BCR::ABL1 inhibitors for use in treating cancer

Abstract

The present disclosure is directed to methods of treating cancer in a subject in need thereof with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the disclosure. Methods for dosing a compound of the disclosure are also provided by the present disclosure.

Description

[0001] Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0002] BCR::ABL1 INHIBITORS FOR USE IN TREATING CANCER

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to and the benefit of U.S. Provisional Application Nos. 63 / 727,087, filed on December 2, 2024; 63 / 742,200 filed on January 6, 2025; 63 / 762,598 filed on February 24, 2025; 63 / 765,328 filed on February 28, 2025; and 63 / 903,650 filed on October 22, 2025; each of which is incorporated by reference herein in its entirety for all purposes.

[0005] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0006] The contents of the electronic sequence listing (TRPH_063_001WO_SeqList_ST26.xml; Size: 44,704 bytes; and Date of Creation: November 25, 2025) are herein incorporated by reference in its entirety.

[0007] FIELD

[0008] Provided herein are compounds, preferably compounds inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Ab el son-related protein (ABL2), or a chimeric protein BCR::ABL1, compositions thereof, and methods of their preparation, and methods of inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Abelson-related protein (ABL2), or a chimeric protein BCR::ABL1, and methods for treating diseases wherein modulation of BCR::ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease.

[0009] BACKGROUND

[0010] In chronic myeloid leukemia (CML) the Philadelphia chromosome (Ph), formed by the t(9,22) reciprocal chromosome, translocates in a haematopoietic stem cell. This chromosome carries the BCR::ABL1 oncogene which encodes the chimeric BCR::ABL1 protein.

[0011] CML is a cancer that occurs when the blood-forming cells of the bone marrow overproduce white blood cells. In the United States, CML is an orphan indication with approximately 8,930 new cases expected to be diagnosed in 2023. Drugs that inhibit the tyrosine kinase activity of BCR::ABL1 via an ATP competitive mechanism, such as Gleevec® / Glivec® (imatinib), Tasigna® (nilotinib) and Sprycel® (dasatinib), may be effective in treating CML; however, some patients relapse due to the emergence of drug-resistant clones. Despite

[0012] 1

[0013] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 improvements in outcomes with active-site targeting TKIs, many patients do not achieve longterm disease control with these therapies due to resistance or intolerance, leading patients to cycle through prior generation treatments. As a result, physicians and patients are seeking additional efficacious therapies for people whose tolerability, co-morbidity and / or drug-drug interaction profiles change over time, limiting their available treatment options, quality of life and the effectiveness of mainstay therapies. Allosteric BCR::ABL1 TKIs are the only class of drug to show efficacy and tolerability benefits compared with active-site TKIs, and represent an important advancement in the treatment of CML.

[0014] Asciminib, the only currently approved allosteric BCR::ABL1 inhibitor, requires three hours of fasting with each dose, twice-daily dosing in multiple clinical settings and dose modifications and avoidance of many co-administered medications due to CYP -mediated drug interactions.

[0015] Accordingly, clinically efficacious treatments using compounds that inhibit the activity of BCR::ABL1 and BCR::ABL1 mutations via the ATP binding site, the myristoyl binding site or a combination of both sites are lacking, and the present disclosure aims to satisfy this presently unmet clinical need.

[0016] SUMMARY

[0017] In an aspect, the present disclosure is directed to a method of treating, cancer in a subject in need thereof, comprises administering to the subject a compound of Formula (I) or Formula

[0018] (I ): or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0019] L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-;

[0020] R1is optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR6R7, S(O)2NR6R7, NR6COR7, or NR6SO2R7, or C(O)OR6;

[0021] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0022] R2is H, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl;

[0023] R3is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR6, or NR6R7; or

[0024] R2and R3together with the intervening atoms form cycloalkyl or heterocycloalkyl, preferably an optionally substituted Cs-Cs cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;

[0025] R4is optionally substituted Ci-Ce alkyl, preferably C1-C3 haloalkyl, such as CF3 or CF2CI, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0026] X is O or S;

[0027] Y is CH, C-(Ci-C2 alkyl), or C-halo or N;

[0028] Z is CR5or N;

[0029] R5is H or halogen;

[0030] R6is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl; and

[0031] R7is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl; or

[0032] R6and R7together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocycle;

[0033] (I’), or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0034] 3

[0035] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 ring A’ is selected from C3-6 cycloalkyl, 4-7-membered heterocyclyl, Ce-io aryl or 5-7- membered heteroaryl;

[0036] Ri’ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 haloalkoxy;

[0037] Mi is selected from N or CRa;

[0038] M2 is selected from NRa or C(Ra)2;

[0039] M3 is selected from N or CRa; each Ra is independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 haloalkoxy;

[0040] R2’ and R3’ are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-7-membered heterocyclyl, Ce-io aryl or 5-7-membered heteroaryl; and n is 0, 1 or 2.

[0041] In some embodiments, the present disclosure is directed to a method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 40%.

[0042] In some embodiments, the present disclosure is directed to a method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 60%.

[0043] In some embodiments, the present disclosure is directed to a method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof by administering a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the

[0044] 4

[0045] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 pharmaceutical composition comprising a compound of the disclosure to the subject, wherein the cancer is a leukemia.

[0046] In some embodiments, the present disclosure is directed to a method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, wherein the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered with food.

[0047] In some embodiments, the present disclosure is directed to a method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, wherein the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered without food.

[0048] In some embodiments, the present disclosure is directed to a kit comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, and printed instructions for using a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure in a subject for the treatment for leukemia.

[0049] In some embodiments, the present disclosure is directed to a method of inhibiting tyrosine kinase enzymatic activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-related protein (ABL2), and a chimeric protein BCR::ABL1, comprising administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 40%.

[0050] In some embodiments, the present disclosure is directed to a method of inhibiting tyrosine kinase enzymatic activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-related protein (ABL2), and a chimeric protein BCR::ABL1, comprising administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under

[0051] 5

[0052] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 fed conditions and Cmax of the compound if administered under fasted conditions is less than about 60%.

[0053] In some embodiments, the present disclosure is directed to a method of treating a disease, wherein modulation of BCR::ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease, in a subject, comprising administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 40%.

[0054] In some embodiments, the present disclosure is directed to a method of treating a disease, wherein modulation of BCR::ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease, in a subject, comprising administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 60%.

[0055] In some embodiments, the present disclosure is directed to a method of treating leukemia in a subject comprising administering to the subject a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0056] In some embodiments, a compound of the disclosure is prepared as provided in U.S. Patent No. 10,889,571; U.S. Patent Publication No. 2024 / 0400582; and WO 2024 / 199447; the contents of each of which are incorporated by reference.

[0057] In some embodiments, the present disclosure provides a method of treating a cancer, the method comprising administering a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, to a subject in need thereof at a dosage disclosed herein.

[0058] In some embodiments, the present disclosure provides a method of treating a cancer, the method comprising administering a composition comprising a compound of the disclosure, or the

[0059] 6

[0060] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 pharmaceutically acceptable salt thereof, to a subject in need thereof at a dosage disclosed herein.

[0061] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof for use in treating a cancer in a subject in need thereof at a dosage disclosed herein.

[0062] In some embodiments, the present disclosure provides a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure for use in treating a cancer in a subject in need thereof at a dosage disclosed herein.

[0063] In some embodiments, the present disclosure provides a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure for use in treating leukemia in a subject in need thereof at a dosage disclosed herein.

[0064] In some embodiments, described herein is use of a composition (e.g., a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof) in the manufacture of a medicament for the treatment of a cancer in a subject in need thereof at a dosage disclosed herein.

[0065] In some embodiments, described herein is use of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure in the manufacture of a medicament for the treatment of a cancer in a subject in need thereof at a dosage disclosed herein.

[0066] In some embodiments, described herein is use of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure in the manufacture of a medicament for the treatment of leukemia in a subject in need thereof at a dosage disclosed herein.

[0067] In some embodiments, provided herein is a method of inhibiting tyrosine kinase enzymatic activity of a protein selected from the group consisting of Abelson protein (ABL1), Abelson-related protein (ABL2), and a chimeric protein BCR::ABL1, comprising contacting an effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, to the protein.

[0068] In some embodiments, provided herein is a method of treating a disease, wherein modulation of BCR::ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease, in a subject, comprising administering to the subject a

[0069] 7

[0070] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure.

[0071] In some embodiments, provided herein is a method of treating leukemia in a subject comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0072] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is administered to a fed subject at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 40%.

