Methods of treating solid tumor using heteroaromatic macrocyclic ether compounds

Abstract

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

Description

Attorney Docket No.14709-046-228 METHODS OF TREATING SOLID TUMOR USING HETEROAROMATIC MACROCYCLIC ETHER COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Serial Nos.63 / 572,682, filed April 1, 2024, and 63 / 742,829, filed January 7, 2025, each of which is incorporated herein by reference in its entirety. BACKGROUND

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

[0003] ROS1 is an RTK proto-oncogene, with ROS1 rearrangements detected in 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, HLA-DRB1, LIMA1, LRIG3, MSN, MYH9, MYO5C, OPRM1, SLC6A17 (putative), SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, TPR, WNK1, ZCCHC8 and CCDC6. Other fusion partners include CAPRIN1, CEP85L, CHCHD3, CLIP1 (putative), EEF1G, KIF21A (putative), KLC1, SART3, SLC4A4, ST13 (putative), TRIM24 (putative), ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1.

[0004] NTRK1, NTRK2 and NTRK3 are RTK proto-oncogenes that encode TRK-family kinases, with NTRK1, NTRK2 and NTRK3 chromosomal rearrangements detected at low frequency in many cancers. For treatment of ROS1-positive or ALK-positive patients, however, NAI-5000260062v1 -1-Attorney Docket No.14709-046-228 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.

[0005] Existing agents used to treat oncogenic ROS1 and ALK have substantial deficiencies. These deficiencies may represent one or more of the following: associated TRK inhibition, limited CNS activity, and inadequate activity against resistance mutations. Treatment of 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 G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227* (where * indicates a mutation that results in a premature stop codon and hence protein truncation). SUMMARY

[0006] Provided herein are methods of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for treating, preventing or managing cancer (e.g., solid tumor). Also provided are uses of the compounds provided herein in the manufacture of a medicament for treating, preventing or managing cancer, such as the cancer described herein. Also provided are uses of the compounds provided herein for treating, preventing or managing cancer, such as the cancer described herein. Also provided are compounds provided herein for use in treating, preventing or managing cancer, such as the cancer described herein. Also provided are compounds provided herein for use in a method of treating, preventing or managing cancer, such as the cancer described herein, wherein the method comprises administering to a subject in need thereof an effective amount of a compound provided herein.

[0007] In one embodiment, provided herein is a method of treating solid tumor, comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1: NAI-5000260062v1 -2-Attorney Docket No.14709-046-228 or a stereoisomer, or a mixture of pharmaceutically acceptable saltthereof, and wherein the solid one or more mutations comprising: a mutation at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227; and / or a mutation selected from the group consisting of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C; or a combination thereof.

[0008] In certain embodiments, the one or more ROS1 mutations comprise a mutation at G2032 and one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227. In certain embodiments, the one or more ROS1 mutations comprise a mutation at G2032 and one or more mutations of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C. In certain embodiments, the compound is Compound 1.

[0009] In one embodiment, the mutation at G1917 is G1917D; and / or the mutation at I1934 is I1934N or I1934S; and / or the mutation at G1957 is G1957A; and / or the mutation at V1979 is V1979A or V1979L; and / or the mutation at E1990 is E1990A or E1990D; and / or the mutation at L2000 is L2000R; and / or the mutation at D2113 is D2113G; and / or the mutation at Q2022 is Q2022P; and / or the mutation at M2128 is M2128T; and / or the mutation at H2074 is H2074R; and / or the mutation at H2165 is H2165Q or H2165R; and / or the mutation at L2223 is L2223*; and / or the mutation at Y2227 is Y2227*. In one embodiment, the one or more ROS1 mutations are selected from the group consisting of G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*, or a combination thereof. In one embodiment, the one or more ROS1 mutations comprise a mutation of G2032R and L2223*. In one embodiment, the one or more ROS1 mutations comprise a mutation of G2032R and Y2227*. In one embodiment, the solid tumor further comprises a NAI-5000260062v1 -3-Attorney Docket No.14709-046-228 ROS1 fusion. In one embodiment, * indicates a mutation that results in a premature stop codon and hence protein truncation. In one particular embodiment, * indicates a nonsense mutation; i.e., mutation into a premature stop codon, resulting in protein truncation.

[0010] In one embodiment, the one or more ROS1 mutations comprise: (i) one or more mutations selected from the group consisting of G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G and L2155S; and (ii) one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227, and / or of L1982V, L1982W, S1986T, F2004I, F2004L, and / or F2075C.

[0011] In one embodiment, the one or more ROS1 mutations comprise: (i) one or more mutations selected from the group consisting of G2032R, S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, and G2101A; and (ii) one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227, and / or of L1982V, L1982W, S1986T, F2004I, F2004L, and / or F2075C.

[0012] In one embodiment, the one or more ROS1 mutations comprise (i) one or more mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, 1981Tins, M2001T, and / or L2155; and (ii) one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227.

[0013] In one embodiment, the one or more ROS1 mutations comprise a mutation at F2004 and of L1982V. In one embodiment, the one or more ROS1 mutations comprise F2004C and L1982V. In one embodiment, the one or more ROS1 mutations comprise F2004I and L1982V. In one embodiment, the one or more ROS1 mutations comprise F2004L and L1982V. In one embodiment, the one or more ROS1 mutations comprise F2004V and L1982V.

[0014] In one embodiment, provided herein is a method of treating a patient with solid tumor, comprising administering to said patient a therapeutically effective amount of Compound 1: NAI-5000260062v1 -4-Attorney Docket No.14709-046-228or a stereoisomer, or a mixture or a pharmaceutically acceptable salt thereof, and wherein the solid tumor is endometrial stromal sarcoma or duodenal adenocarcinoma.

[0015] 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 lung cancer. In one embodiment, the solid tumor is advanced ROS1-positive non-small cell lung cancer (NSCLC).

[0016] In one embodiment, the solid tumor is metastatic ROS1-positive solid tumor. In one embodiment, the solid tumor is central nervous system (CNS) (e.g., brain) metastatic ROS1- positive solid tumor. In one embodiment, the solid tumor is metastatic ROS1-positive lung cancer. In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC. In one embodiment, the solid tumor is CNS (e.g., brain) metastatic ROS1-positive NSCLC.

[0017] In one embodiment, the patient is naïve to tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the patient has been treated with one or more prior TKI therapies. In one embodiment, the patient has been treated with one prior ROS1 TKI therapy (e.g., crizotinib, entrectinib, lorlatinib, ceritinib, cabozantinib, taletrectinib, unecritinib, HG030, iruplinalkib, AGP-2449, SAF-189, foritinib, or repotrectinib). In one embodiment, the patient has been treated with two or more prior ROS1 TKI therapies. In one embodiment, the patient’s tumor does not have a known oncogenic driver alteration other than ROS1.

[0018] In one embodiment, the compound is administered at an amount of from about 5 mg to about 400 mg once (QD) or twice (BID) daily. In one embodiment, the compound is administered at an amount of from about 50 mg to about 250 mg (by weight of Compound 1) once (QD) or twice (BID) daily. In one embodiment, the compound is administered at an amount of about 50 mg (by weight of Compound 1) twice (BID) daily. In one embodiment, the compound is administered at an amount of about 100 mg (by weight of Compound 1) once (QD) NAI-5000260062v1 -5-Attorney Docket No.14709-046-228 daily. In one embodiment, the compound is administered: (a) at an amount of about 100 mg, about 75 mg, or about 50 mg (by weight of Compound 1) once (QD) daily to a patient 18 years old; (b) at an amount of about 100 mg, about 75 mg, or about 50 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing 40 kg; or (c) at an amount of about 75 mg, about 50 mg, or about 25 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 shows the efficacious unbound in vitro concentration (Ceff,u) of various ROS1 TKI. Viability (CellTiter-Glo) plotted as relative luminescence (y-axis) on days 0 – 21 (x- axis). Mean ± SEM (n=3) plotted with outliers excluded. Dashed lines, vehicle treatment. Unfilled circles indicate the efficacious unbound in vitro concentrations (in vitro Ceff,u). Clinical Cavg,u are as described in Table 1. Window indicates Cavg,u ÷ Ceff,u.

[0020] Figure 2 shows that workflow of the ENU mutagenesis screen study.

[0021] Figure 3 shows the study design for the ENU mutagenesis screen study. Unbound concentrations were calculated using the fraction unbound in 10% fetal bovine serum.

[0022] Figure 4 shows the results from the ENU mutagenesis screen study in CD74- ROS1 cells. Clinical Cavg,uvalues are as described in Table 1.

[0023] Figure 5 shows the results from the ENU mutagenesis screen study in CD74- ROS1 G2032R cells. Clinical Cavg,uvalues are as described in Table 1.

[0024] Figure 6 shows a potency heatmap of ROS1 TKIs against 28 resistant clones from ENU screen. Parental refers to Ba / F3 CD74-ROS1. Resistant clones from the ENU screen harbor indicated ROS1 mutations. Cell viability was measured after 3 days. Data represent an average IC50(nM) from n 2 testing.

[0025] Figure 7A shows a crystal structure of the ROS1 G2032R kinase domain in complex with Compound 1 to 2.2 Å resolution. Figure 7B shows a space filling model of the complex of Compound 1 with the ROS1 G2032R kinase domain. Figure 7C shows that the aminopyridine of Compound 1 forms two canonical hydrogen bonds with residues E2027 and M2029 in the hinge region of the ROS1 G2032R kinase domain. Figure 7D shows that the fluorobenzene of Compound 1 inserts into a shallow cavity at the floor of the pocket, positioning the ortho-hydrogen atom for interaction with the carbonyl of R2083 of the ROS1 G2032R kinase domain. NAI-5000260062v1 -6-Attorney Docket No.14709-046-228

[0026] Figure 8A shows an overlap of the wild-type ROS1 and ROS1 G2032R structures. Figure 8B shows a binding pocket analysis for the wild-type ROS1 and ROS1 G2032R structures. Figure 8C shows a modeling of ATP in the ROS1 G2032R structure.

[0027] Figure 9A shows an analysis of the P-loop of the wild-type ROS1 and ROS1 G2032R structures. Figure 9B shows an analysis of the B-factor of the wild-type ROS1 and ROS1 G2032R structures.

[0028] Figure 10A shows a crystal packing analysis illustrating that the R2032 side chain extends into the solvent front. Figure 10B shows a dihedral analysis for R2032 in the ROS1 G2032R structure. Figure 10C compares overlays of ROS1-bound Compound 1, lorlatinib, and crizotinib, respectively, onto the ROS1 G2032R structure. Figure 10D shows molecular dynamics simulations illustrating the gauche+and gauche- conformations for R2032.

[0029] Figure 11 shows a thermodynamic cycle used to compute the impact of Gly to Arg mutation by relating the free energy of wild-type and mutant kinases in the absence (top) and presence (bottom) of the TKI.

[0030] Figure 12A shows FEP predicted affinity changes ( GFEP) and reportedexperimental data ( Gbiochem) for 6 approved or investigational ROS1 TKIs. Figure 12B showsa correlation of the predicted affinity changes ( GFEP) and reported experimental data( Gbiochem) in the Gly to Arg direction (left), in the Arg to Gly direction (middle), and anaverage of both directions (right). DETAILED DESCRIPTION DEFINITIONS

[0031] 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. NAI-5000260062v1 -7-Attorney Docket No.14709-046-228

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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) NAI-5000260062v1 -8-Attorney Docket No.14709-046-228 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.

[0037] 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.

[0038] 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.

[0039] In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound. A diastereomerically enriched mixture may NAI-5000260062v1 -9-Attorney Docket No.14709-046-228 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.

[0040] 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 Unless explicitly statedotherwise, a drawing of one tautomer of a moiety or a compound encompasses all of the possible tautomers.

[0041] 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”.

[0042] 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 NAI-5000260062v1 -10-Attorney Docket No.14709-046-228 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).

[0043] 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).

[0044] 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.

[0045] As used herein and unless otherwise specified, “cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth, including solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include but not limited to sarcomas and carcinomas. Examples of cancers of the blood include but not limited to leukemias, lymphomas and myeloma. Cancer includes, but not limited to a primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is NAI-5000260062v1 -11-Attorney Docket No.14709-046-228 a new primary cancer in a person with a history of previous cancer of different type from latter one.

[0046] As used herein and unless otherwise specified, “abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous). In one embodiment of the methods provided herein, the abnormal cell growth is cancer.

[0047] In some embodiments, the abnormal cell growth is cancer mediated by a c-ros oncogene (ROS1). In some embodiments, the abnormal cell growth is cancer driven by ROS1. In some embodiments, the abnormal cell growth is at least partially driven by ROS1. In some such embodiments, the ROS1 is a genetically altered ROS1. In other embodiments, the abnormal cell growth is cancer mediated by an anaplastic lymphoma kinase (ALK). In some such embodiments, the ALK kinase is a genetically altered ALK kinase. In some embodiments, the abnormal cell growth is cancer, in particular lung cancer (e.g. NSCLC). In some such embodiments, the NSCLC is mediated by ROS1 or ALK. In specific embodiments, the cancer is lung cancer (e.g. NSCLC) mediated by genetically altered ALK or genetically altered ROS1.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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. NAI-5000260062v1 -12-Attorney Docket No.14709-046-228

[0052] 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.

[0053] 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”.

[0054] 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.

[0055] 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. NAI-5000260062v1 -13-Attorney Docket No.14709-046-228

[0056] 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, methylsulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, acetate, succinate, sulfate, tartrate, teoclate, and tosylate. COMPOUNDS

[0057] In one embodiment, the compound used in the methods provided herein is a compound of the following formula, also referred to as “Compound 1”:or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. Compound 1 has the chemical name of (19R)-3-ethyl-16-fluoro-10,19-dimethyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0², .0 ,¹².0¹³,¹ ]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-amine, and is described in WO 2021 / 226208, the entirety of which is incorporated herein by reference. As used herein, “Compound 1,” “Compound 1 free base,” “Compound 1 (free base),” and “free base Compound 1” are used interchangeably.

[0058] It is to be understood that, unless otherwise specified, when the compound as described herein is provided as a pharmaceutically acceptable salt thereof, that the weight amount refers to the portion exclusive of the salt portion (i.e. as the Compound 1 free base).

[0059] In one embodiment, Compound 1 (free base) is used in the methods provided herein. In one embodiment, a tautomer of Compound 1 is used in the methods provided herein. In one embodiment, Compound 1 substantially free of the (S)-enantiomer is used in the methods provided herein. As used herein, “substantially free” means the (S)-enantiomer is present in less NAI-5000260062v1 -14-Attorney Docket No.14709-046-228 than about 10 wt% of Compound 1 (e.g. less than about 5 wt% or less than about 0.05 wt% of Compound 1). In one embodiment, Compound 1 substantially pure with the enantiomeric purity of at least about 98% (e.g.99% or 99.5%). In one embodiment, a pharmaceutically acceptable salt of Compound 1 is used in the methods provided herein. In one embodiment, the pharmaceutically acceptable salt is a besylate salt. In one embodiment, the pharmaceutically acceptable salt is a phosphate salt.

[0060] In one embodiment, the compound used in the methods provided herein is a solid form of Compound 1. In one embodiment, the solid form is a Form 1 of Compound 1 described in WO2023 / 056405, which is incorporated herein by reference.

[0061] In one embodiment, the solid form (e.g., a crystalline form) of Compound 1 is characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2°) 10.7, 15.0,and 21.2º 2 . In one embodiment, the XRPD pattern further comprises peaks at approximately(e.g., ± 0.2°) 17.4 and 21.3º 2 . In one embodiment, the XRPD pattern further comprises peaksat approximately (e.g., ± 0.2°) 12.0, 12.2, and 13.9º 2 . In another embodiment, the XRPDpattern further comprises peaks at approximately (e.g., ± 0.2°) 21.6 and 24.0º 2 . In oneembodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2°) 10.7, 15.0, 17.4,20.8, 21.2, 21.3, 21.6, 24.0 and 25.2º 2 . In one embodiment, the XRPD pattern comprisespeaks at approximately (e.g., ± 0.2°) 10.7, 12.0, 12.2, 13.9, 15.0, 17.4, 18.4, 20.8, 21.2, 21.3,21.6, 24.0 and 25.2º 2 .

[0062] In one embodiment, the (S)-enantiomer of Compound 1 is used in the methods provided herein. In one embodiment, a tautomer of the (S)-enantiomer of Compound 1 is used in the methods provided herein. In one embodiment, a pharmaceutically acceptable salt of the (S)- enantiomer of Compound 1 is used in the methods provided herein.

[0063] In one embodiment, the racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a tautomer of the racemic mixture of Compound 1 is used in the methods provided herein. In one embodiment, a pharmaceutically acceptable salt of the racemic mixture of Compound 1 is used in the methods provided herein. METHODS OF USE

[0064] In one embodiment, provided herein are methods of treating cancer comprising administering a heteroaromatic macrocyclic ether compound, such as Compound 1, or a NAI-5000260062v1 -15-Attorney Docket No.14709-046-228 stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0065] In one embodiment, provided herein are methods of using a heteroaromatic macrocyclic ether compound (e.g., Compound 1), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for treating, preventing or managing solid tumor.

[0066] In one embodiment, provided herein is a method of treating a patient with solid tumor, comprising administering to said patient a therapeutically effective amount of Compound 1:or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and wherein the solid tumor has one or more ROS1 mutations comprising: a mutation at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227; and / or a mutation selected from the group consisting of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C; or a combination thereof.

[0067] In one embodiment, provided herein is a method of treating a patient with solid tumor, comprising administering to said patient a therapeutically effective amount of Compound 1:NAI-5000260062v1 -16-Attorney Docket No.14709-046-228 1, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and wherein the solid tumor is endometrial stromal sarcoma or duodenal adenocarcinoma.

[0068] In one embodiment, the cancer is lung cancer, (e.g., non-small cell lung cancer or bronchus cancer), inflammatory myofibroblastic tumor (IMT), 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 (ALCL), diffuse large B-cell lymphoma (DLBCL), 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, atypical meningioma, pancreatic cancer, salivary gland carcinoma, inflammatory hepatocellular adenoma, uterine cancer (e.g. endometrial uterine cancer or uterine sarcoma (e.g. endometrial stromal sarcoma)), intestinal cancer (e.g., small intestinal cancer (e.g., duodenal cancer (e.g., duodenal adenocarcinoma), ileal cancer, or jejunal cancer)), or spitzoid tumor.

[0069] 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), liver hepatocellular carcinoma, non-melanoma skin cancer, pancreatic cancer, papillary thyroid carcinoma, salivary gland carcinoma, spitzoid neoplasm, lung cancer e.g. non-small cell lung cancer (NSCLC) or bronchus cancer, small cell lung cancer, mesothelioma, bile duct cancer, ovarian cancer, e.g., serous ovarian carcinoma, endometrial cancer, uterine corpus endometrial carcinoma, 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, uterine endometrioid carcinoma, Penile cancer, bladder cancer, gallbladder carcinoma, breast cancer, e.g., triple negative breast cancer, colon cancer, thyroid cancer, e.g., papillary thyroid cancer, spitzoid tumor, inflammatory hepatocellular adenoma, glioma, neuroblastoma, myelodysplastic / myeloproliferative neoplasm, mature T and NK neoplasm, mature B-cell neoplasm, mature B- NAI-5000260062v1 -17-Attorney Docket No.14709-046-228 cell lymphoma, thymic tumor, head and neck cancer, head and neck carcinoma, small bowel cancer, gastrointestinal stromal tumor, salivary gland cancer, biliary tract cancer, appendiceal cancer, gastrointestinal neuroendocrine tumor, hepatobiliary cancer, anal cancer, soft tissue sarcoma, peripheral nervous system cancer, CNS cancer, medulloblastoma, bone cancer, bone sarcoma, prostate cancer, germ cell tumor, or embryonal tumor.

[0070] In one embodiment, the cancer is liver hepatocellular carcinoma, non-melanoma skin cancer, small cell lung cancer, mesothelioma, endometrial cancer, uterine corpus endometrial carcinoma, uterine endometrioid carcinoma, Penile cancer, bladder cancer, gallbladder carcinoma, myelodysplastic / myeloproliferative neoplasm, mature T and NK neoplasm, mature B-cell neoplasm, mature B-cell lymphoma, thymic tumor, head and neck cancer, head and neck carcinoma, small bowel cancer, gastrointestinal stromal tumor, salivary gland cancer, biliary tract cancer, appendiceal cancer, gastrointestinal neuroendocrine tumor, hepatobiliary cancer, anal cancer, soft tissue sarcoma, peripheral nervous system cancer, CNS cancer, medulloblastoma, bone cancer, bone sarcoma, prostate cancer, germ cell tumor, or embryonal tumor.

[0071] In one embodiment, the solid tumor is advanced solid tumor. In one embodiment, the solid tumor is locally advanced solid tumor. In one embodiment, the advanced solid tumor is relapsed after, refractory to, or resistant to the prior treatment by a tyrosine kinase inhibitor (TKI). In one embodiment, the solid tumor is lung cancer. In one embodiment, the solid tumor is non-small cell lung cancer (NSCLC). In one embodiment, the solid tumor is ROS1 positive (e.g. ROS1 fusion) 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 metastatic to the CNS (also referred to herein as “CNS metastatic” or “metastatic CNS”). In one embodiment, the solid tumor is metastatic lung cancer. In one embodiment, the solid tumor is metastatic NSCLC. In one embodiment, the solid tumor is NSCLC metastatic to the CNS. As used herein and unless otherwise specified, “advanced tumor” refers to a tumor that cannot be cured or grows beyond the initial site of origin, either locally advanced or metastatic.

[0072] In one embodiment, the solid tumor (or cancer) is ROS1 positive. In one embodiment, the solid tumor is ROS1 positive lung cancer. In one embodiment, the solid tumor is ROS1 positive NSCLC. In one embodiment, the solid tumor is advanced ROS1 positive solid NAI-5000260062v1 -18-Attorney Docket No.14709-046-228 tumor. In one embodiment, the solid tumor is locally advanced ROS1 positive solid tumor. In one embodiment, the solid tumor is advanced ROS1 positive lung cancer. 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 lung cancer. 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 one or more ROS1 mutations comprising: (i) a mutation at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227; and / or (ii) a mutation selected from the group consisting of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C; or (iii) a combination thereof. In certain embodiments, the solid tumor has a ROS1 mutation at G2032 and one or more ROS1 mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227. In certain embodiments, the solid tumor has a ROS1 mutation at G2032 and one or more ROS1 mutations at L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C. In one embodiment, the mutation at G1917 is G1917D; and / or the mutation at I1934 is I1934N or I1934S; and / or the mutation at G1957 is G1957A; and / or the mutation at V1979 is V1979A or V1979L; and / or the mutation at E1990 is E1990A or E1990D; and / or the mutation at L2000 is L2000R; and / or the mutation at D2113 is D2113G; and / or the mutation at Q2022 is Q2022P; and / or the mutation at M2128 is M2128T; and / or the mutation at H2074 is H2074R; and / or the mutation at H2165 is H2165Q or H2165R; and / or the mutation at L2223 is L2223*; and / or the mutation at Y2227 is Y2227*. In one embodiment, the one or more ROS1 mutations are selected from the group consisting of G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*, or a combination thereof. In one embodiment, the one or more ROS1 mutations comprise a co-mutation of G2032R and one or more of L2223* or Y2227*. In one embodiment, the one or more ROS1 mutations further comprises G2032R. In one embodiment, the one or more ROS1 mutations further comprises G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the solid tumor (or cancer) further comprises a ROS1 fusion. NAI-5000260062v1 -19-Attorney Docket No.14709-046-228

[0073] In one embodiment, the patient has not been treated with a prior therapy. In one embodiment, the patient is naïve to (i.e. not receiving) any tyrosine kinase inhibitor (TKI) therapy.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] As used herein, “immunotherapy” refers to the treatment of a disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. The immunotherapy can regulate the immune effector cells (e.g. lymphocytes, macrophages, dendritic cells, natural killer NAI-5000260062v1 -20-Attorney Docket No.14709-046-228 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).

[0079] 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.

[0080] 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 anticancer therapy selected from the group consisting of ROS1 TKI (e.g., investigational ROS1 TKI, crizotinib, entrectinib, repotrectinib, taletrectinib, and lorlatinib) and chemotherapy.

[0081] 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.

[0082] In one embodiment, the prior therapy is a prior ROS1 TKI therapy. In one embodiment, the ROS1 TKI is crizotinib, entrectinib, lorlatinib, ceritinib, cabozantinib, gilteritinib, taletrectinib, unecritinib, HG030, iruplinalkib, AGP-2449, SAF-189, foritinib, or repotrectinib. In one embodiment, the prior ROS1 TKI is one or more selected from the group consisting of crizotinib, entrectinib, repotrectinib, taletrectinib, and lorlatinib.

[0083] 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 NAI-5000260062v1 -21-Attorney Docket No.14709-046-228 ROS1 TKI is repotrectinib. In one embodiment, the patient has been treated with lorlatinib and repotrectinib. In one embodiment, the ROS1 TKI is taletrectinib.

