.

[0015] In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.

[0016] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term“consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

[0017] The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term “consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0018] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. Unless specifically stated or obvious from context otherwise, as used herein, 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”, it includes administering the compound to an individual patient or a patient population.

[0019] As used herein and unless otherwise specified, an “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, or from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A Ci-Ce straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

[0020] Moreover, the term “alkyl” (or “lower alkyl”) as used throughout the specification, examples, and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted andunsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonylsubstituted alkyls, -CF3, -CN, and the like.

[0021] The term “Cx y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2-yalkenyl” and “C2-yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0022] As used herein and unless otherwise specified, “oxidized form” refers to an oxidized derivative of a specified compound. In certain embodiments, the oxidized form can be derived from the specified compound via transfer of an oxygen atom to the specified compound, removal of one or more hydrogen atoms from the specified compound, and / or an increase in the degree of unsaturation of the specified compound. In certain embodiments, the specified compound can be derived from the specified compound by oxidation occurring in vivo, in vitro, or under storage conditions of the specified compound (for example, under ambient conditions). In certain embodiments, the oxidized form is an “oxidized metabolite” (i.e. a derivative generated during metabolism, for example by digestion or another bodily chemical process).

[0023] As used herein and unless otherwise specified, “stereoisomers” refer to the various stereoisomeric forms of a compound that comprises one or more asymmetric centers or stereohindrance in the structure. In some embodiments, a stereoisomer is an enantiomer, a mixture of enantiomers, an atropisomer, or a tautomer thereof. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer (e.g. an atropisomer), or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. In some embodiments, compounds provided herein may be atropisomers. In certain embodiments, atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. Stereoisomers can 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 can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33'2125 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0024] In certain embodiments, compounds provided herein may be racemic. In certain embodiments, compounds provided herein may be enriched in one enantiomer. For example, a compound provided herein may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or greater ee. In certain embodiments, compounds provided herein may have more than one stereocenter. In certain such embodiments, compounds provided herein may be enriched in one or more diastereomer. For example, a compound provided herein may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de.

[0025] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound. An enantiomerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more particularly at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up 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% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains about 98grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer.

[0026] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound. A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more particularly at least about 75, about 90, about 95, or even about 99 mol percent.

[0027] In some embodiments, a moiety in a compound exists as a mixture of tautomers.A “tautomer” is a structural isomer of a moiety or a compound that readily interconverts with another structural isomer. For example, a pyrazole ring has two tautomers:which differ in the positions of the pi-bonds and a hydrogen atom. Unless explicitly stated otherwise, a drawing of one tautomer of a moiety or a compound encompasses all of the possible tautomers.

[0028] The term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human adult at least of 40 years old. In certain embodiments, the subject is a human adult at least of 50 years old. In certain embodiments, the subject is a human adult at least of 60 years old. In certain embodiments, the subject is a human adult at least of 70 years old. In certain embodiments, the subject is a human adult at least of 18 years old or at least of 12 years old. As used herein and unless otherwise specified, a human subject to which administration of a therapeutic (e.g., a compound as described herein) is contemplated in order to treat, prevent or manage a disease, disorder, or condition, or symptoms thereof, is also called a “patient”.

[0029] As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. These effects are also called “prophylactic” effects. Thus, as used herein and unless otherwise specified, the terms “prevention” and “preventing” refer to an approach for obtaining beneficial or desired results including, but not limited, to prophylactic benefit. For prophylactic benefit, a therapeutic can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. In one embodiment, a therapeutic is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) for prophylactic benefit (e g., it protects the subject against developing the unwanted condition).

[0030] As used herein and unless otherwise specified, the terms “treatment” and “treating” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In one embodiment, “treatment” comprises administration of a therapeutic after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0031] As used herein and unless otherwise indicated, the term “managing” encompasses preventing the recurrence of the particular disease or disorder in a patient who had suffered from it, lengthening the time a patient who had suffered from the disease or disorder remains in remission, reducing mortality rates of the patients, and / or maintaining a reduction in severity or avoidance of a symptom associated with the disease or condition being managed.

[0032] An “effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A “therapeutically effective amount”, as used herein, 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.

[0033] A “response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others.

[0034] As used herein and unless otherwise indicated, the term “relapsed” refers to a disorder, disease, or condition that responded to prior treatment (e.g., achieved a complete response) then had progression. The prior treatment can include one or more lines of therapy.

[0035] As used herein and unless otherwise indicated, the term “refractory” refers to a disorder, disease, or condition that has not responded to prior treatment that can include one or more lines of therapy.

[0036] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percents of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0037] The term “between” includes the endpoint numbers on both limits of the range. For example, the range described by “between 3 and 5” is inclusive of the numbers “3” and “5”.

[0038] As used herein and unless otherwise specified, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describes 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 tetra-alkyl ammonium salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(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.

[0039] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0040] 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.COMPOUNDS

[0041] Provided herein are certain heteroaromatic macrocyclic ether compounds, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the compounds are CNS-penetrant, TRK-sparing, ALK and / or ROS1 inhibitors.

[0042] In one embodiment, provided herein is a compound of Formula (I):(I), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl;R2 is H or methyl;L is CH2, CH(OH), or C=O; and provided that, when L is CH2, then at least one of Ri and R2 is H.

[0043] In one embodiment, Ri is H. In one embodiment, Ri is ethyl.

[0044] In one embodiment, R2 is H. In one embodiment, R2is methyl.

[0045] In one embodiment, Ri and R2 are both H.

[0046] In one embodiment, L is CH2. In one embodiment, when L is CH2, then at least one of Ri and R2 is H. In one embodiment, L is CH2, and Ri is H. In one embodiment, L is CH2, and R2is H. In one embodiment, L is CH2, and both Ri and R2are H.

[0047] In one embodiment, L is CH(OH). In one embodiment, when L is CH(OH), then at least one of Ri and R2is H. In one embodiment, L is CH(OH), and Ri is H. In one embodiment, L is CH(OH), and R2is H. In one embodiment, L is CH(OH), and both Ri and R2are H. In one embodiment, L is CH(OH) and the carbon is of the R chirality. In one embodiment, L is CH(OH) and the carbon is of the S chirality.

[0048] In one embodiment, L is C=O. In one embodiment, L is C=O, Ri is ethyl, and R2 is methyl. In one embodiment, L is C=O, Ri is H, and R2is methyl. In one embodiment, L is C=O, Ri is ethyl, and R2is H. In one embodiment, L is C=O, Ri is H, and R2is H.

[0049] In one embodiment, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof.

[0050] In one embodiment, the compound is a metabolite.

[0051] In one embodiment, provided herein is a compound which is an oxidized form of a compound of Formula (II):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; and R2 is H or methyl.

[0052] In one embodiment, the oxidized form is a compound of Formula (Ila):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; and R2 is H or methyl.

[0053] In one embodiment, the oxidized form is a compound of Formula (Ila-i):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; and R2 is H or methyl.

[0054] In one embodiment, the oxidized form is a compound of Formula (Ila-ii):(Ila-ii), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; andR2 is H or methyl.

[0055] In one embodiment, the oxidized form is a compound of Formula (lib):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; and R2 is H or methyl.

[0056] In one embodiment, the oxidized form is a compound of Formula (lie):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; andR2 is H or methyl.

[0057] In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), Ri is H. In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), Ri is ethyl.

[0058] In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), R2 is H. In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), R2 is methyl.

[0059] In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), Ri is H and R2 is H. In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), Ri is H and R2 is methyl.

[0060] In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), Ri is ethyl and R2 is H. In one embodiment, in the oxidized form of Formula (II), (Ila), (lib), or (lie), Ri is ethyl and R2 is methyl.

[0061] In one embodiment, the oxidized form is selected from the group consisting of:Table 1.

[0062] In one embodiment, the compounds provided herein, including any compound specifically provided in the tables above, have an enantiomeric excess of at least about 1%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 75%, about 90%, about 95%, or about 99%. In one embodiment, the enantiomeric excess is at least 50%. In one embodiment, the enantiomeric excess is at least 75%. In one embodiment, the enantiomeric excess is at least 90%. In one embodiment, the enantiomeric excess is at least 95%. In one embodiment, the enantiomeric excess is at least 99%. In one embodiment, the compounds are R- enantiomer compounds (with regard to the chiral center to which the oxygen is attached to), as provided in, e.g., Table 1.

[0063] In another set of embodiments, provided herein are the corresponding S- enantiomer compounds of the / ^-enantiomer compounds provided herein, including any compound specifically provided in the tables above. In another set of embodiments, provided herein are the corresponding racemic mixtures of the 7?-enantiomer compounds provided herein, including any compound specifically provided in the tables above.

[0064] In one embodiment, the compound provided herein is in the form of a free base. In one embodiment, the compound is in the form of a pharmaceutically acceptable salt. In one embodiment, the salt is selected from the group consisting of alkyl ammonium salts, dialkyl ammonium salts, trialkyl ammonium salts, tetra-alkyl ammonium salts, L-arginine salts, benenthamine salts, benzathine salts, betaine salts, calcium hydroxide salts, choline salts, deanol salts, diethanolamine salts, diethylamine salts, 2-(diethylamino)ethanol salts, ethanolamine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, IH-imidazole salts, lithium salts, L-lysine salts, magnesium salts, 4-(2-hydroxyethyl)morpholine salts, piperazine salts, potassium salts, l-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, Na salts, Ca salts, K salts, Mg salts, and Zn salts. In one embodiment, the pharmaceutically acceptable salt is a solvate comprising a solvent molecule selected from the group consisting of water, methanol, ethanol, and dimethylformamide.

[0065] It is to be understood that, unless otherwise specified, when a compound as described herein is provided as a pharmaceutically acceptable salt (or solvate) thereof, that the weight amount refers to the portion exclusive of the salt (or solvent) portion (i.e., as the free base form of the compound).METHODS OF USE

[0066] In one embodiment, provided herein are methods of treating cancer comprising administering a compound provided herein or a pharmaceutical composition provided herein. In one embodiment, provided herein are methods of using a compound provided herein or a pharmaceutical composition provided herein for treating, preventing or managing cancer.

[0067] In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is a hematologic malignancy.

[0068] In In one embodiment, the cancer is a ROS1 positive cancer. In one embodiment, the cancer comprises expression of an oncogenic ROS1 gene or oncogenic ROS1 gene-fusion. In one embodiment, the oncogenic ROS1 gene or oncogenic ROS1 gene-fusion contains one or more mutations of the human ROS I gene. In one embodiment, the mutations in the oncogenic ROS1 gene or oncogenic ROS1 gene-fusion results in expression of a ROS1 protein with a G2032R mutation.

[0069] In one embodiment, the cancer is an ALK positive cancer. In one embodiment, the cancer comprises expression of an oncogenic ALK gene or oncogenic ALK gene-fusion. In one embodiment, the oncogenic ALK gene or the oncogenic ALK gene-fusion contains one or more mutations of the human ALK gene. In one embodiment, the mutations in the oncogenic ALK gene or the oncogenic ALK gene-fusion results in expression of an ALK protein with one or more mutations selected from the group consisting of G1202R, LI 196M, G1269A, D1203N, and I1171N.

[0070] In one embodiment, the cancer is lung cancer, bile duct cancer, colorectal cancer, angiosarcoma, sarcoma, hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, neuroblastoma, hematological cancer, 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, cholangiocarcinoma, or spitzoid neoplasm.

[0071] In one embodiment, the solid tumor is advanced solid tumor. In one embodiment, the solid tumor is locally advanced solid tumor. In one embodiment, the advanced solid tumor is relapsed after, refractory to, or resistant to the prior treatment by a tyrosine kinase inhibitor (TKI). In one embodiment, the solid tumor is non-small cell lung cancer (NSCLC). In one embodiment, the solid tumor is advanced NSCLC. In one embodiment, the solid tumor is locally advanced NSCLC. In one embodiment, the solid tumor is metastatic. In one embodiment, the solid tumor is CNS metastatic. In one embodiment, the solid tumor is metastatic NSCLC. In one embodiment, the solid tumor is CNS metastatic NSCLC. As used herein and unless otherwise specified, “advanced tumor” refers to a tumor that cannot be cured or grows beyond the initial site of origin, either locally advanced or metastatic.

[0072] In one embodiment, the solid tumor (or cancer) is ALK positive. In one embodiment, the solid tumor is ALK positive NSCLC. In one embodiment, the solid tumor is advanced or metastatic ALK positive solid tumor. In one embodiment, the solid tumor is advanced ALK positive solid tumor. In one embodiment, the solid tumor is advanced ALK positive NSCLC. In one embodiment, the solid tumor is metastatic ALK positive solid tumor. In one embodiment, the solid tumor is locally advanced or metastatic ALK positive solid tumor.In one embodiment, the solid tumor is locally advanced ALK positive solid tumor. In one embodiment, the solid tumor is CNS metastatic ALK positive solid tumor. In one embodiment, the solid tumor is metastatic ALK positive NSCLC. In one embodiment, the solid tumor is CNS metastatic ALK positive NSCLC. In one embodiment, the solid tumor is a locally advanced or metastatic solid tumor harboring an ALK rearrangement or activating ALK mutation.

