HETEROAROMATIC MACROCYCLIC ETHER COMPOUNDS AND

ISOTOPOLOGUES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of priority to U.S. Serial No. 63/397,495, filed August

12, 2022, which is incorporated herein by reference in its entirety.

BACKGROUND

[002] 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).

[003] ROS1 is an RTK proto-oncogene, with ROS1 rearrangements detected in non- small cell lung cancer (NSCLC), glioblastoma, inflammatory myofibroblastic tumor (IMT), cholangiocarcinoma, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, and spitzoid melanoma. Oncogenic ROS1 gene fusions contain the kinase domain of ROS1 (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.

[004] 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 ROS1-positive or ALK-positive patients, however, 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.

[005] 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 ROS1-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, G2101A, 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, L1196M, G1269A, C1156Y, I1171T, I1171N, I1171S, F1174L, V1180L, S1206Y, E1210K, 1151Tins, F1174C, G1202del, D1203N, S1206Y, S1206C, L1152R, L1196Q, L1198P, L1198F, R1275Q, L1152P, C1156T, and F1245V.

[006] 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. A need still exists for developing additional heteroaromatic macrocyclic ether compounds and/or isotopologues of heteroaromatic macrocyclic ether compounds that are more metabolically stable, or have different pharmacokinetic profdes.

SUMMARY

[007] Provided herein are heteroaromatic macrocyclic ether compounds and isotopologues thereof, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. [008] 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 R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , and L are as defined herein or elsewhere.

[009] In one embodiment, provided herein is a compound of Formula (XII):

(XII), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₄ , and L are as defined herein or elsewhere.

[0010] In one embodiment, provided herein is a compound of Formula (VIII):

(VIII), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein R ₁₄ is as defined herein or elsewhere.

[0011] Also provided herein are pharmaceutical compositions, comprising a compound provided herein and a pharmaceutically acceptable carrier or excipient.

[0012] 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.

[0013] 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.

[0014] 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 DESCRIPTION

DEFINITIONS

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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 C ₁ -C ₆ straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

[0021] 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 and unsubstituted 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), -CF ₃ , -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CF ₃ , -CN, and the like.

[0022] The term “C _x-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 “C _x-y alkyl” 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. C ₀ alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C _2-y alkenyl” and “C _2-y alkynyl” 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. [0023] As used herein and unless otherwise specified, a “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated. “Cycloalkyl” includes monocyclic, bicyclic, and multi cyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. Cycloalkyl includes fused, bridged, or spiro cycloalkyl. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl can be substituted or unsubstituted.

[0024] As used herein and unless otherwise specified, the terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, 3- to 10-membered rings, or 3- to 7-membered rings, whose ring structures include at least one heteroatom, one to four heteroatoms, or one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0025] As used herein and unless otherwise specified, the term “isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.

[0026] The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. As used herein, an “isotopologue” is an isotopically enriched compound.

[0027] The term “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.

[0028] The term “isotopic enrichment factor” refers to the ratio between the isotopic composition and the natural isotopic composition of a specified isotope.

[0029] With regard to the compounds provided herein, when a particular atomic position is designated as deuterium or “D,” it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.0156%. A position designated as deuterium typically has a minimum isotopic enrichment factor of, in certain embodiments, at least about 1000 (about 15% deuterium incorporation), at least about 2000 (about 30% deuterium incorporation), at least about 3000 (about 45% deuterium incorporation), at least about 3500 (about 52.5% deuterium incorporation), at least about 4000 (about 60% deuterium incorporation), at least about 4500 (about 67.5% deuterium incorporation), at least about 5000 (about 75% deuterium incorporation), at least about 5500 (about 82.5% deuterium incorporation), at least about 6000 (about 90% deuterium incorporation), at least about 6333.3 (about 95% deuterium incorporation), at least about 6466.7 (about 97% deuterium incorporation), at least about 6600 (about 99% deuterium incorporation), or at least about 6633.3 (about 99.5% deuterium incorporation) at each designated deuterium atom.

[0030] The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0031] 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, including racemic 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 33:2725 (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.

[0032] 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.

[0033] 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 98 grams 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.

[0034] 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.

[0035] 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.

[0036] 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”.

[0037] 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).

[0038] 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).

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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”. [0046] 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, 1H-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2- hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, pharmaceutically acceptable salts include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

[0047] 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.

[0048] 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

[0049] Provided herein are heteroaromatic macrocyclic ether compounds and isotopologues thereof, 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, ROS1 and/or ALK inhibitors.

[0050] Isotopic enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. (See, e.g., Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999)).

[0051] Without being limited by a particular theory, isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[0052] Replacement of an atom for one of its isotopes may often result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner etal., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0053] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.

[0054] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profdes relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses.

[0055] Therefore, isotopic enrichment at certain positions of a compound provided herein may produce a detectable KIE that affects the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. In certain embodiments, the deuterium enrichment is performed on the site of C-H bond cleavage during metabolism.

[0056] Furthermore, racemization of many compounds involves the breaking of a C-H bond at the chiral center and may be retarded by selective incorporation of deuterium.

[0057] In one embodiment, provided herein is an isotopologue of a compound of the following formula (also referred to as “Compound 1”): 1 , or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. Compound 1 has been described in International Patent Application Publication No. WO 2021/226208, the entirety of which is incorporated herein by reference. In one embodiment, provided herein is a compound where the -NH ₂ group in Compound 1 is further modified. In one embodiment, provided herein is an isotopologue of the further modified Compound 1. In one embodiment, the isotopologue is a deuterium enriched isotopologue.

[0058] 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: each of R ₁ , R ₆ , and R ₉ is independently CH ₃ , CH ₂ D, CHD ₂ , or CD ₃ ; each of R ₂ , R ₃ , R ₄ , R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , and R ₁₃ is independently H or D; each of R ₈ and L is independently CH ₂ , CHD, or CD ₂ ; and at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , and L is or comprises D.

[0059] As used herein and unless otherwise specified, a non-hydrogen group “comprises D” means that at least one hydrogen in the group is D. For example, “R ₁ comprises D” means R ₁ is CH ₂ D, CHD ₂ , or CD ₃ , i.e., R ₁ is not CH ₃ .

[0060] In one embodiment, the compound is a compound of Formula (II):

(II), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the compound is a compound of Formula (III):

(III), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment, the compound is a compound of Formula (III- A):

(III-A), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof. [0063] In one embodiment, the compound is a compound of Formula (IV): (IV), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the compound is a compound of Formula (V):

(V), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the compound is a compound of Formula (VI): (VI), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment, provided herein is a compound of Formula (XII):

(XII), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: each of R ₁ , R ₆ , and R ₉ is independently CH ₃ , CH ₂ D, CHD ₂ , or CD ₃ ; each of R ₂ , R ₃ , R ₄ , R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , and R ₁₃ is independently H or D; each of R ₈ and L is independently CH2, CHD, or CD ₂ ; at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , and L is or comprises D;

R ₁₄ is C _1-4 alkyl, -C(R ₁₅ R ₁₆ )-NH ₂ , -C(R ₁₅ R ₁₆ )-phenyl, C _3-6 cycloalkyl, -CH ₂ OR ₁₇ , - CO ₂ R ₁₈ , -CO ₂ -C(R ₁₅ R ₁₆ )-phenyl, -COR ₁₉ , -CH ₂ OP(O)(OR ₂₀ )(OR ₂₁ ), or 3- to 6-membered heterocyclyl; each of R ₁₅ and R ₁₆ is independently H or C _1-4 alkyl; each of R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , and R ₂₁ is independently H, C _1-4 alkyl, or C _3-6 cycloalkyl; wherein each of the alkyl, cycloalkyl, heterocyclyl, and phenyl is independently optionally substituted by 1-5 occurrences of R ^a ; and each R ^a is independently halo, CF ₃ , CN, NO ₂ , -OH, -B(OH) ₂ , C _1-4 alkyl, -CO ₂ H, or - CO ₂ (C _1-4 alkyl).

[0067] In one embodiment, provided herein is a compound of Formula (XII):

(XII), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein: each of R ₁ , R ₆ , and R ₉ is independently CH ₃ , CH ₂ D, CHD ₂ , or CD ₃ ; each of R ₂ , R ₃ , R ₄ , R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , and R ₁₃ is independently H or D; each of R ₈ and L is independently CH ₂ , CHD, or CD ₂ ; at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , and L is or comprises D;

R ₁₄ is C _1-4 alkyl, -C(R ₁₅ R ₁₆ )-NH2, -C(R ₁₅ R ₁₆ )-phenyl, C _3-6 cycloalkyl, -CH ₂ OR ₁₇ , - CO ₂ R ₁₈ , -CO ₂ -C(R ₁₅ R ₁₆ )-phenyl, -COR ₁₉ , -CH ₂ OP(O)(OR ₂₀ )(OR ₂₁ ), -CH ₂ OC(O)R ₂₂ , or 3- to 6- membered heterocyclyl; each of R ₁₅ and R ₁₆ is independently H or C _1-4 alkyl; each of R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , and R ₂₂ is independently H, C _1-5 alkyl, or C _3-6 cycloalkyl; wherein each of the alkyl, cycloalkyl, heterocyclyl, and phenyl is independently optionally substituted by 1-5 occurrences of R ^a ; and each R ^a is independently halo, CF ₃ , CN, NH ₂ , NO ₂ , -OH, -B(OH) ₂ , C _1-4 alkyl, -CO ₂ H, or -CO ₂ (C _1-4 alkyl).