[0084] 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.

[0085] In one embodiment, the solid tumor is metastatic ROS1-positive NSCLC, and the patient is naïve to TKI therapy and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] In one embodiment, the solid tumor is advanced ROS1-positive lung cancer (e.g. NSCLC), and the patient is naïve to TKI therapy and has been treated with up to one prior platinum-based chemotherapy with or without immunotherapy.

[0091] In one embodiment, the solid tumor is advanced ROS1-positive lung cancer (e.g 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.

[0092] In one embodiment, the solid tumor is advanced ROS1-positive lung cancer (e.g. NSCLC), and the patient has been treated with one prior ROS1 TKI therapy and one prior platinum-based chemotherapy with or without immunotherapy. NAI-5000260062v1 -22-Attorney Docket No.14709-046-228

[0093] In one embodiment, the solid tumor is advanced ROS1-positive lung cancer (e.g. 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.

[0094] 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.

[0095] In one embodiment, the compound used herein (Compound 1 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 Compound 1.

[0096] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered at an amount of from about 5 mg to about 500 mg (by weight of the free base Compound 1) per day. In one embodiment, the compound is administered at an amount of from about 25 mg to about 400 mg per day. In one embodiment, the compound is administered at an amount of from about 50 mg to about 300 mg per day. In one embodiment, the compound is administered at an amount of from about 75 mg to about 250 mg per day. In one embodiment, the compound is administered at an amount of from about 100 mg to about 200 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 NAI-5000260062v1 -23-Attorney Docket No.14709-046-228 mg per day. In one embodiment, the amount is about 150 mg per day. In one embodiment, the amount is about 200 mg per day. In one embodiment, the amount is about 250 mg per day. In one embodiment, the amount is about 300 mg per day. As used herein, the weight amount refers to the weight amount of the free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0097] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered at an amount of from about 5 mg to about 500 mg (by weight of the free base, Compound 1) 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 NAI-5000260062v1 -24-Attorney Docket No.14709-046-228 about 50 mg once daily. In one embodiment, the amount is about 75 mg once daily. In one embodiment, the amount is about 100 mg once daily. In one embodiment, the amount is about 125 mg once daily. In one embodiment, the amount is about 150 mg once daily. In one embodiment, the amount is about 200 mg once daily. In one embodiment, the amount is about 250 mg once daily. In one embodiment, the amount is about 300 mg once daily. As used herein, the weight amount refers to the weight amount of the free base Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0098] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered at an amount of from about 5 mg to about 500 mg (by weight of the free base, Compound 1) 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 NAI-5000260062v1 -25-Attorney Docket No.14709-046-228 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 Compound 1. In certain embodiments, the compound used herein is Compound 1.

[0099] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered to a patient 18 years old. In one embodiment, the compound is administered at an amount of from about 25 mg about 125 mg (by weight of Compound 1) once (QD) daily to a patient 18 years old. In one embodiment, the amount is from about 50 mg to about 100 mg once daily. In one embodiment, the amount is about 100 mg once daily. In one embodiment, the amount is about 75 mg once daily. In one embodiment, the amount is about 50 mg once daily. In one embodiment, the amount is about 25 mg once daily.

[0100] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered to a patient 12 and < 18 years old.

[0101] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is administered to a patient 12 and < 18 years old and weighing 40 kg. In one embodiment, the compound is administered at an amount of from about 25 mg about 125 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing 40 kg. In one embodiment, the amount is from about 50 mg to about 100 mg once daily. In one embodiment, the amount is about 100 mg once daily. In one embodiment, the amount is about 75 mg once daily. In one embodiment, the amount is about 50 mg once daily. In one embodiment, the amount is about 25 mg once daily.

[0102] In one embodiment, the compound used herein (Compound 1 or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof) is NAI-5000260062v1 -26-Attorney Docket No.14709-046-228 administered to a patient 12 and < 18 years old and weighing < 40 kg. In one embodiment, the compound is administered at an amount of from about 15 mg to about 100 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg. In one embodiment, the amount is from about 25 mg to about 75 mg once daily. In one embodiment, the amount is about 75 mg once daily. In one embodiment, the amount is about 50 mg once daily. In one embodiment, the amount is about 25 mg once daily. In one embodiment, the amount is about 20 mg once daily. In one embodiment, the amount is about 15 mg once daily.

[0103] In one embodiment, the compound is initially administered at an amount of about 25 mg to 75 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg, and subsequently increased by 25 mg (by weight of Compound 1) once (QD) daily when the patient’s weight increases to 40 kg. In one embodiment, the compound is initially administered at an amount of about 75 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg, and subsequently increased to about 100 mg (by weight of Compound 1) once (QD) daily when the patient’s weight increases to 40 kg. In one embodiment, the compound is initially administered at an amount of about 50 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg, and subsequently increased to about 75 mg (by weight of Compound 1) once (QD) daily when the patient’s weight increases to 40 kg. In one embodiment, the compound is initially administered at an amount of about 25 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg, and subsequently increased to about 50 mg (by weight of Compound 1) once (QD) daily when the patient’s weight increases to 40 kg.

[0104] In one embodiment, the compound is administered orally.

[0105] In one embodiment, the compound is administered in the form of one or more tablets. In one embodiment, the tablet has a unit dose strength of about 5 mg by weight of the free base Compound 1. In one embodiment, the table has a unit dose strength of about 25 mg by weight of the free base Compound 1.

[0106] 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 NAI-5000260062v1 -27-Attorney Docket No.14709-046-228 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 IC50 values, among other means. In one embodiment, the selectivity of ROS1 over ALK is measured by the ratio of the IC50value against ALK to the IC50value against ROS1.

[0107] 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 IC50 values, among other means. In one embodiment, the selectivity of ROS1 over TRK is measured by the ratio of the IC50value against TRK to the IC50 value against ROS1.

[0108] 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.

[0109] 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. NAI-5000260062v1 -28-Attorney Docket No.14709-046-228

[0110] 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).

[0111] 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. For example, in one embodiment, the ROS1 comprises mutations at one or more of amino acid positions 1917, 1934, 1957, 1979, 1990, 2000, 2113, 2022, 2128, 2074, 2165, 2223, and 2227. In one embodiment, the ROS1 comprises one or more mutations selected from the group consisting of G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*.

[0112] Cancers treated by methods provided herein include, but are not limited to, lung cancer, (e.g., non-small cell lung cancer or bronchus cancer), inflammatory myofibroblastic tumor (IMT), 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 (ALCL), diffuse large B-cell lymphoma (DLBCL), 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, atypical meningioma, pancreatic cancer, salivary gland carcinoma, inflammatory hepatocellular adenoma, and spitzoid tumor.

[0113] 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 NAI-5000260062v1 -29-Attorney Docket No.14709-046-228 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.

[0114] 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 (including nonsense mutations; i.e., mutations into a premature stop codon), 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 ROS1 “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 (including nonsense mutations; i.e., mutations into a premature stop codon), insertions, inversions, duplications, translocations, or amplifications or a fragment thereof, as long as the mutant retains kinase phosphorylation activity. In one embodiment, the solid tumor has one or more ROS1 mutations comprising deletions, substitutions (including nonsense mutations; i.e., mutations into a premature stop codon), insertions, inversions, duplications, translocations, or amplifications at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227; or a mutation selected from the group consisting of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C; or a combination thereof. In some embodiments, the mutations occur on the same chromosome. In some embodiments, the mutations occur on different chromosomes. A person of skill in the art would understand that protein numbering is relative to a reference sequence and would be able to determine the reference sequence based on the amino acid at a position. As used herein and unless otherwise specified, the ROS1 numbering provided herein is based on the reference sequence as described in Uniprot Entry: P08922 (by the UniProt Consortium – UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Res.53:D0- D0 (2025)). In certain embodiments, the reference sequence is described in NCBI Reference Sequence: NP_002935.2 (proto-oncogene tyrosine-protein kinase ROS isoform 1 precursor NAI-5000260062v1 -30-Attorney Docket No.14709-046-228 [Homo sapiens]) (National Library of Medicine (US), National Center for Biotechnology Information; 2004).

[0115] In one embodiment, the solid tumor has one or more ROS1 mutations comprising 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 mutations comprise point mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227; or a mutation selected from the group consisting of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C; or a combination thereof. In one embodiment, the ROS1 point mutations are selected from the group consisting of G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*, or a combination thereof. In one embodiment, the one or more ROS1 mutations comprise G1917D. In one embodiment, the one or more ROS1 mutations comprise I1934N. In one embodiment, the one or more ROS1 mutations comprise I1934S. In one embodiment, the one or more ROS1 mutations comprise G1957A. In one embodiment, the one or more ROS1 mutations comprise V1979A. In one embodiment, the one or more ROS1 mutations comprise V1979L. In one embodiment, the one or more ROS1 mutations comprise L1982V. In one embodiment, the one or more ROS1 mutations comprise L1982W. In one embodiment, the one or more ROS1 mutations comprise S1986T. In one embodiment, the one or more ROS1 mutations comprise E1990A. In one embodiment, the one or more ROS1 mutations comprise E1990D. In one embodiment, the one or more ROS1 mutations comprises L2000R. In one embodiment, the one or more ROS1 mutations comprise F2004I. In one embodiment, the one or more ROS1 mutations comprise F2004L. In one embodiment, the one or more ROS1 mutations comprise D2113G. In one embodiment, the one or more ROS1 mutations comprise Q2022P. In one embodiment, the one or more ROS1 mutations comprise M2128T. In one embodiment, the one or more ROS1 mutations comprise H2074R. In one embodiment, the one or more ROS1 mutations comprise F2075C. In one embodiment, the one or more ROS1 mutations comprise H2165Q. In one embodiment, the one or more ROS1 mutations comprise H2165R. In one embodiment, the one or more ROS1 mutations comprise L2223*. In one embodiment, the one or more ROS1 mutations comprise Y2227*. In one embodiment, the one or more ROS1 mutations comprise a co-mutation. In one embodiment, one NAI-5000260062v1 -31-Attorney Docket No.14709-046-228 or more ROS1 mutations comprise a co-mutation of G2032R and one or more of L2223* or Y2227*. In one embodiment, the one or more ROS1 mutations comprise a co-mutation of G2032R and L2223*. In one embodiment, the one or more ROS1 mutations comprise a co- mutation of G2032R and Y2227*.

[0116] In one embodiment, the one or more ROS1 mutations further comprise (or comprise, i.e., without necessarily further to other mutations provided herein) mutations 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 mutations further comprise (or comprise) mutations selected from the group consisting of 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 one or more ROS1 mutations further comprise (or comprise) G2032R. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) S1986F. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) S1986Y. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) L2026M. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) D2033N. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) L2086F. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) F2004C. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) F2004V. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) G2101A. In one embodiment, the one or more ROS1 mutations further comprise (or comprise) L1982F. In certain embodiments, the one or more ROS1 mutations comprise a mutation at G2032 and one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227. In certain embodiments, the one or more ROS1 mutations comprise a mutation at G2032 and one or more mutations of L1982V, L1982W, S1986T, F2004I, F2004L, and / or F2075C. In certain embodiments, the compound is Compound 1.

[0117] In one embodiment, the one or more ROS1 mutations comprise a mutation of G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, or D2033N. NAI-5000260062v1 -32-Attorney Docket No.14709-046-228

[0118] 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, HLA-DRB1, LIMA1, LRIG3, MSN, MYH9, MYO5C, OPRM1, SLC6A17 SLMAP, SRSF6, TFG, TMEM106B, TPD52L1, TPR, WNK1, ZCCHC8,CCDC6,CAPRIN1, CEP85L, CHCHD3, CLIP1, EEF1G, KIF21A, KLC1, SART3, SLC4A4, ST13, TRIM24, ERC1, FIP1L1, HLAA, KIAA1598, MYO5A, PPFIBP1, PWWP2A, FN1, YWHAE, CCDC30, NCOR2, NFKB2, APOB, PLG, RBP4, and GOLGB1. In one embodiment, the ROS1 fusion is CD74-ROS1 fusion. In one embodiment, the ROS1 fusion is SDC4-ROS1 fusion. In one embodiment, the ROS1 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.

[0119] In one embodiment, the ROS1 mutation comprises one ROS1 rearrangement and one or more ROS1 point mutations. In one embodiment, the ROS1 mutation comprises a CD74- ROS1 rearrangement, and one or more ROS1 point mutations selected from point mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and Y2227. In one embodiment, the ROS1 mutation comprises a CD74-ROS1 rearrangement, and one or more ROS1 point mutations selected from selected from G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*.

[0120] In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 G1917D. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 I1934N. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 I1934S. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 G1957A. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 V1979A. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 V1979L. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 L1982V. In one NAI-5000260062v1 -33-Attorney Docket No.14709-046-228 embodiment, the one or more ROS1 mutations comprise CD74-ROS1 L1982W. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 S1986T. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 E1990A. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 E1990D. In one embodiment, the one or more ROS1 mutations comprises CD74-ROS1 L2000R. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 F2004I. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 F2004L. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 D2113G. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 Q2022P. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 M2128T. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 H2074R. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 F2075C. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 H2165Q. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 H2165R. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 L2223*. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 Y2227*. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 G2032R / L2223*. In one embodiment, the one or more ROS1 mutations comprise CD74-ROS1 G2032R / Y2227*.

[0121] 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., OncomineTMDx 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.

[0122] 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 NAI-5000260062v1 -34-Attorney Docket No.14709-046-228 subject having a cancer and previously administered a first ROS1 inhibitor, has one or more ROS1 inhibitor resistance mutations; and administering a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof 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 mutation (e.g. substitution or non-sense mutation) at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227, e.g., G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*. Other ROS1 inhibitor resistance mutations are known in the art. See, for example, WO 2023 / 056431, which is incorporated by reference in its entirety. 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).

[0123] 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) ROS1.

[0124] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the CNS metastases is brain metastases. In one embodiment, the cancer is a ROS1+ cancer.

[0125] In some embodiments, the compound is an inhibitor of human tropomyosin receptor kinase A, B, or C. In certain embodiments, the IC50of the compound for inhibition of mutant or non-mutant ROS1 or ALK is no more than one-fifth of the IC50of the compound for inhibition of wild-type tropomyosin receptor kinase A, B, or C. TRK inhibition, particularly in NAI-5000260062v1 -35-Attorney Docket No.14709-046-228 the central nervous system (CNS), has been associated with adverse reactions, including dizziness / ataxia / gait disturbance, paraesthesia, weight gain and cognitive changes.

[0126] In some embodiments, provided is a method of minimizing treatment-related adverse events in a subject in need of treatment for cancer (e.g., a ROS1 positive cancer), the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and wherein the method minimizes treatment-related 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.

[0127] 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.

[0128] In some embodiments, TRK-related CNS treatment-related 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, NAI-5000260062v1 -36-Attorney Docket No.14709-046-228 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).

[0129] In one embodiment, provided herein is a method for preventing or limiting TRK- related treatment-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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the method prevents the occurrence of the TRK-related CNS adverse event. In one embodiment, the method limits the frequency of occurrence of the TRK-related CNS adverse event. In one embodiment, the method limits the severity of the TRK-related side effect. In one embodiment, provided herein is a method for treating CNS metastases of a cancer with reduced TRK-related side effect, comprising administering to a subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the reduction / limiting / prevention in CNS side effect or adverse event is determined in a statistical sample, as compared to a standard of care treatment, e.g., an approved 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.

[0130] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is a ROS1-associated cancer. In one embodiment, the cancer is a ROS1+ cancer.

[0131] 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 NAI-5000260062v1 -37-Attorney Docket No.14709-046-228 compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0132] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0133] 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 or bronchus cancer), inflammatory myofibroblastic tumor (IMT), 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 (ALCL), diffuse large B-cell lymphoma (DLBCL), 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, atypical meningioma, pancreatic cancer, salivary gland carcinoma, inflammatory hepatocellular adenoma, or spitzoid tumor.

[0134] 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. In one embodiment, the cancer is bronchus cancer. In one embodiment, the cancer is ROS1+ bronchus cancer. In one embodiment, the cancer is relapsed or refractory bronchus cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ bronchus cancer. In one embodiment, the cancer is newly diagnosed bronchus cancer. In one embodiment, the cancer is newly diagnosed ROS1+ bronchus cancer. NAI-5000260062v1 -38-Attorney Docket No.14709-046-228

[0135] In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is 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 newly diagnosed glioblastoma. In one embodiment, the cancer is newly diagnosed ROS1+ glioblastoma.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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 NAI-5000260062v1 -39-Attorney Docket No.14709-046-228 cancer. In one embodiment, the cancer is newly diagnosed colorectal cancer. In one embodiment, the cancer is newly diagnosed ROS1+ colorectal cancer.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is esophageal squamous cell carcinoma (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.

[0145] 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. NAI-5000260062v1 -40-Attorney Docket No.14709-046-228 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] In one embodiment, the cancer is glioma (e.g. Grade 1, Grade 2, Grade 3, or Grade 4). In one embodiment, the cancer is ROS1+ glioma. 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. NAI-5000260062v1 -41-Attorney Docket No.14709-046-228

[0150] In one embodiment, the cancer is pancreatic cancer. 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. In one embodiment, the cancer is newly diagnosed pancreatic cancer. In one embodiment, the cancer is newly diagnosed ROS1+ pancreatic cancer.

[0151] In one embodiment, the cancer is inflammatory hepatocellular adenoma. 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 inflammatory hepatocellular adenoma. In one embodiment, the cancer is newly diagnosed ROS1+ inflammatory hepatocellular adenoma.

[0152] In one embodiment, the cancer is uterine cancer. In one embodiment, the cancer is ROS1+ uterine cancer. In one embodiment, the cancer is relapsed or refractory uterine cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ uterine cancer. In one embodiment, the cancer is newly diagnosed uterine cancer. In one embodiment, the cancer is newly diagnosed ROS1+ uterine cancer. In one embodiment, the uterine cancer is endometrial uterine cancer. In one embodiment, the uterine cancer is uterine sarcoma. In one embodiment, the uterine cancer is endometrial stromal sarcoma.

[0153] In one embodiment, the cancer is intestinal cancer. In one embodiment, the cancer is ROS1+ intestinal cancer. In one embodiment, the cancer is relapsed or refractory intestinal cancer. In one embodiment, the cancer is relapsed or refractory ROS1+ intestinal cancer. In one embodiment, the cancer is newly diagnosed intestinal cancer. In one embodiment, the cancer is newly diagnosed ROS1+ intestinal cancer. In one embodiment, the intestinal cancer is small intestinal cancer. In one embodiment, the intestinal cancer is duodenal cancer. In one embodiment, the intestinal cancer is duodenal adenocarcinoma. In one embodiment, the intestinal cancer is ileal cancer. In one embodiment, the intestinal cancer is jejunal cancer.

[0154] In one embodiment, the cancer (or ROS1+ cancer) is a hematological cancer. In one embodiment, the cancer (or ROS1+ 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 NAI-5000260062v1 -42-Attorney Docket No.14709-046-228 addition to hematological cancer, methods for treating other blood disorder or hematologic malignancy that is ROS1+ is also provided herein.

[0155] In one embodiment, the cancer is ALCL. In one embodiment, the cancer is ROS1+ 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 newly diagnosed ALCL. In one embodiment, the cancer is newly diagnosed ROS1+ ALCL.

[0156] In one embodiment, the cancer is DLBCL. In one embodiment, the cancer is ROS1+ 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 newly diagnosed DLBCL. In one embodiment, the cancer is newly diagnosed ROS1+ DLBCL.

[0157] 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 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 newly diagnosed large B-cell lymphoma. In one embodiment, the cancer is newly diagnosed ROS1+ 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.

[0158] 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.

[0159] In one embodiment, the subject is previously untreated. In one embodiment, the subject is treatment naïve to tyrosine kinase inhibitor (TKI) therapy. In one embodiment, the subject has received one or more prior lines of therapy. In one embodiment, the subject has received two or more prior lines of therapy. In one embodiment, the subject has developed resistance to one or more of the prior lines of therapy. In one embodiment, the 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, unecritinib, HG030, iruplinalkib, AGP-2449, SAF-189, foritinib, and ensartinib. In one embodiment, the prior TKI therapy is a prior ROS1 TKI therapy. In one embodiment, the prior ROS1 TKI is one NAI-5000260062v1 -43-Attorney Docket No.14709-046-228 or more selected from crizotinib, entrectinib, lorlatinib, ceritinib, cabozantinib, taletrectinib, unecritinib, HG030, iruplinalkib, AGP-2449, SAF-189, foritinib, and repotrectinib. In one embodiment, the prior ROS1 TKI is one or more selected from crizotinib, entrectinib, lorlatinib, ceritinib, cabozantinib, taletrectinib, and repotrectinib.

[0160] 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.

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

[0162] In one embodiment, the cancer (or ROS1+ cancer) is resistant to a tyrosine kinase inhibitor (TKI).

[0163] In one embodiment, the cancer is resistant lung cancer. In one embodiment, the cancer is resistant bronchus 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.

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

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

[0166] 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.

[0167] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. NAI-5000260062v1 -44-Attorney Docket No.14709-046-228

[0168] In one embodiment, the patient is an adult patient. In one embodiment, the patient is a pediatric patient.

[0169] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0170] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant of at least 1 prior TKI therapy.

[0171] In one embodiment, provided herein is a method for treating an adult patient with metastatic NSCLC that is ROS1+ with a ROS1 mutation, comprising administering to the patient a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein the patient has progressed on or is intolerant of at least 1 prior TKI therapy.

[0172] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

[0173] 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, e.g., a compound of Formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise mutations (e.g. substitutions or non-sense mutations) at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227. In one embodiment, the NAI-5000260062v1 -45-Attorney Docket No.14709-046-228 one or more ROS1 inhibitor resistance mutations comprise mutations selected from the group consisting of G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*, or combinations thereof. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise G1917D. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise I1934N. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise I1934S. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise G1957A. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise V1979A. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise V1979L. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise L1982V. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise L1982W. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise S1986T. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise E1990A. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise E1990D. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise L2000R. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise F2004I. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise F2004L. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise D2113G. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise Q2022P. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise M2128T. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise H2074R. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise F2075C. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise H2165Q. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise H2165R. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise L2223*. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise Y2227*. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise a mutation of G2032R and L2223* or Y2227*. Ine one embodiment, the one or more ROS1 inhibitor resistance mutations comprise a mutation of G2032R and L2223*. In one embodiment, the one or more ROS1 inhibitor resistance mutations comprise a mutation of G2032R and Y2227*. NAI-5000260062v1 -46-Attorney Docket No.14709-046-228

[0174] In one embodiment, the one or more ROS1 inhibitor resistance mutations further comprise (or comprise) G2032R. In one embodiment, the one or more ROS1 inhibitor resistance mutations further comprise (or comprise) G2032R and one or more of S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, or G2101A. In one embodiment, the ROS1 inhibitor resistance mutation further comprise (or comprise) L2086F.

[0175] 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.

[0176] 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. ROS1 G2032R STRUCTURE AND METHOD OF USE

[0177] In one embodiment, provided herein is a computer-implemented method for indicating the binding affinity (or determining the binding affinity) of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R), the method comprising: determining, based at least on a three-dimensional representation of the crystal structure of ROS1 G2032R, a co-crystal structure of a ROS1 G2032R-ligand complex comprising the ligand bound to ROS1 G2032R; determining a binding free energy of the ROS1 G2032R-ligand complex; and indicating (or determining), based at least on the binding free energy of the ROS1 G2032R-ligand complex, a binding affinity between ROS1 G2032R and the ligand.

[0178] In one embodiment, the binding free energy of the ROS1 G2032R-ligand complex corresponds to a difference between an energy of ROS1 G2032R and the ligand in a bound state and an energy of ROS1 G2032R and the ligand in an unbound state.

[0179] In one embodiment, the three-dimensional representation identifies a type of each amino acid residue in ROS1 G2032R, and where the three-dimensional representation further includes, for each amino acid residue in ROS1 G2032R, atomic coordinates for each constituent atom and a connectivity therebetween. NAI-5000260062v1 -47-Attorney Docket No.14709-046-228

[0180] In one embodiment, the crystal structure of ROS1 G2032R matches to or is generated from the structure of ROS1 G2032R in a co-crystal structure of a ROS1 G2032R- Compound 1 complex comprising Compound 1 bound to ROS1 G2032R.

[0181] In one embodiment, the co-crystal structure of a ROS1 G2032R-Compound 1 complex matches to the ROS1 G2032R-Compound 1 co-crystal structure as described in PDB:9QEK, the entirety of which is incorporated herein by reference. In one embodiment, the co-crystal structure of a ROS1 G2032R-Compound 1 complex matches to the ROS1 G2032R- Compound 1 co-crystal structure shown in Figure 7A (or any one of Figures 7B-D, 8A-8C, 9A- 9B, 10A-10D, as applicable). In one embodiment, the co-crystal structure of a ROS1 G2032R- Compound 1 complex matches to the atomic coordinates described in Table A. Table A is also described in U.S. Serial No.63 / 742,829 (to which this application claims the benefit of priority to), filed January 7, 2025, which is incorporated herein by reference in its entirety.