[0073] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound, is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 2,000 ng*h / mL to about 2,200 ng*h / mL.

[0074] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 2,500 ng*h / mL to about 2,600 ng*h / mL.

[0075] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 2,200 ng*h / mL to about 2,300 ng*h / mL.

[0076] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 160 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 6,500 ng*h / mL to about 6,700 ng*h / mL.

[0077] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 70 ng / mL to about 150 ng / mL.

[0078] 8

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[0080] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 250 ng / mL to about 350 ng / mL.

[0081] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 350 ng / mL to about 460 ng / mL.

[0082] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fed conditions, wherein after administration the Cmax of the compound is from about 200 ng / mL to about 330 ng / mL.

[0083] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 160 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 800 ng / mL to about 950 ng / mL.

[0084] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the second TKI binds to the active site of the BCR:ABL-1.

[0085] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 0.1% (IS).

[0086] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 0.1 % (IS) to about 1% (IS).

[0087] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 1% (IS).

[0088] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 1 % (IS) to about 10% (IS).

[0089] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 10% (IS).

[0090] 9

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[0092] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of greater than 10% (IS).

[0093] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound of Formula (I) is Compound 5a: (Compound 5 a), or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound of Formula (I) is Compound 5:

[0095] (Compound 5), or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound of Formula (I1) is Compound 234: (Compound 234), or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the compound of Formula (I1) is Compound 243:

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[0099] (Compound 243), or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising (i) a compound of Formula (I), or a pharmaceutically acceptable salt thereof; and (ii) an excipient.

[0101] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 50 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0102] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 80 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0103] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 100 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0104] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 160 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0105] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 175 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0106] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 250 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0107] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 320 mg of the compound of Formula (I) is present in the pharmaceutical composition.

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[0109] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 350 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0110] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 400 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0111] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 500 mg of the compound of Formula (I) is present in the pharmaceutical composition.

[0112] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein the compound of Formula (I) is present as a salt.

[0113] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising: (i) Compound 5, or a pharmaceutically acceptable salt thereof; and (ii) an excipient.

[0114] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 50 mg of Compound 5 is present in the pharmaceutical composition.

[0115] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 80 mg of Compound 5 is present in the pharmaceutical composition.

[0116] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 100 mg of Compound 5 is present in the pharmaceutical composition.

[0117] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 160 mg of Compound 5 is present in the pharmaceutical composition.

[0118] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 175 mg of Compound 5 is present in the pharmaceutical composition.

[0119] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 250 mg of Compound 5 is present in the pharmaceutical composition.

[0120] 12

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[0122] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 320 mg of Compound 5 is present in the pharmaceutical composition.

[0123] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 350 mg of Compound 5 is present in the pharmaceutical composition.

[0124] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 400 mg of Compound 5 is present in the pharmaceutical composition.

[0125] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 500 mg of Compound 5 is present in the pharmaceutical composition.

[0126] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein Compound 5 is present as a salt.

[0127] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising (i) a compound of Formula (I’), or a pharmaceutically acceptable salt thereof; and (ii) an excipient.

[0128] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 50 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0129] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 80 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0130] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 100 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0131] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 160 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0132] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 175 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0133] 13

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[0135] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 250 mg of the compound of Formula (I’) is present in the pharmaceutical composition.

[0136] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 320 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0137] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 350 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0138] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 400 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0139] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 500 mg of the compound of Formula (F) is present in the pharmaceutical composition.

[0140] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein the compound of Formula (F) is present as a salt.

[0141] In some embodiments, the present disclosure is directed to a pharmaceutical composition comprising: (i) Compound 243, or a pharmaceutically acceptable salt thereof; and (ii) an excipient.

[0142] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 50 mg of Compound 243 is present in the pharmaceutical composition.

[0143] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 80 mg of Compound 243 is present in the pharmaceutical composition.

[0144] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 100 mg of Compound 243 is present in the pharmaceutical composition.

[0145] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 160 mg of Compound 243 is present in the pharmaceutical composition.

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[0148] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 175 mg of Compound 243 is present in the pharmaceutical composition.

[0149] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 250 mg of Compound 243 is present in the pharmaceutical composition.

[0150] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 320 mg of Compound 243 is present in the pharmaceutical composition.

[0151] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 350 mg of Compound 243 is present in the pharmaceutical composition.

[0152] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 400 mg of Compound 243 is present in the pharmaceutical composition.

[0153] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein about 500 mg of Compound 243 is present in the pharmaceutical composition.

[0154] In some embodiments, the present disclosure is directed to a pharmaceutical composition disclosed herein, wherein compound 243 is present as a salt.

[0155] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject was previously administered asciminib; during the course of the administration of asciminib to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 5 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

[0156] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject was previously administered asciminib; during the course of the administration of asciminib to the subject, BCR: :ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and

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[0158] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 following the administration of Compound 243 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

[0159] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject wherein the subject was previously administered a tyrosine kinase inhibitor (TKI) that binds to the ATP -binding site of the BCR::ABL1 protein; during the course of the administration of the previously- administered TKI to the subject, BCR::ABL-1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 5 to the subject, BCR::ABL-1 transcript levels in the subject decreased to less than 0.1% (IS).

[0160] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject was previously administered a tyrosine kinase inhibitor (TKI) that binds to the ATP -binding site of the BCR::ABL1 protein; during the course of the administration of the previously- administered TKI to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 243 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

[0161] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject wherein: the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject expresses a mutant form of BCR:ABL1 containing (ii-a) a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H and E459K; or (ii-b) multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T3151, (iii) E255V and T3151, (iv) H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

[0162] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject, wherein: the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject

[0163] 16

[0164] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 expresses a mutant form of BCR:ABL1 containing (ii-a) an amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H and E459K; or (ii-b) multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T3151, (iii) E255V and T3151, (iv) H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

[0165] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject expresses a mutant form of BCR:ABL1 containing (ii-a) a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F; or (ii-b) multiple amino acid mutations selected from (i) G250E and T3151, (ii) Y253H and T3151, (iii) E255V and T3151, (iv) H396R and T315I, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

[0166] In some embodiments, the present disclosure is directed to a method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject expresses a mutant form of BCR:ABL1 containing (ii-a) an amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F; or (ii-b) multiple amino acid mutations selected from (i) G250E and T3151, (ii) Y253H and T3151, (iii) E255V and T3151, (iv) H396R and T315I, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

[0167] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein Compound 5 is administered at a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg.

[0168] 17

[0169] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0170] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein Compound 243 is administered at a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg.

[0171] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein Compound 5 or Compound 243 is administered as a pharmaceutically acceptable salt.

[0172] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein a pharmaceutically acceptable salt of Compound 5 is administered in an amount such that a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg of Compound 5 is provided.

[0173] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein a pharmaceutically acceptable salt of Compound 243 is administered in an amount such that a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg of Compound 243 is provided.

[0174] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject is able to receive a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or OATP1B1 / 3.

[0175] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or OATP1B1 / 3.

[0176] In some embodiments, the present disclosure is directed to a method disclosed herein further comprising advising the subject that the administration according to a method of any one of the embodiments disclosed herein does not alter a concurrent treatment with a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or OATP1B1 / 3.

[0177] In some embodiments, the present disclosure is directed to a method disclosed herein further comprising advising the subject that administration of a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or OATP1B1 / 3 does not alter the concurrent administration according to the method of any one of the previous embodiments.

[0178] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP3A4.

[0179] 18

[0180] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0181] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP2C19.

[0182] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP2D6.

[0183] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP2C8.

[0184] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP3A.

[0185] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP2C9.

[0186] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of BCRP.

[0187] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of OATP1B1 / 3.

[0188] In some embodiments, the present disclosure is directed to a method disclosed herein, wherein the subject concurrently receives a substrate of CYP3A4, and / or CYP2C19.

[0189] In some embodiments, the present disclosure is directed to a method of treating a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, and a statin to the subject in need thereof.

[0190] In some embodiments, the present disclosure is directed to a method of treating a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, and a statin to the subject in need thereof.

[0191] In some embodiments, the present disclosure is directed to a method of treating a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, and a substrate of CYP3A4 to the subject in need thereof.

[0192] In some embodiments, the present disclosure is directed to a method of treating a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, and a substrate of CYP3 A4 in need thereof.

[0193] In some embodiments, the present disclosure is directed to a method of co-administrating pharmaceutically active compounds, the method comprising: (a) administering to a subject Compound 5, Compound 243, or a pharmaceutically acceptable salt thereof; and (b) administering to the subject a statin.