[0068] In one embodiment, the compound is a compound of Formula (XII-A):

(XII-A) or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof.

[0069] In one embodiment, at least one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L is or comprises D. In one embodiment, at least two of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L are or comprise D. In one embodiment, at least three of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L are or comprise D. In one embodiment, at least four, five, six, seven, eight, nine, ten, eleven, or all of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L are or comprise D. In one embodiment, all of the unspecified groups (e.g, R ₁₂ and R ₁₃ ) are not or do not comprise D.

[0070] In one embodiment, one of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L is or comprises D (while others are not or do not comprise D). In one embodiment, two of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L are or comprise D. In one embodiment, three of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L are or comprise D. In one embodiment, four, five, six, seven, eight, nine, ten, eleven, or all of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , and L are or comprise D. In one embodiment, all of the unspecified groups (e.g., R ₁₂ and R ₁₃ ) are not or do not comprise D.

[0071] In one embodiment, at least one of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L is or comprises D. In one embodiment, at least two of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, at least three of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, at least four of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, at least five of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, at least six of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, all of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, all of the unspecified groups (e.g., R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ , and R ₁₃ ) are not or do not comprise D. [0072] In one embodiment, one of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L is or comprises D (while others are not or do not comprise D). In one embodiment, two of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, three of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, four of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, five of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, six of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, all of R ₁ , R ₂ , R ₆ , R ₇ , R ₈ , R ₉ , and L are or comprise D. In one embodiment, all of the unspecified groups (e.g., R ₃ , R ₄ , R ₅ , R ₁₀ , R ₁₁ , R ₁₂ , and R ₁₃ ) are not or do not comprise D.

[0073] In one embodiment, at least one of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ is or comprises D. In one embodiment, at least two of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D In one embodiment, at least three of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D. In one embodiment, at least four of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D. In one embodiment, all of the unspecified groups (e.g., R ₃ , R ₄ , R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , and L) are not or do not comprise D.

[0074] In one embodiment, one of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ is or comprises D (while others are not or do not comprise D). In one embodiment, two of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D. In one embodiment, three of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D. In one embodiment, four of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D. In one embodiment, all of R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are or comprise D. In one embodiment, all of the unspecified groups (e.g., R ₃ , R ₄ , R ₅ , R ₇ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , and L) are not or do not comprise D.

[0075] In one embodiment, R ₁ is CH ₃ . In one embodiment, R ₁ is CH ₂ D. In one embodiment, R ₁ is CHD ₂ . In one embodiment, R ₁ is CD ₃ . In one embodiment, R ₆ is CH ₃ . In one embodiment, R ₆ is CH ₂ D. In one embodiment, R ₆ is CHD ₂ . In one embodiment, R ₆ is CD ₃ .

In one embodiment, R ₉ is CH ₃ . In one embodiment, R ₉ is CH ₂ D. In one embodiment, R ₉ is CHD ₂ . In one embodiment, R ₉ is CD ₃ . In one embodiment, R ₂ is H. In one embodiment, R ₂ is

D. In one embodiment, R ₃ is H. In one embodiment, R ₃ is D. In one embodiment, R ₄ is H. In one embodiment, R ₄ is D. In one embodiment, R ₅ is H. In one embodiment, R ₅ is D. In one embodiment, R ₇ is H. In one embodiment, R ₇ is D. In one embodiment, R ₁₀ is H. In one embodiment, R ₁₀ is D. In one embodiment, R ₁₁ is H. In one embodiment, R ₁₁ is D. In one embodiment, R ₁₂ is H. In one embodiment, R ₁₂ is D. In one embodiment, R ₁₃ is H. In one embodiment, R ₁₃ is D. In one embodiment, R ₈ is CH ₂ . In one embodiment, R ₈ is CHD. In one embodiment, R ₈ is CD ₂ . In one embodiment, L is CH ₂ . In one embodiment, L is CHD. In one embodiment, L is CD ₂ . In one embodiment, R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, all of the unspecified groups are not or do not comprise D.

[0076] In one embodiment, R ₁ is CD ₃ , and R ₂ is D. In one embodiment, R ₁ is CD ₃ , and R ₆ is CD ₃ . In one embodiment, R ₁ is CD ₃ , and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₁ is CD ₃ , and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, R ₂ is D, and R ₆ is CD ₃ . In one embodiment, R ₂ is D, and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₂ is D, and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, all of the unspecified groups are not or do not comprise D.

[0077] In one embodiment, R ₁ is CD ₃ , R ₂ is D, and R ₆ is CD ₃ . In one embodiment, R ₁ is CD ₃ , R ₂ is D, and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₁ is CD ₃ , R ₂ is D, and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, R ₁ is CD ₃ , R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₁ is CD ₃ , R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, R ₂ is D, R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₂ is D, R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, all of the unspecified groups are not or do not comprise D.

[0078] In one embodiment, R ₁ is CD ₃ , R ₂ is D, R ₆ is CD3, and R ₈ -R ₉ is CD ₂ CH ₃ . In one embodiment, R ₁ is CD3, R ₂ is D, R ₆ is CD ₃ , and R ₈ -R ₉ is CD ₂ CD ₃ . In one embodiment, all of the unspecified groups are not or do not comprise D.

[0079] In one embodiment, all of R ₃ , R ₄ , and R ₅ are H. In one embodiment, all of R ₃ , R ₄ , and R ₅ are D. In one embodiment, both R ₁₀ and R ₁₁ are H. In one embodiment, both R ₁₀ and R ₁₁ are D. In one embodiment, all of R ₃ , R ₄ , R ₅ , R ₁₀ , and R ₁₁ are H.

[0080] In one embodiment, provided herein is a compound of Formula (VIII): (VIII), or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

R ₁₄ is C _1-4 alkyl, -C(R ₁₅ R ₁₆ )-NH ₂ , -C(R ₁₅ R ₁₆ )-phenyl, C _3-6 cycloalkyl, -CH ₂ OR ₁₇ , - CO ₂ R ₁₈ , -CO ₂ -C(R ₁₅ R ₁₆ )-phenyl, -COR ₁₉ , -CH20P(0)(OR ₂₀ )(OR ₂₁ ), or 3- to 6-membered heterocyclyl; each of R ₁₅ and R ₁₆ is independently H or C _1-4 alkyl; each of R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , and R ₂₁ is independently H, C _1-4 alkyl, or C _3-6 cycloalkyl; wherein each of the alkyl, cycloalkyl, heterocyclyl, and phenyl is independently optionally substituted by 1-5 occurrences of R ^a ; and each R ^a is independently halo, CF ₃ , CN, NO ₂ , -OH, -B(OH) ₂ , C _1-4 alkyl, -CO ₂ H, or - CO ₂ ( C _1-4 alkyl).

[0081] In one embodiment, provided herein is a compound of Formula (VIII): or a stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt thereof, wherein:

R ₁₄ is C _1-4 alkyl, -C(R ₁₅ R ₁₆ )-NH2, -C(R ₁₅ R ₁₆ )-phenyl, C _3-6 cycloalkyl, -CH2OR17, - CO ₂ R ₁₈ , -CO ₂ -C(R ₁₅ R ₁ 6)-phenyl, -COR ₁₉ , -CH ₂ OP(0)(OR ₂ O)(OR ₂₁ ), -CH ₂ OC(O)R ₂₂ , or 3- to 6- membered heterocyclyl; each of R ₁₅ and R ₁₆ is independently H or C _1-4 alkyl; each of R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , and R ₂₂ is independently H, C _1-5 alkyl, or C _3-6 cycloalkyl; wherein each of the alkyl, cycloalkyl, heterocyclyl, and phenyl is independently optionally substituted by 1-5 occurrences of R ^a ; and each R ^a is independently halo, CF ₃ , CN, NH ₂ , NO ₂ , -OH, -B(OH) ₂ , C _1-4 alkyl, -CO ₂ H, or -CO ₂ (C _1-4 alkyl).

[0082] In one embodiment, the compound is a compound of Formula (IX):

(IX), or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, R ₁₄ is C _1-4 alkyl.

[0084] In one embodiment, R ₁₄ is -C(R ₁₅ R ₁₆ )-NH ₂ . In one embodiment, R ₁₄ is -CH ₂ -

NH2.

[0085] In one embodiment, R ₁₄ is C _3-6 cycloalkyl.

[0086] In one embodiment, R ₁₄ is -CH ₂ OR ₁₇ . In one embodiment, R ₁₄ is -CH ₂ OH. In one embodiment, R ₁₄ is -CH2O(CI-4 alkyl). In one embodiment, R ₁₄ is -CH ₂ O(C _3-6 cycloalkyl).

[0087] In one embodiment, R ₁₄ is -CO ₂ R18. In one embodiment, R ₁₄ is -CO ₂ H. In one embodiment, R ₁₄ is -CO ₂ (C _1-4 alkyl). In one embodiment, R ₁₄ is -CO ₂ (C _3-6 cycloalkyl).

[0088] In one embodiment, R ₁₄ is -COR ₁₉ . In one embodiment, R ₁₄ is -C(=O)H. In one embodiment, R ₁₄ is -C(=O)CH ₃ . In one embodiment, R ₁₄ is -CO(C _1-4 alkyl). In one embodiment, R ₁₄ is -CO(C _3-6 cycloalkyl).