[0073] In one embodiment, the ALK positive solid tumor or cancer is anaplastic large cell lymphoma, inflammatory myofibroblastic tumors, diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medullary carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, papillary thyroid carcinoma, cholangiocarcinoma, spitzoid tumors, neuroblastoma, or anaplastic thyroid cancer. In certain embodiments, the ALK positive solid tumor is anaplastic thyroid cancer. In one embodiment, the subject has not been treated with a prior therapy. In one embodiment, the subject is naive to (i.e. not receiving) any tyrosine kinase inhibitor (TKI) therapy.

[0074] In one embodiment, the subject has been treated with one or more prior therapies. In one embodiment, the subject has received at least one prior cancer therapy. In one embodiment, the subject has received at least two prior cancer therapies. In one embodiment, the subject has been treated with at least one prior TKI therapy. In one embodiment, the subject has been treated with at least two prior TKI therapies. In one embodiment, the subject has been treated with one prior TKI therapy. In one embodiment, the subject has been treated with two prior TKI therapies. In one embodiment, the subject has been treated with three prior TKI therapies. In one embodiment, the TKI is ALK TKI. In one embodiment, the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib.In certain embodiments, the subject with ALK positive NSCLC has previously received at least one ALK TKI. In certain embodiments, one of the prior ALK TKI is a 2nd or 3rd generation TKI (e.g. ceritinib, alectinib, brigatinib, or lorlatinib). In certain embodiments, the subject with the solid tumor has previously received at least one prior systemic anti cancer therapy. In certain embodiments, the subject with the solid tumor has no satisfactory standard therapy. In certain embodiments, the subject with locally advanced or metastatic ALK positive NSCLC has received 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, brigatinib, or lorlatinib). In certain embodiments, the subject with locally advanced or metastatic ALK positive NSCLC has received 2-3 prior 1st or 2nd-generation ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, orlorl atinib). In certain embodiments, the subject with locally advanced or metastatic ALK positive NSCLC has received 2-3 prior ALK TKIs, with lorlatinib in the 2nd or 3rd line.

[0075] In one embodiment, the subject has not been treated with prior systemic anticancer therapies. In one embodiment, the subject has been treated with up to one prior systemic anticancer therapies. In one embodiment, the subject has been treated with at least one prior systemic anticancer therapies. In one embodiment, the subject has been treated with at least two prior systemic anticancer therapies. In one embodiment, the subject has been treated with one prior systemic anticancer therapies. In one embodiment, the subject has been treated with two prior systemic anticancer therapies.

[0076] In one embodiment, the subject has not been treated with prior chemotherapy. In one embodiment, the subject has been treated with prior chemotherapy. In one embodiment, the subject has been treated with up to two prior chemotherapy. In one embodiment, the subject has been treated with at least one prior chemotherapy. In one embodiment, the subject has been treated with at least two prior chemotherapy. In one embodiment, the subject has been treated with one prior chemotherapy. In one embodiment, the subject has been treated with two prior chemotherapy.

[0077] In one embodiment, the subject has not been treated with prior immunotherapy. In one embodiment, the subject has been treated with prior immunotherapy. In one embodiment, the subject has been treated with up to two prior immunotherapy. In one embodiment, the subject has been treated with at least one prior immunotherapy. In one embodiment, the subject has been treated with at least two prior immunotherapy. In one embodiment, the subject has been treated with one prior immunotherapy. In one embodiment, the subject has been treated with two prior immunotherapy.

[0078] As used herein, “immunotherapy” refers to the treatment of a disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. The immunotherapy can regulate the immune effector cells (e.g. lymphocytes, macrophages, dendritic cells, natural killer cells (NK Cell), cytotoxic T lymphocytes (CTL), etc.) to work together against cancer by targeting abnormal antigens expressed on the surface of tumor cells. Exemplifiedimmunotherapy includes but not limited to checkpoint inhibitors (e.g. anti -cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) inhibitors, and programmed death-ligand 1 (PD-L1) inhibitors). Exemplified PD-1 inhibitors include but are not limited to pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo). Exemplified PD-L1 inhibitors include but are not limited to atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi). Exemplified CTLA-4 inhibitor includes but is not limited to ipilimumab (Yervoy).

[0079] In one embodiment, the solid tumor is advanced or metastatic ALK positive NSCLC, and the subject has been treated with at least one prior ALK TKI therapy. In one embodiment, the at least one prior ALK TKI therapy is ceritinib, alectinib, or brigatinib. In one embodiment, the at least one prior ALK TKI therapy is crizotinib, ceritinib, alectinib, or brigatinib. In one embodiment, the at least one prior ALK TKI therapy is ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the at least one prior ALK TKI therapy is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the subject has been treated with one or more prior systemic anticancer therapies. In one embodiment, the solid tumor is advanced or metastatic ALK positive NSCLC, and the subject has progressed on a prior therapy.

[0080] In one embodiment, the solid tumor is advanced or metastatic ALK positive NSCLC, and the subject has been treated with one prior ALK TKI therapy. In one embodiment, the prior ALK TKI therapy is ceritinib, alectinib, or brigatinib. In one embodiment, the at least one prior ALK TKI therapy is crizotinib, ceritinib, alectinib, or brigatinib. In one embodiment, the at least one prior ALK TKI therapy is ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the at least one prior ALK TKI therapy is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the subject has been treated with < 2 prior chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two prior chemotherapy and / or more than two prior immunotherapy.

[0081] In one embodiment, the solid tumor is advanced or metastatic ALK positive NSCLC, and the subject has been treated with two or three prior ALK TKI therapies. In one embodiment, the two or three prior ALK TKI therapies are selected from crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the subject has been treated with < 2prior chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two prior chemotherapy and / or more than two prior immunotherapy.

[0082] In one embodiment, the solid tumor is advanced or metastatic ALK positive NSCLC, and the subject has been treated with two or three prior ALK TKI therapies. In one embodiment, the solid tumor is advanced or metastatic ALK positive NSCLC, and the subject has been treated with one prior ALK TKI therapy and one ALK TKI is a 2ndor 3rdgeneration TKI (such as ceritinib, alectinib, brigatinib, or lorlatinib). In one embodiment, the second or third prior ALK TKI therapy is lorlatinib. In one embodiment, the subject has been treated with < 2 prior chemotherapy and / or immunotherapy. In one embodiment, the subject has been treated with more than two prior chemotherapy and / or more than two prior immunotherapy.

[0083] In one embodiment, the subject has normal renal function. In one embodiment, the subject has a creatinine clearance of no less than about 90 mL / min (e.g. per Cockcroft-Gault formula). In one embodiment, the subject has a creatinine clearance of no less than about 80 mL / min (e.g. per Cockcroft-Gault formula). In one embodiment, the subject has a creatinine clearance of no less than about 60 mL / min (e.g. per Cockcroft-Gault formula).

[0084] In one embodiment, the compound or pharmaceutical composition is administered once daily (QD). In one embodiment, the compound is administered twice daily (BID).

[0085] In one embodiment, the compound is administered at an amount of from about 5 mg to about 400 mg (by weight of the free base) per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 200 mg per day. In one embodiment, the compound is administered at an amount of from about 20 mg to about 200 mg per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 200 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 200 mg per day. In one embodiment, the compound is administered at an amount of from about 5 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 20 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 125 mg per day. In one embodiment, the compound is administered at an amount of from about 20mg to about 125 mg per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 125 mg per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 100 mg per day. In one embodiment, the compound is administered at an amount of from about 20 mg to about 100 mg per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 100 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 250 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 200 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 125 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 100 mg per day. In one embodiment, the compound is administered at an amount of from about 10 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 10 mg to about 100 mg per day. In one embodiment, the compound is administered at an amount of from about 10 mg to about 50 mg per day. In one embodiment, the compound is administered at an amount of from about 10 mg to about 25 mg per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 100 mg per day. In one embodiment, the compound is administered at an amount of from about 15 mg to about 50 mg per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 150 mg per day. In one embodiment, the compound is administered at an amount of from about 100 mg to about 150 mg per day.

[0086] In one embodiment, the compound is administered at 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, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg per day.

[0087] 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. In one embodiment, the amount is about 200 mg per day. In one embodiment, the amount is about 250 mg per day. As used herein, the weight amount refers to the weight amount of the free base of the compound.

[0088] In one embodiment, the compound is administered at an amount of from about 5 mg to about 400 mg (by weight of the free base) once daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 250 mg once daily. In one embodiment, the compound is administered at an amount of about 15 mg to about 200 mg once daily. In one embodiment, the compound is administered at an amount of about 25 mg to about 200 mg once daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 200 mg once daily. In one embodiment, the compound is administered at an amount of from about 50 mg to about 200 mg once daily. In one embodiment, the compound is administered at an amount of from about 5 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 100 mg once daily. In one embodiment, the compound is administered at an amount of about 10 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of about 15 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of about 25 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of about 50 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of about 100 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of about 20 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 150 mg once daily. In one embodiment, the compound is administered at an amount of about 25 mg to about 100 mg once daily. In one embodiment, the compound is administered atan amount of from about 25 mg to about 50 mg once daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 125 mg once daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 100 mg once daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 100 mg once daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 50 mg once daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 100 mg once daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 100 mg once daily. In one embodiment, the compound is administered at an amount of from about 50 mg to about 100 mg once daily. In one embodiment, the compound is administered at an amount of from about 50 mg to about 125 mg once daily. In one embodiment, the compound is administered at an amount of from about 50 mg to about 100 mg once daily. In one embodiment, the compound is administered at 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, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg once daily. 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 daily. In one embodiment, the amount is about 150 mg once daily. In one embodiment, the amount is about 200 mg once daily. In one embodiment, the amount is about 250 mg once daily. As used herein, the weight amount refers to the weight amount of the free base of the compound.

[0089] In one embodiment, the compound is administered at an amount of from about 5 mg to about 400 mg (by weight of the free base) twice daily. In one embodiment, the compoundis administered at an amount of from about 5 mg to about 250 mg twice daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 250 mg twice daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 250 mg twice daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 200 mg twice daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 150 mg twice daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 100 mg twice daily. In one embodiment, the compound is administered at an amount of from about 20 mg to about 200 mg twice daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 200 mg twice daily. In one embodiment, the compound is administered at an amount of from about 5 mg to about 100 mg twice daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 100 mg twice daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 50 mg twice daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 50 mg twice daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 100 mg twice daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 100 mg twice daily. In one embodiment, the compound is administered at an amount of from about 50 mg to about 100 mg twice daily. In one embodiment, the compound is administered at an amount of from about 5 mg to about 150 mg twice daily. In one embodiment, the compound is administered at an amount of from about 10 mg to about 150 mg twice daily. In one embodiment, the compound is administered at an amount of from about 15 mg to about 150 mg twice daily. In one embodiment, the compound is administered at an amount of from about 20 mg to about 150 mg twice daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 150 mg twice daily. In one embodiment, the compound is administered at 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, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg twice daily. In one embodiment, the amount is about 5mg 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. In one embodiment, the amount is about 200 mg twice daily. In one embodiment, the amount is about 250 mg twice daily. As used herein, the weight amount refers to the weight amount of the free base of the compound.

[0090] In one embodiment, the compound is administered orally.

[0091] 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 the free base of the compound. In one embodiment, the tablet has a unit dose strength of about 50 mg by weight of the free base of the compound. In one embodiment, the tablet has a unit dose strength of about 75 mg by weight of the free base of the compound. In one embodiment, the tablet has a unit dose strength of about 100 mg by weight of the free base of the compound. In one embodiment, the tablet has a unit dose strength of about 125 mg by weight of the free base of the compound. In one embodiment, the tablet has a unit dose strength of about 150 mg by weight of the free base of the compound.

[0092] In one embodiment, the compound is administered to a subject with an empty stomach. In one embodiment, the compound is administered to a subject at least 1 hour before and no sooner than 2 hours after ingestion of food and / or beverages other than water. In one embodiment, the compound is administered to a subject with a full stomach. In one embodiment, the compound is administered with the ingestion of food and / or beverages.

[0093] In one embodiment, the subject experiences improvement in one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disturbances, dizziness, ataxia, seizure, psychotic effect, speech disorder, and weight gain, after the administration of compound 1 (e.g. compared to the prior TKI treatment). In oneembodiment, the subject does not experience one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disturbances, dizziness, ataxia, seizure, psychotic effect, speech disorder, and weight gain, after the administration of the compound. In one embodiment, the subject experiences reduced levels of one or more of pALK, pERK, pAKT, and phospho-S6, after the administration of the compound. In one embodiment, the subject experiences reduced levels of pALK, after the administration of the compound. In one embodiment, the subject experiences reduced levels of pERK, after the administration of the compound. In one embodiment, the subject experiences reduced levels of pAKT, after the administration of the compound. In one embodiment, the subject experiences reduced levels of phospho-S6, after the administration of the compound. In one embodiment, the subject experiences increased levels of cleaved PARP, after the administration of the compound. In one embodiment, the subject experiences reduced activity of MAP kinase pathway, PI3K / AKT pathway, or JAK / STAT pathway, or any combination thereof in tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of MAP kinase pathway, PI3K / AKT pathway, or JAK / STAT pathway, or any combination thereof in solid tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of MAP kinase pathway in tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of MAP kinase pathway in solid tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of PI3K / AKT pathway in tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of PI3K / AKT pathway in solid tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of JAK / STAT pathway in tumor, after the administration of the compound. In one embodiment, the subject experiences reduced activity of JAK / STAT pathway in solid tumor, after the administration of the compound. In one embodiment, the subject experiences increased expression level of one or more marker of apoptosis in tumor, after the administration of the compound. In one embodiment, the subject experiences increased expression level of one or more marker of apoptosis in solid tumor, after the administration of the compound. In one embodiment, the subject experiences decreased level of one or more marker of proliferation (e.g. Ki 67) in tumor, after the administration of the compound. In one embodiment, the change in level of one or more marker provided herein is experienced 1 hour after the administration of thecompound. In one embodiment, the change in level of one or more marker provided herein is experienced 12 hours after the administration of the compound.