[0194] 19

[0195] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0196] In some embodiments, the present disclosure is directed to a method of treating cancer in a subject in need thereof, the method comprising administering to the subject Compound 5, Compound 243, or a pharmaceutically acceptable salt thereof, wherein said subject has received administration of a statin for more than 1 week prior to administering to the subject Compound 5, Compound 243, or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the present disclosure is directed to a method of treating a cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a statin, wherein said subject has received administration of Compound 5, Compound 243, or a pharmaceutically acceptable salt thereof for more than 1 week prior to administering to the subject the statin.

[0198] BRIEF DESCRIPTION OF THE DRAWINGS

[0199] The accompanying drawings, which are incorporated into and form a part of the specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating an embodiment of the disclosure and are not to be construed as limiting the disclosure. Further objects, features and advantages will become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the disclosure.

[0200] FIG. 1A depicts the PK profiles following administration, at fasted conditions, of single doses of 20 mg, 40 mg, 80 mg, and 160 mg up to 24 hours postdose. Below limit of quantification (BLQ) values after first measurable concentration are reported as1 / 2*(lower limit of quantification, LLOQ) in the figure. LLOQ is 1 ng / mL. IC90 values shown in figure are as follows: KCL22-S (most sensitive non-T315I cell lines) total IC90 = 15.3 ng / mL; KCL22-r (least sensitive non-T315I cell lines) total IC90 = 72.2 ng / mL.

[0201] FIG. IB depicts the PK profiles following administration, at fasted and fed conditions, of a single dose of 80 mg up to 24 hours postdose. Below limit of quantification (BLQ) values after first measurable concentration are reported as1 / 2*LLOQ in the figure. LLOQ is 1 ng / mL.

[0202] FIGS. 2A and 2B provide schematic representations of Part 1 and Part 2 of a multicenter global Phase I study of Compound 5 in patients with relapsed / refractory chronic phase chronic myeloid leukemia (CML). The study population was chronic phase 2L + CML patients w / wo BCR::ABL1 mutations who have had treatment failure / suboptimal response to > 1 2G-TKI or treatment failure / suboptimal response / intol erance to > 2 active-site TKIs. Prior asciminib was

[0203] 20

[0204] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 allowed. 2G-TKI = dasatinib, nilotinib or bosutinib. R.DE: recommended dose for expansion will be selected following a Part 1 interim analysis. *Dose 1 expected to be > 160mg. Dose 2 targeted be a dose level > 160mg QD with sufficiently non-overlapping exposures and comparable safety to Dose 1.

[0205] FIG. 3 provides a funnel diagram illustrating a measure of efficacy in the multi center global Phase I study of Compound 5 in patients with relapsed / refractory chronic phase chronic myeloid leukemia (CML) as described in FIGs. 2A & 2B. The molecular response assessed centrally evaluating change in BCR::ABL1 International Standard (IS) transcript levels from baseline.

[0206] FIG. 4 provides a bar chart demonstrating meaningful activity in heavily pretreated patients with high baseline BCR: : ABL1. Data cut-off is from October 2024. ' Defined as having a baseline BCR::ABL1 transcript and at least two post-baseline BCR::ABL1 transcript levels (centrally assessed). BL = baseline; TKI # = Number of prior TKIs; Asc? = Prior asciminib; Y = yes; N = no; Mut = BCR::ABL1 Mutation.

[0207] FIG. 5 provides a bar chart showing that 88% of patients with baseline transcript > 1% have decreases in BCR::ABL1 levels on treatment. Eight response evaluable (defined as having centrally assessed baseline and at least two post-baseline BCR::ABL1 transcript levels) patients had baseline transcript >1%; 6 had baseline transcript >10%; 4 had prior asciminib and 3G TKI** . 88% (7 / 8) have decrease in BCR::ABL1 and remain on treatment as of data cut-off. There was one discontinuation due to loss of response after >50% decline in BCR::ABL1 in a 6L patient with T3151 mutation. Data cut-off is from October 2024. **3G TKI= ponatinib / olverembatinib / ELVN-001.

[0208] FIGS. 6A, 6B, 6C, and 6D provide schematics (FIGS. 6A and 6C) and line graphs (FIGS. 6B and 6D), respectively, demonstrating that Compound 5 deepens the response in a patient with a suboptimal response to asciminib. MR2 was attained in a 4L patient previously treated with dasatinib, ponatinib & asciminib with Baseline BCR::ABL1 >1% and after response plateau on asciminib. Data cut-off is from October 2024 (FIGS. A and B) and May 2025 (FIGS. C and D). * Hypertriglyceridemia / elevated liver function tests; MR1 : at least 1-log reduction; MR2: at least a 2-log reduction (i.e., BCR::ABL1IS< 1%); cycle = 28 days.

[0209] FIGS. 7A and 7B provide a schematic and line graph, respectively, demonstrating that Compound 5 produces a rapid deep molecular response in 5L patient with BCR::ABL1 >10%. Surprisingly, MR4 was attained in a patient exposed to imatinib and all 2G TKIs with loss of response to bosutinib and baseline transcript >10%. Further, DMR was attained on Compound 5

[0210] 21

[0211] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 after 3 months. Data cut-off is from March 2025. BL: baseline; MMR: major molecular response; ND: not detectable; LFTs: liver function tests; MR: molecular response, MR4: at least 4-log reduction (i.e., BCR::ABL1IS< 0.01%); cycle = 28 days.

[0212] FIG. 7C provides a schematic and line graph demonstrating that Compound 5 induces early MMR in F317Lm patient with prior treatment failure on asciminib and ELVN-001. Data cut-off is from May 2025. *lipase elevations; BL: baseline; MMR: major molecular response; MR4: at least 4-log reduction (i.e., BCR::ABL1IS< 0.01%); cycle = 28 days.

[0213] FIG. 8 provides results demonstrating that the molecular response shifts with Compound 5 in patients with baseline transcript > 1% are trending favorably compared to asciminib. Compound 5 shows early molecular response shifts in more refractory patient population than an asciminib Phase I study. Asciminib showed <5% and <10% major molecular response (MMR) at 3 months in patients with baseline >10% and >1-10% BCR::ABL1, respectively. At 3 months, Compound 5 in a more refractory population shows: (a) 1 / 5 with baseline > 10% achieving >MMR with 4 / 5 ongoing with decreasing BCR::ABL1 and (b) 1 / 2 with baseline >1-10% achieving MR2 after asciminib and 2 / 2 ongoing with decreasing BCR::ABL1. Data cut-off is from October 2024.

[0214] FIGS. 9A and 9B provide results demonstrating that Compound 5 achieves robust target coverage over mutated and non-mutated BCR::ABL1 variants with QD dosing. FIG. 9A shows linear PK with approximately dose proportional increases in exposure. FIG. 9B shows starting doses attain exposures exceeding in vitro IC90 for multiple CML variants. Cave = Caverage; in vitro IC90 values corrected for protein binding and converted to Ceff in human plasma; *denotes myristoyl mutations or mutations indicated in resistance to allosteric inhibition of BCR::ABL1.

[0215] FIG. 10 provides results demonstrating that Compound 5 is highly potent against multiple BCR::ABL1 mutations in preclinical assays. In vitro ICso values were determined via cytotoxicity assay. The symbol * denotes myristoyl mutations or mutations indicated in resistance to allosteric inhibition of BCR:: ABLE KCL22s is a non-mutant cell line, while all mutations on the plot were developed in a BaF3 cell line background.

[0216] FIG. 11A depicts the PK profiles following administration, at fasted conditions, of single doses of Compound 5 at 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, and 400 mg up to 24 hours postdose.

[0217] FIG. 11B depicts the PK profiles following administration, at fasted and fed conditions, of a single dose of Compound 5 at 80 mg up to 24 hours postdose.

[0218] 22

[0219] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0220] FIGS. 12A and 12B depict the PK profiles of midazolam following administration, at fasted conditions, of midazolam alone, midazolam + 160 mg Compound 5, and midazolam + 400 mg Compound 5 for up to 4 hours post dose (FIG. 12A) and up to 24 hours post dose (FIG. 12B). BLQ values after first measurable concentration are reported as ' / ALLOC in the figure. LLOQ = 0.1 ng / mL.

[0221] FIGS. 13A and 13B depict the PK profiles of 1-OH midazolam (metabolite of midazolam) following administration, at fasted conditions, of midazolam alone, midazolam + 160 mg Compound 5, and midazolam + 400 mg Compound 5 for up to 4 hours post dose (FIG. 13A) and up to 24 hours post dose (FIG. 13B). BLQ values after first measurable concentration are reported as ’ / ALLOQ in the figure. LLOQ = 0.1 ng / mL.