[0089] In one embodiment, R ₁₄ is -CH ₂ OP(O)(OR ₂₀ )(OR ₂₁ ). In one embodiment, R ₁₄ is - CH ₂ OP(O)(OH) ₂ . In one embodiment, R ₁₄ is -CH ₂ OP(O)(OC _1-4 alkyl) ₂ . In one embodiment, R ₁₄ is -CH ₂ OP(O)(OCH ₃ ) ₂ . In one embodiment, R ₁₄ is -CH ₂ OP(O)(O-tert-Bu) ₂ . In one embodiment, R ₁₄ is -CH ₂ OP(O)(OC _3-6 cycloalkyl) ₂ .

[0090] In one embodiment, R ₁₄ is -C(R ₁₅ R ₁₆ )-phenyl. In one embodiment, R ₁₄ is -CO ₂ - C(R ₁₅ R ₁₆ )-phenyl. In one embodiment, R ₁₄ is -CH ₂ -phenyl. In one embodiment, R ₁₄ is -CO ₂ - CH ₂ -phenyl. In one embodiment, the phenyl is substituted with -B(OH) ₂ . In one embodiment, the phenyl is substituted with -B(OH) ₂ at para-position.

[0091] In one embodiment, R ₁₄ is -CH ₂ OC(O)R ₂₂ . In one embodiment, R ₂₂ is C _1-5 alkyl.

In one embodiment, R ₂₂ is C _1-5 alkyl substituted with NH ₂ . In one embodiment, R ₂ 2 is - C(H)NH ₂ R ₂₃ , wherein R ₂₃ is an amino acid side chain. In one embodiment, R ₂₃ is the side chain of valine (i.e., R ₂₃ is -CH(CH ₃ ) ₂ ). In one embodiment, R ₂₃ is the side chain of isoleucine (i.e., R ₂₃ is -CH(CH ₃ )(CH ₂ CH ₃ )). In one embodiment, R ₂₃ is the side chain of glycine, alanine, sarcosine, phenylalanine, or proline. In one embodiment, R ₁₄ is an L-amino acid ester.

[0092] In one embodiment, R ₁₄ is 3- to 6-membered heterocyclyl.

[0093] In one embodiment, the alkyl is methyl. In one embodiment, the alkyl is ethyl. In one embodiment, the alkyl is n-propyl. In one embodiment, the alkyl is n-butyl. In one embodiment, the alkyl is t-butyl.

[0094] In one embodiment, the cycloalkyl is cyclopropyl. In one embodiment, the cycloalkyl is cyclobutyl. In one embodiment, the cycloalkyl is cyclopentyl. In one embodiment, the cycloalkyl is cyclohexyl.

[0095] In one embodiment, the heterocyclyl is azetidinyl. In one embodiment, the heterocyclyl is oxetanyl. In one embodiment, the heterocyclyl is pyrrolidinyl. In one embodiment, the heterocyclyl is tetrahydrofuranyl. In one embodiment, the heterocyclyl is piperidinyl. In one embodiment, the heterocyclyl is tetrahydropyranyl. In one embodiment, the heterocyclyl is tetrahydrothiopyranyl.

[0096] In one embodiment, the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof.

Table 1.

[0097] In one embodiment, the compound is a compound in Table 2, or a pharmaceutically acceptable salt thereof.

Table 2.

[0098] In one embodiment, the compound is a compound in Table 3, or a pharmaceutically acceptable salt thereof.

Table 3.

[0099] In one embodiment, the compound is a compound in Table 4, or a pharmaceutically acceptable salt thereof. Table 4.

[00100] 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 R ₁ and R ₂ are attached to), as provided in, e.g., Table 2 and Table 4.

[00101] In another set of embodiments, provided herein are the corresponding S- enantiomer compounds of the R-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 R-enantiomer compounds provided herein, including any compound specifically provided in the tables above.

[00102] In some embodiments, for the compounds provided herein, including any compound specifically provided in the tables above, each position designated as deuterium independently has a minimum isotopic enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium atom.

[00103] 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.

[00104] 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

[00105] 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.

[00106] In one embodiment, the cancer is a solid tumor. In one embodiment, the cancer is a hematologic malignancy.

[00107] 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 ROS1 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.

[00108] 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.

[00109] In one embodiment, 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.

[00110] In one embodiment, the cancer is anaplastic large cell lymphoma (ALCL), atypical meningioma, breast cancer, cholangiocarcinoma, gastric cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), inflammatory hepatocellular adenoma (HCA), melanoma, pancreatic cancer, papillary thyroid carcinoma, salivary gland carcinoma, serous ovarian carcinoma, or spitzoid neoplasm.

[00111] 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.

[00112] In one embodiment, the solid tumor (or cancer) is ROS1 positive. In one embodiment, the solid tumor is ROS1 positive NSCLC. In one embodiment, the solid tumor is advanced ROS1 positive solid tumor. In one embodiment, the solid tumor is locally advanced ROS1 positive solid tumor. In one embodiment, the solid tumor is advanced ROS1 positive NSCLC. In one embodiment, the solid tumor is locally advanced ROS1 positive NSCLC. In one embodiment, the solid tumor is metastatic ROS1 positive solid tumor. In one embodiment, the solid tumor is CNS metastatic ROS1 positive solid tumor. In one embodiment, the solid tumor is metastatic ROS1 positive NSCLC. In one embodiment, the solid tumor is CNS metastatic ROS1 positive NSCLC. In one embodiment, the solid tumor (or cancer) has a ROS1 mutation. In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutation comprise G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the solid tumor (or cancer) has a ROSI fusion.

[00113] In one embodiment, the patient has not been treated with a prior therapy. In one embodiment, the patient is naive to (i.e. not receiving) any tyrosine kinase inhibitor (TKI) therapy.

[00114] In one embodiment, the patient has been treated with one or more prior therapies. In one embodiment, the patient has been treated with at least one prior TKI therapy. In one embodiment, the patient has been treated with at least two prior TKI therapies. In one embodiment, the patient has been treated with one prior TKI therapy. In one embodiment, the patient has been treated with two prior TKI therapies. In one embodiment, the TKI is ROS1 TKI (e g crizotinib or entrectinib). In one embodiment, the prior TKI therapy is one or more selected from the group consisting of crizotinib, entrectinib, repotrectinib, taletrectinib, and lorlatinib.

[00115] In one embodiment, the patient has not been treated with prior platinum-based chemotherapy. In one embodiment, the patient has been treated with up to one prior platinum- based chemotherapy. In one embodiment, the patient has been treated with at least one prior platinum-based chemotherapy. In one embodiment, the patient has been treated with at least two prior platinum-based chemotherapies. In one embodiment, the patient has been treated with one prior platinum-based chemotherapy. In one embodiment, the patient has been treated with two prior platinum-based chemotherapies.

[00116] As used herein, “platinum -based chemotherapy” refers to chemotherapeutic agents that are coordination complexes of platinum. Exemplified platinum- based chemotherapy includes but not limited to cisplatin, oxaliplatin, nedaplatin, or carboplatin. [00117] In one embodiment, the patient has not been treated with immunotherapy. In one embodiment, the patient has been treated with immunotherapy. In one embodiment, the patient has been treated with at least one prior immunotherapy. In one embodiment, the patient has been treated with at least two prior immunotherapies. In one embodiment, the patient has been treated with one prior immunotherapy. In one embodiment, the patient has been treated with two immunotherapies.

[00118] 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. Exemplified immunotherapy includes but not limited to checkpoint inhibitors (e.g. anti-cytotoxic T- lymphocyte-associated protein 4 (CTLA-4) and anti-programmed cell death protein 1 (PD-1) antibodies). 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).

[00119] In one embodiment, the patient has not been treated with chemotherapy. In one embodiment, the patient has been treated with at least one prior line of chemotherapy. In one embodiment, the patient has been treated with at least two prior lines of chemotherapy.

[00120] In one embodiment, the patient has been treated with at least three prior lines of anticancer therapy. In one embodiment, the patient has been treated with at least two prior lines of anti cancer therapy selected from the group consisting of ROS1 TKI (e.g., investigational ROS1 TKI, crizotinib, lorlatinib, entrectinib, taletrectinib, repotrectinib) and chemotherapy.

[00121] In one embodiment, the patient has been treated with at least one line of ROS1 TKI and one line of chemotherapy. In one embodiment, the patient has been treated with at least two lines of ROS1 TKI and one line of chemotherapy. In one embodiment, the patient has been treated with at least three lines of ROS1 TKI and one line of chemotherapy. In one embodiment, the patient has been treated with at least two lines of chemotherapy. In one embodiment, the patient has been treated with at least one line of ROS1 TKI and two lines of chemotherapy. In one embodiment, the patient has been treated with at least two lines of ROS1 TKI and two lines of chemotherapy. In one embodiment, the patient has been treated with at least three lines of ROS1 TKI and two lines of chemotherapy.

[00122] In one embodiment, the ROS1 TKI is crizotinib. In one embodiment, the ROS1 TKI is entrectinib. In one embodiment, the ROS1 TKI is lorlatinib. In one embodiment, the ROS1 TKI is repotrectinib. In one embodiment, the patient has been treated with lorlatinib and repotrectinib. In one embodiment, the ROS1 TKI is taletrectinib.

[00123] In one embodiment, the solid tumor is metastatic ROS1-positive solid tumor, and the patient has been treated with at least one prior ROS1 TKI therapy.

[00124] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC, and the patient is naive to TKI therapy and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy.