[0094] In some embodiments, the cancer is a disease of uncontrolled cell proliferation that results from alterations in certain genes. Some of these alterations occur in genes that encode receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that transmit signals from outside the cell to promote cell survival, growth, and proliferation. Aberrant RTK activation can lead to excessive cell growth and hence cancer. Generally, RTKs contain an N- terminal domain that binds extracellular ligands, a transmembrane domain, and a C-terminal kinase domain that catalyzes intracellular signal transduction.

[0095] In some embodiments, the compound is an inhibitor of human anaplastic lymphoma kinase (ALK). ALK, also known as cluster of differentiation 246 (CD246), is an RTK encoded by the ALK gene. ALK and ROS1 are evolutionarily related; both belong to the insulin receptor superfamily, and their kinase domains share around 80% sequence similarity. A few ALK ligands in humans have been identified, including pleiotrophin and midkine growth factors. While the roles of ALK in humans remain inconclusive, much evidence from mouse studies suggests that it is important for the development of the nervous system. Like ROS1, ALK chromosomal rearrangements also lead to constitutively active fusion proteins that promote oncogenic transformation through MAPK, JAK / STAT, or other signaling pathways. ALK rearrangements represent 3-5% of NSCLC, roughly half of anaplastic large-cell lymphoma (ALCL), and a subset of many other cancers, with the predominant fusions being EML4-ALK for NSCLC and NPM1-ALK for ALCL. Oncogenic point mutations and amplification of ALK have also been observed, albeit at a much lower frequency than translocations. Crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are FDA-approved TKIs for the treatment of ALK- positive NSCLC and other cancers, either in front-line or after prior therapy. Crizotinib, for example, shows an overall response rate of 60-80% and median progression-free survival of 8-11 months, which is comparable to its activity in ROSl-positive NSCLC. Despite an initial response, many resistance mutations have emerged to the aforementioned FDA-approved TKIs. Some of these mutations, such as the combined LI 196M gatekeeper and G1202R solvent front mutation, are resistant to all of the approved drugs. New treatments of ALK-positive cancer harboring resistance mutations are a need in the art.

[0096] In one embodiment, a compound provided herein selectively inhibits ALK. In one embodiment, the compound selectively inhibits ALK over ROS1. By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 1.5, greater than a factor of about 2, than a factor of about 3, greater than a factor of about 4, greater than a factor of about 5, or greater than a factor of about 10, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ALK over ROS1 is measured by the ratio of the IC50 value against ROS1 to the IC50 value against ALK.

[0097] In one embodiment, the compound selectively inhibits ALK over TRK (e.g., TRKA, TRKB, and / or TRBC). By way of non-limiting example, the ratio of selectivity can be greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 50, greater than a factor of about 100, greater than a factor of about 200, greater than a factor of about 400, greater than a factor of about 600, greater than a factor of about 800, greater than a factor of about 1000, greater than a factor of about 1500, greater than a factor of about 2000, greater than a factor of about 5000, or greater than a factor of about 10,000, where selectivity can be measured by ratio of IC50 values, among other means. In one embodiment, the selectivity of ALK over TRK is measured by the ratio of the IC50 value against TRK to the IC50 value against ALK.

[0098] In one embodiment, provided herein is a method for selectively inhibiting ALK over ROS1 wherein the inhibition takes place in a cell. In one embodiment, provided herein is a method for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) wherein the inhibition takes place in a cell. In one embodiment, the method comprises contacting ALK with an effective amount of a compound provided herein. In an embodiment, such contact occurs in a cell. In an embodiment, such contact occurs in a cell in a mammal such as a human. In an embodiment, such contact occurs in a cell in human subject having a cancer provided herein.

[0099] In one embodiment, provided herein is a method for selectively inhibiting ALK over ROS1 wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound or a pharmaceutical composition provided herein to said subject. In certain embodiments, provided herein is a method of treating a subject suffering from a cancer associated with ALK, said method comprising selectively inhibiting ALK over ROS1 by administering an amount of a compound or a pharmaceuticalcomposition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ALK over RO SI .

[0100] In one embodiment, provided herein is a method for selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering an effective amount of a compound or a pharmaceutical composition provided herein to said subject. In certain embodiments, provided herein is a method of treating a subject suffering from a cancer associated with ALK, said method comprising selectively inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC) by administering an amount of a compound or a pharmaceutical composition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ALK over TRK (e.g., TRKA, TRKB, and / or TRBC).

[0101] As used herein and unless otherwise specified, inhibition of ALK includes inhibition of wild type ALK, or a genetically altered ALK such as a mutation, a rearrangement, or amplification or copy gain thereof, or a partially deleted ALK protein.

[0102] Cancers treated by methods of the present disclosure include, but are not limited to, lung cancer, e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovarian carcinoma, melanoma, e.g., spitzoid melanoma, glioblastoma, bile duct cancer, 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 cancer, neuroblastoma, epithelioid hemangioendothelioma, colon cancer, and spitzoid tumor.

[0103] In one embodiment, cancers treated by methods of the present disclosure include cancers originating from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by methods of the present disclosure include cancers that are drug resistant to treatments directed at one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC.

[0104] In one embodiment, the cancer in a method provided herein is anaplastic lymphoma kinase positive (ALK+). As used herein and unless otherwise specified, an “ALKpositive” (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriate (e.g., inappropriately high) expression of an ALK gene and / or the presence of a mutation in an ALK gene and / or the presence of a partially deleted ALK protein, and / or a mutation in the ALK protein, and / or is mediated by ALK, and / or that responds to inhibition of ALK. In one embodiment, “ALK positive” (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of an ALK gene and / or the presence of a mutation in an ALK gene, or is mediated by ALK. In one embodiment, “ALK positive” (ALK+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by the presence of a partially deleted ALK protein (e.g., NB1, AskaSS). In one embodiment, “ALK positive” (ALK+) cancer is mediated by a genetically altered ALK. In some embodiments, the cancer, disease, or disorder carries ALK wild-type gene or genetically altered ALK gene. In one embodiment, “ALK positive” (ALK+) cancer is mediated by a fusion protein comprising a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM, EML4, TPR, TFG, ATIC, CLTC1, TPM4, MSN AL017, and MYH9. In one embodiment, the fusion protein is one or more of an EML4-ALK fusion protein, an NPM-ALK fusion protein, or a TPR- ALK fusion protein. In some embodiments, the genetically altered ALK is an EML4-ALK fusion protein. In some embodiments, the EML4-ALK fusion protein is a wild-type protein. In some embodiments, the EML4-ALK fusion protein comprises at least one resistance mutation. In some embodiments, the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of L1196M, G1202R, D1203N, L1152P / R, F1174C / L / V, C1156Y, Il 17 IN, G1123S, S1206Y, G1269S / A, and T1151 LI 152insT. In some embodiments, the EML4-ALK fusion protein comprises at least one mutation selected from the group consisting of G1202R, G1202K, L 1196M, G1269A, G1269V, C 1156Y, Il 171 T, 1117 IN, Il 171 S, F 11741, F 1174L, F 1174S, V1180L, S1206Y, E1129K, E1210K, T1151M, T1151_L1152insT, F1174C, G1202del, D1203N, S1206C, S1206F, LI 152R, LI 196Q, LI 198P, LI 198F, LI 198H, R1275Q, LI 152P, C1156T, F1245C, T1151K, I1268V, Fl 174V, LI 198Q, S1206A, and F1245V.

[0105] In one embodiment, “ALK positive” (ALK+) cancer is mediated by a fusion protein comprising a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by a gene selected from the group consisting of NPM gene. In some embodiments, the genetically altered ALK is an NPM-ALK fusion protein. In some embodiments, the fusionprotein comprises a fragment of a protein encoded by an ALK gene and a fragment of a protein encoded by a TPR gene. In some embodiments, the genetically altered ALK is a TPR-ALK fusion protein. In some embodiments, the TPR-ALK fusion protein contains a wild-type kinase domain. In some embodiments, the TPR-ALK fusion protein comprises at least one resistance mutation. In some embodiments, the TPR-ALK fusion protein comprises a LI 196M mutation.

[0106] In one embodiment, the mutation alters the biological activity of an ALK nucleic acid molecule or polypeptide. As used herein and unless otherwise specified, a “mutation” or “mutant” of ALK comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, amplifications, or missense mutations, in the amino acid or nucleotide sequences of ALK, or fragments thereof. As used herein and unless otherwise specified, an ALK “rearrangement” refers to genetic translocations involving the ALK gene that may result in ALK fusion genes and / or ALK fusion proteins. The ALK fusion can also include one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications or a fragment thereof, as long as the mutant retains kinase phosphorylation activity.

[0107] In some embodiments, provided here is a method of treating a cancer in a subject, comprising identifying a generically altered ALK in the subject and administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the ALK mutation comprises one or more ALK point mutations. In some embodiments, cancers treated by methods of the present disclosure include one or more mutations in ALK kinase. In one embodiment, the one or more ALK point mutations are selected from point mutations at T1151, LI 152, Cl 156, Il 171, Fl 174, VI 180, LI 196, LI 198, G1202, D1203, S1206, El 129, E1210, F1245, G1269, and R1275. In one embodiment, the one or more ALK point mutations is selected from R1060H, F 1 174C7I / L / S / V, F1245C / I / L / V, R1275L / Q, T1 15 IM, Ml I66R, 11171 N, 11171 S, 11171N, Il 183T, L1196M, 1200V, L12 4F, LI 240V, D1270G, Y1278S, R1192P, G1 128A, G1286R, and T1343I. In one embodiment, the one or more ALK point mutations are selected from G1202R, G1202K, L 1196M, G1269A, G1269V, C 1156Y, Il 171 T, 1117 IN, Il 171 S, F 11741, F 1174L, F 1174S, V1180L, S1206Y, El 129K, E1210K, T1151M, T1151 LI 152insT, Fl 174C, G1202del,D1203N, S1206Y, S1206C, S1206F, LI 152R, LI 196Q, LI 198P, LI 198F, LI 198H, R1275Q, L 1152P, C 1156T, F 1245C, T 115 IK, 11268 V, F 1174V, L 1198Q, S 1206A, and F 1245V. In one embodiment, the ALK mutation is G1202R. In one embodiment, the ALK mutation is LI 196M. In one embodiment, the ALK mutation is G1269A. In one embodiment, the ALK mutation is G1269V. In one embodiment, the ALK mutation is LI 198F. In one embodiment, the ALK mutation is LI 198H. In one embodiment, the ALK mutation is T115 IM. In one embodiment, the ALK mutation is Fl 174L. In one embodiment, the ALK mutation is Fl 1741. In one embodiment, the ALK mutation is Fl 174S. In one embodiment, the ALK mutation is II 171N. In one embodiment, the ALK mutation is II 171 S. In one embodiment, the ALK mutation is Il 171T. In one embodiment, the ALK mutation is II 171N. In one embodiment, the ALK mutation is El 129K. In one embodiment, the ALK mutation is S1206F. In one embodiment, the ALK mutation is E1210K. In one embodiment, the ALK mutation is D1203N. In one embodiment, the ALK mutation is R1275G. In one embodiment, the ALK mutation is F1245C. In one embodiment, the ALK mutation is T115 IK. In one embodiment, the ALK mutation is I1268V. In one embodiment, the ALK mutation is Fl 174V. In one embodiment, the ALK mutation is LI 198Q. In one embodiment, the ALK mutation is S1206A.

[0109] As used herein and unless otherwise specified, a “co-mutation” refers to cooccurring mutations, i.e. when two or more mutations are present at the same time, for example in the same cell and on the same allele, in the same cell but on different alleles, or in different cells.

[0110] As used herein and unless otherwise specified, a “compound mutation” refers two or more mutations located on the same allele. A compound mutation is a subset of co-mutations. Compound mutations are also sometimes referred to as dual mutations if there are two mutations located on the same allele.

[0111] In some embodiments, the ALK mutation is co-mutation of G1202R and one or more mutations selected from L1196M, G1269A, T115 IM, Fl 174S, and LI 198F. In one embodiment, the ALK mutation is G1202R / L1196M compound mutation. In one embodiment, the ALK mutation is G1202R / G1269A compound mutation. In one embodiment, the ALK mutation is G1202R / L1198F compound mutation. In one embodiment, the ALK mutation is G1202R / T115 IM compound mutation. In one embodiment, the ALK mutation isG1202R / F1174S compound mutation. In one embodiment, the ALK mutation isG1202R / F1174L compound mutation. In one embodiment, the ALK mutation is co-mutation of C1156Y and one or more mutations selected from L1256F, S1206F, Fl 174V, and Fl 1741. In one embodiment, the ALK mutation is Cl 156Y / L1256F compound mutation. In one embodiment, the ALK mutation is Cl 156Y / S1206F compound mutation. In one embodiment, the ALK mutation is Cl 156Y / F1174V compound mutation. In one embodiment, the ALK mutation is Cl 156Y / F11741 compound mutation. In one embodiment, the ALK mutation is comutation of LI 196M and one or more mutations selected from LI 198H, Il 179V, and L1256F. In one embodiment, the ALK mutation is LI 196M / L1198H compound mutation. In one embodiment, the ALK mutation is LI 196M / Il 179V compound mutation. In one embodiment, the ALK mutation is LI 196M / L1256F compound mutation.