[0222] FIGS. 14A and 14B depict the PK profiles of omeprazole following administration, at fasted conditions, of omeprazole alone, omeprazole + 160 mg Compound 5, and omeprazole + 400 mg Compound 5 for up to 4 hours post dose (FIG. 14 A) and up to 16 hours post dose (FIG. 14B). BLQ values after first measurable concentration are reported as ’ / ALLOQ in the figure. LLOQ = 10 ng / mL.

[0223] FIGS. 15A and 15B depict the PK profiles of 5-OH-omeprazole (metabolite of omeprazole) following administration, at fasted conditions, of omeprazole alone, omeprazole + 160 mg Compound 5, and omeprazole + 400 mg Compound 5 for up to 4 hours post dose (FIG. 15A) and up to 12 hours post dose (FIG. 15B). BLQ values after first measurable concentration are reported as ’ / ALLOQ in the figure. LLOQ = 10 ng / mL.

[0224] FIGS. 16A and 16B depict the PK profiles of digoxin following administration, at fasted conditions, of digoxin alone, digoxin + 160 mg Compound 5, and digoxin + 400 mg Compound 5 for up to 4 hours post dose (FIG. 16A) and up to 72 hours post dose (FIG. 16B). BLQ values after first measurable concentration are reported as ’ / ALLOQ in the figure. LLOQ = 0.1 ng / mL.

[0225] FIG. 17 compares drug-drug interactions for Compound 5 based on the results of Example 4 against warnings and restrictions found on the asciminib drug label.

[0226] DETAILED DESCRIPTION

[0227] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0228] 23

[0229] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0230] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0231] As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination. For example, a composition consisting essentially of the elements as defined herein would not exclude other elements that do not materially affect the basic and novel characteristic(s) of the claims. “Consisting of’ shall mean excluding more than trace amount of, e.g., other ingredients and substantial method steps recited. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0232] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0233] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0234] As used herein, the term “patient” refers to mammals and includes humans and nonhuman mammals. Examples of patients include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.

[0235] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject in need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A

[0236] 24

[0237] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. Examples of a subject in need thereof include, but are not limited to mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, a subject in need thereof refers to a human.

[0238] As used herein, the term “pharmaceutically acceptable” refers to safe and non-toxic, preferably for in vivo, more preferably, for human administration.

[0239] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically-acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0240] Included in the present teachings are pharmaceutically acceptable salts of the compound. Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of compounds include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, succinic, and trifluoroacetic acid acids). Compounds with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0241] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary

[0242] 25

[0243] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.

[0244] As used herein, the term “pharmaceutical composition” is a formulation containing a compound of the disclosure of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the subject or patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of the compound include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0245] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected into the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the subject or patient should preferably be closely monitored during and for a reasonable period after treatment.

[0246] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0247] As used herein, the term “prodrug” refers to a compound that, after administration, is metabolized or otherwise converted to a biologically active or more active compound (or drug)

[0248] 26

[0249] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 with respect to at least one property. A prodrug, relative to the drug, is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered. A prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavor (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference). A prodrug may be synthesized using reactants other than employing the corresponding drug.

[0250] As used herein, the term “salt” refers to an ionic compound formed between an acid and a base.

[0251] As used herein, the term “treating” or “treatment” of a disease in a subject refers to 1) preventing the disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a subject or a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the disclosure contemplate any one or more of these embodiments or aspects of treatment.

[0252] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.

[0253] The term “fed conditions” refers to the consumption or uptake of calories, in either solid or liquid forms, or calories, in any suitable form, before or at the same time when a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical

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[0255] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 composition comprising a compound of the disclosure is administered. For example, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure may be administered to the subject (e.g., a human) within minutes or hours of consuming calories (e.g., a meal). In some embodiments, the active ingredients may be administered to the subject (e.g., a human) within 5- 10 minutes, about 30 minutes, about 60 minutes, about 90 minutes, about 120 minutes, or about 150 minutes of consuming calories.

[0256] The term "‘fasted conditions” refers to a subject (e.g., a human) fasting at least about 1 hour before or after being administered a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure.

[0257] As used herein, the term “optional” or “optionally” as used throughout the specification means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0258] As used herein, the term “stereoisomer” or “stereoisomers” refer to compounds that differ in the stereogenicity of the constituent atoms such as, without limitation, in the chirality of one or more stereocenters or related to the cis or trans configuration of a carbon-carbon or carbonnitrogen double bond. Stereoisomers include enantiomers and diastereomers.

[0259] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of the compound. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms, such as solvates, prodrugs, or isotopomers, of the compound. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the disclosure. All forms of the compound are also embraced by the disclosure, such as crystalline or noncrystalline forms of the compound. Compositions comprising a compound of the disclosure of the disclosure are also intended, such as a composition of substantially pure a compound of the disclosure, including a specific stereochemical form thereof. Compositions comprising a mixture of two or more stereochemical forms of the compound in any ratio are also embraced by the disclosure, such that racemic, non-racemic, enantioenriched and scalemic mixtures of the compound are embraced.

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[0262] Unless explicitly indicated otherwise, the terms “approximately” and “about” are synonymous. In one embodiment, “approximately” and “about” refer to the recited amount, value, or duration ± 5%, ± 4.5%, ± 4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5% ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01%. In another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5%. In yet another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±1%. In yet another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±0.5%. In yet another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±0.1%.

[0263] As used herein, the phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0264] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally

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[0266] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0267] Abbreviations

[0268] Compounds

[0269] In some embodiments, the compound is of Formula (I)

[0270] (I), or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein:

[0271] L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-;

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[0274] R1is optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR6R7, S(O)2NR6R7, NR6COR7, or NR6SO2R7, or C(O)OR6;

[0275] R2is H, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl;

[0276] R3is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR6, or NR6R7; or

[0277] R2and R3together with the intervening atoms form cycloalkyl or heterocycloalkyl, preferably an optionally substituted Cs-Cs cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;

[0278] R4is optionally substituted Ci-Ce alkyl, preferably C1-C3 haloalkyl, such as CF3 or CF2CI, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;

[0279] X is O or S;

[0280] Y is CH, C-(Ci-C2 alkyl), or C-halo or N;

[0281] Z is CR5or N;

[0282] R5is H or halogen;

[0283] R6is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl; and

[0284] R7is H, optionally substituted Ci-Ce alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl; or

[0285] R6and R7together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocycle.

[0286] In some embodiments, the compound of Formula I is other than (i) lH-Benzimidazole-7- carboxylic acid, 5-[[(4-methoxyphenyl)sulfonyl]amino]-l -methyl- or (ii) lH-Benzimidazole-7- carboxylic acid, 5-[[(4-ethoxyphenyl)sulfonyl]amino]-l -methyl-.

[0287] In some embodiments, the compound is of Formula (F):

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[0290] (I ), or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, or solvate thereof, wherein: ring A’ is selected from C3-6 cycloalkyl, 4-7-membered heterocyclyl, Ce-io aryl or 5-7- membered heteroaryl;

[0291] Ri’ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 haloalkoxy;

[0292] Mi is selected from N or CRa;

[0293] M2 is selected from NRa or C(Ra)2;

[0294] M3 is selected from N or CRa; each Ra is independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 haloalkoxy;

[0295] R2’ and R3’ are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-7-membered heterocyclyl, Ce-io aryl or 5-7-membered heteroaryl; and n is 0, 1 or 2.

[0296] In some embodiments of the present disclosure, provided is the compound represented by formula (I’), stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein: ring A’ is Ce-io aryl or 5-6-membered heteroaryl;

[0297] Ri is selected from C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, Ci- 3 alkoxy, C13 alkylthio or C1-3 haloalkoxy;

[0298] Mi is selected from N or CH;

[0299] M2 is selected from NH or CH2;

[0300] M3 is selected from N or CH; and

[0301] R2 or R3 are each independently selected from C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 alkylthio or C1-3 haloalkoxy.

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[0304] In some embodiments of the present disclosure, the compound represented by formula (I) is further as described in general formula (II’):

[0305] In some embodiments of the present disclosure, the compound represented by formula (F) is further as described in general formula (II-a’ ):

[0306] In some embodiments of the present disclosure, the compound represented by formula (I’) is further as described in general formula (II-b’):

[0307] In some embodiments, ring A’ is phenyl or pyridyl;

[0308] Ri’ is selected from C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or C1-3 haloalkoxy;

[0309] Mi is N;

[0310] M2 is NH;

[0311] M3 is N; and

[0312] R2’ and R3’ are each independently selected from hydrogen, C1-3 alkyl or C1-3 haloalkyl.