[00125] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC, and the patient has been treated with one prior ROS1 TKI therapy and has not been treated with prior platinum-based chemotherapy or immunotherapy.

[00126] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC, and the patient has been treated with one prior ROS1 TKI therapy and one prior platinum-based chemotherapy with or without immunotherapy.

[00127] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC, and the patient has been treated with at least two prior ROS1 TKI therapies and up to one prior platinum- based chemotherapy with or without immunotherapy.

[00128] In one embodiment, the solid tumor is metastatic ROS1-positive solid tumor, and the patient has progressed on a prior therapy. In one embodiment, the prior therapy is a prior ROS1 TKI therapy. In one embodiment, the prior therapy is a prior chemotherapy (e.g., platinum-based chemotherapy). In one embodiment, the prior therapy is a prior immunotherapy. [00129] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC, and the patient is naive to TKI therapy and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy.

[00130] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC, and the patient has been treated with one prior ROS1 TKI therapy and has not been treated with prior platinum-based chemotherapy or immunotherapy.

[00131] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC, and the patient has been treated with one prior ROS1 TKI therapy and one prior platinum-based chemotherapy with or without immunotherapy.

[00132] In one embodiment, the solid tumor is advanced ROS1-positive NSCLC, and the patient has been treated with at least two prior ROS1 TKI therapies and up to one prior platinum- based chemotherapy with or without immunotherapy.

[00133] In one embodiment, the solid tumor is advanced ROS1-positive solid tumor, and the patient has progressed on a prior therapy. In one embodiment, the prior therapy is a prior ROS1 TKI therapy.

[00134] In one embodiment, the ROS1 TKI is crizotinib. In one embodiment, the ROS1 TKI is entrectinib.

[00135] In one embodiment, the compound is administered to the patient for one or more days. In one embodiment, the compound is administered to the patient for at least one treatment cycle. In one embodiment, one treatment cycle is at least 7 days. In one embodiment, one treatment cycle is at least 14 days. In one embodiment, one treatment cycle is at least 21 days. In one embodiment, one treatment cycle is at least 28 days.

[00136] 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 one embodiment, 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.

[00137] In one embodiment, the patient only experiences nausea after the administration of the compound . In one embodiment, the patient does not experience a neurologic adverse event after the administration of the compound . In one embodiment, the patient does not experience one or more CNS adverse event selected from the group consisting of 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). In one embodiment, the neurologic adverse event is one or more selected from the group consisting of cognitive impairment, mood disorders, sleep disturbances, dizziness, and ataxia. In one embodiment, the patient does not experience an adverse event of weight gain and/or glucose metabolism disorders. In one embodiment, the glucose metabolism disorder is hyperglycemia (e.g., diabetes). In one embodiment, the glucose metabolism disorder is hypoglycemia.

[00138] In one embodiment, the patient has a complete response after one or more cycles of treatment. In one embodiment, the patient has a partial response after one or more cycles of treatment. In one embodiment, the patient has reached stable disease after one or more cycles of treatment. In one embodiment, the patient has not experienced progressive disease after one or more cycles of treatment.

[00139] As used herein and unless otherwise specified, Complete Response (CR) refers to the disappearance of all target lesion(s). In some embodiments of CR, any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) refers to at least a 30% decrease in the sum of diameters of target lesion(s). Progressive Disease (PD) refers to at least a 20% increase in the sum of diameters of target lesion(s). In some embodiments of PD, in addition to the relative increase of 20%, the sum also demonstrates an increase of at least 5 mm. In some embodiments, the appearance of one or more new lesion(s) is also considered progression. Stable Disease (SD) refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Additional description of these terms according to RECIST 1.1 can be found in EUROPEAN JOURNAL OF CANCER 45 (2009) 228 - 247.

[00140] In one embodiment, the patient has brain metastases. In one embodiment, the patient has brain metastases and experiences no intracranial progression after at least one treatment cycle.

[00141] In one embodiment, the patient has at least about 5% to about 100% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 35% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 45% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 55% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 65% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 75% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 85% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has at least about 100% reduction of ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the patient has undetectable ROS1 allele variant in circulating tumor DNA after at least one treatment cycle. In one embodiment, the ROS1 allele variant is G2032R.

[00142] In one embodiment, the prior therapy is a prior ROS1 TKI therapy. In one embodiment, the ROS1 TKI is crizotinib, entrectinib, taletrectinib, or repotrectinib.

[00143] In one embodiment, provided herein is a method of reducing a lesion in a subject having a ROS1-positive solid tumor (e.g., NSCLC), comprising

(i) obtaining a first radiological measurement of the size of the lesion;

(ii) administering a pharmaceutically effective amount of the compound once daily for one or more days; and

(iii) obtaining a second radiological measurement of the size of the lesion; wherein the second measurement is at most 100% of the first measurement

[00144] In one embodiment, the second measurement is at most about 90% of the first measurement. In one embodiment, the second measurement is at most about 80% of the first measurement. In one embodiment, the second measurement is at most about 70% of the first measurement. In one embodiment, the second measurement is at most about 60% of the first measurement. In one embodiment, the second measurement is at most about 50% of the first measurement. In one embodiment, the second measurement is about 0.01% to about 90% of the first measurement. In one embodiment, the second measurement shows no detectable lesion.

[00145] In one embodiment, the compound used herein (the compound or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered once daily (QD). In one embodiment, the compound is administered twice daily (BID). In certain embodiments, the compound used herein is the compound .

[00146] In one embodiment, the compound is administered at an amount of from about 1 mg to about 1000 mg (by weight of the free base form of the compound ) per day. In one embodiment, the compound is administered at an amount of from about 5 mg to about 500 mg per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 250 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 25 mg to about 150 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 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 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 about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, or about 200 mg per day In one embodiment, the amount is about 5 mg per day. In one embodiment, the amount is about 10 mg per day. In one embodiment, the amount is about 15 mg per day. In one embodiment, the amount is about 20 mg per day. In one embodiment, the amount is about 25 mg per day. In one embodiment, the amount is about 30 mg per day. In one embodiment, the amount is about 35 mg per day. In one embodiment, the amount is about 40 mg per day. In one embodiment, the amount is about 45 mg per day. In one embodiment, the amount is about 50 mg per day. In one embodiment, the amount is about 75 mg per day. In one embodiment, the amount is about 100 mg per day. In one embodiment, the amount is about 125 mg per day. In one embodiment, the amount is about 150 mg per day. As used herein, the weight amount refers to the weight amount of the free base form of the compound.

[00147] In one embodiment, the compound is administered at an amount of from about 1 mg to about 1000 mg (by weight of the free base form of the compound ) once daily. In one embodiment, the compound is administered at an amount of from about 5 mg to about 500 mg once daily. In one embodiment, the compound is administered at an amount of from about 25 mg to about 250 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 25 mg to about 150 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 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 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, or about 200 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. As used herein, the weight amount refers to the weight amount of the free base form of the compound.

[00148] In one embodiment, the compound is administered at an amount of from about 1 mg to about 1000 mg (by weight of the free base form of the compound ) twice daily. In one embodiment, the compound is administered at an amount of from about 5 mg to about 500 mg twice daily. In one embodiment, the compound is 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 25 mg to about 250 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 10 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 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, or about 200 mg twice daily. In one embodiment, the amount is about 5 mg twice daily. In one embodiment, the amount is about 10 mg twice daily. In one embodiment, the amount is about 15 mg twice daily. In one embodiment, the amount is about 20 mg twice daily. In one embodiment, the amount is about 25 mg twice daily. In one embodiment, the amount is about 30 mg twice daily. In one embodiment, the amount is about 35 mg twice daily. In one embodiment, the amount is about 40 mg twice daily. In one embodiment, the amount is about 45 mg twice daily. In one embodiment, the amount is about 50 mg twice daily. In one embodiment, the amount is about 75 mg twice daily. In one embodiment, the amount is about 100 mg twice daily. In one embodiment, the amount is about 125 mg twice daily. In one embodiment, the amount is about 150 mg twice daily. As used herein, the weight amount refers to the weight amount of the free base form of the compound.

[00149] In one embodiment, the compound is administered orally. In one embodiment, the compound is administered in the form of one or more tablets.

[00150] 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 fasted status. In one embodiment, the compound is administered to a subject without food. In one embodiment, the compound is administered to a subject at least 1 hour before and 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 to a subject at fed status. In one embodiment, the compound is administered to a subject with food. In one embodiment, the compound is administered with the ingestion of food and/or beverages.

[00151] In one embodiment, the patient experiences improvement in one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disturbances, dizziness, ataxia, and weight gain, after the administration of the compound. In one embodiment, the patient does not experience one or more symptoms selected from the group consisting of cognitive impairment, mood disorders, sleep disturbances, dizziness, ataxia, and weight gain, after the administration of the compound. In one embodiment, the patient experiences reduced levels of one or more of pROS1, ROS1, pAKT, and pERK, after the administration of the compound. In one embodiment, the patient experiences reduced expression level of one or more MAP kinase pathway genes in tumor, after the administration of the compound. In one embodiment, the patient experiences reduced expression level of one or more MAP kinase pathway genes in solid tumor, after the administration of the compound. In one embodiment, the one or more MAP kinase pathway genes are selected from the group consisting of DUSP6, FOS, IL1R1, and SPRY4.

[00152] 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.