[0112] In one embodiment, the ALK mutation is G1202R / L1196M dual mutation. In one embodiment, the ALK mutation is G1202R / G1269A dual mutation. In one embodiment, the ALK mutation is G1202R / L1198F dual mutation. In one embodiment, the ALK mutation is G1202R / T1151M dual mutation. In one embodiment, the ALK mutation is G1202R / F1174S dual mutation. In one embodiment, the ALK mutation is G1202R / F1174L dual mutation. In one embodiment, the ALK mutation is Cl 156Y / L1256F dual mutation. In one embodiment, the ALK mutation is Cl 156Y / S1206F dual mutation. In one embodiment, the ALK mutation is Cl 156Y / F1174V dual mutation. In one embodiment, the ALK mutation is Cl 156Y / F11741 dual mutation. In one embodiment, the ALK mutation is LI 196M / L1198H dual mutation. In one embodiment, the ALK mutation is LI 196M / Il 179V dual mutation. In one embodiment, the ALK mutation is LI 196M / L1256F dual mutation.

[0113] 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, cancers treated by methods of the present disclosure include ALK fusions. 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 with one of the fusion partners selected from the group consisting of EML4, TFG, KIF5B, KLC1, STRN, HIP1, TPR, BIRC6, DCTN1, SQSTM1, S0CS5, SEC31A, CLTC, PRKAR1A, PPM1B, EIF2AK3, CRIM1, CEBPZ,PICALM, CLIP!, BCL11 A, GCC2, LM07, PHACTR1, CMTR1, VIT, DYSF, ITGAV, PLEKHA7, CUX1, VK0RC1L1, FBXO36, SPTBN1, EML6, FBXO11, CLIP4, CAMKMT, NCOA1, MYT1L, SRBD1, SRD5A2, NYAP2, MPRIP, ADAM17, ALK, LPIN1, WDPCP, CEP55, ERC1, SLC16A7, 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, TANCI, 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, MSN, AL017, MYH9 and KIF5B. In one embodiment, the ALK mutation is EML4-ALK, 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 (vl) and variant 3 (v3) being the most prevalent clinically. In one embodiment, the ALK mutation is NPM1-ALK. In one embodiment, the ALK mutation is STRN-ALK.

[0114] In one embodiment, the ALK mutation comprises one ALK rearrangement and one or more ALK point mutations. In one embodiment, the ALK mutation is EML4-ALK wt (variant 1). In one embodiment, the ALK mutation is EML4-ALK (variant 2). In one embodiment, the ALK mutation is EML4-ALK (variant 3). In one embodiment, the ALK mutation is EML4-ALK wt (variant 4, 5, 6, or 7). In one embodiment, the ALK mutation is EML4-ALK G1202R. In one embodiment, the ALK mutation is EML4-ALK II 171N. In one embodiment, the ALK mutation is EML4-ALK II 171S. In one embodiment, the ALK mutation is EML4-ALK II 171T. In one embodiment, the ALK mutation is EML4-ALK LI 196M. In one embodiment, the ALK mutation is EML4-ALK D1203N. In one embodiment, the ALK mutation is EML4-ALK LI 196M / G1202R. In one embodiment, the ALK mutation is EML4- ALK G1202R / G1269A. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1196M. In one embodiment, the ALK mutation is EML4-ALK G1202R / L1198F. In one embodiment, the ALK mutation is EML4-ALK G1202R / T1151M. In one embodiment, theALK mutation is EML4-ALK G1202R / F1174S. In one embodiment, the ALK mutation is EML4-ALK G1202R / F1174L.

[0115] In one embodiment, the ALK positive solid tumor is characterized by the presence of a mutation in an ALK gene. In one embodiment, the ALK mutation comprises one or more ALK rearrangement, one or more ALK point mutation, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, Fl 174S, S1206Y, E1210K, T1151M, T1151 L1152insT, D1203N, S1206C, LI 152R, LI 196Q, LI 198P, LI 198F, R1275Q, LI 152P, Cl 156T, or F1245V, or a combination thereof. In one embodiment, the ALK mutation comprises G1202R. In one embodiment, the ALK mutation comprises Fl 174S or Fl 174L. In one embodiment, the ALK mutation comprises II 171 S. In one embodiment, the ALK mutation comprises II 171T. In one embodiment, the ALK mutation comprises II 171N. In one embodiment, the ALK mutation comprises Fl 171M. In one embodiment, the ALK mutation comprises D1203N and one selected from II 171 S, Il 171T, Il 171N, and II 171M. In one embodiment, the ALK mutation comprises Cl 156Y and one selected from II 171 S, 11171 T, I1171N, and I1171M. In one embodiment, the ALK mutation comprises R1275Q. In one embodiment, the ALK mutation comprises Ti l 5 IM. In one embodiment, the ALK mutation comprises one or more compound mutations. In one embodiment, the compound mutation is G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, or G1202R / F1174S. In one embodiment, the compound mutation is G1202R / L1196M. In one embodiment, the compound mutation is G1202R / G1269A. In one embodiment, the compound mutation is G1202R / L1198F. In one embodiment, the compound mutation is G1202R / F1174S. In one embodiment, the ALK positive solid tumor is characterized by the presence of a partially deleted ALK protein. In one embodiment, the ALK mutation is Ex2-3del. In one embodiment, the ALK mutation is Ex2- 17del.

[0116] In one embodiment, partially deleted ALK proteins influence proliferative and metastatic properties of cancer cells. ALK protein can become partially deleted through various mechanisms. The first mechanism is shedding, where the 80-kDa extracellular domain of the ALK protein is post-translationally cleaved near residue Asn654, leaving the 140-kDa C- terminal transmembrane and intracellular domains on the cell. Shedding has been observed in many ALK-expressing cell lines, most notably from a neuroblastoma disease background.Shedding increases cancer cell migration and proliferation in preclinical models of cancer, both in vitro and in vivo (Moog-Lutz, JBC (2005), Huang, Cell Reports (2021)). The second mechanism is alternative transcription initiation (ATI), where transcription of the ALK gene begins at an alternative initiation site downstream of the original site, resulting in the absence of exons 1-18 and part of exon 19. ALK ATIs have been identified in 11% of melanomas as well as a small portion of lung cancers and anaplastic thyroid cancers. Expression of ALK ATI transforms Ba / F3 and NIH3T3 cells, conferring them with oncogenic potential. One patient with ALK ATI has shown clinical response to an ALK inhibitor therapy, suggesting that ALK ATI may be a targetable driver mutation (Wiesner, Nature (2015)). The third mechanism is partial deletion of the ALK gene, for example through a chromosomal rearrangement event. Multiple deletion variants have been identified, including deletion of exons 2-3, exons 1-5, exons 4-11, and exons 2-17, and some of these variants have been shown to activate ALK signaling as well as transform Ba / F3 orNIH3T3 cells. ALK partial deletions have been detected in neuroblastomas, sarcomas, and lymphomas. (Okubo, Oncogene (2012); Cazes, Can Res (2013); Fransson, Genes Chromosomes & Cancer (2014); Fleuren, Can Res (2017); Fukuhara, Hematol Oncol (2017)).

[0117] In one embodiment, the ALK+ cancer is determined by an FDA-approved test or other tests known in the art. The tests that can be used include, but not limited to, e.g., FoundationOne CDx™ (FICDx) (a sequencing based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) and selected gene rearrangements, as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) using DNA isolated from formalin-fixed paraffin embedded (FFPE) tumor tissue specimens); VENTANA ALK (D5F3) CDx Assay (qualitative detection of the anaplastic lymphoma kinase (ALK) protein in formalin-fixed, paraffin- embedded (FFPE) non-small cell lung carcinoma (NSCLC) tissue stained with the BenchMark XT or BenchMark ULTRA automated staining instrument); and Vysis ALK Break Apart FISH Probe Kit test (a qualitative test to detect rearrangements involving the ALK gene via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin-embedded (FFPE) non- small cell lung cancer (NSCLC) tissue specimens). In one embodiment, the test is a fluorescence in situ hybridization (FISH) test, e.g., Vysis ALK Break Apart FISH Probe Kit test. Additional information for FDA-approved tests can be found at, e.g.,https: / / www.fda.gov / MedicalDevices / ProductsandMedicalProcedures / InVitroDiagnostics / ucm30 3030.htm; and additional information for Vysis ALK Break Apart FISH Probe Kit can be found at, e.g., https: / / www.molecular.abbott / us / en / products / oncology / vysis-alk-break-apart-fish-probe- kit; the entirety of which are incorporated herein by reference.

[0118] In one embodiment of any of the methods described herein, the presence of an ALK mutation in the sample indicates that the subject has or is at increased risk for developing an ALK positive (e.g. ALK-driven) cancer. In other embodiments, the presence of the mutation in the sample indicates that the subject has or is at increased risk for developing an ALK positive (e g. ALK-driven) cancer refractory to treatment with a TKI. In particular embodiments, the presence of the mutation in the sample indicates that the subject has or is at increased risk for developing an ALK positive (e.g. ALK-driven) cancer refractory to treatment with to one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and ASP3026. In particular embodiments, the presence of the mutation in the sample indicates that the subject has or is at increased risk for developing an ALK positive (e.g. ALK-driven) cancer refractory to treatment with to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In some embodiments, the ALK protein or ALK-fusion protein includes a contiguous sequence of between 30 and 1620 amino acids that has at least 95% identity to the amino acid sequence of the ALK [Homo sapiens] (NCBI Reference Sequence: NP 004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiments, the ALK protein or ALK-fusion protein includes a contiguous sequence of between 30 and 1620 amino acids that has at least about 85% identity to the amino acid sequence of the ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiments, where the ALK protein or ALK-fusion protein includes a contiguous sequence of between 30 and 1620 amino acids that has at least about 90% identity to the amino acid sequence of the ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiments, where the ALK protein or ALK-fusion protein includes a contiguous sequence of between 30 and 1620 amino acids that has at least about 95% identity to the amino acid sequence of the ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence). In another non-limiting embodiments, where the ALK protein or ALK-fusion protein includes a contiguous sequence of between 30 and 1620 amino acids that has at least about 85-90%, 91-93%, 94%,95%, 96%, 97%, 98%, or 99% identity to the amino acid sequence of ALK [Homo sapiens] (NCBI Reference Sequence: NP_004295.2 or UniProt Sequence No.: Q9UM73 sequence).

[0119] Also provided are methods of treating a subject having a cancer (e.g., an ALK positive cancer) that include: determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered a first ALK inhibitor, has one or more ALK inhibitor resistance mutations; and administering the compound or a pharmaceutically acceptable salt thereof as a monotherapy or in combination with another anticancer agent to the subject if the subject has a cancer cell that has one or more ALK inhibitor resistance mutations. In some embodiments, the one or more ALK inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first ALK inhibitor. In some embodiments, the one or more ALK inhibitor resistance mutations include one or more ALK inhibitor resistance mutations. For example, the one or more ALK inhibitor resistance mutations can include one or more point mutations at one or more of amino acid positions 1202, 1196, 1269, 1156, 1171, 1174, 1180, 1206, 1210, 1151, 1203, 1152, 1198, 1275, and 1245, e.g., G1202R, LI 196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, F1174S, V1180L, S1206Y, E1210K, T 115 IM, T 1151_L 1152insT, F 1174C, G1202del, D 1203N, S 1206Y, S 1206C, L 1152R, L 1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V. In some embodiments, another anticancer agent is any anticancer agent known in the art. For example, another anticancer agent can be another ALK inhibitor (e.g., a second ALK inhibitor).

[0120] In one embodiment, a compound provided herein is a CNS-penetrating compound. In one embodiment, after the administration of an effective amount of a compound provided herein (e.g., orally or intravenously), the compound is able to penetrate CNS (e.g., blood-brain barrier) and achieve a concentration in CNS (e.g., brain) that is still sufficient to inhibit (e.g., selectively inhibit) ALK.

[0121] In one embodiment, provided herein is a method for treating CNS metastases of a cancer, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the CNS metastases is brain metastases. In one embodiment, the cancer is an ALK+ cancer.

[0122] In one embodiment, the solid tumor (or cancer) is leukocyte receptor tyrosine kinase (LTK) positive. In one embodiment, the solid tumor is LTK positive breast invasiveductal 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(l ):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 are incorporated herein by reference in their entirety.

[0123] In one embodiment, the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C. In certain embodiments, the IC50 of the compound for inhibition of mutant or non-mutant ALK is no more than one-fifth of the IC50 of the compound for inhibition of wildtype tropomyosin receptor kinase A, B, or C. TRK inhibition, particularly in the central nervous system (CNS), has been associated with adverse reactions, including dizziness / ataxia / gait disturbance, paraesthesia, weight gain and cognitive changes.