[0313] In some embodiments, Ri’ is selected from -CHF2, -CF3, -CF2CI, -OCHF2, -OCF3 or - OCF2CI; and

[0314] R2’ and R3’ are each independently selected from -CH3, -CH2CH3, -CHF2, -CF3 or - CF2CI.

[0315] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.

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[0318] Table 1. Compounds of the present disclosure

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[0389] In some embodiments, the compound is selected from Compound 1, 2a, 3, 4, 5a, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 25, 26, 27, 28a, 29, 30, 31, 32a, 33a, 34a, 35a, 36a, 37, 38a, 39a, 40a, 41a, 42a, 43a, 44a, 45a, 46a, 47a, 48a, 49a, 50, 51, 52, 53, 54, 55, 56a, 57a, 58a, 59a, 61a, 63, 64a, 66a, 67a, 68, 70a, 71a, 72, 76a, 77a, 80, 81, 82, 83a, 85, 86, 87a, 89, 90a, 91, 92, 93, 94, 96a, 97, 99a, 100, 102a, 104, 105a, 107, 108, 109, 110a, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123a, 125a, 127, 128, 130, 131a, 132a, 133a, 134, 136, 139, 140, 141a, 142a, 143, 144a, 145, 146a, 147, 148a, 149a, 150a, 151, 152a, 153a, 154a, 155a, 156a, 157a, 158a, 159a, 160a, 161a, 162a, 163a, 164a, 165a, 166a, 167a, 168a, 169a, 170a, 170, 171a, 173a, 174a, 175a, 176a, 177a, 178a, 179a, 182a, 184, 185a, 186, 187a, 189a, 190, 192a, 193, 194, 195a, 196a, 197a, 198a, 199a, 200a, 201, 202a, 203a, 204a, 205a, 206a, 207a, 208a, 210a, 212, 213, 214a, 215a, 216a, 217a, 218, 219a, 220a, 221a, 222a, 223a, 224a, 226a, 227a, 228a, 229a, 230a, 232a, 233, 234, 235, 236, 237, 238, 239, 240, or 241, or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof.

[0390] In some embodiments, the compound is selected from Compound 2, 5, 24, 28, 32, 33, 34,

[0391] 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 56, 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 69,

[0392] 70, 71, 73, 74, 75, 76, 77, 78, 79, 83, 84, 87, 88, 90, 95, 96, 98, 99, 101, 102, 103, 105, 106, 110, 123, 124, 125, 126, 129, 131, 132, 133, 135, 137, 138, 141, 142, 144, 146, 148, 149, 150, 152,

[0393] 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 171, 172,

[0394] 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 185, 187, 188, 189, 191, 192, 195, 196,

[0395] 197, 198, 199, 200, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 214, 215, 216, 217, 219,

[0396] 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 242, 243, 244, 245, 246, 247,

[0397] 248, 249, or 250, or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof.

[0398] In some embodiments, the compound is selected from Compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,

[0399] 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,

[0400] 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,

[0401] 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109,

[0402] 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128,

[0403] 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147,

[0404] 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166,

[0405] 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185,

[0406] 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204,

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[0409] 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250, or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof.

[0410] In some embodiments, the compound is selected from:

[0411] Compounds 1-250 of U.S. Provisional Application No. 63 / 727,087;

[0412] Compounds 1-250 of U.S. Provisional Application No. 63 / 742,200;

[0413] Compounds 1-250 of U.S. Provisional Application No. 63 / 762,598;

[0414] Compounds 1-250 of U.S. Provisional Application No. 63 / 765,328; and

[0415] Compounds 1, 2a, 2, 3, 4, 5a, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 24, 25, 26, 27, 28a, 28, 29, 30, 31, 32a, 32, 33a, 33, 34a, 34, 35a, 35, 36a, 36, 37, 38a, 38, 39a, 39, 40a, 40, 41a, 41, 42a, 42, 43a, 43, 44a, 44, 45a, 45, 46a, 46, 47a, 47, 48a, 48, 49a, 49, 50, 51, 52, 53, 54, 55, 56a, 56, 57a, 57, 58a, 58, 59a, 59, 60, 61a, 61, 62, 63, 64a, 64, 65, 66a, 66, 67a, 67, 68, 69, 70a, 70, 71a, 71, 72, 73, 74, 75, 76a, 76, 77a, 77, 78, 79, 80, 81, 82, 83a, 83, 84, 85, 86, 87a, 87, 88, 89, 90a, 90, 91, 92, 93, 94, 95, 96a, 96, 97, 98, 99a, 99, 100, 101, 102a, 102, 103, 104, 105a, 105, 106, 107, 108, 109, 110a, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123a, 123, 124, 125a, 125, 126, 127, 128, 129, 130, 131a, 131, 132a, 132, 133a, 133, 134, 135, 136, 137, 138, 139, 140, 141a, 141, 142a, 142, 143, 144a, 144, 145, 146a, 146, 147, 148a, 148, 149a, 149, 150a, 150, 151, 152a, 152, 153a, 153, 154a, 154, 155a, 155, 156a, 156, 157a, 157, 158a, 158, 159a, 159, 160a, 160, 161a, 161, 162a, 162, 163a, 163, 164a, 164, 165a, 165, 166a, 166, 167a, 167, 168a, 168, 169a, 169, 170a, 170, 171a, 171, 172, 173a, 173, 174a, 174, 175a, 175, 176a, 176, 177a, 177, 178a, 178, 179a, 179, 180, 181, 182a, 182, 183, 184, 185a, 185, 186, 187a, 187, 188, 189a, 189, 190, 191, 192a, 192, 193, 194, 195a, 195, 196a, 196, 197a, 197, 198a, 198, 199a, 199, 200a, 200, 201, 202a, 202, 203a, 203, 204a, 204, 205a, 205, 206a, 206, 207a, 207, 208a, 208, 209, 210a, 210, 211, 212, 213, 214a, 214, 215a, 215, 216a, 216, 217a, 217, 218, 219a, 219, 220a, 220, 221a, 221, 222a, 222, 223a, 223, 224a, 224, 225, 226a, 226, 227a, 227, 228a, 228, 229a, 229, 230a, 230, 231, 232a, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, and 250 (also referred to as Compounds 1-250 or the compounds of Table 1) of U.S. Provisional Application No. of 63 / 903,650, or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, or solvate thereof.

[0416] In some embodiments, provided is a compound of formula (I) such as those provided in Table 1 (Compounds 1-250), or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, or solvate thereof.

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[0419] In some embodiments, the compound is a free base.

[0420] In some embodiments, the compound is a pharmaceutically acceptable salt.

[0421] In the descriptions herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment, or aspect provided herein with respect to R1of formula (I) may be combined with every description, variation, embodiment, or aspect of R2, R3, R4, R5, R6, R7, X, L, Y, and / or Z the same as if each and every combination were specifically and individually listed. Every description, variation, embodiment, or aspect provided herein with respect to Ri of formula (I’) may be combined with every description, variation, embodiment, or aspect of Ring A’, R2’, R3’, Mi, M2, M3, and / or n the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (I) and formula (I’), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.

[0422] In some embodiments, the compound of the present disclosure (also referred to as “compound” or “compound of the disclosure”, herein) is of Formulae I, F, IF, II-a’, Il-b ’ , or of Table 1, including tautomers, N-oxides, isotopomers, prodrugs, stereoisomers, as well as pharmaceutically acceptable salts, or solvates of any of the foregoing, according to any of the embodiments herein.

[0423] In some embodiments, the compound of the present disclosure is of Formula I or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0424] In some embodiments, the compound of the present disclosure is of Formula I’ or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0425] In some embodiments, the compound of the present disclosure is of Formula IF or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0426] In some embodiments, the compound of the present disclosure is of Formula II-a’ or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

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[0429] In some embodiments, the compound of the present disclosure is of Formula II-b’ or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0430] In some embodiments, the compound of the present disclosure is of Table 1 or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0431] In some embodiments, the compound of the present disclosure is Compound 5 or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0432] In some embodiments, the compound of the present disclosure is Compound 243 or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt of any of the foregoing, or solvate thereof.

[0433] In some embodiments, the compound of the present disclosure is Compound 5 or a tautomer, or pharmaceutically acceptable salt of any of the foregoing.

[0434] In some embodiments, the compound of the present disclosure is Compound 243 or a tautomer, or pharmaceutically acceptable salt of any of the foregoing.