[00153] In some embodiments, the compound provided herein is an inhibitor of human ROS1. ROS1 is an RTK encoded by the ROS1 gene. The ligands and biological functions of human ROS1 are unknown, but its homologs in some other species have been shown to bind extracellular ligands and stimulate cell differentiation. For example, mouse ROS1 is essential for male gamete maturation and reproduction. In humans, ROS1 chromosomal rearrangements are a well-documented cause of cancer, representing 1-2% of non-small cell lung cancer (NSCLC) and a subset of many other cancers. These rearrangements result in the fusion of the C-terminus of ROS1 with the N-terminus of various partner proteins, the most common of which is CD74. ROS1 fusions have constitutive kinase activity that drives tumor growth through MAPK, PI3K, and JAK/STAT signaling pathways. Small-molecule tyrosine kinase inhibitors (TKIs) have been used to target ROSI fusions in cancer, including crizotinib and entrectinib.

Crizotinib was the first FDA-approved TKI for the treatment of ROSI -positive NSCLC. Despite an initial response, most patients acquire resistance to crizotinib and relapse. The predominant mechanism of resistance is the G2032R mutation in the solvent front, which dramatically reduces crizotinib affinity. No inhibitors with activity against ROS1-G2032R fusions have been FDA- approved, indicating a need in the art.

[00154] In one embodiment, a compound provided herein selectively inhibits ROS1. In one embodiment, the compound selectively inhibits ROS1 over ALK. 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, greater than a factor of about 3, greater than a factor of about 4, greater than a factor of about 5, greater than a factor of about 10, greater than a factor of about 20, greater than a factor of about 30, greater than a factor of about 50, or greater than a factor of about 100, where selectivity can be measured by ratio of IC ₅₀ values, among other means. In one embodiment, the selectivity of ROS1 over ALK is measured by the ratio of the IC ₅₀ value against ALK to the IC ₅₀ value against ROS1.

[00155] In one embodiment, the compound selectively inhibits ROS1 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, greater than a factor of about 10,000, or greater than a factor of about 20,000, where selectivity can be measured by ratio of IC ₅₀ values, among other means. In one embodiment, the selectivity of ROS1 over TRK is measured by the ratio of the IC ₅₀ value against TRK to the IC ₅₀ value against ROS1.

[00156] In one embodiment, provided herein is a method for selectively inhibiting ROS1 over ALK wherein the inhibition takes place in a cell. In one embodiment, provided herein is a method for selectively inhibiting ROS1 over TRK (e g., TRKA, TRKB, and/or TRBC) wherein the inhibition takes place in a cell. In one embodiment, the method comprises contacting ROS1 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 patient having a cancer provided herein.

[00157] In one embodiment, provided herein is a method for selectively inhibiting ROS1 over ALK 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 ROS1, said method comprising selectively inhibiting ROS1 over ALK by administering an amount of a compound or a pharmaceutical composition provided herein to said subject, wherein said amount is sufficient for selective inhibiting ROS1 over ALK.

[00158] In one embodiment, provided herein is a method for selectively inhibiting ROS1 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 ROS1, said method comprising selectively inhibiting ROS1 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 ROS1 over TRK (e g , TRKA, TRKB, and/or TRBC).

[00159] In one embodiment, provided herein is a method 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. In one embodiment, the method further comprises contacting the cell with one or more additional therapeutic agents. In one embodiment, the additional therapeutic agent is a TKI.

[00160] As used herein and unless otherwise specified, inhibition of ROS1 includes inhibition of wild type ROS1, or a mutation thereof; inhibition of ALK includes inhibition of wild type ALK, or a mutation thereof; and inhibition of TRK includes inhibition of wild type TRK, or a mutation thereof.

[00161] Cancers treated by methods provided herein include, but are not limited to, lung cancer, e.g., non-small cell lung cancer, inflammatory myofibroblastic tumor, ovarian cancer, e.g., serous ovarian 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. [00162] Cancers treated by methods provided herein include cancers originating from one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC. In certain embodiments, cancers treated by methods provided herein include cancers that are drug resistant to treatments directed at one or more oncogenic proteins selected from ROS1, ALK, TRKA, TRKB, and TRKC.

[00163] In one embodiment, the cancer in a method provided herein is ROS1 positive (ROS1+). As used herein and unless otherwise specified, a “ROS1 positive” (ROS1+) cancer, disease, or disorder refers to a cancer, disease, or disorder characterized by inappropriately high expression of a ROS1 gene and/or the presence of a mutation in a ROS1 gene. In one embodiment, the mutation alters the biological activity of a ROS1 nucleic acid molecule or polypeptide. As used herein and unless otherwise specified, a “mutation” or “mutant” of ROS1 comprises one or more deletions, substitutions, insertions, inversions, duplications, translocations, or amplifications in the amino acid or nucleotide sequences of ROS1, or fragments thereof. As used herein and unless otherwise specified, a ROSl “rearrangement” refers to genetic translocations involving the ROS1 gene that may result in ROS1 fusion genes and/or ROS1 fusion proteins. The ROS1 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.

[00164] In one embodiment, the ROS1 mutation comprises one or more ROS1 point mutations. In some embodiments, cancers treated by methods provided herein include one or more mutations in ROS1 kinase. In one embodiment, the one or more ROS1 point mutations are selected from point mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, 1981Tins, M2001T, and L2155. In one embodiment, the one or more ROS1 point mutations are selected from G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, and L2086F. In one embodiment, the ROS1 mutation is G2032R. In one embodiment, the ROS1 mutation is S1986F. In one embodiment, the ROS1 mutation is S1986Y. In one embodiment, the ROS1 mutation is L2026M. In one embodiment, the ROS1 mutation is D2033N. In one embodiment, the ROS1 mutation is L2086F. In one embodiment, the ROS1 mutation is F2004C. In one embodiment, the ROS1 mutation is F2004V. In one embodiment, the ROS1 mutation is G2101 A. In one embodiment, the ROS1 mutation is LT982F. In one embodiment, the ROS1 mutation is co-mutation of G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N.

[00165] In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements (in one embodiment, one rearrangement). In one embodiment, the ROS1 mutation comprises one or more ROS1 fusions (in one embodiment, one fusion). In some embodiments, cancers treated by methods provided herein include ROS1 fusions. In one embodiment, the ROS1 fusion is with one of the fusion partners selected from SLC34A2, CD74, TPM3, SDC4, EZR, LRIG3, KDELR2, CEP72, CLTL, CTNND2, GOPC (e.g., GOPC-S, GOPC- L.), GPRC6A, LIMA 1, LRIG3, MSN, MYO5C, OPRM1, SLC6A 17 SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, ZCCHC8,CCDC6,CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, STI 3, TRIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is SDC4-ROS1 fusion. In one embodiment, the ROS T fusion is EZR-ROS1 fusion. In one embodiment, the ROS1 fusion is SLC34A2-ROS1 fusion. In one embodiment, the ROS1 fusion is GOPC-ROS1 fusion (e g., GOPC-ROS1-S, GOPC-ROS1-L). In one embodiment, the ROS1 fusion is CEP85L-ROS1 fusion.

[00166] In one embodiment, the ROS1 mutation comprises one ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, GOPC-ROS1 (e g., GOPC-ROS1-S, GOPC-ROS1-L), and CEP85L-ROS1, and one or more ROS1 point mutations selected from F2004C, F2004V, and G2032R. In one embodiment, the ROS1 mutation comprises one or more ROS1 rearrangements from CD74-ROS1, EZR-ROS1, and SLC34A2-ROS1, and ROS1 point mutation of G2101A.

[00167] In one embodiment, the ROS1 mutation is CD74-ROS1 F2004C. In one embodiment, the ROS1 mutation is CD74-ROS1 F2004V. In one embodiment, the ROS1 mutation is CD74-ROS1 G2101A. In one embodiment, the ROS1 mutation is CD74-ROS1 G2032R. In one embodiment, the ROS1 mutation is CD74-ROS1 S1986F. In one embodiment, the ROS1 mutation is CD74-ROS1 L2026M. In one embodiment, the ROS1 mutation is CD74- ROS1 D2033N. In one embodiment, the ROS1 mutation is EZR-ROS1 F2004C, In one embodiment, the ROS1 mutation is EZR-ROS1 F2004V. In one embodiment, the ROS1 mutation is EZR-ROS1 G2101A. In one embodiment, the ROS1 mutation is EZR-ROS1 G2032R. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004C. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 F2004V. In one embodiment, the ROS1 mutation is SLC34A2-ROS1 G2101A. In one embodiment, the ROS1 mutation is SLC34A2- ROS1 G2032R. In one embodiment, the ROS1 mutation is GOPC-ROS1 F2004C (e.g, GOPC- ROS1-S F2004C, GOPC-ROS1-L F2004C). In one embodiment, the ROS1 mutation is GOPC- ROS1 F2004V (e.g., GOPC-ROS1-S F2004V, GOPC-ROS1-L F2004V). In one embodiment, the ROS1 mutation is GOPC-ROS1 G2032R (e.g, GOPC-ROS1-S G2032R, GOPC-ROS1-L G2032R). In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004C. In one embodiment, the ROS1 mutation is CEP85L-ROS1 F2004V. In one embodiment, the ROS1 mutation is CEP85L-ROS1 G2032R. In one embodiment, the ROS1 mutation is GOPC-ROS1 L1982F (e.g., GOPC-ROS1-S L1982F, GOPC-ROS1-L L1982F). In one embodiment, the ROS1 mutation is CD74-ROS1 L1982F.