[0182] One skilled in the art can determine whether a crystal / co-crystal structure is one of the crystal / co-crystal structures provided herein by performing one or more characterization techniques for crystal / co-crystal structures and determining whether the resulting data “matches” the reference data. Characterization data that “matches” those of a reference crystal / co-crystal structure is understood by those skilled in the art to correspond to the same crystal / co-crystal structure as the reference crystal / co-crystal structure. In analyzing whether data “match,” a person of ordinary skill in the art understands that particular characterization data points may vary to a reasonable extent while still describing a given crystal / co-crystal structure, due to, for example, experimental error and routine sample-to-sample analysis variation.

[0183] In one embodiment, the ligand is a chemical compound (e.g., a small molecule compound).

[0184] In one embodiment, the binding free energy of the protein-ligand complex is determined by performing one or more rounds of molecular dynamics simulation and applying a free energy perturbation processing to a result of the one or more rounds of molecular dynamics simulation.

[0185] In one embodiment, provided herein is a computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: NAI-5000260062v1 -48-Attorney Docket No.14709-046-228 (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 G2032R-ligand complex comprising the ligand bound to ROS1 G2032R provided herein, such that the amino acid residue at position 2032 is changed from arginine (R) to glycine (G) (i.e., R G modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB); andwherein GBindicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

[0186] In one embodiment, provided herein is a computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 G2032R-ligand complex comprising the ligand bound to ROS1 G2032R provided herein, such that the amino acid residue at position 2032 is changed from arginine (R) to glycine (G) (i.e., R G modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB);(ii-a) modifying a three-dimensional representation of a crystal structure of a ROS1 G2032R protein provided herein, such that the amino acid residue at position 2032 is changed from arginine (R) to glycine (G) (i.e., R G modification); (ii-b) determining a change in the free energy of the protein as a result of themodification ( GA);(iii) determining a shift between GB and GA ( G);wherein G indicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

[0187] In one embodiment, the three-dimensional representation of the co-crystal structure is modified by incrementally truncating the amino acid residue at position 2032 such that it is gradually changed from arginine (R) to glycine (G). NAI-5000260062v1 -49-Attorney Docket No.14709-046-228

[0188] In one embodiment, the free energy of the complex is determined based on the free energy of one or more intermediate complexes in which the ROS1 G2032R exhibits an incremental truncation of the amino acid residue at position 2032. In one embodiment, the free energy of the protein is determined based on the free energy of one or more intermediate protein in which the ROS1 G2032R exhibits an incremental truncation of the amino acid residue at position 2032.

[0189] In one embodiment, provided herein is a computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type)-ligand complex comprising the ligand bound to the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), such that the amino acid residue at position 2032 is changed from glycine (G) to arginine (R) (i.e., G R modification); determining a change in the free energy of the complex as a result of themodification ( GB); andwherein GB indicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

[0190] In one embodiment, provided herein is a computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type)-ligand complex comprising the ligand bound to the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), such that the amino acid residue at position 2032 is changed from glycine (G) to arginine (R) (i.e., G R modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB);NAI-5000260062v1 -50-Attorney Docket No.14709-046-228 (ii-a) modifying a three-dimensional representation of a crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), such that the amino acid residue at position 2032 is changed from glycine (G) to arginine (R) (i.e., G R modification); (ii-b) determining a change in the free energy of the protein as a result of themodification ( GA);(iii) determining a shift between GB and GA ( G);wherein G indicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

[0191] In one embodiment, the three-dimensional representation of the co-crystal structure is modified by incrementally increasing the amino acid residue at position 2032 such that it is gradually changed from glycine (G) to arginine (R).

[0192] In one embodiment, the free energy of the complex is determined based on the free energy of one or more intermediate complexes in which the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type) exhibits an incremental increase of the amino acid residue at position 2032. In one embodiment, the free energy of the protein is determined based on the free energy of one or more intermediate proteins in which the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type) exhibits an incremental increase of the amino acid residue at position 2032.

[0193] In one embodiment, the co-crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type)-ligand complex is determined based at least on a three- dimensional representation of the crystal structure of the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type) (e.g., as described in PDB:3ZBF, 4UXL, 7Z5W, or 7Z5X).

[0194] In one embodiment, the methods provided herein (e.g., the binding free energy of the ROS1 G2032R-ligand complex, the R G modification, the G R modification, the average of the R G modification and the G R modification, or combination thereof) can be used to screenligands (e.g., smallcompounds) that can bind to ROS1 G2032R with high affinity. In one embodiment, the methods provided herein can be used to predict whether a ligand (e.g., a small molecule compound) can bind to ROS1 G2032R with high affinity.

[0195] In one embodiment, the average of the G of R G modification and the G of G R modification indicates the shift between the bindingof the ligand against NAI-5000260062v1 -51-Attorney Docket No.14709-046-228 ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

[0196] In one embodiment, provided herein is a system, comprising: at least one data processor; and at least one memory storing instruction, which when executed by at least one data processor, result in operations comprising the method provided herein.