[0124] In some embodiments, provided is a method of minimizing adverse events in a subject in need of treatment for cancer (e g., an ALK positive cancer), the method comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, and wherein the method minimizes adverse events associated with TRK inhibitors. In some embodiments, the cancer is an ALK-associated (or ALK+) cancer. In some embodiments, the adverse events are TRK-related CNS adverse events.

[0125] As used herein “minimizing” adverse events refers to a reduction in the incidence of adverse events in a subject or patient population compared to the paradigmatic incidence of adverse events in a subject or patient population treated with TRK inhibitors (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 over 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 adverse eventsrefers to minimizing TRK-related CNS adverse events. In some embodiments, minimizing TRK-related CNS adverse events means less than 40% of the patient population has a TRK- related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10% or less than 5% of the patient population has a TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means less than 12% of the patient population have more than one TRK-related CNS adverse event. In some embodiments, minimizing TRK-related CNS adverse events means 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 have more than one TRK-related CNS adverse event.

[0126] In some embodiments, TRK-related CNS adverse events refers to one or more of the following: dizziness, ataxia, gait disturbance, paraesthesia, weight gain, hyperphagia, paresthesias, abnormal movement, cognitive changes, speech effects (e.g, dysarthria, slow speech, or speech disorder), mood disorder (e.g., irritability, anxiety, depression, affect lability, personality change, mood swings, affective disorder, aggression, agitation, mood altered, depressed mood, euphoric mood, or mania), and cognitive disorder (e.g., memory impairment, cognitive disorder, amnesia, confusion, disturbance in attention, delirium, mental impairment, attention deficit / hyperactivity disorder, dementia, sleep disturbance, or reading disorder).

[0127] In one embodiment, provided herein is a method for preventing or limiting TRK- related CNS side effect or adverse event in a cancer treatment, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the method prevents the occurrence of the TRK-related CNS adverse event. In one embodiment, the method limits the frequency of occurrence of the TRK- related CNS adverse event. In one embodiment, the method limits the severity of the TRK- related side effect. In one embodiment, provided herein is a method for treating CNS metastases of a cancer with reduced TRK-related side effect, comprising administering to a subject in need thereof an effective amount of the compound or a pharmaceutically acceptable salt thereof. In one embodiment, the reduction / limiting / prevention in CNS side effect or adverse event is determined in a statistical sample, as compared to a standard of care treatment, e g., an approved ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib) for ALK+ cancer. In one embodiment, the TRK-related side effect is a TRKB-related CNS side effect. In oneembodiment, the TRK -related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paraesthesia, weight gain, cognitive impairment, a mood disorder, or sleep disturbance.

[0128] 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 or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a cancer mediated by ALK. In one embodiment, the cancer is an ALK-associated cancer. In one embodiment, the cancer is an ALK+ cancer. In one embodiment, the cancer is identified to be ALKA

[0129] In one embodiment, provided herein is a method for treating an ALK+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

[0130] In one embodiment, provided herein is a method for treating cancer in a subject, comprising: (i) identifying the cancer in the subject to be ALK+, and (ii) administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.

[0131] In one embodiment, the cancer (or ALK+ cancer) is a solid tumor. In one embodiment, the cancer (or ALK+ cancer) is lung cancer, e.g., non-small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, e.g., cholangiocarcinoma, ovarian cancer, e.g., serous ovarian carcinoma, 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 cancer, spitzoid tumor, pancreatic cancer, inflammatory hepatocellular adenoma, or neuroblastoma. In one embodiment, the cancer (or ALK+ cancer) is ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER;breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, inirahepaticcholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary- analogue carcinoma, acute myeloid leukemia, congenital mesobl stic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer.

[0132] 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 advanced or metastatic non-small cell lung cancer. In one embodiment, the cancer is ALK+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ALK+ 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 ALK+ non-small cell lung cancer.

[0133] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is relapsed or refractory glioblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma.

[0134] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ALK+ IMT. In one embodiment, the cancer is relapsed or refractory IMT. In one embodiment, the cancer is relapsed or refractory ALK+ IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ALK+ IMT.

[0135] In one embodiment, the cancer is bile duct cancer. In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ALK+ cholangiocarcinoma. In one embodiment, the cancer is relapsed or refractory cholangiocarcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ALK+ cholangiocarcinoma. In one embodiment, the cholangiocarcinoma patient has STRN-ALK fusion mutation. In one embodiment, the cholangiocarcinoma patient has progressed on alectinibtreatment. In one embodiment, the cholangiocarcinoma patient has acquired G1202R resistance mutation.

[0136] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ALK+ ovarian cancer. In one embodiment, the cancer is relapsed or refractory ovarian cancer. In one embodiment, the cancer is relapsed or refractory ALK+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ALK+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian carcinoma. In one embodiment, the ovarian cancer is high grade serous ovarian carcinoma.

[0137] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ALK+ gastric cancer. In one embodiment, the cancer is relapsed or refractory gastric cancer. In one embodiment, the cancer is relapsed or refractory ALK+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ALK+ gastric cancer.

[0138] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ALK+ colorectal cancer. In one embodiment, the cancer is relapsed or refractory colorectal cancer. In one embodiment, the cancer is relapsed or refractory ALK+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ALK+ colorectal cancer.

[0139] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ALK+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory angiosarcoma. In one embodiment, the cancer is relapsed or refractory ALK+ angiosarcoma. In one embodiment, the cancer is newly diagnosed angiosarcoma. In one embodiment, the cancer is newly diagnosed ALK+ angiosarcoma.

[0140] In one embodiment, the cancer is sarcoma. In one embodiment, the cancer is soft- tissue sarcoma. In one embodiment, the cancer is synovial sarcoma. In one embodiment, the cancer is one or more selected from the group consisting of inflammatory myofibroblastic tumor, Leiomyosarcoma, and neurofibroma. In one embodiment, the cancer is one or more selected from the group consisting of Ewing sarcoma, fibrosarcoma, osteosarcoma, pulmonary sarcoma, uterine carcinosarcoma, and uterine leiomyosarcoma.

[0141] In one embodiment, the cancer is melanoma. In one embodiment, the cancer is spitzoid tumor. In one embodiment, the cancer is spitzoid melanoma. In one embodiment, the cancer is ALK+ spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory ALK+ spitzoid melanoma. In one embodiment, the cancer is newly diagnosed spitzoid melanoma. In one embodiment, the cancer is newly diagnosed ALK+ spitzoid melanoma.

[0142] In one embodiment, the cancer is epithelioid hemangioendothelioma. In one embodiment, the cancer is ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory ALK+ epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ALK+ epithelioid hemangioendothelioma.

[0143] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ESCC. In one embodiment, the cancer is ALK+ ESCC. In one embodiment, the cancer is relapsed or refractory ESCC. In one embodiment, the cancer is relapsed or refractory ALK+ ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ALK+ ESCC.

[0144] In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal medullary carcinoma. In one embodiment, the cancer is ALK+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal medullary carcinoma. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ALK+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ALK+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ALK+ renal cell carcinoma.

[0145] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ALK+ breast cancer. In one embodiment, the cancer is relapsed or refractory breast cancer. Inone embodiment, the cancer is relapsed or refractory ALK+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ALK+ breast cancer. In one embodiment, the breast cancer is triple negative breast cancer.

[0146] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ALK+ colon cancer. In one embodiment, the cancer is relapsed or refractory colon cancer. In one embodiment, the cancer is relapsed or refractory ALK+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ALK+ colon cancer.

[0147] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid cancer. In one embodiment, the cancer is ALK+ papillary thyroid cancer. In one embodiment, the cancer is relapsed or refractory papillary thyroid cancer. In one embodiment, the cancer is relapsed or refractory ALK+ papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed ALK+ papillary thyroid cancer.

[0148] In one embodiment, the cancer is ALK+ glioma (e.g. Grade 1, Grade 2, Grade 3, or Grade 4). In one embodiment, the cancer is relapsed or refractory glioma. In one embodiment, the cancer is relapsed or refractory ALK+ glioma. In one embodiment, the cancer is newly diagnosed ALK+ glioma. In one embodiment, the cancer is ALK+ glioblastoma. In one embodiment, the cancer is newly diagnosed ALK+ glioblastoma. In one embodiment, the cancer is relapsed or refractory glioblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ glioblastoma. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ALK+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory neuroblastoma. In one embodiment, the cancer is relapsed or refractory ALK+ neuroblastoma. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ neuroblastoma.

[0149] In one embodiment, the cancer is ALK+ pancreatic cancer. In one embodiment, the cancer is relapsed or refractory pancreatic cancer. In one embodiment, the cancer is relapsed or refractory ALK+ pancreatic cancer, one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ pancreatic cancer.

[0150] In one embodiment, the cancer is ALK+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is relapsed or refractory inflammatory hepatocellular adenoma. In one embodiment, the cancer is relapsed or refractory ALK+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ALK+ inflammatory hepatocellular adenoma.

[0151] In one embodiment, the cancer is hematological cancer. In one embodiment, the cancer is ALK+ hematological cancer.

[0152] In one embodiment, the cancer is ALK+ lymphoma. In one embodiment, the lymphoma is non-Hodgkin lymphoma. In one embodiment, the lymphoma is ALK+ nonHodgkin lymphoma. In one embodiment, the lymphoma is ALK+ anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

[0153] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ALK+ ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ ALCL. In one embodiment, the cancer is relapsed or refractory ALK+ ALCL. In one embodiment, the cancer is newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ALK+ ALCL.

[0154] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ALK+ DLBCL. In one embodiment, the cancer is newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ALK+ DLBCL.

[0155] In one embodiment, the cancer is 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 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 ALK+ large B-cell lymphoma. In one embodiment, the cancer (or ALK+ cancer) is new diagnosed. In one embodiment, the cancer (or ALK+ cancer) is previously untreated.

[0156] In one embodiment, the cancer is one or more selected from the group consisting of acinar adenocarcinoma, adrenocortical carcinoma, anaplastic astrocytoma, anaplastic largecell lymphoma, B-cell acute lymphocytic leukemia, B-cell lymphoma, breast cancer, cervical squamous cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, colorectal adenocarcinoma, cutaneous melanoma, diffuse large B-cell lymphoma, diffuse-type gastric cancer, endocervical adenocarcinoma, endometrial adenocarcinoma, epithelial ovarian cancer, esophageal cancer, Ewing sarcoma, fallopian tube serous carcinoma, fibrosarcoma, gallbladder carcinoma, ganglioglioma, gastroesophageal junction adenocarcinoma, glioblastoma, head and neck cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, highgrade serous carcinoma, inflammatory myofibroblastic tumor, leiomyosarcoma, neurofibroma, soft tissue sarcoma, invasive ductal carcinoma, low-grade serous carcinoma, lung adenocarcinoma, medulloblastoma, melanoma, mucinous cystadenocarcinoma, mucoepidermoid carcinoma, mucoepidermoid carcinoma, multiple myeloma, neuroblastoma, non-Hodgkins lymphoma, osteosarcoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, papillary cell renal cell carcinoma, papillary thyroid carcinoma, pericardial mesothelioma, peritoneal mesothelioma, prostate adenocarcinoma, pulmonary sarcoma, renal cell carcinoma, salivary gland cancer, small cell lung carcinoma, small intestine cancer, smooth muscle tumor of uncertain malignant potential, squamous cell carcinoma, stomach cancer, thyroid cancer, urothelial carcinoma, uterine carcinosarcoma, uterine corpus endometrial carcinoma, uterine leiomyosarcoma, uterine papillary serous carcinoma, and uterine sarcoma.

[0157] In one embodiment, the cancer (or ALK+ cancer) is newly diagnosed. In one embodiment, the cancer (or ALK+ cancer) is previously untreated.

[0158] In one embodiment, the cancer (or ALK+ cancer) is relapsed or refractory. In one embodiment, the cancer is relapsed. In one embodiment, the cancer (or ALK+ cancer) is refractory. In one embodiment, the cancer (or ALK+ cancer) is refractory to an inhibitor of wildtype ALK. In one embodiment, the cancer (or ALK+ cancer) is refractory to an inhibitor of genetically altered ALK. In one embodiment, the cancer (or ALK+ cancer) is refractory to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the cancer (or ALK+ cancer) is refractory to one or more of crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the cancer (or ALK+ cancer) is refractory to one or more of crizotinib, ceritinib, alectinib, brigatinib, ASP3026, and lorlatinib.

[0159] In one embodiment, the cancer (or ALK+ cancer) is intolerable to one or more of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. In one embodiment, the cancer (or ALK+ cancer) is intolerable to one or more of crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the cancer (or ALK+ cancer) is intolerable to one or more of crizotinib, ceritinib, alectinib, brigatinib, ASP3026 and lorlatinib. As used herein, the term “intolerant to” a drug refers to a subject (e.g. a patient) who must discontinue or suspend treatment with a drug because of unacceptable side effects. The subject (e.g. patient) can be intolerant either from the initial administration of the therapy or become intolerant over time in response to the therapy.