[00168] In one embodiment, the ROS1+ cancer is determined by an FDA-approved test or other tests known in the art. The tests that can be used include, e.g., Oncomine™ Dx Target Test by Thermo Fisher Scientific, (a qualitative in vitro diagnostic test that uses targeted high- throughput, parallel-sequencing technology to detect sequence variations in 23 genes in DNA and RNA isolated from formalin-fixed, paraffin-embedded tumor (FFPE) tissue samples from patients with non-small cell lung cancer (NSCLC) using the Ion PGM Dx System); Vysis ROS1 Break Apart FISH Probe Kit (a qualitative test to detect rearrangements involving ROS1 gene rearrangements at 6q22 via fluorescence in situ hybridization (FISH) in formalin-fixed, paraffin- embedded (FFPE) non-small cell lung cancer (NSCLC) tissue specimens) or Reverse transcription-Polymerase Chain Reaction (RT-PCR) or Next Generation Sequencing (NGS) via a local diagnostic test.

[00169] Also provided are methods of treating a subject having a cancer (e.g, a ROS1 positive cancer) that include: determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered a first ROS1 inhibitor, has one or more ROS1 inhibitor resistance mutations; and administering a compound provided herein as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has a cancer cell that has one or more ROS1 inhibitor resistance mutations. In some embodiments, the one or more ROS1 inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first ROS1 inhibitor. In some embodiments, the one or more ROS1 inhibitor resistance mutations include one or more ROS1 inhibitor resistance mutations. For example, the one or more ROS1 inhibitor resistance mutations can include a substitution at one or more of amino acid positions 2032, 2033, 1986, 2026, 1951, 1935, 1947, 1971, 1974, 1982, 2004, 2020, 2060, 2075, 2089, 2098, 2101, 2113, 2155, 2032, and 2086, e.g., G2032R, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G, L2155S, L2032K, and L2086F. In some embodiments, another anticancer agent is any anticancer agent known in the art. For example, another anticancer agent can be another ROS1 inhibitor (e.g., a second ROS1 inhibitor).

[00170] 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) ROSE

[00171] 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 a compound provided herein. In one embodiment, the CNS metastases is brain metastases. In one embodiment, the cancer is a ROS1+ cancer.

[00172] In some embodiments, the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C. In certain embodiments, the IC ₅₀ of the compound for inhibition of mutant or non-mutant ROS1 or ALK is no more than one-fifth of the IC ₅₀ of the compound for inhibition of wild-type 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.

[00173] In some embodiments, provided is a method of minimizing adverse events in a subject in need of treatment for cancer (e.g., a ROS1 positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, and wherein the method minimizes adverse events associated with TRK inhibitors In some embodiments, the cancer is a ROS1 -associated cancer. In some embodiments, the adverse events are one or more of TRK-related CNS adverse events.

[00174] 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 events refers 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.

[00175] 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).

[00176] 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 a compound provided herein. 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 a compound provided herein. 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 ROS1 and/or ALK inhibitor (e.g., crizotinib, entrectinib, lorlatinib, or repotrectinib) for ROS1+ and/or ALK+ cancer. In one embodiment, the TRK-related side effect is a TRKB-related CNS side effect. In one embodiment, the TRK-related CNS side effect or adverse event is dizziness, ataxia, gait disturbance, paraesthesia, weight gain, cognitive impairment, a mood disorder, or sleep disturbance.

[00177] 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. In one embodiment, the cancer is a ROS1 -associated cancer. In one embodiment, the cancer is a ROS1+ cancer. In one embodiment, the cancer is identified to be ROS1

[00178] In one embodiment, provided herein is a method for treating a ROS1+ cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein.

[00179] In one embodiment, provided herein is a method for treating cancer in a subject, comprising: (i) identifying the cancer in the subject to be ROS1+, and (ii) administering to the subject a therapeutically effective amount of a compound provided herein.

[00180] In one embodiment, the cancer (or ROS1+ cancer) is a solid tumor. In one embodiment, the cancer (or ROS1+ cancer) is an advanced solid tumor. In one embodiment, the cancer (or ROS1+ cancer) is a locally advanced solid tumor. In one embodiment, the cancer (or ROS1+ 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.

[00181] In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is non-small cell lung cancer. In one embodiment, the cancer is ROS1+ non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory non-small cell lung cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed non-small cell lung cancer. In one embodiment, the cancer is newly diagnosed ROS1+ non-small cell lung cancer.

[00182] 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 ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma.

[00183] In one embodiment, the cancer is IMT. In one embodiment, the cancer is ROS1+ IMT. In one embodiment, the cancer is relapsed or refractory IMT. In one embodiment, the cancer is relapsed or refractory ROS1+ IMT. In one embodiment, the cancer is newly diagnosed IMT. In one embodiment, the cancer is newly diagnosed ROS1+ IMT.

[00184] In one embodiment, the cancer is bile duct cancer. In one embodiment, the cancer is cholangiocarcinoma. In one embodiment, the cancer is ROS1+ cholangiocarcinoma. In one embodiment, the cancer is relapsed or refractory cholangiocarcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed cholangiocarcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ cholangiocarcinoma.

[00185] In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is ROS1+ ovarian cancer. In one embodiment, the cancer is relapsed or refractory ovarian cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ ovarian cancer. In one embodiment, the cancer is newly diagnosed ovarian cancer. In one embodiment, the cancer is newly diagnosed ROS1+ ovarian cancer. In one embodiment, the ovarian cancer is serous ovarian carcinoma. In one embodiment, the ovarian cancer is high grade serous ovarian carcinoma.

[00186] In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is ROS1+ gastric cancer. In one embodiment, the cancer is relapsed or refractory gastric cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ gastric cancer. In one embodiment, the cancer is newly diagnosed gastric cancer. In one embodiment, the cancer is newly diagnosed ROS1+ gastric cancer.

[00187] In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is ROS1+ colorectal cancer. In one embodiment, the cancer is relapsed or refractory colorectal cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ colorectal cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colorectal cancer.

[00188] In one embodiment, the cancer is angiosarcoma. In one embodiment, the cancer is ROS1+ angiosarcoma. In one embodiment, the cancer is relapsed or refractory angiosarcoma. In one embodiment, the cancer is relapsed or refractory ROS1+ angiosarcoma. In one embodiment, the cancer is newly diagnosed angiosarcoma. In one embodiment, the cancer is newly diagnosed ROS1+ angiosarcoma.

[00189] 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 ROS1+ spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory spitzoid melanoma. In one embodiment, the cancer is relapsed or refractory ROS1+ spitzoid melanoma. In one embodiment, the cancer is newly diagnosed spitzoid melanoma. In one embodiment, the cancer is newly diagnosed ROS1+ spitzoid melanoma.

[00190] In one embodiment, the cancer is epithelioid hemangioendothelioma. In one embodiment, the cancer is ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory epithelioid hemangioendothelioma. In one embodiment, the cancer is relapsed or refractory ROS1+ epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed epithelioid hemangioendothelioma. In one embodiment, the cancer is newly diagnosed ROS1+ epithelioid hemangioendothelioma. [00191] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is ESCC. In one embodiment, the cancer is ROS1+ ESCC. In one embodiment, the cancer is relapsed or refractory ESCC. In one embodiment, the cancer is relapsed or refractory ROS1+ ESCC. In one embodiment, the cancer is newly diagnosed ESCC. In one embodiment, the cancer is newly diagnosed ROS1+ ESCC.

[00192] In one embodiment, the cancer is kidney cancer. In one embodiment, the cancer is renal medullary carcinoma. In one embodiment, the cancer is ROS1+ renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory renal medullary carcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed renal medullary carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal medullary carcinoma. In one embodiment, the cancer is renal cell carcinoma. In one embodiment, the cancer is ROS1+ renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory renal cell carcinoma. In one embodiment, the cancer is relapsed or refractory ROS1+ renal cell carcinoma. In one embodiment, the cancer is newly diagnosed renal cell carcinoma. In one embodiment, the cancer is newly diagnosed ROS1+ renal cell carcinoma.

[00193] In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is ROS1+ breast cancer. In one embodiment, the cancer is relapsed or refractory breast cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ breast cancer. In one embodiment, the cancer is newly diagnosed breast cancer. In one embodiment, the cancer is newly diagnosed ROS1+ breast cancer. In one embodiment, the breast cancer is triple negative breast cancer.

[00194] In one embodiment, the cancer is colon cancer. In one embodiment, the cancer is ROS1+ colon cancer. In one embodiment, the cancer is relapsed or refractory colon cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ colon cancer. In one embodiment, the cancer is newly diagnosed colon cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colon cancer.

[00195] In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is papillary thyroid cancer. In one embodiment, the cancer is ROS1+ papillary thyroid cancer. In one embodiment, the cancer is relapsed or refractory papillary thyroid cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed papillary thyroid cancer. In one embodiment, the cancer is newly diagnosed ROS1+ papillary thyroid cancer.

[00196] In one embodiment, the cancer is ROS1+ 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 ROS1+ glioma. In one embodiment, the cancer is newly diagnosed ROS1+ glioma. In one embodiment, the cancer is ROS1+ glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma. In one embodiment, the cancer is relapsed or refractory glioblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ glioblastoma. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is ROS1+ neuroblastoma. In one embodiment, the cancer is relapsed or refractory neuroblastoma. In one embodiment, the cancer is relapsed or refractory ROS1+ neuroblastoma, one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ neuroblastoma.