[0197] In one embodiment, provided herein are non-transitory computer readable medium storing instructions, which when executed by at least one data processor, result in operations comprising the method provided herein. Table A. atomic coordinates of co-crystal structure of a ROS1 G2032R-Compound 1 complex HEADER ---- 14-FEB-24 xxxx TITLE --- COMPND --- REMARK 3 REMARK 3 REFINEMENT. REMARK PROGRAM : REFMAC 5.8.0425 REMARK 3 AUTHORS : MURSHUDOV,SKUBAK,LEBEDEV,PANNU, REMARK 3 STEINER,NICHOLLS,WINN,LONG,VAGIN REMARK 3 REMARK 3 REFINEMENT TARGET : MAXIMUM LIKELIHOOD REMARK 3 REMARK 3 DATA USED IN REFINEMENT. REMARK 3 RESOLUTION RANGE HIGH (ANGSTROMS) : 2.20 REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS) : 34.73 REMARK 3 DATA CUTOFF (SIGMA(F)) : NONE REMARK 3 COMPLETENESS FOR RANGE (%) : 73.38 REMARK 3 NUMBER OF REFLECTIONS : 11767 REMARK 3 REMARK 3 FIT TO DATA USED IN REFINEMENT. REMARK 3 CROSS-VALIDATION METHOD : THROUGHOUT REMARK 3 FREE R VALUE TEST SET SELECTION : RANDOM REMARK 3 R VALUE (WORKING + TEST SET) : 0.20392 REMARK 3 R VALUE (WORKING SET) : 0.20178 REMARK 3 FREE R VALUE : 0.26853 REMARK 3 FREE R VALUE TEST SET SIZE (%) : 3.0 NAI-5000260062v1 -52-Attorney Docket No.14709-046-228 REMARK 3 FREE R VALUE TEST SET COUNT : 370 REMARK 3 REMARK 3 FIT IN THE HIGHEST RESOLUTION BIN. REMARK 3 TOTAL NUMBER OF BINS USED : 20 REMARK 3 BIN RESOLUTION RANGE HIGH : 2.205 REMARK 3 BIN RESOLUTION RANGE LOW : 2.262 REMARK 3 REFLECTION IN BIN (WORKING SET) : 93 REMARK 3 BIN COMPLETENESS (WORKING+TEST) (%) : 7.86 REMARK 3 BIN R VALUE (WORKING SET) : 0.314 REMARK 3 BIN FREE R VALUE SET COUNT : 3 REMARK 3 BIN FREE R VALUE : 0.358 REMARK 3 REMARK 3 NUMBER OF NON-HYDROGEN ATOMS USED IN REFINEMENT. REMARK 3 ALL ATOMS : 2290 REMARK 3 REMARK 3 B VALUES. REMARK 3 FROM WILSON PLOT (A**2) : NULL REMARK 3 MEAN B VALUE (OVERALL, A**2) : 66.203 REMARK 3 OVERALL ANISOTROPIC B VALUE. REMARK 3 B11 (A**2) : 0.35 REMARK 3 B22 (A**2) : 0.35 REMARK 3 B33 (A**2) : -1.15: REMARK 3 B23 (A**2) : -0.00 REMARK 3 REMARK 3 ESTIMATED OVERALL COORDINATE ERROR. REMARK 3 ESU BASED ON R VALUE (A): 0.467 REMARK 3 ESU BASED ON FREE R VALUE (A): 0.293 REMARK 3 ESU BASED ON MAXIMUM LIKELIHOOD (A): 0.222 REMARK 3 ESU FOR B VALUES BASED ON MAXIMUM LIKELIHOOD (A**2): 19.342 REMARK 3 REMARK 3 CORRELATION COEFFICIENTS. REMARK 3 CORRELATION COEFFICIENT FO-FC : 0.959 REMARK 3 CORRELATION COEFFICIENT FO-FC FREE : 0.922 REMARK 3 REMARK 3 RMS DEVIATIONS FROM IDEAL VALUES COUNT RMS WEIGHT REMARK 3 BOND LENGTHS REFINED ATOMS (A): 2304 ; 0.003 ; 0.012 REMARK 3 BOND LENGTHS OTHERS (A): 2225 ; 0.001 ; 0.016 REMARK 3 BOND ANGLES REFINED ATOMS (DEGREES): 3123 ; 0.999 ; 1.858 NAI-5000260062v1 -53-Attorney Docket No.14709-046-228 REMARK 3 BOND ANGLES OTHERS (DEGREES): 5117 ; 0.333 ; 1.771 REMARK 3 TORSION ANGLES, PERIOD 1 (DEGREES): 271 ; 5.797 ; 5.000 REMARK 3 TORSION ANGLES, PERIOD 2 (DEGREES): 15 ; 4.335 ; 5.000 REMARK 3 TORSION ANGLES, PERIOD 3 (DEGREES): 404 ;13.368 ;10.000 REMARK 3 CHIRAL-CENTER RESTRAINTS (A**3): 347 ; 0.042 ; 0.200 REMARK 3 GENERAL PLANES REFINED ATOMS (A): 2652 ; 0.003 ; 0.020 REMARK 3 GENERAL PLANES OTHERS (A): 524 ; 0.001 ; 0.020 REMARK 3 REMARK 3 ISOTROPIC THERMAL FACTOR RESTRAINTS. COUNT RMS WEIGHTREMARK 3 NUMBER OF TLS GROUPS : 1 REMARK 3 ATOM RECORD CONTAINS SUM OF TLS AND RESIDUAL B FACTORS REMARK 3 REMARK 3 TLS GROUP : 1 REMARK 3 NUMBER OF COMPONENTS GROUP : 1 REMARK 3 COMPONENTS C SSSEQI TO C SSSEQI REMARK 3 RESIDUE RANGE : A 1933 A 2401 REMARK 3 ORIGIN FOR THE GROUP (A): 35.7225 -11.8802 -1.5551 REMARK 3 T TENSORNAI-5000260062v1 -54-Attorney Docket No.14709-046-228 REMARK 3 L11: 0.6603 L22: 1.0993 REMARK 3 L33: 0.5239 L12: 0.5799 REMARK 3 L13: 0.0016 L23: 0.5431 REMARK 3 S TENSOR REMARK 3 S11: 0.1718 S12: 0.0028 S13: -0.0294 REMARK 3 S21: 0.0806 S22: -0.1772 S23: 0.0642 REMARK 3 S31: -0.0648 S32: -0.1161 S33: 0.0054 REMARK 3 REMARK 3 REMARK BULK SOLVENT MODELLING. REMARK 3 METHOD USED : MASK REMARK 3 PARAMETERS FOR MASK CALCULATION REMARK 3 VDW PROBE RADIUS : 1.20 REMARK 3 ION PROBE RADIUS : 0.80 REMARK 3 SHRINKAGE RADIUS : 0.80 REMARK 3 REMARK 3 OTHER REFINEMENT REMARKS: REMARK HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS REMARK 3 U VALUES : WITH TLS ADDED REMARK 3 CISPEP 1 GLU A 2020 PRO A 2021 0.00 CRYST1 106.020 106.020 50.510 90.00 90.00120.00 P 64 SCALE1 0.009432 0.005446 0.000000 0.00000 SCALE2 -0.000000 0.010891 0.000000 0.00000 SCALE3 0.000000 -0.000000 0.019798 0.00000 ATOM 1 N SER A1933 17.616 -15.293 -25.372 1.0095.12 N ANISOU 1 N SER A1933 11192 12531 12418 1515 -1801 -1713 N ATOM 2 CA SER A1933 18.983 -15.288 -24.786 1.0094.79 C ANISOU 2 CA SER A1933 11224 12444 12345 1450 -1683 -1658 C ATOM 3 C SER A1933 19.323 -16.664 -24.212 1.0095.34 CANISOU 3 C SER A1933 11229 12546 12448 1367 -1577 -1716C ATOM 4 O SER A1933 18.984 -16.965 -23.068 1.0095.21O ANISOU 4 O SER A1933 11131 12519 12523 1355 -1517 -1762 O ATOM 5 CB SER A1933 19.115 -14.208 -23.740 1.0094.52 C ANISOU 5 CB SER A1933 11203 12339 12372 1486 -1653 -1622C ATOM 6 OG SER A1933 20.434 -14.165 -23.216 1.0092.83O ANISOU 6 OG SER A1933 11061 12084 12126 1425 -1549 -1569 O ATOM 7 N ILE A1934 19.996 -17.489 -25.026 1.0093.81 N ANISOU 7 N ILE A1934 11076 12387 12178 1307 -1554 -1714 N ATOM 8 CA ILE A1934 20.470 -18.799 -24.608 1.0091.60 C NAI-5000260062v1 -55-Attorney Docket No.14709-046-228 ANISOU 8 CA ILE A1934 10749 12127 11926 1227 -1458 -1760 C ATOM 9 C ILE A1934 21.912 -18.649 -24.127 1.0092.48 C ANISOU 9 C ILE A1934 10937 12183 12015 1177 -1366 -1700C ATOM 10 O ILE A1934 22.767 -18.187 -24.878 1.0094.87O ANISOU 10 O ILE A1934 11340 12471 12233 1164 -1371 -1644O ATOM 11 CB ILE A1934 20.346 -19.822 -25.758 1.0090.37 C ANISOU 11 CB ILE A1934 10582 12038 11714 1190 -1482 -1806C ATOM 12 CG1 ILE A1934 18.909 -19.913 -26.294 1.0089.68C ANISOU 12 CG1 ILE A1934 10419 12009 11645 1242 -1584 -1867C ATOM 13 CG2 ILE A1934 20.866 -21.197 -25.331 1.0087.84C ANISOU 13 CG2 ILE A1934 10213 11728 11431 1109 -1383 -1855C ATOM 14 CD1 ILE A1934 18.794 -20.477 -27.699 1.0090.65C ANISOU 14 CD1 ILE A1934 10567 12196 11679 1219 -1641 -1890C ATOM 15 N GLU A1935 22.173 -19.049 -22.875 1.0093.25N ANISOU 15 N GLU A1935 10989 12250 12189 1143 -1285 -1714N ATOM 16 CA GLU A1935 23.488 -18.910 -22.267 1.0091.67C ANISOU 16 CA GLU A1935 10849 11996 11984 1098 -1205 -1661C ATOM 17 C GLU A1935 24.466 -19.920 -22.869 1.0085.71 CANISOU 17 C GLU A1935 10116 11254 11193 1029 -1157 -1671 CATOM 18 O GLU A1935 24.075 -21.030 -23.225 1.0088.82 OANISOU 18 O GLU A1935 10451 11693 11603 1001 -1155 -1732 OATOM 19 CB GLU A1935 23.403 -19.113 -20.754 1.0093.92 C ANISOU 19 CB GLU A1935 11079 12248 12358 1076 -1143 -1675 CATOM 20 CG GLU A1935 22.654 -18.001 -20.023 1.0096.59 C ANISOU 20 CG GLU A1935 11403 12560 12737 1134 -1169 -1666 CATOM 21 CD GLU A1935 22.593 -18.189 -18.515 1.0099.84 CANISOU 21 CD GLU A1935 11769 12940 13225 1098 -1100 -1684 CATOM 22 OE1 GLU A1935 22.972 -19.279 -18.032 1.00100.06 O ANISOU 22 OE1 GLU A1935 11772 12969 13276 1031 -1044 -1706 O ATOM 23 OE2 GLU A1935 22.177 -17.241 -17.817 1.00101.61 O ANISOU 23 OE2 GLU A1935 11988 13135 13483 1132 -1103 -1676 O ATOM 24 N ASN A1936 25.740 -19.516 -22.968 1.0079.15 N ANISOU 24 N ASN A1936 9367 10382 10322 1001 -1114 -1616 N ATOM 25 CA ASN A1936 26.799 -20.359 -23.499 1.0076.89 C C C C O O CNAI-5000260062v1 -56-Attorney Docket No.14709-046-228 ANISOU 28 CB ASN A1936 9531 10482 10263 928 -1092 -1620 C ATOM 29 CG ASN A1936 28.164 -20.970 -25.525 1.0084.97 C C O O N N N N C C C C O O C C C C C C C C N N C C C C O O C C C C C C N N CNAI-5000260062v1 -57-Attorney Docket No.14709-046-228 ANISOU 48 CA ALA A1939 8304 9109 9408 578 -660 -1738 C ATOM 49 C ALA A1939 36.033 -23.979 -24.231 1.0071.57 C C O O C C N N C C C C O O C C C C C C C C C C C C C C N N C C C C O O C C CNAI-5000260062v1 -58-Attorney Docket No.14709-046-228 ANISOU 68 CG PRO A1941 9573 10318 10879 272 -306 -2058 C ATOM 69 CD PRO A1941 40.065 -25.379 -26.158 1.0081.23 C C N N C C C C O O C C C C C C N N C C N N N N N N C C C C O O C C C C C C ONAI-5000260062v1 -59-Attorney Docket No.14709-046-228 ANISOU 88 OE1 GLU A1943 12786 13770 15256 58 -32 -2575 O ATOM 89 OE2 GLU A1943 44.299 -29.806 -28.830 1.00108.94 O O N N C C C C O O C C C C C C C C N N N N C C C C O O C C C C C C C C N N CNAI-5000260062v1 -60-Attorney Docket No.14709-046-228 ANISOU 108 CA THR A1946 7897 8417 10836 363 -545 -1919 C ATOM 109 C THR A1946 47.894 -28.608 -16.140 1.0069.44 C C O O C C O O C C N N C C C C O O C C C C C C C C N N C C C C O O C C C C CNAI-5000260062v1 -61-Attorney Docket No.14709-046-228 ANISOU 128 CD ARG A1948 8484 8836 11628 358 -644 -1813 C ATOM 129 NE ARG A1948 52.169 -26.404 -15.885 1.0078.84 N N C C N N N N N N C C C C O O C C C C C C C C N N C C C C O O C C C C C C CNAI-5000260062v1 -62-Attorney Docket No.14709-046-228 ANISOU 148 CD2 LEU A1950 9294 8849 11897 193 -1452 -1038 C ATOM 149 N LEU A1951 45.886 -27.272 -4.676 1.0070.30 N N C C C C O O C C C C C C C C N N C C C C O O N N C C C C O O C C O O N N CNAI-5000260062v1 -63-Attorney Docket No.14709-046-228 ANISOU 168 CA GLY A1954 9764 9608 11232 71 -943 -1088 C ATOM 169 C GLY A1954 35.337 -27.317 -3.481 1.0081.20 C C O O N N C C C C O O N N C C C C O O C C C C C C O O O O N N C C C C O O CNAI-5000260062v1 -64-Attorney Docket No.14709-046-228 ANISOU 188 CB VAL A1959 7285 7253 9093 288 -952 -1141 C ATOM 189 CG1 VAL A1959 41.201 -24.464 -6.775 1.0061.43 C C C C N N C C C C O O C C C C C C C C C C C C C C O O N N C C C C O O C C CNAI-5000260062v1 -65-Attorney Docket No.14709-046-228 ANISOU 208 CG GLU A1961 8458 8536 10730 380 -787 -1364 C ATOM 209 CD GLU A1961 49.630 -21.743 -9.096 1.0077.52 C C O O O O N N C C C C O O N N C C C C O O C C O O C C N N C C C C O O C C NNAI-5000260062v1 -66-Attorney Docket No.14709-046-228 ANISOU 228 N VAL A1965 10391 10824 12117 264 -202 -1942 N ATOM 229 CA VAL A1965 47.692 -22.590 -23.913 1.0089.86 C C C C O O C C C C C C N N C C C C O O C C C C O O O O N N C C C C O O C CCNAI-5000260062v1 -67-Attorney Docket No.14709-046-228 ANISOU 248 CG1 ILE A1967 13697 14007 14871 430 -382 -1634 C ATOM 249 CG2 ILE A1967 42.447 -18.182 -21.135 1.00113.74 C C C C N N C C C C O O C C C C C C C C N N C C C C O O N N C C C C O O C C ONAI-5000260062v1 -68-Attorney Docket No.14709-046-228 ANISOU 268 OG SER A1972 14553 14486 15187 236 -77 -1676 O ATOM 269 N GLY A1973 49.967 -17.811 -25.476 1.00108.77 N N C C C C O O N N C C C C O O C C C C C C O O O O N N C C C C O O C C C C CNAI-5000260062v1 -69-Attorney Docket No.14709-046-228 ANISOU 288 CG2 ILE A1975 10716 10732 11831 267 -125 -1674 C ATOM 289 CD1 ILE A1975 46.104 -17.096 -20.065 1.0088.94 C C N N C C C C O O C C C C C C C C N N N N C C C C O O C C C C C C N N C C CNAI-5000260062v1 -70-Attorney Docket No.14709-046-228 ANISOU 308 C ALA A1978 6716 6936 8470 464 -710 -1339 C ATOM 309 O ALA A1978 41.514 -22.433 -12.835 1.0058.61 O ANISOU 309 O ALA A1978 6784 7040 8445 488 -679 -1358 O ATOM 310 CB ALA A1978 42.766 -21.191 -10.160 1.0055.34 C ANISOU 310 CB ALA A1978 6431 6538 8057 445 -722 -1243 C ATOM 311 N VAL A1979 42.104 -24.134 -11.461 1.0058.13 N ANISOU 311 N VAL A1979 6662 6889 8533 446 -752 -1346 N ATOM 312 CA VAL A1979 41.152 -25.089 -12.014 1.0059.50 C ANISOU 312 CA VAL A1979 6804 7091 8710 451 -754 -1383 C C C O O C C C C C CN ANISOU 318 N LYS A1980 7238 7535 9054 440 -784 -1346 N ATOM 319 CA LYS A1980 38.064 -26.020 -9.985 1.0066.86 C ANISOU 319 CA LYS A1980 7770 8053 9578 411 -809 -1328 C ATOM 320 C LYS A1980 37.466 -27.273 -10.625 1.0065.47 C ANISOU 320 C LYS A1980 7544 7888 9440 408 -811 -1381 C ATOM 321 O LYS A1980 36.963 -27.206 -11.745 1.0066.67 O ANISOU 321 O LYS A1980 7674 8096 9559 438 -783 -1428 O ATOM 322 CB LYS A1980 37.036 -24.932 -9.653 1.0071.24 C ANISOU 322 CB LYS A1980 8364 8658 10043 424 -787 -1309 C ATOM 323 CG LYS A1980 36.107 -25.212 -8.483 1.0076.68 C ANISOU 323 CG LYS A1980 9073 9342 10719 382 -799 -1289 C ATOM 324 CD LYS A1980 35.213 -24.027 -8.131 1.0081.73 C ANISOU 324 CD LYS A1980 9743 10025 11283 395 -771 -1280 C ATOM 325 CE LYS A1980 34.372 -24.258 -6.910 1.0085.85 C ANISOU 325 CE LYS A1980 10287 10540 11793 341 -772 -1269 C ATOM 326 NZ LYS A1980 35.173 -24.418 -5.692 1.0086.86 N ANISOU 326 NZ LYS A1980 10457 10606 11939 282 -800 -1214 N ATOM 327 N THR A1981 37.540 -28.415 -9.923 1.0063.44 N ANISOU 327 N THR A1981 7275 7576 9251 369 -847 -1372 N ATOM 328 CA THR A1981 37.091 -29.688 -10.473 1.0065.42 C NAI-5000260062v1 -71-Attorney Docket No.14709-046-228 ANISOU 328 CA THR A1981 7478 7825 9551 361 -848 -1424 C ATOM 329 C THR A1981 35.757 -30.087 -9.847 1.0065.91 C C O O C C O O C C N N C C C C O O C C C C C C C C N N C C C C O O C C C C CNAI-5000260062v1 -72-Attorney Docket No.14709-046-228 ANISOU 348 CD LYS A1983 11590 11350 13740 -27 -1089 -1274 C ATOM 349 CE LYS A1983 35.722 -38.235 -4.414 1.0096.70 C C N N N N C C C C O O C C C C C C C C N N N N C CATOM 362 C GLY A1985 30.107 -39.245 -8.468 1.0091.98 C ANISOU 362 C GLY A1985 10772 11060 13116 -18 -830 -1660 C ATOM 363 O GLY A1985 29.680 -39.877 -7.505 1.0092.50 O ANISOU 363 O GLY A1985 10889 11075 13180 -92 -836 -1637 O ATOM 364 N SER A1986 29.997 -37.916 -8.578 1.0091.39 N ANISOU 364 N SER A1986 10698 11056 12968 23 -814 -1650 N ATOM 365 CA SER A1986 29.320 -37.115 -7.570 1.0092.79 C ANISOU 365 CA SER A1986 10928 11260 13067 -13 -798 -1620C ATOM 366 C SER A1986 27.822 -37.069 -7.871 1.0094.00C ANISOU 366 C SER A1986 11042 11500 13172 -25 -743 -1699C ATOM 367 O SER A1986 27.390 -37.467 -8.952 1.0092.90O ANISOU 367 O SER A1986 10836 11410 13051 8 -723 -1770 O ATOM 368 CB SER A1986 29.933 -35.733 -7.464 1.0092.00CNAI-5000260062v1 -73-Attorney Docket No.14709-046-228 ANISOU 368 CB SER A1986 10849 11184 12923 33 -809 -1573 C ATOM 369 OG SER A1986 30.205 -35.178 -8.742 1.0089.73 O ANISOU 369 OG SER A1986 10504 10955 12635 114 -798 -1609 O ATOM 370 N THR A1987 27.036 -36.595 -6.895 1.0097.06 N ANISOU 370 N THR A1987 11471 11905 13501 -76 -717 -1692 N ATOM 371 CA THR A1987 25.582 -36.640 -6.966 1.0098.51 C ANISOU 371 CA THR A1987 11618 12159 13653 -102 -663 -1773 C ATOM 372 C THR A1987 25.111 -35.892 -8.211 1.0097.63 C ANISOU 372 C THR A1987 11426 12145 13522 -12 -650 -1834 C O O C C OO ATOM 376 CG2 THR A1987 23.501 -36.407 -5.527 1.00100.64 C ANISOU 376 CG2 THR A1987 11911 12479 13847 -226 -574 -1846 C ATOM 377 N ASP A1988 23.946 -36.297 -8.727 1.0098.37 N ANISOU 377 N ASP A1988 11459 12301 13615 -17 -616 -1924 N ATOM 378 CA ASP A1988 23.375 -35.682 -9.913 1.0097.31 C ANISOU 378 CA ASP A1988 11251 12260 13462 61 -614 -1985 C ATOM 379 C ASP A1988 23.084 -34.211 -9.614 1.0096.05 C ANISOU 379 C ASP A1988 11100 12142 13251 101 -611 -1969 C ATOM 380 O ASP A1988 23.270 -33.355 -10.475 1.0097.05 O ANISOU 380 O ASP A1988 11202 12314 13356 182 -633 -1966 O ATOM 381 CB ASP A1988 22.160 -36.459 -10.400 1.0097.76 C ANISOU 381 CB ASP A1988 11241 12371 13533 39 -583 -2086 C ATOM 382 CG ASP A1988 21.965 -36.482 -11.909 1.0098.73 C ANISOU 382 CG ASP A1988 11291 12564 13657 111 -599 -2144 C ATOM 383 OD1 ASP A1988 21.930 -35.390 -12.512 1.00104.52 O ANISOU 383 OD1 ASP A1988 12007 13352 14353 184 -620 -2140 O ATOM 384 OD2 ASP A1988 21.855 -37.593 -12.471 1.0094.09 O ANISOU 384 OD2 ASP A1988 10669 11974 13105 88 -590 -2193 O ATOM 385 N GLN A1989 22.645 -33.929 -8.381 1.0093.10 N ANISOU 385 N GLN A1989 10766 11749 12858 38 -583 -1958 N ATOM 386 CA GLN A1989 22.415 -32.568 -7.920 1.0094.51 C ANISOU 386 CA GLN A1989 10957 11954 12997 64 -574 -1942 C ATOM 387 C GLN A1989 23.726 -31.784 -7.864 1.0091.56 C ANISOU 387 C GLN A1989 10638 11541 12608 107 -610 -1849 C ATOM 388 O GLN A1989 23.760 -30.608 -8.219 1.0090.78 O NAI-5000260062v1 -74-Attorney Docket No.14709-046-228 ANISOU 388 O GLN A1989 10531 11478 12484 174 -619 -1839 O ATOM 389 CB GLN A1989 21.792 -32.556 -6.524 1.0097.93 C C C C C C O O N N N N C C C C O O C C C C C C O O O O N N C C C C O O C C CNAI-5000260062v1 -75-Attorney Docket No.14709-046-228 ANISOU 408 CG LYS A1991 10376 11423 12503 354 -720 -1849 C ATOM 409 CD LYS A1991 27.544 -33.776 -14.145 1.0095.93 C C C C N N N N C C C C O O C C C C C C C C N N C C C C O O C C C C CC ATOM 427 OE1 GLU A1993 25.000 -24.482 -6.689 1.00110.61 O ANISOU 427 OE1 GLU A1993 13181 13982 14864 323 -612 -1665 O ATOM 428 OE2 GLU A1993 26.990 -24.220 -5.777 1.00107.27 O NAI-5000260062v1 -76-Attorney Docket No.14709-046-228 ANISOU 428 OE2 GLU A1993 12865 13471 14420 279 -628 -1540 O ATOM 429 N PHE A1994 27.306 -27.211 -9.752 1.0073.07 N N C C C C O O C C C C C C C C C C C C C C N N C C C C O O C C C C C C C C NNAI-5000260062v1 -77-Attorney Docket No.14709-046-228 ANISOU 448 N LYS A1996 9076 10097 10809 608 -750 -1692 N ATOM 449 CA LYS A1996 25.065 -22.978 -11.835 1.0083.02 C C C C O O C C C C C C C C N N N N C C C C O O C C C C C C O O O O N N C C CNAI-5000260062v1 -78-Attorney Docket No.14709-046-228 ANISOU 468 C ALA A1998 7472 8253 8829 774 -801 -1506 C ATOM 469 O ALA A1998 29.493 -19.545 -15.436 1.0061.93 O O C C N N C C C C O O C C C C N N C C C C N N N N C C C C O O C C C C C C CNAI-5000260062v1 -79-Attorney Docket No.14709-046-228 ANISOU 488 CD2 LEU A2000 8385 9227 9930 847 -758 -1584 C ATOM 489 N MET A2001 29.263 -16.888 -13.535 1.0065.74 N N C C C C O O C C C C S S C C N N C C C C O O C C O O N N C C C C O O C CCNAI-5000260062v1 -80-Attorney Docket No.14709-046-228 ANISOU 508 CG LYS A2003 9548 10309 10739 1121 -1013 -1475 C ATOM 509 CD LYS A2003 24.123 -15.176 -15.634 1.0084.28 C C C C N N N N C C C C O O C C C C C C C C C C C C C C N N C C C C O O C C CNAI-5000260062v1 -81-Attorney Docket No.14709-046-228 ANISOU 528 CG ASN A2005 8728 8494 8842 1042 -827 -1053 C ATOM 529 OD1 ASN A2005 33.983 -8.731 -18.354 1.0070.52 O O N N N N C C C C O O C C C C N N C C C C N N N N C C C C O O C C C C C CNNAI-5000260062v1 -82-Attorney Docket No.14709-046-228 ANISOU 548 N ASN A2008 6437 6038 6831 816 -503 -999 N ATOM 549 CA ASN A2008 36.433 -6.639 -9.257 1.0048.55 C C C C O O C C C C O O N N N N C C C C O O C C C C C C C C N N C C C C O O CNAI-5000260062v1 -83-Attorney Docket No.14709-046-228 ANISOU 568 CB LEU A2010 6357 6396 7281 625 -608 -1134 C ATOM 569 CG LEU A2010 37.786 -15.407 -10.134 1.0053.17 C C C C C C N N C C C C O O C C C C C C C C N N N N C C C C O O C C C C C C ONAI-5000260062v1 -84-Attorney Docket No.14709-046-228 ANISOU 588 OE1 GLN A2012 7877 8444 9135 701 -738 -1414 O ATOM 589 NE2 GLN A2012 32.127 -19.736 -17.070 1.0067.07 N ANISOU 589 NE2 GLN A2012 7918 8519 9044 765 -768 -1435 N ATOM 590 N LEU A2013 37.721 -18.222 -17.333 1.0066.49 N ANISOU 590 N LEU A2013 8003 8289 8967 654 -620 -1353 N ATOM 591 CA LEU A2013 38.403 -18.161 -18.614 1.0065.47 C C C C O O C C C C C C C C N N C C C C O O N N C C C C O O C C C C CNAI-5000260062v1 -85-Attorney Docket No.14709-046-228 ANISOU 608 CG2 VAL A2015 7005 7844 8388 640 -727 -1657 C ATOM 609 N CYS A2016 35.792 -27.131 -19.136 1.0059.25 N N C C C C O O C C S S N N C C C C O O C C C C C C C C N N C C C C O O C C CNAI-5000260062v1 -86-Attorney Docket No.14709-046-228 ANISOU 628 CG LEU A2018 8761 10020 10682 437 -619 -2101 C ATOM 629 CD1 LEU A2018 33.326 -31.844 -25.452 1.0079.32 C C C C N N C C C C O O C C C C O O N N N N C C C C O O C C C C C C O O O ONNAI-5000260062v1 -87-Attorney Docket No.14709-046-228 ANISOU 648 N PRO A2021 8161 8750 10860 340 -794 -1759 N ATOM 649 CA PRO A2021 36.325 -34.470 -13.917 1.0070.92 C C C C O O C C C C C C N N C C C C O O C C C C C C O O N N N N C C C C O O CNAI-5000260062v1 -88-Attorney Docket No.14709-046-228 ANISOU 668 CB TYR A2023 6242 6842 8269 474 -696 -1618 C ATOM 669 CG TYR A2023 39.051 -29.414 -15.718 1.0056.31 C C C C C C C C C C C C O O N N C C C C O O C C C C C C C C N N C C C C O O CNAI-5000260062v1 -89-Attorney Docket No.14709-046-228 ANISOU 688 CB ILE A2025 6666 7095 8154 540 -608 -1494 C ATOM 689 CG1 ILE A2025 39.534 -24.068 -17.548 1.0061.58 C C C C C C N N C C C C O O C C C C C C C C N N C C C C O O C C C C C C O O ONAI-5000260062v1 -90-Attorney Docket No.14709-046-228 ANISOU 708 OE2 GLU A2027 6994 6882 7691 648 -534 -1123 O ATOM 709 N LEU A2028 44.236 -17.034 -12.503 1.0053.30 N N C C C C O O C C C C C C C C N N C C C C O O C C C C S S C C N N C C C CO NAI-5000260062v1 -91-Attorney Docket No.14709-046-228 ANISOU 728 O GLU A2030 6341 6089 7827 274 -722 -1068 O ATOM 729 CB GLU A2030 49.929 -14.552 -7.966 1.0061.41 C C C C C C O O O O N N C C- C ANISOU 736 C GLY A2031 5681 5345 6859 240 -716 -965 C ATOM 737 O GLY A2031 47.046 -13.984 -1.812 1.0045.63 O ANISOU 737 O GLY A2031 5531 5150 6655 193 -744 -929 O ATOM 738 N ARG A2032 46.472 -15.201 -3.624 1.0050.06 N ANISOU 738 N ARG A2032 6026 5733 7262 265 -735 -983 N ATOM 739 CA ARG A2032 45.681 -16.177 -2.888 1.0053.45 C ANISOU 739 CA ARG A2032 6454 6155 7697 240 -788 -960 C ATOM 740 C ARG A2032 44.426 -15.474 -2.372 1.0051.92 C ANISOU 740 C ARG A2032 6311 5996 7418 231 -750 -941 C ATOM 741 O ARG A2032 44.063 -14.416 -2.880 1.0051.50 O ANISOU 741 O ARG A2032 6281 5972 7314 263 -690 -952 O ATOM 742 CB ARG A2032 46.550 -16.874 -1.830 1.0058.60 C ANISOU 742 CB ARG A2032 7099 6756 8410 190 -869 -930 C ATOM 743 CG ARG A2032 47.819 -17.478 -2.420 1.0062.47 C C C C N N C C N N NNAI-5000260062v1 -92-Attorney Docket No.14709-046-228 ANISOU 748 NH2 ARG A2032 10163 9703 11882 92 -1198 -871 N ATOM 749 N ASP A2033 43.747 -16.072 -1.388 1.0049.93 N N C C C C O O C C C C O O O O N N C C C C O O C C C C C C C C N N C C C CONAI-5000260062v1 -93-Attorney Docket No.14709-046-228 ANISOU 768 O LEU A2035 7044 6362 7582 -206 -822 -754 O ATOM 769 CB LEU A2035 41.201 -14.591 4.816 1.0053.61 C C C C C C C C N N C C C C O O C C O O C C N N C C C C O O C C C C C C C C CNAI-5000260062v1 -94-Attorney Docket No.14709-046-228 ANISOU 788 CE1 TYR A2037 5987 5493 6889 156 -574 -931 C ATOM 789 CE2 TYR A2037 47.655 -8.022 -0.344 1.0049.78 C ANISOU 789 CE2 TYR A2037 6264 5698 6951 133 -498 -900C ATOM 790 CZ TYR A2037 48.708 -8.385 -1.165 1.0048.53C ANISOU 790 CZ TYR A2037 6065 5526 6846 151 -508 -924C ATOM 791 OH TYR A2037 49.463 -7.424 -1.772 1.0048.67O ANISOU 791 OH TYR A2037 6098 5537 6855 161 -448 -945O ATOM 792 N LEU A2038 45.963 -10.838 3.867 1.0048.29N ANISOU 792 N LEU A2038 6125 5496 6727 -86 -703 -801N ATOM 793 CA LEU A2038 45.944 -9.928 5.001 1.0050.08 C ANISOU 793 CA LEU A2038 6408 5727 6894 -156 -674 -789 C ATOM 794 C LEU A2038 46.852 -10.444 6.116 1.0051.27C ANISOU 794 C LEU A2038 6580 5848 7050 -236 -761 -750C ATOM 795 O LEU A2038 47.640 -9.682 6.677 1.0052.21O ANISOU 795 O LEU A2038 6723 5961 7154 -274 -756 -744O ATOM 796 CB LEU A2038 44.507 -9.740 5.487 1.0050.54C ANISOU 796 CB LEU A2038 6497 5810 6894 -184 -624 -800C ATOM 797 CG LEU A2038 43.556 -9.045 4.507 1.0050.99CANISOU 797 CG LEU A2038 6535 5893 6944 -106 -543 -839 CATOM 798 CD1 LEU A2038 42.114 -9.177 4.965 1.0051.73 CANISOU 798 CD1 LEU A2038 6641 6009 7004 -132 -510 -860 CATOM 799 CD2 LEU A2038 43.931 -7.583 4.320 1.0052.45 CANISOU 799 CD2 LEU A2038 6740 6077 7110 -85 -475 -852 CATOM 800 N ARG A2039 46.735 -11.740 6.424 1.0051.87 NANISOU 800 N ARG A2039 6652 5905 7151 -261 -843 -724 NATOM 801 CA ARG A2039 47.466 -12.346 7.527 1.0052.38 CANISOU 801 CA ARG A2039 6747 5935 7219 -340 -942 -679 CATOM 802 C ARG A2039 48.966 -12.343 7.243 1.0054.31 CANISOU 802 C ARG A2039 6947 6150 7538 -313 -1000 -678 CATOM 803 O ARG A2039 49.755 -12.035 8.135 1.0053.85 OANISOU 803 O ARG A2039 6917 6076 7467 -373 -1047 -655O ATOM 804 CB ARG A2039 46.920 -13.749 7.819 1.0053.38C ANISOU 804 CB ARG A2039 6883 6040 7357 -367 -1015 -652C ATOM 805 CG ARG A2039 45.542 -13.664 8.456 1.0055.41C ANISOU 805 CG ARG A2039 7197 6326 7529 -427 -959 -655C ATOM 806 CD ARG A2039 44.964 -15.000 8.862 1.0058.46C ANISOU 806 CD ARG A2039 7606 6690 7914 -472 -1023 -628C ATOM 807 NE ARG A2039 43.706 -14.793 9.587 1.0061.60N ANISOU 807 NE ARG A2039 8061 7117 8225 -547 -957 -642 N ATOM 808 CZ ARG A2039 42.967 -15.746 10.138 1.0064.01CNAI-5000260062v1 -95-Attorney Docket No.14709-046-228 ANISOU 808 CZ ARG A2039 8408 7412 8501 -613 -985 -626 C ATOM 809 NH1 ARG A2039 43.354 -17.006 10.073 1.0066.16 N ANISOU 809 NH1 ARG A2039 8675 7639 8823 -612 -1085 -588 N ATOM 810 NH2 ARG A2039 41.839 -15.435 10.755 1.0065.61 N ANISOU 810 NH2 ARG A2039 8655 7644 8628 -683 -908 -653 N ATOM 811 N LYS A2040 49.356 -12.679 6.006 1.0054.75 N ANISOU 811 N LYS A2040 6931 6198 7672 -228 -996 -709 N ATOM 812 CA LYS A2040 50.760 -12.656 5.625 1.0057.76 C ANISOU 812 CA LYS A2040 7257 6552 8135 -201 -1036 -725 C ATOM 813 C LYS A2040 51.327 -11.233 5.684 1.0058.44 C ANISOU 813 C LYS A2040 7359 