[0160] In one embodiment, the subject is previously untreated. In one embodiment, the subject is treatment naive to 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 subject has progressed on 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 a treatment with one or more of crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, and ensartinib. In one embodiment, the subject has progressed on the prior treatment of crizotinib, alectinib, ceritinib, brigatinib, or lorlatinib. In one embodiment, the subject has progressed on the prior treatment of crizotinib, alectinib, ceritinib, brigatinib, or lorlatinib, and at least one other TKI. In one embodiment, the subject has progressed on the prior treatment of crizotinib. In one embodiment, the subject has progressed on the prior treatment of alectinib. In one embodiment, the subject has progressed on the prior treatment of ceritinib. In one embodiment, the subject has progressed on the prior treatment of brigatinib. In one embodiment, the subject has progressed on the prior treatment of lorlatinib. In one embodiment, the prior therapy comprises one or more chemotherapies. In one embodiment, the subject has progressed on the prior treatment of TKI (e.g. one or more from crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib) and one or more chemotherapies. In one embodiment, the prior therapy comprises two or more chemotherapies. In one embodiment, the prior therapy comprises one or more immunotherapies. In one embodiment, the subject has progressed on the prior treatment of TKI (e.g. one or more from crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib) and one or more immunotherapies. Inone embodiment, the prior therapy comprises two or more immunotherapies. In one embodiment, the one or more chemotherapies and / or one or more immunotherapies are in addition to the TKI therapy.

[0161] In one embodiment, the cancer is advanced cancer, e.g. relapsed after, refractory to, progressed on, or resistant to the prior treatment by a TKI. In some embodiments, the cancer is locally advanced.

[0162] In one embodiment, the cancer (or ALK+ cancer) is resistant to a tyrosine kinase inhibitor (TKI). In one embodiment, the cancer (or ALK+ cancer) is resistant to a prior tyrosine kinase inhibitor (TKI).

[0163] In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is resistant non-small cell lung cancer. In one embodiment, the cancer is non-small cell lung cancer resistant to a TKI. In one embodiment, the cancer is ALK+ non-small cell lung cancer resistant to a TKI.

[0164] In one embodiment, the cancer is lung cancer (e.g., NSCLC). In one embodiment, the cancer is advanced lung cancer, e.g. relapsed after, or refractory to, prior treatment by a TKI.

[0165] In one embodiment, a compound provided herein is administered as first-line treatment. In one embodiment, a compound provided herein is administered as second-line treatment. In one embodiment, a compound provided herein is administered as third or fourthline treatment.

[0166] In one embodiment, the cancer (or ALK 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 ALK+ NSCLC.

[0167] In one embodiment, provided herein is a method for treating a subject with metastatic ALK+ non-small cell lung cancer (NSCLC), comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0168] In one embodiment, the subject is an adult subject of more than 18 years old. In one embodiment, the subject is a pediatric subject of no more than 18 years old. In oneembodiment, the subject is a pediatric subject of at least 12 years old but no more than 18 years old. In one embodiment, the subject is a patient.

[0169] In one embodiment, provided herein is a method for treating an adult subject with metastatic ALK+ NSCLC, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0170] In one embodiment, provided herein is a method for treating an adult subject with metastatic ALK+ NSCLC, comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, wherein the subject has progressed on or is intolerant of at least 1 prior TKI therapy.

[0171] In one embodiment, provided herein is a method for treating an ALK-associated (or ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0172] In one embodiment, provided herein is a method for treating an ALK-associated (e.g. ALK+) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), and wherein the cancer has been identified as having one or more ALK inhibitor resistance mutations, the method comprising administering o the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions at an amino acid position selected from 1151, 1196, 1198, 1202, and 1269. In one embodiment, the one or more ALK inhibitor resistance mutations comprise one or more amino acid substitutions selected from T1151M, LL196M, L1198F, G1202R, and G1269A. In one embodiment, the one or more ALK inhibitor resistance mutations is G1202R. In one embodiment, the one or more ALK inhibitor resistance mutations comprise G1202R and one or more of L1196M, L1198F, G1269A, and Ti l 5 IM.

[0173] In one embodiment, provided herein is a method for treating an adult subject with metastatic NSCLC that is ALK+ with mutation G1202R, comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceuticallyacceptable salt thereof, wherein the subject has progressed on or is intolerant of at least 1 prior TKI therapy.

[0174] In one embodiment, provided herein is a method for treating an ALK-associated (e.g. ALKA) cancer in a subject in need thereof, wherein the cancer has developed resistance to a tyrosine kinase inhibitor (TKI), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof.

[0175] In one embodiment, the cancer or disease is in a pediatric subject (including an infantile subject). In one embodiment, the cancer is systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatric subjects 1 year of age or older, and young adults. In another embodiment, the cancer is relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ALK+ in pediatric subjects 1 year of age or older, and young adults.

[0176] In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is ceritinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigatinib. In one embodiment, the TKI is lorlatinib. In one embodiment, the TKI is a first generation ALK TKI (e.g., crizotinib). In one embodiment, the TKI is a second generation ALK TKI (e.g., certinib, alectinib, or brigatinib). In one embodiment, the TKI is a third generation ALK TKI (e.g., lorlatinib).

[0177] In certain embodiments, the subject has relapsed after the first-line treatment of the cancer. In certain embodiments, the subject has relapsed after the first-line treatment of the cancer with one ALK TKI selected from crizotinib, certinib, alectinib, and brigatinib. In certain embodiments, the subject has relapsed after the treatment of the cancer with at least one ALK TKI selected from crizotinib, certinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject has relapsed after the second-line treatment of the cancer. In other embodiments, the subject has relapsed after the second-line treatment of the cancer with one or more ALK TKI selected from crizotinib, certinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject has relapsed after the third-line treatment of the cancer. In other embodiments, thesubject has relapsed after second-line treatment or the third-line treatment of the cancer with lorlatinib in the second or third line.

[0178] In certain embodiments, the subject has developed resistance after the first-line treatment of the cancer. In certain embodiments, the subject has developed resistance after the first-line treatment of the cancer with one ALK TKI selected from crizotinib, certinib, alectinib, and brigatinib. In certain embodiments, the subject has developed resistance after the treatment of the cancer with at least one ALK TKI selected from crizotinib, certinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject has developed resistance after the second-line treatment of the cancer. In other embodiments, the subject has developed resistance after the second-line treatment of the cancer with one or more ALK TKI selected from crizotinib, certinib, alectinib, brigatinib, and lorlatinib. In other embodiments, the subject has developed resistance after the third-line treatment of the cancer. In other embodiments, the subject has developed resistance after the second-line treatment or third-line treatment of the cancer with lorlatinib in the second or third line.

[0179] In one embodiment, the compound is administered to the patient QD for one or more days. In one embodiment, the compound is administered to the patient BID for one or more days. In one embodiment, the compound is administered to the patient QD for at least one treatment cycle. In one embodiment, the compound is administered to the patient BID 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 15 days. In one embodiment, one treatment cycle is at least 21 days. In one embodiment, one treatment cycle is at least 28 days. In one embodiment, the compound is administered to the patient for at least one treatment cycle (e.g. 21 days). In one embodiment, the compound is administered to the patient for at least two treatment cycles (e.g. 42 days). In one embodiment, the compound is administered to the patient for at least three treatment cycles (e.g. 63 days).

[0180] In one embodiment, the patient does not experience a Grade 4 adverse event after the administration of the compound. In one embodiment, the patient does not experience a Grade 3 adverse event after the administration of the compound. In one embodiment, the patient does not experience a Grade 2 adverse event after the administration of the compound. In oneembodiment, the patient does not experience a Grade 1 adverse event after the administration of the compound. As used here and unless otherwise specified, the grade of the adverse event follows the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grades, which is incorporated here by reference. In some embodiments, the adverse event is TEAE. In some embodiments, the adverse event is TRAE.

[0181] In some embodiments, the administration of the compound or a pharmaceutically acceptable salt is once daily. In some embodiments, the administration of the compound or a pharmaceutically acceptable salt is twice daily. In some embodiments, the administration of the compound or a pharmaceutically acceptable salt is once daily continuously for the dosing period. In some embodiments, the administration of the compound or a pharmaceutically acceptable salt is twice daily continuously for the dosing period.

[0182] In one embodiment, the prior therapy is a prior ALK TKI therapy. In one embodiment, the ALK TKI is one or more selected from lorlatinib, crizotinib, ceritinib, alectinib, and brigatinib. In one embodiment, the prior therapies are an ALK TKI therapy and a systematic therapy. In one embodiment, the ALK TKI is one or more selected from lorlatinib, crizotinib, ceritinib, alectinib, brigatinib and the systematic therapy is one or more selected from pemetrexed, cisplatin, carboplatin, bevacizumab, datopotamab deruxtecan, trastuzumab deruxtecan (T-DXd, DS-8201a), and a checkpoint inhibitor (e.g. pembrolizumab, nivolumab, atezolizumab). In certain embodiments, the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, a cytotoxic T-lymphocyte-associated modulator (e.g., CTLA-4 inhibitors), an LAG-3 inhibitor, or a TIM-3 inhibitor. In certain embodiments, the PD-1 inhibitor or PD-L1 inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, cemiplimab, and dostarlimab. In certain embodiments, the PD-1 inhibitor is selected from pembrolizumab, nivolumab, atezolizumab, cemiplimab (LIBTAYO®), sintilimab, spartalizumab (PDR001), pidilizumab (CureTech), MEDI0680 (Medimmune), dostarlimab (TSR-042), PF-06801591 (Pfizer), sintilimab, toripalimab, tislelizumab (BGB-A317), camrelizumab (INCSHR1210, SHR- 1210), AMP-224 (Amplimmune), CBT-501 (CBT Pharmaceuticals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IB 1308 (Innovent Biologies), INCSHR1210 (Incyte), also known as SHR-1210 (Hengrui Medicine), BGBA317 (Beigene), BGB-108 (Beigene), BAT-1306 (Bio-Thera Solutions), GLS-010 (Gloria Pharmaceuticals; WuXi Biologies), AK103, AK104, AK105 (Akesio Biopharma; Hangzhou Hansi Biologies; HanzhongBiologics), LZM009 (Livzon), HLX-10 (Henlius Biotech), MEDI0680 (Medimmune), PDF001 (Novartis), PF-06801591 (Pfizer), pidilizumab (CureTech), REGN2810 (Regeneron) and TSR- 042 (Tesaro), CS1003 (CStone Pharmaceuticals), or MEDI0680 (Medimmune). In certain embodiments, the PD-L1 inhibitor is selected from atezolizumab, FAZ053 (Novartis), and BMS- 936559 (Bristol-Myers Squibb), KN035 (Alphamab; 3DMed; Ascletis Pharma), Envafolimab (TRACON Pharmaceuticals), BMS 936559 (Bristol-Myers Squibb), CS1001 (CStone Pharmaceuticals, Ligand Pharmaceuticals), CX-072 (CytomX Therapeutics), FAZ053 (Novartis), SHR-1316 (Hengrui Medicine), TQB2450 (Chiatai Tianqing), STI-A1014 (Zhaoke Pharm; Lee's Pharm, Lonza, Sorrento Therapeutics, NantWorks), LYN00102 (Lynkcell), A167 (Harbour BioMed, Kelun Group), BGB-A333 (Beigene), MSB2311 (Mabspace Biosciences), HLX-20 (Henlius Biotech), cosibelimab (Fortress Biotech), LY3300054 or iodapolimab (Eli Lilly), GS-4224 (Gilead Sciences), STLA1015 (Yuhan, Sorrento Therapeutics), BCD-135 (BIOCAD), cosibelimab (Dana-Farber Cancer Institute, TG Therapeutics), APL-502 (Apollomics), AK106 (Akeso Biopharma), MSB2311 (Transcenta Holding), TG-1501 (TG Therapeutics) or FAZ053 (Novartis), MT-6035 (Molecular Templates), icaritin or ZKAB001 (Lonza, Lee’s Pharmaceutical Holdings, Sorrento Therapeutics, Shenogen Pharma Group), TRIDENT Antibody (MacroGenics, Zai Lab), YBL-007 (Anh-Gook Pharmaceutical, Y- Biologics), HTI-1316 (Hengrui Therapeutics), PD-L1 Oncology Project (Weizmann Institute of Sciences), JS003 (Shanghai Junshi Biosciences), ND021 (Numab Therapeutics, CStone Pharmaceuticals), Toca 521 (Tocagen) or STT01 (STCube), DB004 (DotBio), MT-5050 (Molecular Templates), and KD036 (Kadmon).

[0183] In certain embodiments, the methods for treating or preventing cancer can be demonstrated by one or more responses such as increased apoptosis, inhibition of tumor growth, reduction of tumor metastasis, inhibition of tumor metastasis, reduction of microvessel density, decreased neovascularization, inhibition of tumor migration, tumor regression, and increased survival of the subject.COMBINATION TREATMENTS

[0184] In some embodiments, the method of treating or preventing cancer may comprise administering a compound provided herein in combination with one or more additional therapeutic agents, e.g., other chemotherapeutic agent(s).

[0185] As used herein and unless otherwise specified, by “conjointly” or “in combination with”, it is not intended to imply that the other agent and a compound provided herein must be administered at the same time and / or formulated for delivery together, although these methods of delivery are within the scope of this disclosure. The compound provided herein can be administered concurrently 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 before), or subsequent 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 after), one or more other agents (e.g., one or more other additional agents). In general, each therapeutic agent is administered at a dose and / or on a time schedule determined for that particular agent. The other therapeutic agent can be administered with the compound provided herein in a single composition or separately in a different composition. Triple therapy is also contemplated herein.