[00197] In one embodiment, the cancer is ROS1+ pancreatic cancer. In one embodiment, the cancer is relapsed or refractory pancreatic cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ pancreatic cancer, one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ pancreatic cancer.

[00198] In one embodiment, the cancer is ROS1+ inflammatory hepatocellular adenoma. In one embodiment, the cancer is relapsed or refractory inflammatory hepatocellular adenoma. In one embodiment, the cancer is relapsed or refractory ROS1+ inflammatory hepatocellular adenoma, one embodiment, the cancer is newly diagnosed neuroblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ inflammatory hepatocellular adenoma.

[00199] In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is a hematological cancer. In one embodiment, the cancer (or ROS1+ cancer, or ALK+ cancer) is lymphoma. In one embodiment, the lymphoma is non-Hodgkin lymphoma. In one embodiment, the lymphoma is anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), or large B-cell lymphoma. In addition to hematological cancer, methods for treating other blood disorder or hematologic malignancy that is ROS1+ or ALK+ are also provided herein. [00200] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ROS1+ ALCL. In one embodiment, the cancer is ALK+ ALCL. In one embodiment, the cancer is relapsed or refractory ALCL. In one embodiment, the cancer is relapsed or refractory ROS1+ 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 ROS1+ ALCL. In one embodiment, the cancer is newly diagnosed ALK+ ALCL.

[00201] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ROS1+ DLBCL. In one embodiment, the cancer is ALK+ DLBCL. In one embodiment, the cancer is relapsed or refractory DLBCL. In one embodiment, the cancer is relapsed or refractory ROS1 + 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 ROS1+ DLBCL. In one embodiment, the cancer is newly diagnosed ALK+ DLBCL.

[00202] In one embodiment, the cancer is large B-cell lymphoma. In one embodiment, the cancer is ROS1+ large B-cell lymphoma. In one embodiment, the cancer is ALK+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ROS1+ large B-cell lymphoma. In one embodiment, the cancer is relapsed or refractory ALK+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ROS1+ large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ALK+ large B-cell lymphoma.In one embodiment, the cancer (or ROS1+ cancer) is new diagnosed. In one embodiment, the cancer (or ROS1+ cancer) is previously untreated.

[00203] In one embodiment, the cancer (or ROS1+ cancer) is relapsed or refractory. In one embodiment, the cancer is relapsed. In one embodiment, the cancer (or ROS1+ cancer) is refractory.

[00204] 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 resi stance to one or more of the prior lines of therapy. In one embodiment, the prior therapy comprises a tyrosine kinase inhibitor (TKI). In one embodiment, the prior TKI therapy comprises 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 prior therapy comprises one or more chemotherapies. In one embodiment, the one or more chemotherapies are in addition to the TKI therapy.

[00205] In one embodiment, the cancer is advanced cancer, e.g. relapsed after, refractory to, or resistant to the prior treatment by a TKI.

[00206] In one embodiment, the cancer (or ROS1+ cancer) is resistant to a tyrosine kinase inhibitor (TKI).

[00207] 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 ROS1+ non-small cell lung cancer resistant to a TKI.

[00208] 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.

[00209] 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 fourth- line treatment.

[00210] In one embodiment, the cancer (or ROS1+ cancer) is metastatic. In one embodiment, the cancer has CNS metastases. In one embodiment, the cancer has brain metastases. In one embodiment, the cancer is metastatic non-small cell lung cancer (NSCLC). In one embodiment, the cancer is metastatic ROS1+ NSCLC.

[00211] In one embodiment, provided herein is a method for treating a patient with metastatic ROS1+ non-small cell lung cancer (NSCLC), comprising administering to the patient a therapeutically effective amount of a compound provided herein.

[00212] In one embodiment, the patient is an adult patient. In one embodiment, the patient is a pediatric patient. [00213] In one embodiment, provided herein is a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein.

[00214] In one embodiment, provided herein is a method for treating an adult patient with metastatic ROS1+ NSCLC, comprising administering to the patient a therapeutically effective amount of a compound provided herein, wherein the patient has progressed on or is intolerant of at least 1 prior TK1 therapy.

[00215] In one embodiment, provided herein is a method for treating an adult patient with metastatic NSCLC that is ROS1+ with solvent front mutation G2032R, comprising administering to the patient a therapeutically effective amount of a compound provided herein, wherein the patient has progressed on or is intolerant of at least 1 prior TKI therapy.

[00216] In one embodiment, provided herein is a method for treating a ROS1 -associated (or ROS1+) 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.

[00217] In one embodiment, provided herein is a method for treating a ROS1 -associated (or ROS1+) 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 ROS1 inhibitor resistance mutations, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise one or more amino acid substitutions at an amino acid position selected from 1986, 2004, 2026, 2032, and 2033. In one embodiment, the one or more ROS I inhibitor resistance mutations comprise one or more amino acid substitutions selected from S1986F, S1986Y, F2004C, F2004V, L2026M, G2032R, D2033N, L2086F, and G2101A. In one embodiment, the one or more ROS1 inhibitor resistance mutations is G2032R. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitor resistance mutation is L2086F.

[00218] In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorl atinib, entrectinib, repotrectinib, cabozantinib, foretinib, merestinib, taletrectinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib.

[00219] In certain embodiments, the subject has relapsed after first-line treatment of the cancer. In other embodiments, the subject has relapsed after second-line treatment of the cancer.

[00220] 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

[00221] 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).

[00222] 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. [00223] Chemotherapeutic agents that may be conjointly administered with compounds provided herein include: 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2- sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10- dihydroanthracene-2-sulfonate, ABT-263, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine (beg), bicalutamide, bleomycin, bortezomib, β-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: 1-amino-4-phenylamino-9,10-dioxo-9, 10- dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo- 9, 10-dihydroanthracene-2-sulfonate, 1 -amino-4- [4-aminophenylamino]-9, 10-dioxo-9, 10- dihydroanthracene-2-sulfonate, 1-amino-4-[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, 1-amino-4-[2-anthracenylamino]-9, 10-dioxo-9,10- dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline 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 ROS1 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).

[00224] Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds provided herein may be conjointly administered with one or more combination therapies. Examples of combination therapies with which compounds provided herein may be conjointly administered are included in Table 5.

Table 5: Exemplary combinatorial therapies for the treatment of cancer

[00225] 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.

[00226] 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.

[00227] In some embodiments, the combination therapy comprises conjoint administration of a solid form or pharmaceutical composition provided herein with ERK1/2 inhibitors such as ASN007, GDC-0994, KO-947, LTT462, LY3214996, MK-8353, ulixertinib.

[00228] In some embodiments, the combination therapy comprises conjoint administration of a compound provided herein with MEK inhibitors, such as trametinib, cobimetinib, binimetinib, selumetinib, PD-325901, CI-1040, and TAK-733.

[00229] In some embodiments, the combination therapy comprises conjoint administration of a compound provided herein with a MET inhibitor selected from JNJ-38877605, PF- 04217903, foretinib, AMG 458, tivantinib, cabozantinib, crizotinib, capmatinib hydrochloride, tepotinib hydrochloride, and savolitinib.

[00230] In some embodiments, the combination therapy comprises conjoint administration of a compound provided herein with a SHP2 inhibitor selected from TNO-155, RMC-4630, JAB-3068, or RLY-1971.

[00231] In some embodiments, the combination therapy comprises conjoint administration of a compound provided herein with a RAS inhibitor selected from aliskiren, captopril, losartan, irbesartan, olmesartan, candesartan, valsartan, fimasartan, azilsartan, telmisartan, eprosartan, benazepril, enalapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril.

[00232] In some embodiment, the combination therapy comprises administration of a compound provided herein in combination with a TKI. In one embodiment, the TKI is a ROS1 inhibitor. In one embodiment, the TKI is an ALK inhibitor. In one embodiment, the TKI is crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, entrectinib, repotrectinib, cabozantinib, foretinib, taletrectinib, merestinib, masitinib, or ensartinib. In one embodiment, the TKI is crizotinib. In one embodiment, the TKI is entrectinib. In one embodiment, the TKI is alectinib. In one embodiment, the TKI is brigatinib.

[00233] In some embodiments, the combination therapy comprises conjoint administration of a compound provided herein with anti-PD-1 therapy. In certain embodiments, the combination therapy comprises conjoint administration of a compound provided herein with oxaliplatin. In other embodiments, the combination therapy comprises conjoint administration of a compound provided herein with doxorubicin.

[00234] In certain embodiments, a compound provided herein may be conjointly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound provided herein may be conjointly administered with radiation therapy. In certain embodiments, a compound provided herein may be conjointly administered with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any combination of these.

[00235] In certain embodiments, compounds provided herein may be conjointly administered with one or more other compounds provided herein. Moreover, such combinations may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of cancer, immunological or neurological diseases, such as the agents identified above. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents with a compound provided herein provides a synergistic effect. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents provides an additive effect. PHARMACEUTICAL COMPOSITIONS

[00236] 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.

[00237] 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.

[00238] 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 non- human 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.

[00239] 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 ascorbic acid 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.

[00240] 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.

[00241] 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. [00242] 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.

[00243] 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.

[00244] 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. [00245] 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.

[00246] 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.

[00247] 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 or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00248] 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.

[00249] 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.

[00250] 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. [00251] 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.

[00252] 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.