[0435] In some embodiments, the compound of the present disclosure is Compound 5, or pharmaceutically acceptable salt thereof.

[0436] In some embodiments, the compound of the present disclosure is Compound 243, or a pharmaceutically acceptable salt thereof.

[0437] In some embodiments, the compound of the present disclosure is a pharmaceutically acceptable salt of Compound 243.

[0438] In some embodiments, the compound of the present disclosure is a pharmaceutically acceptable salt of Compound 5.

[0439] In some embodiments, the compound of the present disclosure is Compound 5.

[0440] In some embodiments, the compound of the present disclosure is Compound 243.

[0441] Pharmaceutical Compositions and Formulations

[0442] Pharmaceutical compositions of compounds disclosed herein, or pharmaceutically acceptable salts thereof, are embraced by this disclosure.

[0443] Thus, the disclosure includes pharmaceutical compositions comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutically acceptable salt is an

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[0445] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the disclosure may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0446] “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compound provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed a compound of the disclosure.

[0447] The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and / or diluents therefore, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5thEd., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and / or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0448] The term “dosage holiday”, also referred to as “drug holiday,” refers to a period of time wherein the subject is not administered or administered at a lower dosage of the therapeutic. The timing of a dosage holiday depends on the timing of the regular dosing regimen and the purpose for taking the dosage holiday (e.g., to regain drug sensitivity and / or to reduce unwanted side

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[0450] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 effects of continuous, long- term administration). In some embodiments, the dosage holiday may be a reduction in the dosage of the drug (e.g., to below the therapeutically effective amount for a certain interval of time). In other embodiments, administration of the dosage is stopped for a certain interval of time before administration is started again at the same or different dosing regimen (e.g., at a lower or higher dose and / or frequency of administration). A dosage holiday of the disclosure may thus be selected from a wide range of time-periods and dosage regimens.

[0451] In some embodiments, compounds of the disclosure may be in a purified form and compositions comprising compounds of the disclosure in purified forms are detailed herein. Compositions comprising compounds of the disclosure or a salt thereof are provided, such as compositions of substantially pure compounds of the disclosure. In some embodiments, a composition containing compounds of the disclosure or a salt thereof is in substantially pure form. In some embodiments, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than a compound disclosed herein comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound disclosed herein intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than a compound disclosed herein or a salt thereof. In some embodiments, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound disclosed herein or a salt thereof is provided wherein the composition contains or no more than 0.5% impurity.

[0452] In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15% or preferably no more than 10% or more preferably no more than 5% or even more preferably no more than 3% and most preferably no more than 1%

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[0454] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 impurity, which impurity may be compound disclosed herein in a different stereochemical form. For instance, and without limitation, a composition of substantially pure (R) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (S) form of the compound.

[0455] In some embodiments, compounds disclosed herein are prepared for administration to a subject in need thereof, such as a human. In another variation, compositions are provided containing compounds disclosed herein in substantially pure form. In some embodiments, the disclosure embraces pharmaceutical compositions comprising compounds disclosed herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, methods of administering compounds disclosed herein are provided.

[0456] Compounds of the disclosure may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. Compounds of the disclosure may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil- in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0457] Compounds of the disclosure can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining a compound of the disclosure as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising compounds of the disclosure may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21sted. (2005), which is incorporated herein by reference.

[0458] Compounds of the disclosure may be administered to subjects (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the

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[0460] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0461] Compounds of the disclosure can be formulated in a tablet in any dosage form described. Compositions comprising compounds of the disclosure are also described. In some embodiments, the composition comprises a compound of the disclosure and a pharmaceutically acceptable carrier or excipient. In some embodiments, a composition of substantially pure compound of the disclosure is provided.

[0462] Methods of Use / Treatments

[0463] Described herein is a method of treating a cancer by administering to the subject an effective amount of the compound, or a pharmaceutically acceptable salt thereof, or the corresponding pharmaceutical composition comprising a compound of the disclosure. Compositions detailed herein, such as a pharmaceutical composition containing compounds of the disclosure, or salts thereof, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. Compounds of the disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the compounds may also be used in in vitro methods, such as in vitro methods of administering compounds of the disclosure, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition comprising compounds of the disclosure to cells for screening purposes and / or for conducting quality control assays.

[0464] In some embodiments, provided herein is a method of inhibiting tyrosine kinase enzymatic activity of a protein selected from Abelson protein (ABL1), Ab el son-related protein (ABL2), or a chimeric protein BCR::ABL1, comprising contacting an effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, to the protein. In one embodiment, provided herein is a method of inhibiting tyrosine kinase enzymatic activity of Abelson protein (ABL1) comprising contacting an effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure to ABL1. In another embodiment, provided herein is a method of inhibiting tyrosine kinase enzymatic activity of

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[0467] Abelson-related protein (ABL2) comprising contacting an effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure to ABL2. In a further embodiment, provided herein is a method of inhibiting tyrosine kinase enzymatic activity of a chimeric protein BCR::ABL1 comprising contacting an effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure to the chimeric protein. In some embodiments, provided herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure. In some embodiments, a compound of the disclosure, or salt thereof, or the composition is administered according to a dosage described herein.

[0468] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure are believed to be effective for treating a variety of diseases and disorders. In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure may be used in a method of treating a disease mediated by ABL1, ABL2, and / or BCR::ABL1.

[0469] In some embodiments, provided herein is a method of treating a disease, wherein modulation of BCR::ABL1 activity prevents, inhibits, or ameliorates the pathology and / or symptomology of the disease, in a subject, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure. In one embodiment, provided herein is a method of treating a disease, wherein modulation of BCR::ABL1 activity prevents the pathology and / or symptomology of the disease, in a subject, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure. In one embodiment, provided herein is a method of treating a disease, wherein modulation of BCR::ABL1 activity inhibits the pathology and / or symptomology of the disease, in a subject, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure. In one embodiment, provided herein is a method of treating a disease, wherein modulation of BCR::ABL1 activity ameliorates the pathology and / or symptomology of the disease, in a subject,

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[0471] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure.

[0472] In some embodiments, the disease is leukemia. In some embodiments, the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL). In some embodiments, the leukemia is chronic myeloid leukemia (CML).

[0473] In some embodiments, provided herein is a method of treating leukemia in a subject comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure. In some embodiments, provided herein is a method of treating leukemia in a subject comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the leukemia is chronic myeloid leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

[0474] In some embodiments, the leukemia treated herein is CML or ALL, and the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib. In some embodiments, the leukemia is CML or ALL, and the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and bafetinib.

[0475] In some embodiments, the leukemia is resistant to treatment. In some embodiments, the leukemia is resistant to treatment with imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib. In some embodiments, the CML is resistant to standard-of-care treatment such as treatment with one or more of imatinib, nilotinib, and dasatinib. In some embodiments, the leukemia progressed during a prior treatment. In some embodiments the prior treatment comprised administration of imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and / or bafetinib.

[0476] In some embodiments, the method further comprises administering a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

[0477] In some embodiments, the AML is secondary AML, which develops after myelodysplastic syndromes (MDS) or myeloproliferative neo-plasms (MPN).

[0478] In some embodiments, provided herein is a method of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound, or

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[0480] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure. In some embodiments, the cancer is melanoma, hereditary leiomyomatosis, renal cell carcinoma (HLRCC), or other solid tumors.

[0481] In some embodiments, the cancer is B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, breast cancer, head and neck cancer, soft tissue sarcoma, ovarian cancer, pancreatic cancer, follicular lymphoma, or mantle cell lymphoma.

[0482] In some embodiments, the cancer to be treated is a lymphoma. Lymphomas which can be treated by the disclosed methods include Non-Hodgkin’s lymphoma; Burkitt’s lymphoma; small lymphocytic lymphoma; lymphoplasmacytic lymphoma; MALT lymphoma; follicular lymphoma; diffuse large B-cell lymphoma; and T-cell lymphoma.

[0483] Lymphoma is a malignancy in the lymphatic cells of the immune system (e.g. B cells, T cells, or natural killer (NK) cells). Lymphomas often originate in the lymph nodes and present as solid tumors. They can metastasize to other organs such as the brain, bone, or skin. Extranodal sites are often located in the abdomen. Lymphomas are closely related to the lymphoid leukemia and in some cases a particular form of cancer is categorized as both a lymphoma and a leukemia.

[0484] Leukemias, which can be treated by the disclosed methods, include acute lymphoblastic leukemia (ALL); Burkitt’s leukemia; B-cell leukemia; B-cell acute lymphoblastic leukemia; chronic lymphocytic leukemia (CLL); acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML); and T-cell acute lymphoblastic leukemia (T-ALL).