[0186] Chemotherapeutic agents that may be conj ointly administered with compounds provided herein include: l-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2- sulfonate (acid blue 25), l-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, l-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, l-amino-4-[l-naphthylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, l-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, l-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, P-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, 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, pemexetred, pentostatin, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, 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 conjointly administered with compounds provided herein include: ABT-263, dexamethasone, 5-fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds provided herein include: l-amino-4-phenylamino-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate (acid blue 25), l-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo- 9,10-dihydroanthracene-2-sulfonate, l-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, l-amino-4-[l-naphthylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, 1 -amino-4-[4-fluoro-2-carboxyphenylamino]-9, 10-dioxo-9, 10- dihydroanthracene-2-sulfonate, l-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, APCP, P-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4- dinitrobenzenesulfonate, sumarin, and tonapofylline. In some embodiments, the chemotherapy agents are biologies such as ADCs or MET antibodies. In some embodiments, the chemotherapy agent is a MET inhibitor, a MEK inhibitor, a RET inhibitor, another ALK inhibitor, or RO SI inhibitor. In some embodiments, the compound as described herein is used with one or more platininum based chemotherapy and / or immunotherapy (e.g. checkpoint inhibitors).

[0187] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds provided herein may be conjointly administered with one ormore combination therapies. Examples of combination therapies with which compounds provided herein may be conjointly administered are included in Table 2.Table 2: Exemplary combinatorial therapies for the treatment of cancer

[0188] In certain embodiments, the conjoint therapies provided herein comprise conjoint administration 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 effect cell death. Other immuno-oncology agents can suppress tumor- mediated inhibition of the native immune response or otherwise activate the immune response and thus facilitate recognition of the tumor 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, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED 14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immuno-oncology agents are selected from anti-CD73 monoclonal antibody (mAb), anti-CD39 mAb, anti-PD-1 mAb, and anti-CTLA4 mAb. Thus, in some embodiments, the methods provided herein comprise conjoint administration of one or more immuno-oncology agents, such as the agents mentioned above.

[0189] In some embodiments, the combination therapy comprises conjoint administration of a compound provided herein with SH2 inhibitors, such as CGP78850, CPG85793, C90, C126, G7-18NATE, G7-B1, and NSC642056.

[0190] Acquired ALK fusion confers EGFR inhibitor resistance. See von Buttlar, X. et alJTO Clin Res Rep. 2021 Jun; 2(6): 100179; Schrock, A.B. et alJ Thorac Oncol. 2018 Sep; 13(9): 1312-1323. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with an EGFR inhibitor, such as erlotinib,osimertinib, cetuximab, gefitinib, necitumumab, lapatinib, neratinib, panitumumab, vandetanib, and necitumumab. In one embodiment, the EGFR inhibitor is erlotinib. In one embodiment, the EGFR inhibitor is osimertinib. In one embodiment, the EGFR inhibitor is gefitnib.

[0191] In some embodiments, provided herein is a method of treating an epidermal growth factor receptor (EGFR)-associated cancer, comprising administering to a subject in need thereof a combination comprising a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, or stereoisomer thereof, and therapeutically effective amount of a second agent, wherein the second agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, cetuximab, gefitinib, necitumumab, lapatinib, neratinib, panitumumab, vandetanib, and necitumumab. In one embodiment, the EGFR inhibitor is erlotinib. In one embodiment, the EGFR inhibitor is osimertinib. In one embodiment, the EGFR inhibitor is gefitnib. In some embodiments, the subject has at least one EGFR mutation. In some embodiments, the at least one EGFR mutations is in one or more exons of 18, 19, 20, and 21 and / or TM. In some embodiments, the subject has at least one receptor tyrosine kinase (RTK) mutation. In some embodiments, the RTK mutation is an ALK mutation. In some embodiments, the EGFR-associated cancer is NSCLC, pancreatic cancer, breast cancer, or colon cancer. In some embodiments, the EGFR-associated cancer is mediated by EGFR.

[0192] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a Raf (e.g. A-Raf, B-Raf, or C-Raf also known as Raf-1) inhibitor. In certain embodiments, the Raf inhibitor inhibits a Raf mutant. In certain embodiments, the Raf inhibitor is a B-Raf inhibitor. In certain embodiments, the B-Raf inhibitor inhibits a B-Raf mutant. In certain embodiments, the B-Raf mutant is a V600 mutant. In certain embodiments, the B-Raf mutant is a V600E mutant. In certain embodiments, the Raf inhibitor is dabrafenib, Y3009120, MLN2480 / TAK-580 (tovorafenib), CCT196969, CCT241161, BGB659, PLX7904, naporafenib, PLX-8394, or lifirafenib.

[0193] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a PIK3CA inhibitor, such as 5-(2,6-di-morpholin-4-yl- pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine, inavolisib, gedatolisib, buparlisib, zandelisib, miransertib mesylate, izorlisib, or panulisib. In some embodiments, the PIK3CAinhibitor is a PI3K inhibitor, such as dactolisib, apitolisib, gedatolisib, SF1 126, omipalisib, samotolisib, bimiralisib, paxalisib, voxtalisib buparlisib, CH5132799, pilaralisib, ZSTK474, sonolisib, pictilisib, copanlisib, B591, TG-100-115, RIDR-PI-103 alpelisib (a) or serabelisib (a).

[0194] ALK tyrosine kinase inhibitors are used in the treatment of cancer (e.g. a solid tumor) that are driven by constitutive ALK activity. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a CDK4 inhibitor or a CDK6 inhibitor, such as ribociclib, palboclib, trilaciclib, abemaciclib, or dalpiciclib.

[0195] Signal transducer and activator of transcription 3 (STAT3) is activated in many cancers, including those with constitutively active tyrosine kinases such as ALK. See Taniguchi, K al Sci. Rep. 2021 Mar 23; 11(1): 6685, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a STAT3 inhibitor, such as HL-237, OPB-111077, danvatirsen, C-188-9, KT-333, DUET-01, ENMD-1198, or WP-1066.

[0196] T-LAK cell-oriented protein kinase (TOPK, also referred to as PDZ binding kinase, gene symbol PBK) was identified as a substrate of ALK. Treatment of ALK fusion-driven human cancer cells with an ALK inhibitor and a TOPK inhibitor has shown anti-tumor activity. See Xiao, J. el al Cell Death Dis. 2022 Sep 27; 13(9): 828, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a STAT3 inhibitor, such as SKLB-C05, ADA-07, OTS-964, or HI-032 (HITOPK-032).

[0197] In ALK fusion-driven NSCLC, EML4 is the major fusion partner. Wild-type EML4 is a microtubule-associated protein that is reported to promote microtubule stabilization in interphase. More than 10 distinct EML4-ALK variants have been identified, with variants 1 and 3 (VI and V3) being the most prevalent. EML4-ALK V3 localizes to interphase microtubules and the mitotic spindle. Accordingly, treatment of EML3-ALK V3-expressing cells with a combination of ALK inhibitor and a microtubule modulator (e.g. stabilizer or destabilizer) results in synergistic antiproliferative activity in vitro. See Lucken, K. et al Mol. Cancer Res. 2022 Jun 3; 20(6): 854, which is incorporated herein by reference in its entirety. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with taxanes (e.g. paclitaxel, nab-paclitaxel, docetaxel, and cabazitaxel), epothilones (e.g. epothilone Aepothilone D, ixabepilone, and sagopilone) tirbanibulin, eribulin mesilate, vinflunine, vinorelbine, narcosine, vincristine sulfate, or vinblastine sulfatec colchicine.

[0198] HER2-directed therapies in combination with ALK inhibitor therapy may be beneficial for patients with HER2 amplification and ALK fusions. See Tsui, D.C.C. el al Clin. Lung Cancer 2022 Mar; 23(2): e99. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a HER2-directed therapy, such as trastuzumab, pertuzumab, margetuximab, ado-trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (fam-trastuzumab deruxtecan), tucatinib, neratinib, lapatinib, disitamab vedotin, mobocertinib, trastuzumab hayluronidase, pyrotinib maleate, dacomitinib, or afatinib.

[0199] Combinations of ALK TKI and anti -angiogenic agents may provide patient benefit, for example delaying progression of of ALK fusion-positive cancers such as NSCLC. See Lin, J. J. et al ESMO Open 2022 Feb; 7(1): 100342. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with an anti-angiogenic agent, such as axitinib, bevacizumab, cabozantinib, everolimus, lenalidomide (Revlimid®), lenvatinib mesylate, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, vandetanib, ziv-aflibercept, sulfatinib, aplidine, anlotinib hydrochloride, fruquintinib, tivozanib, conbercept, apatinib mesylate, ponatinib, cabozantinib S-malate, aflibercept, sunitinib malate, or anecortave acetate.

[0200] In vitro, the JNK pathway was determined to be active upon extended high-dose treatment of ALK fusion-driven cells with ALK tyrosine kinase inhibitors (TKI), and may enable resistance to ALK TKIs to emerge (Cancer Lett, 2021 Dec 1;522: 119-128). Accordingly, JNK inhibition may sensitize ALK fusion-driven cells to ALK TKIs in vitro and provide increased durability of antitumor activity. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a JNK inhibitor, such as SP600125, BMS-986360, or JNK-401.

[0201] Patients with ALK fusion-positive and TP53-mutated NSCLC may have a worse progression-free survival compared to those patients with ALK fusion-positive and wild-type TP53 NSCLC. In preclinical studies, p53-mutated ALK fusion-positive cells were resistant to apoptosis induction by ALK tyrosine kinase inhibition, but combination treatment with a proteosome inhibitor appeared to induce apoptosis and provide increased antitumor activity inALK / TP53 co-mutated NSCLC tumors compared to single agent activity. See Tanimoto, A. et al Clin. Cancer Res. 2021 Mar 1; 27(5): 1410. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a proteosome inhibitor, such as izazomib, carfilzomib, or bortezomib.

[0202] In ALK fusion-driven cells, ALK signaling may include activation of the mammalian target of rapamycin (mTOR). The combination of an ALK inhibitor and mTOR inhibitor may induce increased cell cycle arrest in ALK fusion-positive anaplastic large cell lymphoma (ALCL) cells. See Kim, D. et al Anticancer Res. 2020 Mar; 40(3): 1395. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a mTOR inhibitor, such as everolimus, ABL009, temserolimus, zotarolimus, rapamycin, or umirolimus.

[0203] The transcriptional regulator YAP1 may be activated following treatment of ALK+ cells with an ALK inhibitor. This effect can be attenuated by combinatorial inhibition of ALK and YAP1. See Tsuji, T. et al Nat. Conmnin. 2020; 11 :74. In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a YAP1 inhibitor, such as narciclasine, MYF-03-69, verteporfin, IAG-933, ION-537, IK-930, or VT-3989.

[0204] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with MEK inhibitors, such as trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CL1040, and TAK-733. See “N Phase IB / II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC”, Clinical Trial Identifier: NCT03202940, Last Updated on March 9, 2021, which is incorporated herein by reference in its entirety.

[0205] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a MET inhibitor selected from INJ-38877605, PF-04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib. See Tanizaki J. et al Br J Cancer, 2012 Feb 14; 106(4):763-7, which is incorporated herein by reference in its entirety.

[0206] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a SHP2 inhibitor, such as TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[0207] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a RAS inhibitor, such as adagrasib and sotorasib.

[0208] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with a Trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC). TROP2 is a cell surface transmembrane protein that is highly expressed in >50% non-small cell lung cancer, including lung adenocarcinoma with ALK rearrangement (Inamura, K. et al. Oncotarget. 2017; 8(17):28725-28735). Combination of the compound and TROP2-ADC may be able to provide additional therapeutic benefit than each monotherapy, especially to patients with ALK-independent resistance mechanisms. In some embodiments, the TROP2 ADC is DS- 1062.

[0209] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with an AXL ADC (e.g. enapotamab vedotin). AXL is a receptor tyrosine kinase, with increased expression associated with acquired ALK TKI resistance and epithelial -to-mesenchymal transition (Ref Debruyne et al, Oncogene 2016). Combination of the compound and AXL-ADC may provide additional therapeutic benefit than each monotherapy, especially in ALK TKI resistant patients with increased AXL expression.

[0210] In some embodiments, the combination therapy comprises administration of a compound provided herein in combination with a TKI. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib, masitinib, or ensartinib. In one embodiment, the ALK TKI is crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib. In one embodiment, the ALK TKI is crizotinib. In one embodiment, the ALK TKI is ceritinib. In one embodiment, the ALK TKI is entrectinib. In one embodiment, the ALK TKI is alectinib. In one embodiment, the ALK TKI is brigatinib. In one embodiment, the ALK TKI is lorlatinib.

[0211] In some embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with anti-PD-1 therapy. In certain embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with oxaliplatin. In other embodiments, the combination therapy comprises conjoint administration of a compound of the disclosure with doxorubicin.PHARMACEUTICAL COMPOSITIONS

[0212] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein and a pharmaceutically acceptable carrier or excipient. In one embodiment, the composition is a tablet, a capsule, a granule, a lyophile for reconstitution, a powder, a solution, a syrup, a suppository, an injection, a transdermal delivery system, or a solution suitable for topical administration.

[0213] In one embodiment, the pharmaceutical preparation is suitable for use in a human patient. In one embodiment, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. A compound provided herein may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein.