6657 8188 -210 -964 -747 C ATOM 814 O LYS A2040 52.535 -11.067 5.816 1.0057.37 O ANISOU 814 O LYS A2040 7193 6499 8103 -219 -1004 -755 O ATOM 815 CB LYS A2040 50.978 -13.243 4.227 1.0060.43 C ANISOU 815 CB LYS A2040 7518 6883 8558 -116 -1025 -767 C ATOM 816 CG LYS A2040 51.024 -14.759 4.152 1.0067.00 C ANISOU 816 CG LYS A2040 8312 7676 9467 -106 -1121 -753 C ATOM 817 CD LYS A2040 51.424 -15.260 2.769 1.0071.31 C ANISOU 817 CD LYS A2040 8775 8214 10104 -29 -1103 -807 C ATOM 818 CE LYS A2040 51.335 -16.745 2.619 1.0072.50 C ANISOU 818 CE LYS A2040 8887 8327 10333 -15 -1186 -800 C ATOM 819 NZ LYS A2040 52.287 -17.442 3.483 1.0073.26 N ANISOU 819 NZ LYS A2040 8969 8361 10502 -50 -1311 -768 N ATOM 820 N ALA A2041 50.467 -10.212 5.555 1.0059.43 N ANISOU 820 N ALA A2041 7525 6819 8236 -205 -860 -760 N ATOM 821 CA ALA A2041 50.901 -8.823 5.610 1.0061.34 C ANISOU 821 CA ALA A2041 7788 7075 8442 -215 -785 -780 C ATOM 822 C ALA A2041 51.241 -8.428 7.045 1.0064.02 C ANISOU 822 C ALA A2041 8180 7409 8733 -308 -819 -751 C ATOM 823 O ALA A2041 52.181 -7.671 7.280 1.0061.84 O ANISOU 823 O ALA A2041 7903 7128 8462 -330 -809 -763 O ATOM 824 CB ALA A2041 49.831 -7.917 5.042 1.0060.54 C ANISOU 824 CB ALA A2041 7715 7005 8283 -177 -674 -801 C ATOM 825 N ARG A2042 50.451 -8.946 7.990 1.0068.51 N ANISOU 825 N ARG A2042 8797 7981 9250 -369 -856 -716 N ATOM 826 CA ARG A2042 50.590 -8.623 9.399 1.0071.21 C ANISOU 826 CA ARG A2042 9203 8324 9529 -473 -886 -687 C ATOM 827 C ARG A2042 51.766 -9.394 9.993 1.0078.60 C ANISOU 827 C ARG A2042 10126 9223 10516 -511 -1019 -653 C ATOM 828 O ARG A2042 52.655 -8.806 10.605 1.0089.63 O NAI-5000260062v1 -96-Attorney Docket No.14709-046-228 ANISOU 828 O ARG A2042 11535 10615 11905 -557 -1042 -651 O ATOM 829 CB ARG A2042 49.264 -8.973 10.080 1.0068.40 C C C C C C N N C C N N N N N N C C C C O O C C C C S S C C N N C C C C O O CNAI-5000260062v1 -97-Attorney Docket No.14709-046-228 ANISOU 848 CB ALA A2044 10877 10190 11925 -280 -1089 -779 C ATOM 849 N THR A2045 56.315 -9.130 9.571 1.0094.39 N N C C C C O O C C O O C C N N C C C C O O C C C C C C C C C C C C C C N N CNAI-5000260062v1 -98-Attorney Docket No.14709-046-228 ANISOU 868 CA TYR A2047 10665 9815 11134 -733 -990 -791 C ATOM 869 C TYR A2047 57.303 -3.152 11.907 1.0076.15 C C O O C C C C C C C C C C C C C C O O N N C C C C O O N N C C C C O O C C CNAI-5000260062v1 -99-Attorney Docket No.14709-046-228 ANISOU 888 CG PRO A2049 7064 6154 7157 -497 -491 -806 C ATOM 889 CD PRO A2049 52.209 -3.089 10.321 1.0055.52 C C N N C C C C O O C C C C C C C C N N C C C C O O C C C C C C C C N N C C CNAI-5000260062v1 -100-Attorney Docket No.14709-046-228 ANISOU 908 C THR A2052 6097 5147 6159 -134 -81 -913 C ATOM 909 O THR A2052 46.929 0.162 4.052 1.0042.84 O ANISOU 909 O THR A2052 5697 4780 5798 -75 -105 -909O ATOM 910 CB THR A2052 50.064 1.535 4.254 1.0046.29C ANISOU 910 CB THR A2052 6159 5182 6246 -156 -63 -924C ATOM 911 OG1 THR A2052 49.615 1.798 2.927 1.0045.93O ANISOU 911 OG1 THR A2052 6120 5126 6205 -72 -26 -928O ATOM 912 CG2 THR A2052 51.526 1.123 4.245 1.0045.60C ANISOU 912 CG2 THR A2052 6038 5090 6195 -188 -106 -931C ATOM 913 N LEU A2053 47.298 1.888 5.468 1.0046.43N ANISOU 913 N LEU A2053 6214 5217 6208 -170 -15 -929N ATOM 914 CA LEU A2053 45.904 2.295 5.509 1.0049.10C ANISOU 914 CA LEU A2053 6562 5555 6538 -141 29 -946C ATOM 915 C LEU A2053 45.396 2.540 4.089 1.0050.91C ANISOU 915 C LEU A2053 6784 5769 6788 -33 44 -946C ATOM 916 O LEU A2053 44.288 2.137 3.749 1.0054.08O ANISOU 916 O LEU A2053 7164 6181 7201 14 30 -952O ATOM 917 CB LEU A2053 45.710 3.527 6.397 1.0049.82CANISOU 917 CB LEU A2053 6693 5632 6605 -194 107 -973 CATOM 918 CG LEU A2053 44.274 4.055 6.511 1.0049.64 CANISOU 918 CG LEU A2053 6671 5601 6589 -166 161 -1004 CATOM 919 CD1 LEU A2053 43.288 2.953 6.887 1.0050.69 CANISOU 919 CD1 LEU A2053 6771 5765 6722 -182 118 -1010 CATOM 920 CD2 LEU A2053 44.194 5.192 7.513 1.0049.99 CANISOU 920 CD2 LEU A2053 6749 5630 6614 -234 240 -1038 CATOM 921 N VAL A2054 46.213 3.196 3.258 1.0051.74 NANISOU 921 N VAL A2054 6911 5850 6896 0 71 -940 N ATOM 922 CA VAL A2054 45.805 3.523 1.901 1.0052.76 CANISOU 922 CA VAL A2054 7052 5961 7033 92 85 -935 CATOM 923 C VAL A2054 45.601 2.227 1.120 1.0051.76 CANISOU 923 C VAL A2054 6882 5861 6924 135 16 -923C ATOM 924 O VAL A2054 44.616 2.102 0.390 1.0050.16O ANISOU 924 O VAL A2054 6671 5660 6725 203 5 -923O ATOM 925 CB VAL A2054 46.770 4.490 1.182 1.0057.78C ANISOU 925 CB VAL A2054 7732 6562 7657 104 134 -932C ATOM 926 CG1 VAL A2054 48.227 4.040 1.237 1.0060.04C ANISOU 926 CG1 VAL A2054 8002 6859 7951 53 115 -934C ATOM 927 CG2 VAL A2054 46.341 4.750 -0.259 1.0059.52C ANISOU 927 CG2 VAL A2054 7977 6764 7874 191 138 -920 C ATOM 928 N ASP A2055 46.513 1.258 1.298 1.0048.85 N NAI-5000260062v1 -101-Attorney Docket No.14709-046-228 ANISOU 928 N ASP A2055 6481 5510 6569 96 -33 -917 N ATOM 929 CA ASP A2055 46.391 -0.029 0.631 1.0048.35 C C C C O O C C C C O O O O N N C C C C O O C C C C C C C C N N C C C C O O CNAI-5000260062v1 -102-Attorney Docket No.14709-046-228 ANISOU 948 CB VAL A2057 6193 5211 6302 209 62 -989 C ATOM 949 CG1 VAL A2057 40.193 3.739 1.416 1.0048.80 C C C C N N C C C C O O C C C C O O O O N N C C C C O O C C C C C C C C N N CNAI-5000260062v1 -103-Attorney Docket No.14709-046-228 ANISOU 968 CA CYS A2060 6122 5498 6525 346 -153 -1036 C ATOM 969 C CYS A2060 36.771 -1.339 -0.765 1.0048.03 C C O O C C S S N N C C C C O O C C C C C C N N C C C C O O C C C C O O O O NNAI-5000260062v1 -104-Attorney Docket No.14709-046-228 ANISOU 988 N ILE A2063 6886 6424 7413 572 -312 -1034 N ATOM 989 CA ILE A2063 34.999 -5.007 -3.150 1.0056.86 C C C C O O C C C C C C C C N N C C C C O O C C O O N N C C C C O O C C C C CNAI-5000260062v1 -105-Attorney Docket No.14709-046-228 ANISOU 1008 CD LYS A2065 7927 7118 8164 900 -364 -940 C ATOM 1009 CE LYS A2065 35.915 1.700 -8.230 1.0065.37 C C N N N N C C C C O O N N C C C C O O C C S S N N C C C C O O C C C C C C NNAI-5000260062v1 -106-Attorney Docket No.14709-046-228 ANISOU 1028 N TYR A2069 7291 7181 8268 1087 -605 -1233 N ATOM 1029 CA TYR A2069 27.863 -4.470 -9.760 1.0062.91 C C C C O O C C C C C C C C C C C C C C O O N N C C C C O O C C C C C C C C NNAI-5000260062v1 -107-Attorney Docket No.14709-046-228 ANISOU 1048 N GLU A2071 8145 8436 9569 1044 -601 -1469 N ATOM 1049 CA GLU A2071 23.471 -5.604 -6.835 1.0071.31 C C C C O O C C C C C C O O O O N N C C C C O O C CATOM 1062 CG ARG A2072 23.359 -2.764 -12.424 1.0080.15 C ANISOU 1062 CG ARG A2072 9702 9761 10990 1495 -987 -1331 C ATOM 1063 CD ARG A2072 23.847 -1.386 -12.859 1.0084.68 C ANISOU 1063 CD ARG A2072 10377 10258 11539 1546 -1012 -1258 C ATOM 1064 NE ARG A2072 25.190 -1.074 -12.358 1.0088.23 N ANISOU 1064 NE ARG A2072 10913 10680 11927 1475 -927 -1203 N ATOM 1065 CZ ARG A2072 25.485 -0.129 -11.464 1.0094.34 C ANISOU 1065 CZ ARG A2072 11709 11399 12734 1459 -862 -1201 C ATOM 1066 NH1 ARG A2072 24.535 0.634 -10.949 1.0098.10 N ANISOU 1066 NH1 ARG A2072 12127 11836 13310 1509 -868 -1253 N ATOM 1067 NH2 ARG A2072 26.737 0.051 -11.079 1.0095.89 N ANISOU 1067 NH2 ARG A2072 11982 11580 12872 1391 -791 -1152 N ATOM 1068 N MET A2073 23.147 -6.413 -10.963 1.0073.08 N NAI-5000260062v1 -108-Attorney Docket No.14709-046-228 ANISOU 1068 N MET A2073 8633 9031 10103 1290 -862 -1465 N ATOM 1069 CA MET A2073 22.827 -7.663 -11.637 1.0072.55 C C C C O O C C C C S S C C N N C C C C O O C C C C N N C C C C N N N N C C CNAI-5000260062v1 -109-Attorney Docket No.14709-046-228 ANISOU 1088 C PHE A2075 7562 8227 9251 823 -538 -1671 C ATOM 1089 O PHE A2075 23.458 -9.715 -5.400 1.0064.67 O ANISOU 1089 O PHE A2075 7461 8029 9080 826 -516 -1627O ATOM 1090 CB PHE A2075 23.788 -11.340 -7.982 1.0070.15C ANISOU 1090 CB PHE A2075 8149 8790 9714 917 -654 -1575C ATOM 1091 CG PHE A2075 24.473 -12.573 -7.410 1.0071.70C ANISOU 1091 CG PHE A2075 8362 8996 9881 821 -620 -1559C ATOM 1092 CD1 PHE A2075 24.027 -13.851 -7.733 1.0073.19C ANISOU 1092 CD1 PHE A2075 8503 9226 10079 800 -636 -1597C ATOM 1093 CD2 PHE A2075 25.555 -12.451 -6.544 1.0071.13C ANISOU 1093 CD2 PHE A2075 8357 8890 9780 753 -576 -1506C ATOM 1094 CE1 PHE A2075 24.652 -14.973 -7.209 1.0073.65C ANISOU 1094 CE1 PHE A2075 8581 9283 10119 715 -611 -1579C ATOM 1095 CE2 PHE A2075 26.177 -13.578 -6.024 1.0072.29C ANISOU 1095 CE2 PHE A2075 8520 9038 9907 671 -559 -1487C ATOM 1096 CZ PHE A2075 25.724 -14.835 -6.355 1.0072.05C ANISOU 1096 CZ PHE A2075 8444 9040 9888 653 -577 -1522C ATOM 1097 N ILE A2076 22.375 -11.641 -4.897 1.0064.86NANISOU 1097 N ILE A2076 7394 8117 9131 734 -490 -1726 NATOM 1098 CA ILE A2076 22.649 -11.630 -3.469 1.0066.04 CANISOU 1098 CA ILE A2076 7576 8246 9269 625 -412 -1733 CATOM 1099 C ILE A2076 23.671 -12.727 -3.182 1.0065.42 CANISOU 1099 C ILE A2076 7557 8166 9131 545 -411 -1670 CATOM 1100 O ILE A2076 23.393 -13.899 -3.427 1.0067.09 OANISOU 1100 O ILE A2076 7740 8407 9343 520 -427 -1690 OATOM 1101 CB ILE A2076 21.356 -11.840 -2.655 1.0067.41 CANISOU 1101 CB ILE A2076 7673 8438 9498 571 -355 -1846 CATOM 1102 CG1 ILE A2076 20.271 -10.833 -3.040 1.0069.20 CANISOU 1102 CG1 ILE A2076 7823 8663 9806 662 -367 -1920 CATOM 1103 CG2 ILE A2076 21.637 -11.807 -1.151 1.0068.04 CANISOU 1103 CG2 ILE A2076 7800 8498 9554 444 -269 -1854C ATOM 1104 CD1 ILE A2076 18.951 -11.038 -2.315 1.0070.24C ANISOU 1104 CD1 ILE A2076 7865 8816 10007 611 -307 -2048C ATOM 1105 N HIS A2077 24.836 -12.339 -2.644 1.0063.34N ANISOU 1105 N HIS A2077 7373 7869 8824 505 -395 -1598N ATOM 1106 CA HIS A2077 25.980 -13.234 -2.551 1.0062.10C ANISOU 1106 CA HIS A2077 7272 7702 8620 452 -413 -1528C ATOM 1107 C HIS A2077 25.791 -14.226 -1.407 1.0066.37C ANISOU 1107 C HIS A2077 7822 8244 9150 332 -375 -1551C ATOM 1108 O HIS A2077 26.072 -15.410 -1.571 1.0067.37ONAI-5000260062v1 -110-Attorney Docket No.14709-046-228 ANISOU 1108 O HIS A2077 7953 8376 9266 300 -403 -1532 O ATOM 1109 CB HIS A2077 27.285 -12.443 -2.399 1.0059.51 C C C C N N C C C C N N N N C C C C O O C C C C C C N N C C N N N N N N C C CNAI-5000260062v1 -111-Attorney Docket No.14709-046-228 ANISOU 1128 C ASP A2079 8211 8240 9122 59 -367 -1319 C ATOM 1129 O ASP A2079 30.881 -14.737 1.366 1.0065.47 O O C C C C O O O O N N C C C C O O C C C C C C C C N N C C C C O O C C N NCNAI-5000260062v1 -112-Attorney Docket No.14709-046-228 ANISOU 1148 CA ALA A2082 6178 5764 6729 -24 -506 -972 C ATOM 1149 C ALA A2082 38.016 -13.491 2.552 1.0051.71 C C O O C C N N C C C C O O C C C C C C N N C C N N N N N N C C C C O O C C CNAI-5000260062v1 -113-Attorney Docket No.14709-046-228 ANISOU 1168 CG ASN A2084 6846 6732 7723 92 -573 -1116 C ATOM 1169 OD1 ASN A2084 34.248 -17.876 0.158 1.0053.56 O O N N N N C C C C O O C C S S N N C C C C O O C C C C C C C C N N C C C CONAI-5000260062v1 -114-Attorney Docket No.14709-046-228 ANISOU 1188 O VAL A2087 6401 6098 7386 363 -551 -1019 O ATOM 1189 CB VAL A2087 45.020 -10.488 -3.403 1.0046.05 C ANISOU 1189 CB VAL A2087 5699 5290 6505 296 -528 -949C ATOM 1190 CG1 VAL A2087 45.934 -9.288 -3.628 1.0045.82 C ANISOU 1190 CG1 VAL A2087 5703 5247 6458 294 -478 -952 C ATOM 1191 CG2 VAL A2087 44.102 -10.242 -2.211 1.0044.85 C ANISOU 1191 CG2 VAL A2087 5576 5145 6319 262 -530 -928 C ATOM 1192 N SER A2088 45.437 -10.180 -6.672 1.0049.79 N ANISOU 1192 N SER A2088 6165 5788 6962 397 -458 -1011 N ATOM 1193 CA SER A2088 46.098 -10.383 -7.952 1.0051.72 C ANISOU 1193 CA SER A2088 6398 6036 7218 411 -435 -1046 C ATOM 1194 C SER A2088 47.581 -10.724 -7.802 1.0052.67 C ANISOU 1194 C SER A2088 6480 6125 7404 372 -437 -1071 C ATOM 1195 O SER A2088 48.124 -11.440 -8.640 1.0057.26O ANISOU 1195 O SER A2088 7020 6705 8028 373 -435 -1113O ATOM 1196 CB SER A2088 45.921 -9.180 -8.833 1.0052.55C ANISOU 1196 CB SER A2088 6567 6147 7250 438 -379 -1043C ATOM 1197 OG SER A2088 46.447 -8.020 -8.206 1.0056.50OANISOU 1197 OG SER A2088 7113 6624 7728 415 -343 -1024 OATOM 1198 N VAL A2089 48.237 -10.208 -6.754 1.0051.29 NANISOU 1198 N VAL A2089 6316 5927 7243 336 -440 -1052 NATOM 1199 CA VAL A2089 49.684 -10.308 -6.621 1.0051.12 C ANISOU 1199 CA VAL A2089 6260 5877 7286 300 -440 -1080 CATOM 1200 C VAL A2089 50.044 -10.877 -5.251 1.0051.67 C ANISOU 1200 C VAL A2089 6298 5922 7411 264 -511 -1056 C ATOM 1201 O VAL A2089 49.341 -10.627 -4.277 1.0050.93 O ANISOU 1201 O VAL A2089 6238 5833 7277 251 -531 -1013 O ATOM 1202 CB VAL A2089 50.375 -8.947 -6.848 1.0050.84 C ANISOU 1202 CB VAL A2089 6274 5832 7208 285 -369 -1088 C ATOM 1203 CG1 VAL A2089 50.424 -8.576 -8.323 1.0051.24 C ANISOU 1203 CG1 VAL A2089 6353 5896 7219 305 -304 -1121 C ATOM 1204 CG2 VAL A2089 49.735 -7.822 -6.037 1.0050.58 C ANISOU 1204 CG2 VAL A2089 6308 5803 7106 282 -349 -1042 C ATOM 1205 N LYS A2090 51.162 -11.617 -5.205 1.0051.96 N ANISOU 1205 N LYS A2090 6272 5930 7540 245 -548 -1087 N ATOM 1206 CA LYS A2090 51.687 -12.224 -3.990 1.0054.83 C ANISOU 1206 CA LYS A2090 6604 6261 7966 210 -631 -1065 C ATOM 1207 C LYS A2090 52.418 -11.197 -3.135 1.0054.50 C ANISOU 1207 C LYS A2090 6593 6208 7906 170 -619 -1050 C ATOM 1208 O LYS A2090 52.409 -11.305 -1.911 1.0053.48 O NAI-5000260062v1 -115-Attorney Docket No.14709-046-228 ANISOU 1208 O LYS A2090 6477 6065 7776 135 -678 -1009 O ATOM 1209 CB LYS A2090 52.758 -13.290 -4.251 1.0058.80 C C C C C C C C N N N N C C C C O O C C C C O O O O N N C C C C O O C C C CCNAI-5000260062v1 -116-Attorney Docket No.14709-046-228 ANISOU 1228 CD1 TYR A2092 6281 5744 7343 5 -664 -940 C ATOM 1229 CD2 TYR A2092 51.179 -7.538 1.260 1.0050.83 C ANISOU 1229 CD2 TYR A2092 6372 5769 7172 8 -565 -902C ATOM 1230 CE1 TYR A2092 52.482 -9.970 1.368 1.0049.93C ANISOU 1230 CE1 TYR A2092 6141 5606 7223 1 -740 -908C ATOM 1231 CE2 TYR A2092 50.506 -8.661 1.712 1.0050.33C ANISOU 1231 CE2 TYR A2092 6297 5706 7119 0 -634 -876C ATOM 1232 CZ TYR A2092 51.162 -9.878 1.769 1.0049.57C ANISOU 1232 CZ TYR A2092 6147 5584 7102 -4 -722 -876C ATOM 1233 OH TYR A2092 50.514 -10.984 2.226 1.0049.52O ANISOU 1233 OH TYR A2092 6138 5571 7104 -17 -791 -847O ATOM 1234 N THR A2093 54.245 -4.757 -2.730 1.0055.07N ANISOU 1234 N THR A2093 6900 6283 7739 73 -282 -1069N ATOM 1235 CA THR A2093 54.679 -3.504 -3.336 1.0056.89C ANISOU 1235 CA THR A2093 7181 6507 7927 64 -186 -1093C ATOM 1236 C THR A2093 53.984 -3.286 -4.682 1.0056.89C ANISOU 1236 C THR A2093 7223 6516 7874 111 -131 -1096C ATOM 1237 O THR A2093 53.633 -2.157 -5.012 1.0056.77OANISOU 1237 O THR A2093 7283 6496 7791 119 -64 -1082 OATOM 1238 CB THR A2093 56.198 -3.501 -3.492 1.0058.34 CANISOU 1238 CB THR A2093 7314 6673 8179 25 -170 -1152 CATOM 1239 OG1 THR A2093 56.516 -4.804 -3.970 1.0058.03 OANISOU 1239 OG1 THR A2093 7195 6632 8221 42 -225 -1184 OATOM 1240 CG2 THR A2093 56.915 -3.218 -2.184 1.0059.73 CANISOU 1240 CG2 THR A2093 7473 6838 8382 -25 -207 -1147 CATOM 1241 N SER A2094 53.810 -4.359 -5.464 1.0056.14 NANISOU 1241 N SER A2094 7083 6432 7815 140 -162 -1115 N ATOM 1242 CA SER A2094 53.232 -4.255 -6.794 1.0058.35 CANISOU 1242 CA SER A2094 7401 6724 8045 177 -118 -1122 CATOM 1243 C SER A2094 51.771 -3.823 -6.711 1.0058.65 CANISOU 1243 C SER A2094 7499 6775 8010 221 -124 -1068C ATOM 1244 O SER A2094 51.054 -4.247 -5.808 1.0058.67O ANISOU 1244 O SER A2094 7482 6786 8021 229 -179 -1036O ATOM 1245 CB SER A2094 53.342 -5.554 -7.546 1.0058.18C ANISOU 1245 CB SER A2094 7313 6713 8080 193 -152 -1158C ATOM 1246 OG SER A2094 54.701 -5.901 -7.753 1.0061.75O ANISOU 1246 OG SER A2094 7704 7149 8610 156 -138 -1221O ATOM 1247 N PRO A2095 51.276 -3.019 -7.681 1.0059.94N ANISOU 1247 N PRO A2095 7735 6938 8102 248 -71 -1059N ATOM 1248 CA PRO A2095 49.860 -2.653 -7.729 1.0060.10CNAI-5000260062v1 -117-Attorney Docket No.14709-046-228 ANISOU 1248 CA PRO A2095 7801 6967 8067 298 -85 -1015 C ATOM 1249 C PRO A2095 48.996 -3.909 -7.709 1.0057.95 C C O O C C C C C C N N C C C C O O C C C C C C N N C C N N N N N N C C C C ONAI-5000260062v1 -118-Attorney Docket No.14709-046-228 ANISOU 1268 O ILE A2097 6137 5681 6708 462 -399 -975 O ATOM 1269 CB ILE A2097 42.846 -5.527 -8.767 1.0053.98 C C C C C C C C N N C C C C O O C C C C C C N N C C C C O O C C C C C C C C NNAI-5000260062v1 -119-Attorney Docket No.14709-046-228 ANISOU 1288 NZ LYS A2099 6889 6572 7339 673 -473 -1050 N ATOM 1289 N ILE A2100 35.842 -10.519 -6.101 1.0052.45 N ANISOU 1289 N ILE A2100 6428 6297 7203 581 -514 -1076 N ATOM 1290 CA ILE A2100 34.937 -11.412 -5.394 1.0054.28 C ANISOU 1290 CA ILE A2100 6616 6548 7459 547 -524 -1105 C ATOM 1291 C ILE A2100 34.906 -12.746 -6.134 1.0056.31 C ANISOU 1291 C ILE A2100 6832 6826 7735 554 -561 -1121 C ATOM 1292 O ILE A2100 34.848 -12.766 -7.363 1.0054.63 O ANISOU 1292 O ILE A2100 6612 6632 7513 609 -577 -1129 O ATOM 1293 CB ILE A2100 33.529 -10.798 -5.268 1.0055.26 C ANISOU 1293 CB ILE A2100 6719 6689 7587 581 -509 -1143 C ATOM 1294 CG1 ILE A2100 33.572 -9.426 -4.578 1.0055.43 C ANISOU 1294 CG1 ILE A2100 6779 6683 7597 577 -468 -1133 C ATOM 1295 CG2 ILE A2100 32.573 -11.760 -4.557 1.0053.75 C ANISOU 1295 CG2 ILE A2100 6481 6519 7419 537 -510 -1183 C ATOM 1296 CD1 ILE A2100 32.237 -8.702 -4.548 1.0057.16 C ANISOU 1296 CD1 ILE A2100 6971 6911 7836 621 -454 -1176 C ATOM 1297 N GLY A2101 34.969 -13.841 -5.360 1.0059.66 N ANISOU 1297 N GLY A2101 7237 7246 8184 493 -575 -1124 N ATOM 1298 CA GLY A2101 34.811 -15.196 -5.869 1.0062.78 C ANISOU 1298 CA GLY A2101 7590 7657 8607 490 -606 -1145 C ATOM 1299 C GLY A2101 33.763 -15.969 -5.065 1.0066.78 C ANISOU 1299 C GLY A2101 8068 8176 9127 445 -607 -1174 C ATOM 1300 O GLY A2101 32.868 -15.371 -4.464 1.0069.27 O ANISOU 1300 O GLY A2101 8384 8503 9431 437 -579 -1196 O N - N N C C C C O O C C C C O O ONAI-5000260062v1 -120-Attorney Docket No.14709-046-228 ANISOU 1308 OD2 ASP A2102 10499 10627 11661 202 -642 -1228 O ATOM 1309 N PHE A2103 31.130 -18.214 -6.021 1.0077.29 N N C C C C O O C C C C C C C C C C C C C C N N C C C C O O C C C C C C C C NNAI-5000260062v1 -121-Attorney Docket No.14709-046-228 ANISOU 1328 N LEU A2123 11093 10496 11254 -967 -382 -1258 N ATOM 1329 CA LEU A2123 27.416 -21.732 9.714 1.0083.64 C C C C O O C C C C C C C C N N C C C C O O C C C C C C N N C C C C O O C C CNAI-5000260062v1 -122-Attorney Docket No.14709-046-228 ANISOU 1348 CG1 VAL A2125 8865 8184 8560 -1438 94 -1515 C ATOM 1349 CG2 VAL A2125 27.023 -19.171 13.412 1.0068.60 C C N N C C C C O O C C C C C C N N C C N N N N N N C C C C O O C C C C C C CNAI-5000260062v1 -123-Attorney Docket No.14709-046-228 ANISOU 1368 CD2 TRP A2127 7018 6517 7241 -573 -311 -1152 C ATOM 1369 NE1 TRP A2127 33.605 -12.484 7.681 1.0052.97 N N C C C C C C C C C C N N C C C C O O C C C C S S C C N N C C C C O O C C NNAI-5000260062v1 -124-Attorney Docket No.14709-046-228 ANISOU 1388 N PRO A2130 8358 8481 9254 -911 547 -2170 N ATOM 1389 CA PRO A2130 20.516 -10.853 12.868 1.0069.85 C C C C O O C C C C C C N N C C C C O O C C C C C C O O O O N N C C C C O OCNAI-5000260062v1 -125-Attorney Docket No.14709-046-228 ANISOU 1408 CB SER A2132 7869 8228 9053 -587 257 -2076 C ATOM 1409 OG SER A2132 20.788 -12.857 7.159 1.0064.80 O ANISOU 1409 OG SER A2132 7626 8049 8945 -438 232 -2082 O ATOM 1410 N LEU A2133 20.086 -15.091 10.869 1.0070.59 N ANISOU 1410 N LEU A2133 8575 8781 9463 -1003 437 -2172 N ATOM 1411 CA LEU A2133 20.251 -16.106 11.899 1.0074.06 C ANISOU 1411 CA LEU A2133 9127 9207 9802 -1182 458 -2144 C ATOM 1412 C LEU A2133 18.900 -16.517 12.486 1.0076.47 C ANISOU 1412 C LEU A2133 9396 9538 10120 -1306 572 -2289 C ATOM 1413 O LEU A2133 18.652 -17.703 12.703 1.0076.79 O ANISOU 1413 O LEU A2133 9479 9578 10119 -1398 571 -2287 O ATOM 1414 CB LEU A2133 21.185 -15.584 12.992 1.0075.97 C ANISOU 1414 CB LEU A2133 9492 9421 9951 -1290 469 -2074 C ATOM 1415 CG LEU A2133 22.684 -15.605 12.677 1.0077.69 C ANISOU 1415 CG LEU A2133 9781 9607 10129 -1221 350 -1915 C ATOM 1416 CD1 LEU A2133 23.466 -14.840 13.735 1.0077.69 C ANISOU 1416 CD1 LEU A2133 9880 9587 10052 -1317 373 -1871 C ATOM 1417 CD2 LEU A2133 23.208 -17.031 12.563 1.0077.56 C ANISOU 1417 CD2 LEU A2133 9831 9569 10067 -1254 262 -1822 C ATOM 1418 N MET A2134 18.034 -15.534 12.755 1.0077.46 N ANISOU 1418 N MET A2134 9442 9682 10306 -1313 673 -2420 N ATOM 1419 CA MET A2134 16.807 -15.792 13.490 1.0081.19 C ANISOU 1419 CA MET A2134 9883 10176 10787 -1454 800 -2572 C ATOM 1420 C MET A2134 15.685 -16.233 12.546 1.0079.27 C ANISOU 1420 C MET A2134 9498 9966 10653 -1362 803 -2677 C ATOM 1421 O MET A2134 14.866 -17.063 12.933 1.0077.38 O ANISOU 1421 O MET A2134 9253 9743 10402 -1479 871 -2764 O ATOM 1422 CB MET A2134 16.388 -14.560 14.301 1.0088.05 C ANISOU 1422 CB MET A2134 10730 11047 11678 -1519 917 -2679 C ATOM 1423 CG MET A2134 15.838 -13.419 13.470 1.0093.62 C ANISOU 1423 CG MET A2134 11283 11761 12525 -1347 921 -2761 C ATOM 1424 SD MET A2134 15.266 -12.015 14.448 1.00105.48 S ANISOU 1424 SD MET A2134 12747 13258 14071 -1428 1068 -2905 S ATOM 1425 CE MET A2134 16.800 -11.321 15.081 1.00102.68 C ANISOU 1425 CE MET A2134 12540 12868 13603 -1464 1029 -2754 C ATOM 1426 N ASP A2135 15.640 -15.680 11.323 1.0076.41 N ANISOU 1426 N ASP A2135 9025 9613 10392 -1161 730 -2670 N ATOM 1427 CA ASP A2135 14.481 -15.841 10.454 1.0074.61 C ANISOU 1427 CA ASP A2135 8648 9419 10280 -1066 735 -2787 C ATOM 1428 C ASP A2135 14.843 -16.401 9.079 1.0072.41 C NAI-5000260062v1 -126-Attorney Docket No.14709-046-228 ANISOU 1428 C ASP A2135 8332 9149 10031 -905 604 -2698 C ATOM 1429 O ASP A2135 13.945 -16.655 8.280 1.0072.32 O O C C C C O O O O N N C C C C O O N N C C C C O O C C C C C C C C N N C C CNAI-5000260062v1 -127-Attorney Docket No.14709-046-228 ANISOU 1448 C PHE A2138 8671 9554 10705 177 -6 -2203 C ATOM 1449 O PHE A2138 17.866 -12.206 0.915 1.0080.35 O ANISOU 1449 O PHE A2138 9133 10114 11283 267 -66 -2229O ATOM 1450 CB PHE A2138 19.397 -14.117 2.432 1.0076.38C ANISOU 1450 CB PHE A2138 8813 9600 10607 18 -20 -2107C ATOM 1451 CG PHE A2138 20.018 -15.063 3.450 1.0078.02C ANISOU 1451 CG PHE A2138 9116 9794 10733 -129 10 -2060C ATOM 1452 CD1 PHE A2138 19.239 -16.001 4.120 1.0078.78C ANISOU 1452 CD1 PHE A2138 9202 9908 10823 -246 68 -2134C ATOM 1453 CD2 PHE A2138 21.380 -15.013 3.732 1.0076.72C ANISOU 1453 CD2 PHE A2138 9053 9596 10499 -153 -23 -1941C ATOM 1454 CE1 PHE A2138 19.806 -16.860 5.051 1.0079.40C ANISOU 1454 CE1 PHE A2138 9379 9967 10822 -384 86 -2083C ATOM 1455 CE2 PHE A2138 21.942 -15.877 4.660 1.0076.90C ANISOU 1455 CE2 PHE A2138 9164 9601 10451 -285 -10 -1893C ATOM 1456 CZ PHE A2138 21.156 -16.798 5.317 1.0078.13C ANISOU 1456 CZ PHE A2138 9318 9770 10595 -400 40 -1960C ATOM 1457 N THR A2139 18.832 -10.589 2.175 1.0074.40 NANISOU 1457 N THR A2139 8477 9298 10495 211 8 -2180 N ATOM 1458 CA THR A2139 18.639 -9.513 1.213 1.0072.65 C ANISOU 1458 CA THR A2139 8207 9057 10337 361 -48 -2178 CATOM 1459 C THR A2139 19.977 -8.832 0.923 1.0071.54 CANISOU 1459 C THR A2139 8162 8881 10138 406 -89 -2051 CATOM 1460 O THR A2139 21.002 -9.172 1.510 1.0067.33 O ANISOU 1460 O THR A2139 7720 8339 9524 323 -72 -1976 O ATOM 1461 CB THR A2139 17.612 -8.518 1.754 1.0071.15 CANISOU 1461 CB THR A2139 7938 8852 10243 366 17 -2298 CATOM 1462 OG1 THR A2139 18.144 -8.053 2.990 1.0070.25 O ANISOU 1462 OG1 THR A2139 7894 8711 10085 254 104 -2292 O ATOM 1463 CG2 THR A2139 16.247 -9.143 1.984 1.0071.42 CANISOU 1463 CG2 THR A2139 7865 8922 10347 325 60 -2439C ATOM 1464 N THR A2140 19.942 -7.859 0.004 1.0071.51N ANISOU 1464 N THR A2140 8138 8854 10177 537 -147 -2030 N ATOM 1465 CA THR A2140 21.068 -6.974 -0.251 1.0071.15 C ANISOU 1465 CA THR A2140 8176 8768 10089 581 -172 -1929C ATOM 1466 C THR A2140 21.457 -6.242 1.036 1.0069.71C ANISOU 1466 C THR A2140 8041 8553 9891 489 -82 -1939C ATOM 1467 O THR A2140 22.633 -5.983 1.264 1.0071.36O ANISOU 1467 O THR A2140 8339 8741 10033 459 -80 -1851 O ATOM 1468 CB THR A2140 20.706 -5.996 -1.369 1.0070.75CNAI-5000260062v1 -128-Attorney Docket No.14709-046-228 ANISOU 1468 CB THR A2140 8090 8692 10098 730 -242 -1924 C ATOM 1469 OG1 THR A2140 19.464 -5.432 -0.967 1.0077.34 O ANISOU 1469 OG1 THR A2140 8830 9518 11035 745 -204 -2043O ATOM 1470 CG2 THR A2140 20.537 -6.667 -2.720 1.0070.54C ANISOU 1470 CG2 THR A2140 8040 8697 10064 817 -341 -1895C ATOM 1471 N GLN A2141 20.470 -5.930 1.885 1.0068.15N ANISOU 1471 N GLN A2141 7781 8355 9757 436 -4 -2053N ATOM 1472 CA GLN A2141 20.716 -5.228 3.135 1.0069.72 C ANISOU 1472 CA GLN A2141 8019 8527 9944 339 90 -2080 C ATOM 1473 C GLN A2141 21.418 -6.140 4.140 1.0068.87C ANISOU 1473 C GLN A2141 7991 8438 9736 186 134 -2041C ATOM 1474 O GLN A2141 22.208 -5.662 4.951 1.0068.99O ANISOU 1474 O GLN A2141 8081 8430 9698 112 178 -2002O ATOM 1475 CB GLN A2141 19.403 -4.690 3.701 1.0073.28 C ANISOU 1475 CB GLN A2141 8372 8972 10498 322 164 -2227C ATOM 1476 CG GLN A2141 18.676 -3.740 2.757 1.0076.73C ANISOU 1476 CG GLN A2141 8725 9379 11047 478 110 -2268C ATOM 1477 CD GLN A2141 17.176 -3.922 2.786 1.0081.39 CANISOU 1477 CD GLN A2141 9183 9990 11750 491 134 -2415 CATOM 1478 OE1 GLN A2141 16.575 -4.428 1.832 1.0086.01 OANISOU 1478 OE1 GLN A2141 9702 10600 12375 577 57 -2431 O ATOM 1479 NE2 GLN A2141 16.559 -3.537 3.893 1.0085.53 N ANISOU 1479 NE2 GLN A2141 9665 10505 12326 400 245 -2532 N ATOM 1480 N SER A2142 21.127 -7.448 4.101 1.0068.09 N ANISOU 1480 N SER A2142 7879 8378 9611 136 118 -2052 NATOM 1481 CA SER A2142 21.844 -8.399 4.938 1.0066.94 CANISOU 1481 CA SER A2142 7818 8244 9371 1 138 -2000 CATOM 1482 C SER A2142 23.254 -8.621 4.386 1.0063.33 CANISOU 1482 C SER A2142 7443 7774 8846 41 59 -1861 CATOM 1483 O SER A2142 24.173 -8.930 5.142 1.0061.84 OANISOU 1483 O SER A2142 7338 7573 8582 -54 68 -1798O ATOM 1484 CB SER A2142 21.085 -9.695 5.102 1.0068.04C ANISOU 1484 CB SER A2142 7923 8420 9508 -68 150 -2056C ATOM 1485 OG SER A2142 21.095 -10.457 3.904 1.0071.57O ANISOU 1485 OG SER A2142 8338 8888 9967 26 62 -2017O ATOM 1486 N ASP A2143 23.424 -8.446 3.070 1.0062.98 N ANISOU 1486 N ASP A2143 7371 7728 8830 178 -18 -1818 N ATOM 1487 CA ASP A2143 24.744 -8.449 2.454 1.0064.48 C ANISOU 1487 CA ASP A2143 7629 7901 8967 224 -83 -1701 C ATOM 1488 C ASP A2143 25.570 -7.278 2.992 1.0063.11 C NAI-5000260062v1 -129-Attorney Docket No.14709-046-228 ANISOU 1488 C ASP A2143 7518 7689 8769 208 -50 -1661 C ATOM 1489 O ASP A2143 26.769 -7.424 3.224 1.0059.80 O O C C C C O O O O N N C C C C O O C C C C C C N N C C C C O O C C C C C C CNAI-5000260062v1 -130-Attorney Docket No.14709-046-228 ANISOU 1508 CD2 TRP A2145 6674 6622 7478 -606 387 -1890 C ATOM 1509 NE1 TRP A2145 26.436 -8.866 10.896 1.0053.19 N N C C C C C C C C C C N N C C C C O O C C O O N N C C C C O O C C C C C C CNAI-5000260062v1 -131-Attorney Docket No.14709-046-228 ANISOU 1528 CD2 PHE A2147 7990 7699 8788 287 -61 -1340 C ATOM 1529 CE1 PHE A2147 32.514 -4.088 0.569 1.0063.41 C C C C C C N N C C C C O O N N C C C C O O C C C C C C C C N N C C C C O O CNAI-5000260062v1 -132-Attorney Docket No.14709-046-228 ANISOU 1548 CB LEU A2150 6869 6515 7402 -7 -221 -1164 C ATOM 1549 CG LEU A2150 34.999 -7.870 3.206 1.0056.57 C C C C C C N N C C C C O O C C C C C C C C N N C C C C O O C C C C C C C C NNAI-5000260062v1 -133-Attorney Docket No.14709-046-228 ANISOU 1568 NE1 TRP A2152 6859 5994 6493 -938 44 -1167 N ATOM 1569 CE2 TRP A2152 36.876 -6.171 14.079 1.0051.15 C C C C C C C C C C N N C C C C O O C C C C C C O O O O N N C C C C O O C CCNAI-5000260062v1 -134-Attorney Docket No.14709-046-228 ANISOU 1588 CG1 ILE A2154 5665 5087 6017 13 -289 -973 C ATOM 1589 CG2 ILE A2154 40.875 -4.135 4.294 1.0046.28 C ANISOU 1589 CG2 ILE A2154 6002 5322 6260 -15 -229 -952C ATOM 1590 CD1 ILE A2154 38.519 -5.412 2.727 1.0043.98C ANISOU 1590 CD1 ILE A2154 5620 5072 6018 113 -257 -1002C ATOM 1591 N LEU A2155 40.509 -4.205 7.813 1.0051.59N ANISOU 1591 N LEU A2155 6760 6006 6836 -292 -194 -968N ATOM 1592 CA LEU A2155 41.089 -3.176 8.668 1.0052.87 C ANISOU 1592 CA LEU A2155 6966 6156 6963 -359 -149 -971 C ATOM 1593 C LEU A2155 41.828 -3.772 9.868 1.0052.70 C ANISOU 1593 C LEU A2155 6990 6136 6896 -478 -202 -936 C ATOM 1594 O LEU A2155 42.659 -3.085 10.450 1.0054.45 O ANISOU 1594 O LEU A2155 7246 6349 7092 -529 -191 -926O ATOM 1595 CB LEU A2155 40.013 -2.191 9.132 1.0056.67C ANISOU 1595 CB LEU A2155 7453 6642 7436 -379 -53 -1030 C ATOM 1596 CG LEU A2155 39.788 -0.950 8.259 1.0059.65 C ANISOU 1596 CG LEU A2155 7813 7000 7850 -280 6 -1056C ATOM 1597 CD1 LEU A2155 39.620 -1.241 6.779 1.0061.83 CANISOU 1597 CD1 LEU A2155 8046 7272 8171 -154 -28 -1043 CATOM 1598 CD2 LEU A2155 38.567 -0.217 8.774 1.0061.63 CANISOU 1598 CD2 LEU A2155 8056 7251 8110 -301 90 -1123 CATOM 1599 N THR A2156 41.531 -5.025 10.248 1.0051.51 NANISOU 1599 N THR A2156 6844 5993 6734 -525 -263 -917 N ATOM 1600 CA THR A2156 42.265 -5.689 11.319 1.0050.40 C ANISOU 1600 CA THR A2156 6754 5845 6550 -634 -334 -873 CATOM 1601 C THR A2156 43.289 -6.663 10.741 1.0050.87 CANISOU 1601 C THR A2156 6788 5886 6654 -588 -442 -821 CATOM 1602 O THR A2156 43.862 -7.454 11.486 1.0051.31 O ANISOU 1602 O THR A2156 6876 5927 6689 -662 -525 -778 O ATOM 1603 CB THR A2156 41.319 -6.435 12.258 1.0051.43 C ANISOU 1603 CB THR A2156 6921 5988 6632 -735 -333 -883C ATOM 1604 OG1 THR A2156 40.790 -7.521 11.502 1.0049.74O ANISOU 1604 OG1 THR A2156 6665 5775 6458 -675 -375 -878O ATOM 1605 CG2 THR A2156 40.227 -5.544 12.825 1.0052.08 C ANISOU 1605 CG2 THR A2156 7017 6088 6680 -785 -219 -951 C ATOM 1606 N LEU A2157 43.503 -6.622 9.420 1.0050.70 N ANISOU 1606 N LEU A2157 6708 5860 6694 -470 -442 -827 N ATOM 1607 CA LEU A2157 44.452 -7.511 8.768 1.0051.88 C ANISOU 1607 CA LEU A2157 6823 5990 6898 -422 -531 -793 C ATOM 1608 C LEU A2157 44.121 -8.973 9.082 1.0052.18CNAI-5000260062v1 -135-Attorney Docket No.14709-046-228 ANISOU 1608 C LEU A2157 6863 6020 6941 -458 -610 -766 C ATOM 1609 O LEU A2157 45.009 -9.770 9.375 1.0052.38 O ANISOU 1609 O LEU A2157 6892 6020 6989 -486 -705 -725 O C C C C C C C C N N C C C C O O N N C C C C O O C C C C N N C C C CN ANISOU 1627 NE2 HIS A2159 9214 7989 8584 -1077 -742 -648 N ATOM 1628 N GLN A2160 39.872 -12.654 13.523 1.0057.69 N NAI-5000260062v1 -136-Attorney Docket No.14709-046-228 ANISOU 1628 N GLN A2160 7813 6730 7375 -958 -639 -754 N ATOM 1629 CA GLN A2160 38.584 -13.311 13.667 1.0057.35 C C C C O O C C C C C C O O N N N N C C C C O O C C C C C C N N C C C C O O CNAI-5000260062v1 -137-Attorney Docket No.14709-046-228 ANISOU 1648 CB TYR A2162 8410 7280 7454 -1616 -51 -1172 C ATOM 1649 CG TYR A2162 31.729 -11.321 17.183 1.0059.34 C C C C C C C C C C C C O O N N C C C C O O C C C C C C N N C C C C O O C CNNAI-5000260062v1 -138-Attorney Docket No.14709-046-228 ANISOU 1668 N HIS A2165 9554 7864 7746 -2188 -272 -938 N ATOM 1669 CA HIS A2165 32.899 -15.311 21.877 1.0065.71 C C C C O O C C C C N N C C C C N N N N C C C C O O C C O O N N C C C C O O CNAI-5000260062v1 -139-Attorney Docket No.14709-046-228 ANISOU 1688 CB ASN A2167 9016 7654 7968 -1784 -323 -1062 C ATOM 1689 CG ASN A2167 31.464 -20.741 16.263 1.0064.35 C C O O N N N N C C C C O O C C C C C C C C N N C C C C O O C C C C O O O O NNAI-5000260062v1 -140-Attorney Docket No.14709-046-228 ANISOU 1708 N VAL A2170 9748 8556 8546 -2114 222 -1457 N ATOM 1709 CA VAL A2170 27.697 -14.710 18.875 1.0072.18 C C C C O O C C C C C C N N C C C C O O C C C C C C C C N N C C C C O O C C CNAI-5000260062v1 -141-Attorney Docket No.14709-046-228 ANISOU 1728 CG ASN A2172 11215 9954 9614 -2859 797 -1943 C ATOM 1729 OD1 ASN A2172 22.057 -15.889 23.621 1.0081.65 O O N N N N C C C C O O C C C C C C C C C C C C C C O O N N C C C C O O C C CNAI-5000260062v1 -142-Attorney Docket No.14709-046-228 ANISOU 1748 CG1 VAL A2174 9511 9180 9640 -1460 701 -2065 C ATOM 1749 CG2 VAL A2174 26.030 -10.214 16.932 1.0072.58 C C N N C C C C O O C C C C C C O O N N N N C C C C O O C C O O C C N N C C CNAI-5000260062v1 -143-Attorney Docket No.14709-046-228 ANISOU 1768 C GLY A2177 10908 10355 10666 -1919 1094 -2263 C ATOM 1769 O GLY A2177 25.257 -3.722 20.468 1.0083.14 O O N N C C C C O O N N C C C C O O C C C C C C N N C C N N N N N N C C C C ONAI-5000260062v1 -144-Attorney Docket No.14709-046-228 ANISOU 1788 O LEU A2180 8308 7447 7788 -1368 462 -1517 O ATOM 1789 CB LEU A2180 33.072 -5.812 15.693 1.0059.99 C C C C C C C C N N C C C C O O C C C C C C O O O O N N C C C C O O C C C CCNAI-5000260062v1 -145-Attorney Docket No.14709-046-228 ANISOU 1808 CD PRO A2182 8488 7467 7752 -1430 471 -1424 C ATOM 1809 N PRO A2183 38.735 -1.584 15.265 1.0059.77 N N C C C C O O C C C C C C N N C C C C O O C C C C C C N N C C N N N N N N CNAI-5000260062v1 -146-Attorney Docket No.14709-046-228 ANISOU 1828 CA ASN A2185 10645 9515 10065 -956 245 -1116 C ATOM 1829 C ASN A2185 42.516 3.505 14.007 1.0079.37 C C O O C C C C O O N N N N C C C C O O C C S S N N C C C C O O C C C C C C NNAI-5000260062v1 -147-Attorney Docket No.14709-046-228 ANISOU 1848 N ASP A2188 7431 6374 7417 -492 612 -1399 N ATOM 1849 CA ASP A2188 36.573 7.492 12.552 1.0057.75 C ANISOU 1849 CA ASP A2188 7630 6611 7700 -517 684 -1490C ATOM 1850 C ASP A2188 35.550 7.327 11.429 1.0056.39C ANISOU 1850 C ASP A2188 7393 6422 7610 -378 654 -1504C ATOM 1851 O ASP A2188 34.542 6.650 11.600 1.0053.87O ANISOU 1851 O ASP A2188 7029 6127 7312 -391 654 -1550O ATOM 1852 CB ASP A2188 36.482 8.860 13.206 1.0058.47C ANISOU 1852 CB ASP A2188 7736 6666 7814 -561 792 -1556C ATOM 1853 CG ASP A2188 35.179 9.130 13.938 1.0060.78 C ANISOU 1853 CG ASP A2188 7985 6956 8152 -614 881 -1667 C ATOM 1854 OD1 ASP A2188 35.002 8.565 15.034 1.0064.54 O ANISOU 1854 OD1 ASP A2188 8479 7474 8568 -752 910 -1701 O ATOM 1855 OD2 ASP A2188 34.343 9.878 13.391 1.0061.82 O ANISOU 1855 OD2 ASP A2188 8065 7042 8381 -517 918 -1719 O ATOM 1856 N ASP A2189 35.832 7.941 10.278 1.0057.89 N N C C C C O O C C C C O O O O N N C C C C O O CNAI-5000260062v1 -148-Attorney Docket No.14709-046-228 ANISOU 1868 CB LEU A2190 7362 6507 7574 -147 305 -1266 C ATOM 1869 CG LEU A2190 37.520 4.141 7.021 1.0055.44 C C C C C C N N C C C C O O C C C C C C C C N N C C C C C C C C C C N N C C CNAI-5000260062v1 -149-Attorney Docket No.14709-046-228 ANISOU 1888 C ASN A2192 7582 6989 8330 -209 600 -1730 C ATOM 1889 O ASN A2192 29.008 4.270 10.290 1.0060.53 O O C C C C O O N N N N C C C C O O C C C C C C C C N N C C C C O O C C C C SNAI-5000260062v1 -150-Attorney Docket No.14709-046-228 ANISOU 1908 SD MET A2194 8618 7954 8767 -444 193 -1307 S ATOM 1909 CE MET A2194 35.504 -0.049 10.348 1.0065.82 C C N N C C C C O O C C O O C C N N C C C C O O C C C C C C O O N N N N C C CNAI-5000260062v1 -151-Attorney Docket No.14709-046-228 ANISOU 1928 C CYS A2197 7254 7165 8325 -247 421 -1891 C ATOM 1929 O CYS A2197 24.988 -3.322 8.600 1.0056.38 O O C C S S N N C C C C O O C C C C C C C C N N C C C C C C C C C C N N C C CNAI-5000260062v1 -152-Attorney Docket No.14709-046-228 ANISOU 1948 C ALA A2199 7925 8095 9357 -623 820 -2427 C ATOM 1949 O ALA A2199 21.081 -3.292 11.423 1.0066.87 O O C C N N C C C C O O C C C C C C O O N N N N C C C C O O C C C C C C O O ONAI-5000260062v1 -153-Attorney Docket No.14709-046-228 ANISOU 1968 OE2 GLU A2201 10730 11670 13618 -636 1246 -3414 O ATOM 1969 N PRO A2202 17.162 -3.433 9.267 1.0078.79 N N C C C C O O C C C C C C N N C C C C O O C C C C O O O O N N C C C C O OCNAI-5000260062v1 -154-Attorney Docket No.14709-046-228 ANISOU 1988 CB GLN A2204 9096 9484 11442 -115 830 -2702 C ATOM 1989 CG GLN A2204 17.364 2.376 10.619 1.0081.36 C C C C O O N N N N C C C C O O C C C C C C N N C C N N N N N N C C C C O O CNAI-5000260062v1 -155-Attorney Docket No.14709-046-228 ANISOU 2008 CB PRO A2206 7383 7233 9008 502 233 -1858 C ATOM 2009 CG PRO A2206 25.425 1.897 4.950 1.0062.02 C C C C N N C C C C O O C C O O C C N N C C C C O O C C C C C C C C C C C C CNAI-5000260062v1 -156-Attorney Docket No.14709-046-228 ANISOU 2028 CZ PHE A2208 6683 6775 7959 556 -199 -1530 C ATOM 2029 N HIS A2209 25.915 1.777 -3.221 1.0060.73 N N C C C C O O C C C C N N C C C C N N N N C C C C O O C C C C C C N N C C NNAI-5000260062v1 -157-Attorney Docket No.14709-046-228 ANISOU 2048 NH1 ARG A2210 9426 9023 11449 725 371 -2016 N ATOM 2049 NH2 ARG A2210 25.665 9.553 4.763 1.0079.25 N ANISOU 2049 NH2 ARG A2210 9664 9050 11397 648 435 -1899 N ATOM 2050 N ILE A2211 28.010 3.212 0.133 1.0065.21 N N C C C C O O C C C C C C C C N N C C C C O O C C C C C C O O N N N N CNAI-5000260062v1 -158-Attorney Docket No.14709-046-228 ANISOU 2068 CA ASP A2213 8024 7074 8844 937 -59 -1239 C ATOM 2069 C ASP A2213 31.642 7.329 -0.825 1.0061.34 C C O O C C C C O OO ANISOU 2074 OD2 ASP A2213 8925 8042 10167 1189 -178 -1369 O ATOM 2075 N GLN A2214 31.217 6.867 0.360 1.0059.62 N ANISOU 2075 N GLN A2214 7569 6681 8403 744 88 -1315 N ATOM 2076 CA GLN A2214 31.932 7.095 1.608 1.0058.54 C ANISOU 2076 CA GLN A2214 7459 6549 8232 628 173 -1330 C ATOM 2077 C GLN A2214 33.410 6.747 1.453 1.0055.87 C ANISOU 2077 C GLN A2214 7194 6230 7802 577 164 -1252 C ATOM 2078 O GLN A2214 34.274 7.513 1.875 1.0055.84 O ANISOU 2078 O GLN A2214 7246 6197 7772 532 215 -1234 O ATOM 2079 CB GLN A2214 31.351 6.246 2.741 1.0059.92 C ANISOU 2079 CB GLN A2214 7573 6778 8415 534 211 -1399 C ATOM 2080 CG GLN A2214 30.071 6.799 3.357 1.0064.01 C ANISOU 2080 CG GLN A2214 8020 7273 9027 539 263 -1502 C ATOM 2081 CD GLN A2214 30.323 7.767 4.494 1.0067.10 C ANISOU 2081 CD GLN A2214 8435 7632 9428 457 364 -1546 C ATOM 2082 OE1 GLN A2214 29.989 8.955 4.416 1.0068.26 O ANISOU 2082 OE1 GLN A2214 8579 7713 9643 510 395 -1576 O ATOM 2083 NE2 GLN A2214 30.918 7.265 5.568 1.0067.34 N ANISOU 2083 NE2 GLN A2214 8491 7704 9389 325 412 -1549 N ATOM 2084 N LEU A2215 33.682 5.581 0.860 1.0054.49 N ANISOU 2084 N LEU A2215 7012 6104 7586 584 101 -1213 N ATOM 2085 CA LEU A2215 35.029 5.035 0.801 1.0055.24 C ANISOU 2085 CA LEU A2215 7156 6224 7608 529 90 -1154 C ATOM 2086 C LEU A2215 35.926 5.910 -0.072 1.0054.04 C ANISOU 2086 C LEU A2215 7077 6026 7429 574 88 -1099 C ATOM 2087 O LEU A2215 37.050 6.219 0.320 1.0052.15 O ANISOU 2087 O LEU A2215 6886 5779 7150 513 125 -1075 O ATOM 2088 CB LEU A2215 34.979 3.593 0.296 1.0055.49 C NAI-5000260062v1 -159-Attorney Docket No.14709-046-228 ANISOU 2088 CB LEU A2215 7153 6312 7618 535 23 -1136 C ATOM 2089 CG LEU A2215 34.503 2.547 1.309 1.0057.21 C C C C C C N N C C C C O O C C C C C C O OATOM 2100 NE2 GLN A2216 34.929 4.630 -6.267 1.0072.15 N ANISOU 2100 NE2 GLN A2216 9430 8328 9652 933 -227 -948 N ATOM 2101 N LEU A2217 35.334 9.075 -0.991 1.0056.34 N ANISOU 2101 N LEU A2217 7461 6147 7798 722 134 -1093 N ATOM 2102 CA LEU A2217 35.412 10.377 -0.346 1.0056.96 C ANISOU 2102 CA LEU A2217 7568 6162 7909 704 207 -1117 C ATOM 2103 C LEU A2217 36.448 10.341 0.775 1.0054.66 C ANISOU 2103 C LEU A2217 7298 5898 7572 583 279 -1125 C ATOM 2104 O LEU A2217 37.304 11.219 0.848 1.0052.07 O ANISOU 2104 O LEU A2217 7033 5528 7220 557 326 -1104 O ATOM 2105 CB LEU A2217 34.042 10.808 0.178 1.0058.78 C ANISOU 2105 CB LEU A2217 7731 6367 8236 740 223 -1191 C ATOM 2106 CG LEU A2217 33.015 11.209 -0.886 1.0061.55 C ANISOU 2106 CG LEU A2217 8066 6669 8650 869 151 -1187 C ATOM 2107 CD1 LEU A2217 31.656 11.474 -0.260 1.0062.44 C ANISOU 2107 CD1 LEU A2217 8088 6764 8871 896 169 -1278 C ATOM 2108 CD2 LEU A2217 33.489 12.430 -1.660 1.0062.97 C NAI-5000260062v1 -160-Attorney Docket No.14709-046-228 ANISOU 2108 CD2 LEU A2217 8340 6763 8823 927 146 -1132 C ATOM 2109 N PHE A2218 36.375 9.315 1.635 1.0052.89 N N C C C C O O C C C C C C C C C C C C C C N N C C C C O O C C C C C C N N CNAI-5000260062v1 -161-Attorney Docket No.14709-046-228 ANISOU 2128 CZ ARG A2219 10267 8936 10149 630 9 -878 C ATOM 2129 NH1 ARG A2219 41.495 6.127 -5.399 1.0082.68 N N N N N N C C C C O O C C C C O O N N N N C C C C O O C C C C C C C C C C CNAI-5000260062v1 -162-Attorney Docket No.14709-046-228 ANISOU 2148 CE2 PHE A2221 7538 5990 7543 28 690 -1251 C ATOM 2149 CZ PHE A2221 40.456 14.553 6.950 1.0055.94 C C N N C C C C O O C C C C C C C C C C C C C C N N C C C C O O C C C C C C CNAI-5000260062v1 -163-Attorney Docket No.14709-046-228 ANISOU 2168 CD2 LEU A2223 8747 7156 8392 251 338 -912 C ATOM 2169 N ASN A2224 44.528 13.986 0.273 1.0064.64 N ANISOU 2169 N ASN A2224 8987 7023 8550 286 558 -960N ATOM 2170 CA ASN A2224 44.716 15.428 0.354 1.0065.36C ANISOU 2170 CA ASN A2224 9145 7037 8650 281 633 -966C ATOM 2171 C ASN A2224 45.483 15.807 1.617 1.0063.84C ANISOU 2171 C ASN A2224 8945 6860 8451 175 704 -1006C ATOM 2172 O ASN A2224 46.381 16.641 1.559 1.0066.86O ANISOU 2172 O ASN A2224 9385 7205 8811 136 765 -1006O ATOM 2173 CB ASN A2224 43.397 16.194 0.342 1.0070.02C ANISOU 2173 CB ASN A2224 9736 7566 9300 356 634 -979C ATOM 2174 CG ASN A2224 42.789 16.301 -1.036 1.0072.41C ANISOU 2174 CG ASN A2224 10080 7825 9606 463 571 -932C ATOM 2175 OD1 ASN A2224 43.330 15.760 -2.006 1.0073.36O ANISOU 2175 OD1 ASN A2224 10232 7966 9676 475 532 -891O ATOM 2176 ND2 ASN A2224 41.668 16.998 -1.144 1.0077.08N ANISOU 2176 ND2 ASN A2224 10673 8354 10260 538 560 -940N ATOM 2177 N SER A2225 45.106 15.205 2.751 1.0063.83 N ANISOU 2177 N SER A2225 8876 6911 8464 125 698 -1042 NATOM 2178 CA SER A2225 45.721 15.502 4.037 1.0067.33 CANISOU 2178 CA SER A2225 9311 7374 8894 18 757 -1081 CATOM 2179 C SER A2225 47.214 15.175 4.024 1.0071.08 CANISOU 2179 C SER A2225 9800 7883 9323 -50 757 -1068 CATOM 2180 O SER A2225 47.976 15.788 4.767 1.0073.05 OANISOU 2180 O SER A2225 10068 8127 9558 -129 816 -1094 OATOM 2181 CB SER A2225 45.038 14.761 5.150 1.0067.98 CANISOU 2181 CB SER A2225 9328 7512 8988 -29 739 -1116 CATOM 2182 OG SER A2225 45.334 13.370 5.081 1.0071.33 OANISOU 2182 OG SER A2225 9710 8004 9386 -44 661 -1092 OATOM 2183 N ILE A2226 47.614 14.191 3.205 1.0074.86 NANISOU 2183 N ILE A2226 10262 8396 9784 -20 690 -1035 N ATOM 2184 CA ILE A2226 49.015 13.816 3.069 1.0081.98 C ANISOU 2184 CA ILE A2226 11165 9326 10657 -76 684 -1030C ATOM 2185 C ILE A2226 49.788 15.009 2.519 1.0084.66 C ANISOU 2185 C ILE A2226 11577 9605 10981 -84 760 -1031C ATOM 2186 O ILE A2226 50.721 15.495 3.156 1.0083.19O ANISOU 2186 O ILE A2226 11402 9420 10784 -162 811 -1058O ATOM 2187 CB ILE A2226 49.202 12.586 2.156 1.0082.87C ANISOU 2187 CB ILE A2226 11244 9476 10764 -34 605 -1001C ATOM 2188 CG1 ILE A2226 48.422 11.366 2.640 1.0079.28CNAI-5000260062v1 -164-Attorney Docket No.14709-046-228 ANISOU 2188 CG1 ILE A2226 10721 9075 10324 -25 530 -999 C ATOM 2189 CG2 ILE A2226 50.686 12.257 1.983 1.0085.47 C C C C N N C C C C O O C C C C C C C C C C C C C C O O N N C C C C O O C C CNAI-5000260062v1 -165-Attorney Docket No.14709-046-228 ANISOU 2208 CG LYS A2228 14978 12463 14299 131 941 -1033 C ATOM 2209 CD LYS A2228 44.995 20.060 2.211 1.00113.76 C ANISOU 2209 CD LYS A2228 15427 12931 14864 189 927 -1059C ATOM 2210 CE LYS A2228 44.075 20.175 1.036 1.00116.28C ANISOU 2210 CE LYS A2228 15773 13195 15211 310 862 -1017C ATOM 2211 NZ LYS A2228 42.684 20.355 1.457 1.00117.09N ANISOU 2211 NZ LYS A2228 15820 13273 15396 367 847 -1053 N ATOM 2212 N SER A2229 50.170 18.512 4.396 1.00105.83 N ANISOU 2212 N SER A2229 14373 12159 13678 -214 1007 -1118 N ATOM 2213 CA SER A2229 50.953 18.570 5.624 1.00104.71 C ANISOU 2213 CA SER A2229 14206 12058 13520 -325 1040 -1160 C ATOM 2214 C SER A2229 52.187 19.468 5.436 1.00106.14C ANISOU 2214 C SER A2229 14440 12206 13682 -379 1115 -1176 C ATOM 2215 O SER A2229 52.584 20.118 6.432 1.00105.84 O ANISOU 2215 O SER A2229 14406 12168 13639 -462 1177 -1219O ATOM 2216 CB SER A2229 51.358 17.187 6.083 1.00100.64 C ANISOU 2216 CB SER A2229 13621 11628 12987 -366 957 -1155 C ATOM 2217 OG SER A2229 50.233 16.329 6.201 1.0099.92 O ANISOU 2217 OG SER A2229 13486 11565 12911 -321 892 -1140 O HETATM 2218 C1 EDO A2301 34.527 -8.670 21.392 1.0056.61 C ANISOU 2218 C1 EDO A2301 8096 6753 6658 -1972 90 -1187 CHETATM 2219 O1 EDO A2301 34.650 -10.022 21.022 1.0054.32 O ANISOU 2219 O1 EDO A2301 7820 6442 6376 -1946 -18 -1115 O HETATM 2220 C2 EDO A2301 33.261 -8.062 20.934 1.0055.76 C ANISOU 2220 C2 EDO A2301 7893 6669 6624 -1918 226 -1311 CHETATM 2221 O2 EDO A2301 33.042 -8.267 19.562 1.0055.61 OANISOU 2221 O2 EDO A2301 7764 6647 6718 -1732 195 -1310 O HETATM 2222 F LIG A2401 37.344 -17.067 -4.136 1.0060.11 F ANISOU 2222 F LIG A2401 7276 7223 8339 344 -670 -1072 F HETATM 2223 C15 LIG A2401 38.172 -18.074 -3.892 1.0058.08 C ANISOU 2223 C15 LIG A2401 7010 6931 8127 310 -713 -1055C HETATM 2224 C14 LIG A2401 38.529 -18.946 -4.930 1.0056.38C ANISOU 2224 C14 LIG A2401 6750 6715 7957 342 -733 -1078C HETATM 2225 C8 LIG A2401 39.422 -20.007 -4.698 1.0057.65 C ANISOU 2225 C8 LIG A2401 6893 6829 8180 312 -781 -1066C HETATM 2226 C9 LIG A2401 39.685 -20.880 -5.934 1.0057.75C ANISOU 2226 C9 LIG A2401 6851 6846 8244 349 -789 -1105C HETATM 2227 C13 LIG A2401 38.442 -21.632 -6.408 1.0054.49C ANISOU 2227 C13 LIG A2401 6409 6469 7825 362 -784 -1143C HETATM 2228 O LIG A2401 40.387 -20.212 -7.028 1.0056.91ONAI-5000260062v1 -166-Attorney Docket No.14709-046-228 ANISOU 2228 O LIG A2401 6736 6753 8133 394 -759 -1125 O HETATM 2229 C10 LIG A2401 41.651 -19.671 -6.895 1.0051.63 C ANISOU 2229 C10 LIG A2401 6078 6052 7484 387 -758 -1109C HETATM 2230 C11 LIG A2401 42.511 -20.000 -5.858 1.0052.20C ANISOU 2230 C11 LIG A2401 6155 6072 7605 343 -803 -1077C HETATM 2231 C1 LIG A2401 43.784 -19.402 -5.781 1.0050.12C ANISOU 2231 C1 LIG A2401 5895 5781 7366 338 -801 -1069C HETATM 2232 C12 LIG A2401 42.098 -18.729 -7.882 1.0050.72C ANISOU 2232 C12 LIG A2401 5974 5958 7337 422 -712 -1127C HETATM 2233 N LIG A2401 41.314 -18.360 -8.936 1.0050.25N ANISOU 2233 N LIG A2401 5919 5946 7225 464 -679 -1152N HETATM 2234 N1 LIG A2401 43.366 -18.130 -7.813 1.0051.11N ANISOU 2234 N1 LIG A2401 6033 5979 7406 412 -701 -1120N HETATM 2235 C LIG A2401 44.159 -18.481 -6.772 1.0050.22C ANISOU 2235 C LIG A2401 5913 5818 7348 372 -745 -1095C HETATM 2236 C16 LIG A2401 38.688 -18.229 -2.595 1.0059.11C ANISOU 2236 C16 LIG A2401 7175 7022 8261 240 -739 -1016C HETATM 2237 C17 LIG A2401 39.565 -19.281 -2.366 1.0058.34CANISOU 2237 C17 LIG A2401 7066 6880 8220 210 -796 -996 CHETATM 2238 C7 LIG A2401 39.931 -20.170 -3.405 1.0057.49 CANISOU 2238 C7 LIG A2401 6906 6765 8170 249 -817 -1022 CHETATM 2239 C6 LIG A2401 40.822 -21.198 -2.950 1.0057.16 CANISOU 2239 C6 LIG A2401 6854 6666 8197 215 -882 -1000 CHETATM 2240 N2 LIG A2401 40.491 -22.503 -2.776 1.0059.49 NANISOU 2240 N2 LIG A2401 7133 6936 8533 189 -923 -1002 NHETATM 2241 N3 LIG A2401 41.641 -23.068 -2.345 1.0058.97 NANISOU 2241 N3 LIG A2401 7063 6808 8535 167 -987 -974 N HETATM 2242 C18 LIG A2401 41.734 -24.505 -2.016 1.0058.39 CANISOU 2242 C18 LIG A2401 6977 6678 8528 136 -1055 -962 CHETATM 2243 N4 LIG A2401 42.699 -22.214 -2.226 1.0057.83 NANISOU 2243 N4 LIG A2401 6925 6649 8395 175 -989 -958N HETATM 2244 C5 LIG A2401 42.202 -21.020 -2.602 1.0055.63 C C CC CC HETATM 2247 C19 LIG A2401 45.495 -20.351 -2.691 1.0049.30C ANISOU 2247 C19 LIG A2401 5822 5542 7367 214 -971 -965C HETATM 2248 N5 LIG A2401 46.510 -20.427 -3.571 1.0048.84NNAI-5000260062v1 -167-Attorney Docket No.14709-046-228 ANISOU 2248 N5 LIG A2401 5709 5469 7378 247 -964 -1005 N HETATM 2249 N6 LIG A2401 45.998 -20.078 -4.780 1.0047.95 N ANISOU 2249 N6 LIG A2401 5584 5405 7230 291 -892 -1049N HETATM 2250 C2 LIG A2401 44.635 -19.782 -4.690 1.0048.97C ANISOU 2250 C2 LIG A2401 5752 5580 7274 294 -861 -1036C HETATM 2251 C20 LIG A2401 46.908 -20.080 -5.949 1.0047.23C ANISOU 2251 C20 LIG A2401 5440 5310 7192 321 -860 -1105C HETATM 2252 C21 LIG A2401 47.749 -18.798 -5.989 1.0047.12C ANISOU 2252 C21 LIG A2401 5449 5301 7150 319 -816 -1107C HETATM 2253 O HOH W 1 52.321 -1.803 0.728 1.0049.11O HETATM 2254 O HOH W 2 42.617 17.980 7.077 1.0054.19O HETATM 2255 O HOH W 3 31.567 -22.642 -26.516 1.0046.07 O HETATM 2256 O HOH W 4 30.087 -24.634 -26.463 1.0044.61 O HETATM 2257 O HOH W 5 36.007 -31.654 -21.345 1.0055.83O HETATM 2258 O HOH W 6 33.456 -27.978 -22.249 1.0048.46O HETATM 2259 O HOH W 7 32.206 -13.598 -17.953 1.0056.07O HETATM 2260 O HOH W 8 27.738 -6.794 -17.206 1.0064.31O HETATM 2261 O HOH W 9 42.103 -13.733 15.305 1.0060.67 O HETATM 2262 O HOH W 10 45.246 -2.279 -2.327 1.0043.92 O HETATM 2263 O HOH W 11 31.593 -18.198 11.813 1.0053.35 O HETATM 2264 O HOH W 12 31.675 -17.049 24.816 1.0063.72 O HETATM 2265 O HOH W 13 30.088 -24.498 -23.860 1.0052.51 O HETATM 2266 O HOH W 14 38.489 10.075 9.814 1.0051.62 OHETATM 2267 O HOH W 15 38.063 4.188 15.778 1.0057.97 OHETATM 2268 O HOH W 16 39.217 -6.231 -16.527 1.0065.20 OHETATM 2269 O HOH W 17 45.271 -16.476 -14.900 1.0055.98 O HETATM 2270 O HOH W 18 39.307 -17.449 11.244 1.0078.27 O HETATM 2271 O HOH W 19 47.730 -1.146 -5.811 1.0055.48 O HETATM 2272 O HOH W 20 49.005 2.771 7.447 1.0046.29 O HETATM 2273 O HOH W 21 26.585 -12.486 13.679 1.0049.98 O HETATM 2274 O HOH W 22 28.070 -10.158 12.590 1.0057.91 O HETATM 2275 O HOH W 23 51.141 -5.510 -3.701 1.0039.06O HETATM 2276 O HOH W 24 24.327 -16.919 20.442 1.0064.19O HETATM 2277 O HOH W 25 37.620 -9.501 -13.648 1.0049.98O HETATM 2278 O HOH W 26 35.282 -9.637 -16.212 1.0058.08O HETATM 2279 O HOH W 27 25.985 -8.489 -3.333 1.0065.37 O HETATM 2280 O HOH W 28 24.166 -17.172 -3.223 1.0064.16 O HETATM 2281 O HOH W 29 11.611 -16.953 13.077 1.0054.71 O HETATM 2282 O HOH W 30 14.000 -8.054 8.283 1.0063.74 O HETATM 2283 O HOH W 31 29.745 -36.456 -4.277 1.0069.47 O NAI-5000260062v1 -168-Attorney Docket No.14709-046-228 HETATM 2284 O HOH W 32 47.309 18.775 -1.137 1.0086.95 O HETATM 2285 O HOH W 33 32.483 -8.227 23.949 1.0055.60 O O O O O O