[0485] In some embodiments, the cancer to be treated is B-cell neoplasms, B-cell leukemia, B- cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Burkitt's leukemia, acute myelogenous leukemia and / or T-ALL. The maturation of B cells most typically ceases or substantially decreases when the foreign antigen has been neutralized. Occasionally, however, proliferation of a particular B cell will continue unabated; such proliferation can result in a cancer referred to as "B-cell lymphoma" or a "B-cell leukemia." In some embodiments the cancer to be treated is chronic lymphocytic leukemia (CLL) or chronic myelogenous leukemia (CML).

[0486] In some embodiments, cancer which can be treated by the disclosed methods include colon cancer, liver cancer, gastric cancer, intestinal cancer, esophageal cancer, breast cancer, ovarian cancer, head and neck cancer, lung cancer, and thyroid cancer.

[0487] In some embodiments, the subject has not received prior therapy for cancer prior to being administered a compound of the present disclosure.

[0488] In some embodiments, the cancer is relapsed or refractory.

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[0491] In some embodiments, the subject has progressed on prior therapy.

[0492] In some embodiments, the subject has previously received treatment for CML.

[0493] In some embodiments, the subject has previously received a TKI treatment. In some embodiments, the subject has received one prior TKI. In some embodiments, the subject has received two prior TKIs. In some embodiments, the subject has received three prior TKIs. In some embodiments, the subject has received four prior TKIs. In some embodiments, the subject has received five prior TKIs. In some embodiments, the subject has received six prior TKIs. In some embodiments, the subject has received seven prior TKIs. In some embodiments, the subject has received eight prior TKIs. In some embodiments, the subject has received nine prior TKIs. In some embodiments, the subject has received ten prior TKIs.

[0494] In some embodiments, the prior TKI(s) are dasatinib, ponatinib, asciminib, imatinib, nilotinib, bosutinib, olverembatinib, ELVN-001, bafetinib, or combinations thereof.

[0495] In some embodiments, the subject was previously treated with at least one TKI for at least six months prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least twelve months prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least eighteen months prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least twenty -four months prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least three years prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least four years prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least five years prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least six years prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least seven years prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least eight years prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least nine years

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[0497] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 prior to the initiation of administration of a compound of the present disclosure. In some embodiments, the subject was previously treated with at least one TKI for at least ten years prior to the initiation of administration of a compound of the present disclosure.

[0498] In some embodiments, the subject has previously received at least one second generation TKI.

[0499] In some embodiments, the subject was previously treated with asciminib.

[0500] In some embodiments, the subject was previously treated with ponatinib.

[0501] In some embodiments, the subject had intolerance to one or more previously- administered TKI treatments.

[0502] In some embodiments, the subject had intolerance to asciminib.

[0503] In some embodiments, the subject had treatment failure with a previously-administered TKI.

[0504] In some embodiments, the subject had a suboptimal response to a previously- administered TKI.

[0505] In some embodiments, the subject had suboptimal response and intolerance to a previously-administered TKI.

[0506] In some embodiments, the subject had treatment failure and / or sub-optional response to at least one previously-administered second-generation tyrosine kinase inhibitor.

[0507] In some embodiments, the subject relapsed on previous treatment.

[0508] In some embodiments, the subject was refractory to previous treatment.

[0509] In some embodiments, the subject relapsed and was refractory to previous treatment.

[0510] In some embodiments, the subject had treatment failure, sub-optimal response, and / or intolerance to at least two active-site TKIs.

[0511] In some embodiments, the subject had the loss of response to a previously-administered TKI before the initiation of treatment with a compound of the present disclosure.

[0512] In some embodiments, the subject has at least one mutation in their BCR:ABL-1 gene and / or protein that is associated with resistance to BCR:ABL-1 inhibitors.

[0513] In some embodiments, the subject had at least 0.001% BCR::ABL1 (IS)% upon initiation of treatment with a compound of the present disclosure. In some embodiments, the subject had at least 0.01% BCR::ABL1 (IS)% upon initiation of treatment with a compound of the present disclosure. In some embodiments, the subject had at least 0.1% BCR: :ABL1 (IS)% upon initiation of treatment with a compound of the present disclosure. In some embodiments, the subject had at least 1% BCR::ABL1 (IS)% upon initiation of treatment with a compound of the

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[0515] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 present disclosure. In some embodiments, the subject had at least 10% BCR::ABL1 (IS)% upon initiation of treatment with a compound of the present disclosure.

[0516] In another aspect is provided a method of delaying the onset and / or development of a disease or disorder that is mediated by BCR::ABL1 activity in a subject (such as a human) who is at risk for developing the disease or disorder. It is appreciated that delayed development may encompass prevention in the event the subject or patient does not develop the disease or disorder. In some embodiments, an subject or patient at risk of developing a disease or disorder that is mediated by BCR::ABL1 activity has one or more risk factors for developing the disease or disorder, such as a family history of an subject or patient having the disease or disorder, or having an underlying genetic condition that is associated with an increased likelihood of developing the disease or disorder.

[0517] In some embodiments, provided herein is a method of delaying the onset and / or development of leukemia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure provided herein. In some embodiments, provided herein is a method of delaying the onset and / or development of CML in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure provided herein. In some embodiments, provided herein is a method of delaying the onset and / or development of AML in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure provided herein. In some embodiments, provided herein is a method of delaying the onset and / or development of ALL in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure provided herein.

[0518] Methods of treating a disease mediated by BCR::ABL1, such as various leukemias and the like, are well known to the skilled artisan and can be adapted to treating such a disease with a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure provided herein.

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[0521] In some embodiments, the subject is a mammal. In some embodiments, the subject is a primate, dog, cat, rabbit, or rodent. In some embodiments, the subject is a primate. In some embodiments, the subject is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old. In some embodiments, the subject has a genetic condition that is associated with an increased likelihood of developing the disease, such as the leukemia. In some embodiments, the subject has a mutation in the ABL1 and / or ABL2 gene. In some embodiments, the subject is Philadelphia chromosome positive.

[0522] In some embodiments, the patient is a mammal. In some embodiments, the patient is a primate, dog, cat, rabbit, or rodent. In some embodiments, the patient is a primate. In some embodiments, the patient is a human. In some embodiments, the human is at least about or is about any of 18, 21, 30, 50, 60, 65, 70, 75, 80, or 85 years old. In some embodiments, the human is a child. In some embodiments, the human is less than about or about any of 21, 18, 15, 10, 5, 4, 3, 2, or 1 years old. In some embodiments, the patient has a genetic condition that is associated with an increased likelihood of developing the disease, such as the leukemia. In some embodiments, the patient has a mutation in the ABL1 and / or ABL2 gene. In some embodiments, the patient is Philadelphia chromosome positive.

[0523] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure provided herein may be administered to a subject in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the subject’s life. In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered on a daily or intermittent schedule. In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure can be administered to a subject continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months,

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[0525] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 about 6 months or more). Any of the dosing frequencies can employ a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure together with any of the dosages described herein.

[0526] A compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure may be administered to a subject via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral and transdermal.

[0527] The dose of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure administered to a subject may vary with the particular method of administration, and the particular disease. In some embodiments, the amount of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is a therapeutically effective amount.

[0528] Also provided herein are uses of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure described herein, in the manufacture of a medicament. In some embodiments, the manufacture of a medicament is for the treatment of a disease described herein. In some embodiments, the manufacture of a medicament is for the treatment of a disease mediated by ABL1, ABL2, and / or BCR::ABL1.

[0529] In some embodiments, the present disclosure provides a method of treating a cancer comprising administering to a subject in need thereof the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, at a dosage from about 5 mg to about 700 mg.

[0530] In some embodiments, the present disclosure provides a method of treating a cancer comprising administering to a subject in need thereof a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, at a dosage from about 5 mg to about 700 mg.

[0531] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 700 mg.

[0532] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 650 mg.

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[0535] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 600 mg.

[0536] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 550 mg.

[0537] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 500 mg.

[0538] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 450 mg.

[0539] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 400 mg.

[0540] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 350 mg.

[0541] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 300 mg.

[0542] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 250 mg.

[0543] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 200 mg.

[0544] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 150 mg.

[0545] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 100 mg.

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[0548] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 50 mg to about 1000 mg.

[0549] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 50 mg to about 800 mg.

[0550] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 80 mg to about 700 mg.

[0551] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 80 mg to about 500 mg.

[0552] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 80 mg to about 400 mg.