[00253] Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

[00254] 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.

[00255] 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.

[00256] 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.

[00257] 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.

[00258] 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.

[00259] 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.

[00260] 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).

[00261] 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.

[00262] 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.

[00263] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, 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.

[00264] 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.

[00265] 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.

[00266] 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.

[00267] 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.

[00268] 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. A variety 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.

[00269] 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.

[00270] 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.

[00271] 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 et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

[00272] 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 intervals throughout the day, optionally, in unit dosage forms. In 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.

[00273] 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.

[00274] 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).

[00275] 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.

[00276] 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 hydroxy anisole (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.

[00277] 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.

EXAMPLES

Example 1. General Synthetic Methods

[00278] It is to be understood that isotopically enriched compounds provided herein can be prepared by the general methods described herein when corresponding isotopically enriched (e.g., deuterium enriched) starting material, intermediate, and/or reagents are used. Some examples are provided below.

[00279] The starting materials and reagents used in preparing these compounds are either available from commercial supplier such as Aldrich Chemical Co., Bachem, etc., or can be made by methods well known in the art. The schemes are merely illustrative of some methods by which the compounds provided herein can be synthesized and various modifications to these schemes can be made and will be suggested to one of skill in the art having referred to this description. The starting materials and the intermediates and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like and may be characterized using conventional means, including physical constants and spectral data. In some instances, reactions may produce more than one regioisomeric product. In these cases, chromatography may be used to separate the isomers and NOE or NOESY NMR spectroscopy may be used to aid structural assignment.

[00280] Unless specified otherwise, the reactions described herein take place at atmospheric pressure over a temperature range from about -78 °C to about 150 °C. Method A

[00281] Variables R ₁ , R ₂ , R ₆ , R ₈ , and R ₉ are as defined herein. Rx is H or D; and Ry is H or D.

[00282] Triazole A reacts with aldehyde B in the presence of the Grignard reagent to form the secondary alcohol C. Alcohol C is treated with EtrSiRy to provide Compound D, which undergoes the borylation/Suzuki-Miyaura coupling with compound E to provide intermediate F. Intermediate F is mesylated and subsequent S _N 2 reaction with compound H provides the intermediate I. Cyclization of intermediate I in the presence of Pd(OAc) ₂ and a catalyst such as cataCXium A generates the product J.

[00283] Exemplified detailed synthetic procedures can be found in International Patent

Publications WO 2021/226208, WO 2018/059455, and W02023/056405, and U.S. Provisional Application No. 63/251 ,514. The contents of all four applications are hereby incorporated by reference in their entireties.

[00284] Table 6 shows the exemplified compounds that can be synthesized based on Method A as discussed above. The corresponding deuterium reagents are shown in the first column.

Table 6

[00285] Table 7 shows the exemplified synthesis of the corresponding deuterium reagents in Table 6. Exemplified detailed synthetic procedures can be found in International Patent Publications WO 2021/226208 and WO 2018/059455, and U.S. Provisional Application No. 63/251,514.

Table 7.

Method B

[00286] Variables R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , and R ₂₃ are as defined herein.

[00287] As shown in Method B, exemplified compounds provided herein can be synthesized from compound K. Alkylation of compound K in the presence of a base provides compound L (see reaction (i)). Acylation of compound K with a carbonochloridate or acyl chloride provides compound M or N (see reactions (ii) and (iii)). Alkylation of compound K with a corresponding phosphate generates compound O (see reaction (iv)). Detailed exemplified synthetic procedures can be found in Chinese Patent Application Publication CN111362967.

Alkylation of compound K with a corresponding amino ester followed by deprotection generates compound Z, Z-1, or Z-2 (see reactions (v)-(vii)). Detailed exemplified synthetic procedures can be found in WO 2014/047372. [00288] Chiral HPLC separation of compounds L, M, N, O, Z, Z-1, and Z-2 will provide the following compounds: Method C

[00289] As shown in Method C, the exemplified compounds provided herein can be synthesized from compound K. Compound K reacts with pinacol boronic acid aldehyde in the presence of picoline borane provides compound P (see reaction (i)). Carbamoylation of compound K with pinacol boronic acid alcohol provides compound Q (see reactions (ii)).

Detailed exemplified synthetic procedures can be found in Molecules, 2020, 25, 1149.

[00290] Chiral HPLC separation of compounds P and Q will provide the following compounds:

Method D

[00291] Similar to Methods B and C, compound J prepared from Method A can undergo further reactions to generate compounds J7-J13-2.

Example 2. Biochemical Kinase Assay [00292] First, 250 nL of compound dissolved in DMSO (100-fold of the desired concentration) is dispensed into a 384-well plate. A 12.5 pL substrate solution containing ATP (2 mM) and fluorogenic phosphorylation substrate AQT0101 (26 μM for ALK and ROS1,

AssayQuant) or AQT0104 (26 μM for TRKA, AssayQuant) in buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 0.5 mM EGTA, 10 mM MgCh) is added and mixed thoroughly. Then, a 12.5 μL kinase solution containing ALK-wt (1.5 nM, Cama, 08-518), ALK ALK LI 196M/G1202R (3 nM, SignalChem, A19-12NG), ROS1-wt (0.6 nM, Carna, 08-163), ROS1-G2032R (0.5 nM,

SignalChem, R14-12BG), or TRKA-wt (1 nM, BPS Bio, 40280) 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) is added and mixed thoroughly. The plate is sealed and read by SpectraMax Paradigm at λ = 485 nm every 2 minutes for 120 minutes at 30 °C. Initial rates of reaction (v) are calculated from the change in fluorescence intensity over time during the initial, linear portion of the reaction. Finally, apparent inhibitory constants (K _i ^app ) are determined from regression of v and I

(inhibitor concentration) to Morrison Equation (E = enzyme concentration):

[00293] Compound potency can be interpreted by binning K _i ^app values against the targets: bin A for high potency, K _i ^app < 50 nM; bin B for medium potency, 50 nM ≤ K _i ^app ≤ 500 nM; and bin C for low potency, K _i ^app > 500 nM. Compounds are more desirable if they exhibit smaller K _i ^app values against the on-target kinases (ROS1 or ALK) and larger Ki ^app values against the off- target kinase (TRKA). Compounds that potently inhibit the on-target kinases (ROS1 or ALK) are also expected to inhibit ROS1 or ALK 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 (TRKA) are expected to poorly inhibit TRK- family kinases in humans and hence avoid potential clinical toxicity arising from TRKA, TRKB, or TRKC inhibition.

Example 3. Generation of Ba/F3 Stable Cell Lines

[00294] Genes encoding CD74-ROS1 wild-type (wt), CD74-ROS1 G2032R, CD74-ROS1 S1986F, CD74-ROS1 L2026M, CD74-ROS1 D2033N, EML4-ALK wt (variant 1), EML4-ALK G1202R (variant 1), EML4-ALK L1196M/G1202R (variant 1), EML4-ALK G1202R/G1269A (variant 1), EML4-ALK G1202R/L1198F (variant 1), and TPM3-TRKA are synthesized at GeneRay, cloned into the retroviral construct pMSCV-puro (Biovector), and packaged into retroviral particles. The virus is used to infect Ba/F3 cells (RIKEN) at multiplicity of infection = 1 for 1 day. Infected cells are 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 are selected by IL-3 withdrawal and puromycin (0.8 μg/mL) for 7 days. Monoclones are selected by single-cell dilution in IL-3-free medium containing puromycin (0.8 pg/mL). Transformation of desired genes is confirmed by Sanger sequencing and western blot using the following antibodies: ROS1 (CST #3287), ALK (CST #3633), and pan-TRK (Abeam #76291).

Example 4. Cell Proliferation Assay

[00295] Stable cells are plated at 1,000 cells/well (40 μL) in a 384-well plate for 1 day. Test compounds (40 nL) are then added in a 3-fold dilution series using the TEC AN EV0200 liquid handler and incubated for 72 hours. Plates are equilibrated at room temperature for 15 minutes followed by addition of 40 μL CellTiter-Glo reagent (Promega). Luminescence is measured on a plate reader. Half-maximal inhibitory concentration (IC ₅₀ ) is calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression. Compound potency can be interpreted by binning IC ₅₀ values: bin A for high potency, 0.1 nM < IC ₅₀ < 50 nM; bin B for medium potency, 50 nM ≤ IC ₅₀ ≤ 500 nM; and bin C for low potency, IC ₅₀ > 500 nM. Compounds are more desirable if they exhibit smaller IC ₅₀ values against the on- target Ba/F3 cells (ROS1- or ALK-fusion) and larger IC ₅₀ values against the off-target Ba/F3 cells (TRKA-fusion).

[00296] 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 (ROS1- or 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 (TRKA fusion) are expected to poorly inhibit TRK- family kinases in humans and hence avoid the clinical toxicity arising from TRKA, TRKB, or TRKC inhibition. [00297] TRKA selectivity is calculated by dividing a compound’s TRKA potency by its primary target potency (e.g. TPM3-NTRKl-wt IC ₅₀ / CD74-ROS1-wt IC ₅₀ ). Compound selectivity can be interpreted by binning ratio values: bin A for very high selectivity, ratio > 30- fold; bin B for high selectivity, ratio > 10-fold; bin C for moderate selectivity, ratio > 1; and bin D for low selectivity, ratio < 1. Compounds are more desirable if they exhibit higher selectivity ratios.

[00298] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

[00299] 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.