[0198] In certain embodiments, provided herein is a pharmaceutical preparation suitable for use in a human patient, comprising a compound provided herein (e.g., a compound of Formula (I), and one or more pharmaceutically acceptable excipients. In certain embodiments, 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.

[0199] In one embodiment, the pharmaceutical composition comprises a compound of Formula (I): or a stereoisomer, or a mixtureacceptable salt thereof, and a diluent, a binder, a disintegrant, and a lubricant. In one embodiment, Compound 1, or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, in the pharmaceutical composition is free base of Compound 1. In one embodiment, the free base of Compound 1 is amorphous. In one embodiment, the free base of Compound 1 is one of the solid forms of free base of Compound 1 provided herein. In one embodiment, the free base of Compound 1 is Form 1 of the free base of Compound 1.

[0200] In one embodiment, the diluent is mannitol. In one embodiment, the diluent is Pearlitol 100SD, Pearlitol 110 C, Pearlitol 160 C, Pearlitol 25 C, Pearlitol 300 DC, Pearlitol 400 DC, Pearlitol 500 DC, Pearlitol SW-F 200, Parteck M 100, Parteck M 200, or lactose NAI-5000260062v1 -169-Attorney Docket No.14709-046-228 monohydrate. In one embodiment, the diluent is mannitol Pearlitol 50C. In one embodiment, the diluent is mannitol Pearlitol 200SD.

[0201] In one embodiment, the binder is hydroxypropyl cellulose (HPC), silicified microcrystalline cellulose (SMCC), or a mixture thereof. In one embodiment, the binder is HPC. In one embodiment, the binder is SMCC. In one embodiment, the binder is a mixture of HPC and SMCC. In certain embodiments, the binder is carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia, or a mixture thereof.

[0202] In one embodiment, the disintegrant is sodium starch glycolate (SSG). In one embodiment, the disintegrant is cross-linked sodium carboxymethyl cellulose.

[0203] In one embodiment, the lubricant is magnesium stearate. In another embodiment, the lubricant is sodium lauryl sulfate.

[0204] In one embodiment, the diluent is mannitol, the binder is a mixture of HPC and SMCC, the disintegrant is sodium starch glycolate (SSG), and the lubricant is magnesium stearate.

[0205] In one embodiment, the tablets are coated with a non-functional film-coating (e.g., Opadry II Pink).

[0206] In one embodiment, the pharmaceutical composition provided herein is an oral dosage form. In one embodiment, the oral dosage form is a tablet. In one embodiment, the oral dosage form is an immediate release tablet.

[0207] 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. When administered to subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound provided herein and a pharmaceutically acceptable carrier. 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 a preferred 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 NAI-5000260062v1 -170-Attorney Docket No.14709-046-228 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.

[0208] 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.

[0209] 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.

[0210] 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 NAI-5000260062v1 -171-Attorney Docket No.14709-046-228 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.

[0211] 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.

[0212] 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. In certain embodiments, the unit dosage form is a tablet of 5 mg (by weight of free base Compound 1) dose strength. In certain embodiments, the unit dosage form is a tablet of 25 mg (by weight of free base Compound 1) dose strength. 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. NAI-5000260062v1 -172-Attorney Docket No.14709-046-228 Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0213] 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.

[0214] 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.

[0215] 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), NAI-5000260062v1 -173-Attorney Docket No.14709-046-228 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.

[0216] 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.

[0217] 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 profile, 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 preferentially, 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.

[0218] 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- NAI-5000260062v1 -174-Attorney Docket No.14709-046-228 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.

[0219] 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.

[0220] 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).

[0221] 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 preferred embodiments, the active compound will be administered once daily.

[0222] 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. NAI-5000260062v1 -175-Attorney Docket No.14709-046-228 EXAMPLES Example 1. Average clinical exposures of crizotinib, entrectinib, repotrectinib, and Compound 1.

[0223] Methods. Table 1 describes the parameters and the method used for calculating the clinical average unbound concentrations (Cavg,u) of various ROS1 TKIs, using data obtained from FDA documents, peer-reviewed publications, and internal experiments. The clinical Cavg,uindicates the time-averaged concentration of drug in the human plasma at steady state adjusted for fraction unbound in human plasma and expressed in nanomolar (nM).Table 1: Calculating clinical average unbound concentration (clinical Cavg,u). AUC , area underthe curve (unit: concentration × time) from human PK studies over measurement period (unit: time) at steady state ROS1 TKI Clinical Cavg,u C i ti ib 65 MFu(human), fraction unbound in human pla unit: g / mol), and Fu(human) were used tocalculate clinical Cavg,u (unit: nM). Compo2023 data cut.and Compound 1.

[0224] Methods. Ba / F3 CD74-ROS1 and Ba / F3 CD74-ROS1 G2032R cells were seeded in 96-well plates at a density of 2 × 103cells per well. Cells were then treated with tyrosine kinase inhibitors (TKI) for 21 days with media refresh approximately once a week. Ba / F3 CD74- ROS1 cells were treated with crizotinib, entrectinib, repotrectinib, or Compound 1. Ba / F3 CD74- ROS1 G2032R cells were treated with repotrectinib or Compound 1. All compounds were tested at 5 concentrations each in triplicate.

[0225] Cell viability was measured approximately twice a week using the CellTiter-Glo reagent and plotted as relative luminescence over 21 days (Figure 1). The efficacious unbound in vitro concentration (in vitro Ceff,u) is defined as the lowest concentration needed to suppress cell growth below the initial value and is listed for each compound against each cell line in Figure 1. The window between clinical Cavg,uand in vitro Ceff,uindicates the extent to which the average clinical exposure covers the efficacious threshold in vitro. A larger window signifies NAI-5000260062v1 -176-Attorney Docket No.14709-046-228 greater coverage and therefore a potential to have deeper and more sustained target inhibition in humans.

[0226] Findings. The 40 – 104× Cavg,u / Ceff,uwindow of Compound 1 suggests a potential for a deep and sustained inhibition of ROS1 and ROS1 G2032R fusions in humans, both peripherally and in the CNS. The narrower windows observed with the other TKIs (0.6 – 7×) suggests that limited brain penetrance and dose reductions may present greater challenges to their ability maintain efficacious doses both peripherally and in the CNS. Example 3. Mutagenesis screen

[0227] Methods. The workflow for the mutagenesis screen study is depicted in Figure 2. Briefly, Ba / F3 cells (3 × 108cells) expressing CD74-ROS1 or CD74-ROS1 G2032R fusion were treated with N-ethyl-N-nitrosourea (ENU) (100 g / mL) for 16 hours. Cells were washed, recovered in growth media for 24 hours, seeded into 96-well plates at a density of 5 × 104cells / well, and then treated for 28 days with tyrosine kinase inhibitors (TKI) according to the study design in Figure 3. There were 12 treatment groups for CD74-ROS1 cells, which included 4 TKIs (crizotinib, entrectinib, repotrectinib, or Compound 1) at 3 concentrations each. There were 6 treatment groups for CD74-ROS1 G2032R cells, which included 2 TKIs (repotrectinib or Compound 1) at 3 concentrations each. For each treatment group, 5 plates (480 wells) were used. On day 28, the number of resistant wells were counted, and cells from a subset of resistant wells were subjected to Sanger sequencing in the ROS1 kinase domain (defined as amino acid residues 1945 – 2222 according to the Uniprot ID: P08922). Results are shown in Figure 4 and Figure 5.