[0214] The compositions and methods provided herein may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a nonhuman mammal. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In one embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen- free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0215] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound provided herein. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbicacid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including 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) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound provided herein. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0216] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0217] The phrase “pharmaceutically acceptable carrier” as used herein means a pharmaceutically 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 injurious to the subject. Some examples of materials which can serve as pharmaceutically 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (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) buffering agents, 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 solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0218] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, 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, as well as in patents cited therein.

[0219] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. In certain embodiments, the unit dosage form is a tablet. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, from about 5 percent to about 70 percent, or from about 10 percent to about 30 percent.

[0220] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound provided herein, with the 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.

[0221] 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 basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water- in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound provided herein as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0222] To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a 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 compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0223] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active ordispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0224] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profde, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can 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 they release the active ingredient(s) only, or in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0225] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0226] 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.

[0227] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0228] Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0229] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[0230] Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

[0231] 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.

[0232] Dosage forms for the 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 pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0233] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0234] Powders and sprays can contain, in addition to an 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.

[0235] Transdermal patches have the added advantage of providing controlled delivery of a compound provided herein to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0236] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure. Exemplary ophthalmic formulations are described in U.S. 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, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. In one embodiment, the route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

[0237] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0238] Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0239] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions provided herein include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol, and the like), 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 the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0240] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0241] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0242] 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 employed, 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 tissue.

[0243] For use in the methods provided herein, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (or 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0244] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious biopharmaceuticals. Avariety of biocompatible polymers (including hydrogels), including both biodegradable and non- degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0245] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as 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.

[0246] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and like factors well known in the medical arts.

[0247] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence 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 with the compound provided herein. A larger total dose can be delivered by multiple administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher el al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[0248] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. Tn certain embodiments provided herein, the active compound may be administered two or three times daily. In one embodiment, the active compound is administered once daily.

[0249] In certain embodiments, compounds provided herein may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.

[0250] In certain embodiments, conjoint administration of compounds provided herein with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the compound provided herein or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound provided herein and the one or more additional therapeutic agent(s).

[0251] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0252] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate,alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0253] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to limit the disclosure.EXAMPLESExample 1. Synthetic Methods

[0254] Compounds XI and X2 were synthesized using the similar procedure in International Patent Application No. PCT / US2021 / 030940 and / or International Patent Application No.PCT / US2023 / 065434. Characterization of the compounds is summarized in Table 3.Table 3. Characterization of the exemplified compounds.Example 2. Biochemical Kinase Assay

[0255] First, 250 nL of compound dissolved in DMSO (100-fold of the desired concentration) was dispensed into a 384-well plate. A 12.5 pL substrate solution containing ATP (2 mM) and fluorogenic phosphorylation substrate AQT0101 (26 pM for ALK, AssayQuant) or AQT0104 (26 pM for TRKB, AssayQuant) in buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 0.5 mM EGTA, 10 mM MgCk) was added and mixed thoroughly. Then, a 12.5 pL kinase solutioncontaining ALK II 171N / D1203N (4 nM, SignalChem, custom-made) or TRKB-wt (wild-type, 1.5 nM, SignalChem, N17-11G) kinase domains in buffer (50 nM HEPES pH 7.5, 0.01% Brij- 35, 2% glycerol, 0.4 mg / mL BSA, 0.5 mM EGTA, and 10 mM MgCh) was added and mixed thoroughly. The plate was sealed and read by SpectraMax Paradigm at = 485 nm every 2 minutes for 120 minutes at 30 °C. Exemplary data is given in Table 4. Initial rates of reaction (v) were calculated from the change in fluorescence intensity over time during the initial, linear portion of the reaction. Finally, apparent inhibitory constants (Kiapp) were determined from regression of v and I (inhibitor concentration) to Morrison Equation (E = enzyme concentration):

[0256] Compound potency can be interpreted by binning Kiappvalues against the targets: bin A for high potency, Kiapp< 50 nM; bin B for medium potency, 50 nM < Kiapp< 500 nM; and bin C for low potency, Kiapp> 500 nM. Compounds are more desirable if they exhibit smaller Kiappvalues against the on-target kinases (ALK) and larger Kiappvalues against the off-target kinase (TRKB). Compounds that potently inhibit the on -target kinases (ALK) are also expected to inhibit oncoproteins that are expressed in human cancers, providing support for the potential clinical efficacy of such compounds. Similarly, compounds that do not potently inhibit the off- target kinase (TRKB) are expected to poorly inhibit TRK-family kinases in humans and hence avoid potential clinical toxicity arising from TRKA, TRKB, or TRKC inhibition.Table d. Biochemical Assay Activity Summary:Example 3. Generation of Ba / F 3 Stable Cell Lines

[0257] Genes encoding EML4-ALK vl (variant 1), EML4-ALK vl Il 171N / D1203N, EML4- ALK vl LI 196M / G1202R, EML4-ALK vl G1202R, and ETV6-TRKB were synthesized at GeneRay, cloned into the retroviral construct pMSCV-puro (Biovector), and packaged into retroviral particles. The virus was used to infect Ba / F3 cells (R1KEN) at multiplicity of infection = 1 - 10 for 1 day. Infected cells were rescued in media (RPMI-1640 with 10% fetal bovine serum and 1% streptomycin and penicillin) supplemented with mouse IL-3 (10 ng / mL) for 2 days, and stable cell lines were selected by IL-3 withdrawal and puromycin (0.8 pg / mL) for 7 days. In some cases, monoclones were selected by single-cell dilution in IL-3-free medium containing puromycin (0.8 pg / mL). Transformation of desired genes was confirmed by Sanger sequencing and western blot using the following antibodies: ALK (CST #3633) and pan-TRK (Abeam #76291).Example 4. Cell Proliferation Assay

[0258] Stable cells were plated in a 384-well plate. Test compounds were then added in a 3- fold dilution series and incubated for 72 hours. CellTiter-Glo reagent (Promega) was added. Luminescence was measured on a plate reader. Half-maximal inhibitory concentration (ICso) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression. Compound potency can be interpreted by binning ICso values: bin A for high potency, 0.1 nM < ICso < 50 nM; bin B for medium potency, 50 nM < ICso < 500 nM; and bin C for low potency, ICso > 500 nM. Compounds are more desirable if they exhibit smaller ICso values against the on-target Ba / F3 cells (ALK-fusion) and larger ICso values against the off- target Ba / F3 cells (TRKB-fusion). Exemplary data is given in Table 5 (nd is not determined).

[0259] Ba / F3 proliferation is driven by the transduced oncogenes in the same way that cancer cell proliferation in humans is driven by the expression of equivalent oncogenes. Hence, compounds that potently inhibit the proliferation of the on-target Ba / F3 cells (ALK-fusion) are also expected to inhibit human cancers that express equivalent oncogenes, providing support for the potential clinical efficacy of such compounds. Similarly, compounds that do not potently inhibit the off-target Ba / F3 cells (TRKB-fusion) are expected to poorly inhibit TRK-family kinases in humans and hence avoid the clinical toxicity arising from TRKA, TRKB, or TRKC inhibition.Table 5. Cell Assay Activity Summary

[0260] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

[0261] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are encompassed by the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of F ormul a (I) :or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl;R2 is H or methyl;L is CH2, CH(OH),or C=O; and provided that, when L is CH2, then at least one of Ri and R2 is H.

2. The compound of claim 1, wherein Ri is H.

3. The compound of claim 1, wherein Ri is ethyl.

4. The compound of any one of claims 1 to 3, wherein R2 is H.

5. The compound of any one of claims 1 to 3, wherein R2 is methyl.

6. The compound of any one of claims 1 to 5, wherein L is CH2.

7. The compound of any one of claims 1 to 5, wherein L is CH(OH)8. The compound of any one of claims 1 to 5, wherein L is C=O.

9. The compound of claim 1, which is:or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, which is:or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, which is:or a pharmaceutically acceptable salt thereof.

12. A compound which is an oxidized form of a compound of Formula (II):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:Ri is H or ethyl; and R2 is H or methyl.

13. The compound of claim 12, wherein the oxidized form is a compound of Formula (Ila):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 12, wherein the oxidized form is a compound of Formula (Ila):(Ila), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 12, wherein the oxidized form is a compound of Formula (lib):or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 12, wherein the oxidized form is a compound of Formula (lie):(lie), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 12 to 16, wherein the oxidized form is selected from the group consisting of:

18. A compound in Table 1 , or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition, comprising a compound of any one of claims 1 to 18, and a pharmaceutically acceptable carrier or excipient.

20. A method of treating cancer, comprising administering to a subject having the cancer a therapeutically effective amount of a compound of any one of claims 1 to 18, or a pharmaceutical composition of claim 19.

21. The method of claim 20, wherein the cancer is a solid tumor or a hematologic malignancy.

22. The method of claim 21, wherein the cancer is an ALK positive or ROS1 positive cancer.

23. The method of claim 21 or claim 22, wherein the cancer is a solid tumor; and the solid tumor is lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, spitzoid tumor, or neuroblastoma.

24. The method of any one of claims claim 21 to 23, wherein the solid tumor is advanced solid tumor.

25. The method of claim 24, wherein the advanced solid tumor is relapsed after, refractory to, or resistant to the prior treatment by a tyrosine kinase inhibitor (TKI).

26. The method of any one of claims 21 to 25, wherein the solid tumor is non-small cell lung cancer (NSCLC).

27. The method of any one of claims 21 to 25, wherein the solid tumor is cholangiocarcinoma.

28. The method of any one of claims 21 to 25, wherein the solid tumor is neuroblastoma.

29. The method of any one of claims 21 to 25, wherein the solid tumor is soft-tissue sarcoma.

30. The method of any one of claims 21 to 25, wherein the solid tumor is metastatic.

31. The method of claim 30, wherein the solid tumor is CNS metastatic.

32. The method of any one of claims 21 to 31, wherein the solid tumor is ALK positive.

33. The method of claim 32, wherein the ALK positive solid tumor is characterized by the presence of a mutation in an ALK gene.

34. The method of claim 33, wherein the ALK mutation comprises one or more ALK rearrangement, one or more ALK point mutation, or a combination thereof.

35. The method of claim 33 or claim 34, wherein the ALK mutation comprises one or more ALK fusions.

36. The method of claim 35, wherein 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, MSN, AL017, MYH9 and KIF5B.

37. The method of claim 36, wherein the ALK fusion is with NPM1, STRN, or EML4.

38. The method of any one of claims 33 to 37, wherein the ALK mutation comprises G1202R, F1174C, F1174L, I1171N, I1171S, I1171T, L1196M, V1180L, C1156Y, G1202del, G1202K, G1269A, G1269V, F1174S, Fl 1741, S1206Y, E1210K, T1151M, T1151 L1152insT, D 1203N, S 1206C, L 1152R, L 1196Q, L 1198P, L 1198F, R1275Q, L 1152P, C 1156T, El 129K, S1206F, L1198H, F1245C, T1151K, I1268V, Fl 174V, L1198Q, S1206A or F1245V, or a combination thereof.

39. The method of claim 38, wherein the ALK mutation comprises G1202R.

40. The method of claim 38, wherein the ALK mutation comprises Fl 174S or Fl 174L.

41. The method of claim 38, wherein the ALK mutation comprises R1275Q.

42. The method of claim 38, wherein the ALK mutation comprises T115 IM.

43. The method of any one of claims 33 to 42, wherein the ALK mutation comprises one or more compound mutations.

44. The method of claim 43, wherein the compound mutation is G1202R / F1174L.

45. The method of claim 43, wherein the compound mutation is G1202R / T1151M, G1202R / L1196M, G1202R / G1269A, G1202R / L1198F, or G1202R / F1174S.

46. The method of claim 43, wherein the compound mutation is Cl 156Y / L1256F, Cl 156Y / S1206F, Cl 156Y / F1174V, or Cl 156Y / F 11741.

47. The method of claim 43, wherein the compound mutation is LI 196M / L1198H, LI 196M / Il 179V, or LI 196M / L1256F.

48. The method of claim 30, wherein the ALK positive solid tumor is characterized by the presence of a partially deleted ALK protein.

49. The method of claim 21 or claim 22, wherein the cancer is a hematologic malignancy; and the hematologic malignancy is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma.

50. The method of any one of claims 20 to 49, wherein the subject has received at least two prior cancer therapies.

51. A method for selectively inhibiting ROS 1 over TRK, wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 18, or a pharmaceutical composition of claim 19.

52. A method for selectively inhibiting ALK over TRK, wherein the inhibition takes place in a subject suffering from cancer, said method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 18, or a pharmaceutical composition of claim 19.

53. The method of any one of claims 20 to 52, further comprising administering to the subject an effective amount of one or more additional therapeutic agents.

54. The method of claim 53, wherein the additional therapeutic agent is a TKI.

55. The method of claim 54, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, or ensartinib.

56. The method of any one of claims 20 to 55, wherein the subject is a human.

57. A method of decreasing a level of ALK or ROS1 in a cell, comprising contacting the cell with a compound of any one of claims 1 to 18, or a pharmaceutical composition of claim 19.

58. The method of claim 57, further comprising contacting the cell with one or more additional therapeutic agents.

59. The method of claim 58, wherein the additional therapeutic agent is a TKI.

60. The method of claim 59, wherein the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, or ensartinib.

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