[0228] Findings. The in vitro ENU screen against Ba / F3 CD74-ROS1 suggests that Compound 1 effectively prevented on-target resistance as a first-line ROS1 TKI treatment. Its clinical Cavg,u(166 nM) is 20× above 8.2 nM used in the screen, at which only 1 / 480 (0.2%) resistant wells emerged. The 20× window suggests a high confidence that on-target resistance is unlikely both peripherally and in the CNS. By contrast, the in vitro ENU screen suggests that on- target resistance is predicted for crizotinib, entrectinib, and potentially repotrectinib as a first-line ROS1 TKI treatment. Crizotinib clinical Cavg,u (65 nM) approximates 66 nM used in the screen, at which 375 / 480 (78%) resistant wells emerged. ROS1 S1986X, F2004X, G2032R, and other mutations were identified across crizotinib-treated groups. Entrectinib clinical Cavg,u(5 nM) approximates 6.4 nM used in the screen, at which 480 / 480 (100%) resistant wells emerged. ROS1 S1986X, F2004X, G2032R, and other mutations were identified across entrectinib-treated NAI-5000260062v1 -177-Attorney Docket No.14709-046-228 groups. Repotrectinib clinical Cavg,u (39 nM) is 1.4× above 28 nM used in the screen, at which only 1 / 480 (0.2%) resistant wells emerged. However, a decrease in clinical exposure could result in on-target resistance becoming more frequent, such as in the CNS and / or due to dose reduction in 35% of patients10. At 5.6 nM (7× below Cavg,u), 476 / 480 (99%) resistant wells emerged, with ROS1 F2004, G2032R, and other mutations identified.

[0229] The in vitro ENU screen against Ba / F3 CD74-ROS1 G2032R suggests that on- target resistance is unlikely for Compound 1 as a later-line treatment for cancers harboring ROS1 G2032R. The resistance frequency for repotrectinib was nominally higher than that of Compound 1. Compound 1 clinical Cavg,u(166 nM) is 4× above 41 nM used in the screen, at which only 6 / 480 (1.3%) resistance wells emerged. By contrast, repotrectinib clinical Cavg,u(39 nM) is 1.8× below 70 nM used in the screen, at which 158 / 480 (33%) resistance wells emerged. No ROS1 kinase-domain mutations (besides pre-existing G2032R) were identified among 208 clones sequenced, suggesting only off-target resistance pathways in this screen. Example 4. Profiling crizotinib, entrectinib, repotrectinib, and Compound 1 against resistant clones

[0230] Methods. The 28 resistant clones with distinct ROS1 kinase-domain mutations from the ENU mutagenesis screen in Figure 4 were isolated for TKI profiling. Cells were plated in a 384-well plate. Test compounds were then added in a 3-fold dilution series and incubated for 72 hours. CellTiter-Glo reagent (Promega) was added. Luminescence was measured on a plate reader. Half-maximal inhibitory concentration (IC50) was calculated from percent inhibition and inhibitor concentration using four-parameter logistic regression (Figure 6).

[0231] Findings. Compound 1 was the only TKI to achieve single-digit nM potency or better against all clones (IC50< 3 nM), indicating broader preclinical activity against ROS1 resistance mutations than any other TKIs tested. Compound 1 was highly potent against the clone harboring CD74-ROS1 G2032R (IC50 = 1.9 nM), which was 13× more potent than repotrectinib (IC50= 25 nM) and >60× more potent than crizotinib, entrectinib, lorlatinib, and taletrectinib (IC50 = 120 nM to >5 μM). Example 5. ROS1 G2032R structural analysis Crystal structure

[0232] Given Compound 1’s increased activity for ROS1 G2032R compared to other TKIs, a study was conducted to understand its structural mechanism of inhibition. A crystal NAI-5000260062v1 -178-Attorney Docket No.14709-046-228 structure of the ROS1 G2032R kinase domain in complex with Compound 1 to 2.2 Å resolution was solved (Figure 7A–7D). The atomic coordinates of the complex is provided in Table A. The atomic coordinates of the complex is also provided in PDB:9QEK, which is incorporated herein by reference in its entirety.

[0233] ROS1 G2032R is structurally similar to wild-type ROS1 (PDB:3ZBF, 4UXL, 7Z5W, and 7Z5X), with average -carbon root-mean-square deviation (RMSD) of 0.6 Å (Figure 8A). There are slight differences in the positioning of the C helix, but these are also observed among wild-type ROS1 structures, suggesting that the helix may inherently assume several crystallographic states (Figure 8A). The ATP-binding pocket remained largely unchanged in both polarity and size, and docking indicated that the G2032R mutation is unlikely to impede ATP binding (Figure 8B–8C). Recombinant ROS1 displayed slightly higher catalytic efficiency than ROS1 G2032R (kcat / KM = 26 versus 7.5 L / mol / s) but similar Michaelis constants for ATP (KM= 25 versus 14 mol / L), suggesting that the ROS1 G2032R mutant maintains kinase activity and ATP binding.

[0234] The aminopyridine forms two canonical hydrogen bonds with residues E2027 and M2029 in the hinge region (Figure 7C), and the fluorobenzene inserts into a shallow cavity at the floor of the pocket, positioning the ortho-hydrogen atom for interaction with the carbonyl ofR2083 (Figure 7D). CH- interactions were observed between the R2032 sidechain and the -system of the N-ethylpyrazole, and between the terminal methyl groups of L2086 and the - systems of the aminopyridine and fluorobenzene moieties (Figure 7D). The P-loop of ROS1 G2032R is shifted ~1.5 Å upward compared to wild-type ROS1 bound to lorlatinib and displays a lower B-factor, suggesting that the N-methyltriazole group of Compound 1 may reduce the P- loop's degrees of freedom and lock it in this crystallographic state (Figure 9A-9B).

[0235] The R2032 side chain extends into the solvent front (instead of forming hydrogen bonds with the Compound 1 N-ethylpyrazole as previously predicted by Drilon et al., Cancer Discov.2023;13:598–615), which may be a result of an intermolecular electrostatic interaction between the positively charged R2032 and the negative dipole of a neighboring -helix near residue Y2227 (Figure 10A). The and carbon atoms of R2032 adopt a gauche+conformation( 1 angle = 306°), allowing it to engage in multiple CH- interactions with the N-ethylpyrazolering of Compound 1 (Figure 10B). An overlay of ROS1-bound lorlatinib (PDB:4UXL) and crizotinib (PDB:3ZBF) crystal structures onto the ROS1 G2032R protein structure here indicated NAI-5000260062v1 -179-Attorney Docket No.14709-046-228 potential steric clashes between these TKIs and R2032 (Figure 10C). In further support of these observations, molecular dynamics simulations revealed that R2032 adopts the energetically more favorable gauche+conformation with Compound 1, forming favorable hydrogen-bond interactions in some frames (Figure 10D). By contrast, R2032 adopts the energetically less favorable gauche- conformation with lorlatinib, presumably to avoid clashes in the solvent-front region, which may contribute to its potency loss against ROS1 G2032R (Figure 10D). Free-energy perturbation calculations

[0236] ROS1 wild type and G2032R crystal structures not only improved an understanding of Compound 1 binding but also enabled the computational prediction of ROS1 ligand binding affinity. The free-energy perturbation (FEP) methodology was applied to study the impact of the G2032R modification on TKI binding. Beginning with the wild-type ROS1 crystal structure, FEP examined the energetic changes both upon gradual growth of glycine 2032 into arginine and upon TKI binding (Figure 11). FEP was also applied in the reverse direction, beginning with the ROS1 G2032R crystal structure and gradually shrinking arginine 2032 intoglycine. The output of these FEP calculations is a predicted change in binding free energy ( G)between wild-type ROS1 and ROS1 G2032R, with smaller G values corresponding to a smaller influence of the mutant arginine on binding affinity.

[0237] In a set of 6 approved or investigational ROS1 TKIs, FEP predicted affinitychanges ( GFEP) that correlated well with reported experimental data ( Gbiochem) (Figure12A-12B). Compound 1 and repotrectinib clustered toward the bottom-left corner of thecorrelation plot ( G 1.9 kcal / mol), consistent with tolerance for the G2032R mutationimparted by minimal steric bulk in the solvent-front region. By contrast, crizotinib, entrectinib,and lorlatinib clustered toward the top-right corner ( G 2.9 kcal / mol), consistent withG2032R resistance imparted by steric clashes in the solvent-front region.

[0238] Availability of the ROS1 G2032R structure improved prediction accuracy compared to relying on the existing wild-type ROS1 structure alone. While FEP predictions were often similar in both G R and R G directions, large differences were observed for repotrectinib and crizotinib, indicating that the two directions were reciprocal but not necessarily identical (Figure 12A-12B). In this set, the R G prediction displayed better correlation and concordance with experimental data than the G R prediction (R2= 0.85 versus 0.62 and NAI-5000260062v1 -180-Attorney Docket No.14709-046-228 RMSD = 0.77 versus 0.96). These data highlight FEP as a reliable computational approach for predicting changes in ligand binding affinity between wild-type ROS1 and ROS1 G2032R. Example 6: Phase 1 / 2 Clinical Study

[0239] A phase 1 / 2, dose escalation and expansion study is conducted to evaluate the safety and tolerability of Compound 1, determine the recommended phase 2 dose (RP2D), and evaluate the antitumor activity in patients with advanced ROS1-positive (ROS1+) NSCLC and other advanced ROS1-positive solid tumors. This study is an update and expansion of the studies described in Examples 4 and Example 5 of WO2023 / 056431, which is incorporated herein by reference.

[0240] Phase 1 determines the RP2D and, if applicable, the maximum tolerated dose (MTD) of Compound 1 in patients with advanced ROS1-positive solid tumors.

[0241] Phase 2 determines the objective response rate (ORR) as assessed by Blinded Independent Central Review (BICR) of Compound 1 at the RP2D. Secondary objectives include the duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and clinical benefit rate (CBR) of Compound 1 in patients with advanced ROS1- positive NSCLC and other solid tumors.

[0242] In Phase 2, study patients are enrolled into 5 distinct expansion cohorts: • Cohort 2a: ROS1-positive NSCLC naïve to Tyrosine Kinase Inhibitor (TKI) therapy and up to 1 prior chemotherapy and / or immunotherapy. • Cohort 2b: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy. • Cohort 2c: ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior platinum- based chemotherapy with or without immunotherapy. • Cohort 2d: ROS1-positive NSCLC treated with 2 prior ROS1 TKIs and up to 1 prior chemotherapy and / or immunotherapy. • Cohort 2e: ROS1-positive solid tumor and progressed on any prior therapy. Patients with any advanced / metastatic ROS1-positive solid tumor (including patients with ROS1- positive NSCLC not otherwise eligible for any other cohorts) and progressed on any prior therapy (includes, but is not limited to, patients who have progressed on prior ROS1 TKIs). The solid tumors studied in Cohort 2e include, e.g., endometrial stromal sarcoma, duodenal adenocarcinoma, inflammatory myofibroblastic tumors (IMT), pancreatic NAI-5000260062v1 -181-Attorney Docket No.14709-046-228 adenocarcinoma, glioblastoma (GBM) / glioma, ovarian cancer (serous), cholangiocarcinoma, gastric cancer, and thyroid cancer. Other cancers described herein (e.g., the cancers described in the detailed description section) can also be explored in Cohort 2e.

[0243] Inclusion Criteria: 1. Age 18 years a. Phase 2 Cohort 2e only: Age 12 years (Patients ages 12 to 17 are only enrolled in countries and at sites where regulations allow). 2. Disease Criteria: a. Phase 1: Histologically or cytologically confirmed locally advanced or metastatic solid tumor with documented ROS1 rearrangement. b. Phase 2: Cohorts 2a, 2b, 2c and 2d: Histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangement. c. Phase 2: Cohort 2e: Histologically or cytologically confirmed locally advanced or metastatic solid tumor (other than NSCLC) with ROS1 rearrangement. 3. Prior anticancer treatment (except cohort 2a). 4. Phase 1: Must have evaluable disease (target or nontarget) according to RECIST 1.1. Phase 2: Must have measurable disease according to RECIST 1.1. 5. Adequate baseline organ function and bone marrow reserve.

[0244] Exclusion Criteria: 1. Patient's cancer has a known oncogenic driver alteration other than ROS1. 2. Known allergy / hypersensitivity to excipients of Compound 1. 3. Major surgery within 4 weeks of first dose of study drug. 4. Ongoing anticancer therapy. 5. Actively receiving systemic treatment or direct medical intervention on another therapeutic clinical study.

[0245] Recommended Phase 2 Dose: Compound 1 is orally administered. Compound 1 RP2D for further study in Phase 2 is 100 mg QD for adult patients. The RP2D for adolescent patients in Cohort 2e (aged 12 to 17) is 75 mg QD for patients weighing <40 kg and 100 mg QD for patients weighing 40 kg. RP2D can be reduced, e.g., as shown in the table below: Initial dose level Dose level -1 Dose level -2*NAI-5000260062v1 -182-Attorney Docket No.14709-046-228 Adults ( 18 years) 100 mg QD 75 mg QD 50 mg QDAdolescents aged 12-17 years weighing 40 kg 100 mg QD 75 mg QD 50 mg QD tp , y .

[0246] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

[0247] 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. NAI-5000260062v1 -183-

Claims

Attorney Docket No.14709-046-228 WHAT IS CLAIMED IS:

1. A method of treating a patient with solid tumor, comprising administering to said patient a therapeutically effective amount of Compound 1:or a stereoisomer, or a mixture or a pharmaceutically acceptable salt thereof, and wherein the solid tumor has one or more ROS1 mutations comprising: a mutation at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227; and / or a mutation selected from the group consisting of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C; or a combination thereof.

2. The method of claim 1, wherein the one or more ROS1 mutations comprise a mutation at G2032 and one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227.

3. The method of claim 1, wherein the one or more ROS1 mutations comprise a mutation at G2032 and one or more mutations of L1982V, L1982W, S1986T, F2004I, F2004L, and F2075C.

4. The method of any one of claims 1 to 3, wherein: the mutation at G1917 is G1917D; and / or the mutation at I1934 is I1934N or I1934S; and / or the mutation at G1957 is G1957A; and / or the mutation at V1979 is V1979A or V1979L; and / or the mutation at E1990 is E1990A or E1990D; and / or the mutation at L2000 is L2000R; and / or NAI-5000260062v1 -184-Attorney Docket No.14709-046-228 the mutation at D2113 is D2113G; and / or the mutation at Q2022 is Q2022P; and / or the mutation at M2128 is M2128T; and / or the mutation at H2074 is H2074R; and / or the mutation at H2165 is H2165Q or H2165R; and / or the mutation at L2223 is L2223*; and / or the mutation at Y2227 is Y2227*.

5. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations are selected from the group consisting of G1917D, I1934N, I1934S, G1957A, V1979A, V1979L, L1982V, L1982W, S1986T, E1990A, E1990D, L2000R, F2004I, F2004L, D2113G, Q2022P, M2128T, H2074R, F2075C, H2165Q, H2165R, L2223*, and Y2227*, or a combination thereof.

6. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations comprise a mutation of G2032R and L2223*.

7. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations comprise a mutation of G2032R and Y2227*.

8. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations comprise: (i) one or more mutations selected from the group consisting of G2032R, G2032K, D2033N, S1986F, S1986Y, L2026M, L1951R, E1935G, L1947R, G1971E, E1974K, L1982F, F2004C, F2004V, E2020K, C2060G, F2075V, V2089M, V2098I, G2101A, D2113N, D2113G and L2155S; and (ii) one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227, and / or of L1982V, L1982W, S1986T, F2004I, F2004L, and / or F2075C.

9. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations comprise: (i) one or more mutations selected from the group consisting of G2032R, S1986F, S1986Y, F2004C, F2004V, L2026M, D2033N, and G2101A; and (ii) one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227, and / or of L1982V, L1982W, S1986T, F2004I, F2004L, and / or F2075C.

10. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations comprise: (i) one or more mutations at E1935, L1947, L1951, G1971, E1974, L1982, S1986, NAI-5000260062v1 -185-Attorney Docket No.14709-046-228 F2004, E2020, L2026, G2032, D2033, C2060, F2075, L2086, V2089, V2098, G2101, D2113, 1981Tins, M2001T, and / or L2155; and (ii) one or more mutations at G1917, I1934, G1957, V1979, E1990, L2000, D2113, Q2022, M2128, H2074, H2165, L2223, and / or Y2227.

11. The method of any one of claims 1 to 4, wherein the one or more ROS1 mutations comprise a mutation at F2004 and of L1982V.

12. The method of claim 11, wherein the one or more ROS1 mutations comprise F2004C and L1982V.

13. The method of claim 11, wherein the one or more ROS1 mutations comprise F2004I and L1982V.

14. The method of claim 11, wherein the one or more ROS1 mutations comprise F2004L and L1982V.

15. The method of claim 11, wherein the one or more ROS1 mutations comprise F2004V and L1982V.

16. A method of treating a patient with solid tumor, comprising administering to said patient a therapeutically effective amount of Compound 1:or a stereoisomer, or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and wherein the solid tumor is endometrial stromal sarcoma or duodenal adenocarcinoma.

17. The method of any one of claims 1 to 16, wherein the solid tumor is advanced solid tumor.

18. The method of any one of claims 1 to 17, wherein the advanced solid tumor is relapsed after, refractory to, or resistant to the prior treatment by a tyrosine kinase inhibitor (TKI). NAI-5000260062v1 -186-Attorney Docket No.14709-046-228 19. The method of any one of claims 1 to 15 or 17 to 18, wherein the solid tumor is lung cancer.

20. The method of claim 19, wherein the solid tumor is non-small cell lung cancer (NSCLC).

21. The method of any one of claims 1 to 20, wherein the solid tumor is metastatic.

22. The method of claim 21, wherein the solid tumor is CNS metastatic.

23. The method of any one of claims 1 to 22, wherein the solid tumor further comprises a ROS1 fusion.

24. The method of any one of claims 1 to 23, wherein the compound is administered at an amount of from about 50 mg to about 250 mg (by weight of Compound 1) once (QD) or twice (BID) daily.

25. The method of claim 24, wherein the compound is administered at an amount of about 50 mg (by weight of Compound 1) twice (BID) daily.

26. The method of claim 24, wherein the compound is administered at an amount of about 100 mg (by weight of Compound 1) once (QD) daily.

27. The method of claim 24, wherein the compound is administered: (a) at an amount of about 100 mg, about 75 mg, or about 50 mg (by weight of Compound 1) once (QD) daily to a patient 18 years old; (b) at an amount of about 100 mg, about 75 mg, or about 50 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing 40 kg; or (c) at an amount of about 75 mg, about 50 mg, or about 25 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg.

28. The method of claim 24, wherein the compound is administered: (a) at an amount of about 100 mg (by weight of Compound 1) once (QD) daily to a patient 18 years old; (b) at an amount of about 100 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing 40 kg; or (c) at an amount of about 75 mg (by weight of Compound 1) once (QD) daily to a patient 12 and < 18 years old and weighing < 40 kg. NAI-5000260062v1 -187-Attorney Docket No.14709-046-228 29. The method of any one of claims 1 to 28, wherein the compound is administered orally.

30. The method of any one of claims 1 to 29, wherein the compound is Compound 1 free base.

31. A computer-implemented method for indicating the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R), the method comprising: determining, based at least on a three-dimensional representation of the crystal structure of ROS1 G2032R, a co-crystal structure of a ROS1 G2032R-ligand complex comprising the ligand bound to ROS1 G2032R; determining a binding free energy of the ROS1 G2032R-ligand complex; and indicating, based at least on the binding free energy of the ROS1 G2032R-ligand complex, a binding affinity between ROS1 G2032R and the ligand.

32. The method of claim 31, wherein the three-dimensional representation identifies a type of each amino acid residue in ROS1 G2032R, and where the three-dimensional representation further includes, for each amino acid residue in ROS1 G2032R, atomic coordinates for each constituent atom and a connectivity therebetween.

33. The method of claim 31 or 32, wherein the crystal structure of ROS1 G2032R matches to or is generated from the structure of ROS1 G2032R in a co-crystal structure of a ROS1 G2032R- Compound 1 complex comprising Compound 1 bound to ROS1 G2032R.

34. The method of claim 33, wherein the co-crystal structure of a ROS1 G2032R-Compound 1 complex matches to the co-crystal structure shown in Figure 7A or the atomic coordinates described in Table A.

35. The method of any one of claims 31 to 34, wherein the ligand is a chemical compound.

36. The method of any one of claims 31 to 35, wherein the binding free energy of the protein- ligand complex is determined by performing one or more rounds of molecular dynamics simulation and applying a free energy perturbation processing to a result of the one or more rounds of molecular dynamics simulation.

37. A computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the NAI-5000260062v1 -188-Attorney Docket No.14709-046-228 binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 G2032R-ligand complex comprising the ligand bound to ROS1 G2032R, such that the amino acid residue at position 2032 is changed from arginine (R) to glycine (G) (i.e., R G modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB); andwherein GBindicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

38. A computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 G2032R-ligand complex comprising the ligand bound to ROS1 G2032R, such that the amino acid residue at position 2032 is changed from arginine (R) to glycine (G) (i.e., R G modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB);(ii-a) modifying a three-dimensional representation of a crystal structure of a ROS1 G2032R protein, such that the amino acid residue at position 2032 is changed from arginine (R) to glycine (G) (i.e., R G modification); (ii-b) determining a change in the free energy of the protein as a result of themodification ( GA);(iii) determining a shift between GB and GA ( G);wherein G indicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type). NAI-5000260062v1 -189-Attorney Docket No.14709-046-228 39. The method of claim 37 or 38, wherein the three-dimensional representation of the co- crystal structure is modified by incrementally truncating the amino acid residue at position 2032 such that it is gradually changed from arginine (R) to glycine (G).

40. The method of any one of claims 37 to 39, wherein the free energy of the complex is determined based on the free energy of one or more intermediate complexes in which the ROS1 G2032R exhibits an incremental truncation of the amino acid residue at position 2032; and wherein the free energy of the protein is determined based on the free energy of one or more intermediate proteins in which the ROS1 G2032R exhibits an incremental truncation of the amino acid residue at position 2032.

41. A computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type)-ligand complex comprising the ligand bound to the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), such that the amino acid residue at position 2032 is changed from glycine (G) to arginine (R) (i.e., G R modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB); andwherein GB indicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

42. A computer-implemented method for determining the shift between the binding affinity of a ligand against a ROS1 protein exhibiting a G2032R mutation (ROS1 G2032R) and the binding affinity of the ligand against a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), the method comprising: (i-a) modifying a three-dimensional representation of a co-crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type)-ligand complex comprising the ligand bound to the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), NAI-5000260062v1 -190-Attorney Docket No.14709-046-228 such that the amino acid residue at position 2032 is changed from glycine (G) to arginine (R) (i.e., G R modification); (i-b) determining a change in the free energy of the complex as a result of themodification ( GB);(ii-a) modifying a three-dimensional representation of a crystal structure of a ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type), such that the amino acid residue at position 2032 is changed from glycine (G) to arginine (R) (i.e., G R modification); (ii-b) determining a change in the free energy of the of themodification ( GA);(iii) determining a shift between GB and GA ( G);wherein G indicates the shift between the binding affinity of the ligand against ROS1 G2032R and the binding affinity of the ligand against the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type).

43. The method of claim 41 or 42, wherein the three-dimensional representation of the co- crystal structure is modified by incrementally increasing the amino acid residue at position 2032 such that it is gradually changed from glycine (G) to arginine (R).

44. The method of any one of claims 41 to 43, wherein the free energy of the complex is determined based on the free energy of one or more intermediate complexes in which the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type) exhibits an incremental increase of the amino acid residue at position 2032; and wherein the free energy of the protein is determined based on the free energy of one or more intermediate proteins in which the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type) exhibits an incremental increase of the amino acid residue at position 2032.

45. The method of any one of claims 41 to 44, wherein the co-crystal structure of the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type)-ligand complex is determined based at least on a three-dimensional representation of the crystal structure of the ROS1 protein not exhibiting a G2032R mutation (e.g., ROS1 wild type) as described in PDB:3ZBF, 4UXL, 7Z5W, or 7Z5X.

46. A system, comprising: at least one data processor; and NAI-5000260062v1 -191-Attorney Docket No.14709-046-228 at least one memory storing instruction, which when executed by at least one data processor, result in operations comprising the method of any one of claims 31 to 45.

47. A non-transitory computer readable medium storing instruction, which when executed by at least one data processor, result in operations comprising the method of any one of claims 31 to 45. NAI-5000260062v1 -192-

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