[0553] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 160 mg to about 500 mg.

[0554] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 160 mg to about 400 mg.

[0555] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 160 mg to about 320 mg.

[0556] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 400 mg to about 500 mg.

[0557] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 320 mg to about 500 mg.

[0558] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from about 320 mg to about 400 mg.

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[0561] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 50 mg to 1000 mg.

[0562] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 50 mg to 800 mg.

[0563] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 80 mg to 700 mg.

[0564] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 80 mg to 500 mg.

[0565] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 80 mg to 400 mg.

[0566] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 160 mg to 500 mg.

[0567] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 160 mg to 400 mg.

[0568] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 160 mg to 320 mg.

[0569] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 400 mg to 500 mg.

[0570] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 320 mg to 500 mg.

[0571] In some embodiments, the present disclosure provides a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof at a dosage from 320 mg to 400 mg.

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[0574] In some embodiments, the present disclosure provides a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, for use in treating cancer in a subject in need thereof at a dosage from about 5 mg to about 700 mg.

[0575] In some embodiments, the present disclosure provides use of a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, for the treatment of cancer in a subject in need thereof at a dosage from about 5 mg to about 700 mg.

[0576] In some embodiments, the present disclosure provides use of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, for the treatment of cancer in a subject in need thereof at a dosage from about 5 mg to about 700 mg.

[0577] In some embodiments, the present disclosure provides use of a composition comprising a compound of the disclosure, or the pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof at a dosage from about 5 mg to about 700 mg.

[0578] In some embodiments, the present disclosure provides the use of the compound, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, in the manufacture of a medicament for the treatment of cancer in a subject in need thereof at a dosage from about 5 mg to about 700 mg.

[0579] In some embodiments, the compound is a compound of Table 1 (e.g., Compound 5, 10, 20, and 243) administered at the doses described in the embodiments herein.

[0580] In some embodiments, the subject is a mammal.

[0581] In some embodiments, the mammal is human.

[0582] BCR:ABL-1 Variants

[0583] In some embodiments, the BCR:ABL-1 protein is wild-type BCR:ABL-1 protein. In some embodiments, the BCR:ABL-1 protein contains a single amino acid mutation relative to wild-type BCR:ABL-1. In some embodiments, the BRC:ABL-1 protein contains multiple amino acid mutations relative to wild-type BCR:ABL-1.

[0584] In some embodiments, the BCR::ABL1 protein contains a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F. In some embodiments, the BRC:ABL-1

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[0586] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 protein contains an amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F. In some embodiments, the BCR:ABL-1 protein contains multiple amino acid mutations selected from (i) G250E and T3151, (ii) Y253H and T3151, (iii) E255V and T3151, (iv) H396R and T315I, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

[0587] Wild-Type BCR:ABL-1, Isoform P00519 (SEQ ID NO: 1)

[0588] MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSE NDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITP VNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINT ASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWE MERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEI KHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAME YLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPES LAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVY ELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPEL PTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNED ERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALA FTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGG GSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKR AGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAP ASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESP GRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNS DAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPL ISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTF C VS YVD SIQQMRNKF AFRE AINKLENNLRELQICP AT AGSGP AATQDF SKLL S S VKEISDI VQR

[0589] BCR:ABL-1, Isoform P00519 F359V Single Mutant, (SEQ ID NO: 2)

[0590] MLEICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS

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[0593] NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHY RINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDK WEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMK EIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAM EYLEKKNVIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPES LAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVY ELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQAPEL PTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDE RLLPKDKKTNLF S ALIKKKKKTAPTPPKRS S SFREMDGQPERRGAGEEEGRDISNGALAF TPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGS SSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRA GENRSDQ VTRGT VTPPPRLVKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRRQ VT VAPA SGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSSESPGR DKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAVNSDAA

[0594] KPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFIPLISTR VSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLYTFCVS YVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEISDIVQR

[0595] BCR:ABL-1, Isoform P00519 F359C Single Mutant, (SEQ ID NO: 3)

[0596] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNCIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIK WTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEG CPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTL LQAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRLVKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

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[0599] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0600] BCR:ABL-1, Isoform P00519 F359I Single Mutant, (SEQ ID NO: 4)

[0601] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNIIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRS DQVTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0602] BCR:ABL-1, Isoform P00519 H396R Single Mutant, (SEQ ID NO: 5)

[0603] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH

[0604] 115

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[0606] YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTARAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0607] BCR:ABL-1, Isoform P00519 E255V Single Mutant, (SEQ ID NO: 6)

[0608] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGVVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

[0609] 116

[0610] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0611] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0612] BCR:ABL-1, Isoform P00519 T3151 Single Mutant, (SEQ ID NO: 7)

[0613] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRS DQVTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0614] BCR:ABL-1, Isoform P00519 A337V Single Mutant, (SEQ ID NO: 8)

[0615] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH

[0616] 117

[0617] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0618] YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNVVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS

[0619] TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0620] BCR:ABL-1, Isoform P00519 A344P Single Mutant, (SEQ ID NO: 9)

[0621] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMPTQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

[0622] 118

[0623] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0624] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0625] BCR:ABL-1, Isoform P00519 P465S Single Mutant, (SEQ ID NO: 10)

[0626] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC SEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQVTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0627] BCR:ABL-1, Isoform P00519 T315M Single Mutant, (SEQ ID NO: 11)

[0628] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH

[0629] 119

[0630] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0631] YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIMEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0632] BCR:ABL-1, Isoform P00519 V468F Single Mutant, (SEQ ID NO: 12)

[0633] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKFYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

[0634] 120

[0635] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0636] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0637] BCR:ABL-1, Isoform P00519 G250E / T3151 Double Mutant, (SEQ IDNO: 13)

[0638] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGEGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRS DQVTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0639] BCR:ABL-1, Isoform P00519 Y253H / T3151 Double Mutant (SEQ ID NO: 14)

[0640] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH

[0641] 121

[0642] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0643] YRFNTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQHGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS

[0644] TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0645] BCR:ABL-1, Isoform P 00519 E255V / T315I, Double Mutant (SEQ ID NO: 15)

[0646] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGVVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

[0647] 122

[0648] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0649] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0650] BCR:ABL-1, Isoform P00519 H396R / T315I, Double Mutant (SEQ ID NO: 16)

[0651] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTARAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRS DQVTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0652] BCR:ABL-1, Isoform P00519 E255V / V299L, Double Mutant (SEQ ID NO: 17)

[0653] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH

[0654] 123

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[0656] YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGVVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLLQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS

[0657] TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0658] BCR:ABL-1, Isoform P00519 Y253H / F317L Double Mutant, (SEQ IDNO: 18)

[0659] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQHGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIITELMTYGNLLDYLRECNRQEVNAVVLLYMATQI SSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKW TAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGC PEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

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[0662] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0663] BCR:ABL-1, Isoform P00519 A337V / T315I, Double Mutant (SEQ ID NO: 19)

[0664] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNVVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRS DQVTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0665] BCR:ABL-1, Isoform P00519 A344P / T3151, Double Mutant, (SEQ ID NO: 20)

[0666] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH

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[0669] YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMPTQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEA ADEVFKDIMES SPGS SPPNLTPKPLRR QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS

[0670] TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0671] BCR:ABL-1, Isoform P00519 P465S / T3151, Double Mutant, (SEQ ID NO: 21)

[0672] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCS EKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLL QAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEG GLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDIS NGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATG EEEGGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKP ALPRKRAGENRSDQ VTRGT VTPPPRL VKKNEEAADEVFKDIMES SPGS SPPNLTPKPLRR

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[0675] QVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHK HSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLV DAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSS TAFIPLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAG KNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSS VKEISDIVQR

[0676] BCR:ABL-1, Isoform P00519 V468F / T315I, Double Mutant, (SEQ ID NO: 22)

[0677] MLEICLKL VGCKSKKGLS S SS SC YLEEALQRP VASDFEPQGLSEAARWNSKENLL AGPSENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPS NYITPVNSLEKHSWYHGP VSRNAAEYLLS SGINGSFLVRESES SPGQRSISLRYEGRVYH YRINTASDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNY DKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAA VMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQIS SAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWT APESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCP EKFYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVSTLLQ APELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGL NEDERLLPKDKKTNLF S ALIKKKKKTAPTPPKRS S SFREMDGQPERRGAGEEEGRDISNG ALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEE GGGSSSKRFLRSCSASCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALP RKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVT VAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAEESRVRRHKHSS ESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAKTKATSLVDAV NSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTPISPAPVPSTLPSASSALAGDQPSSTAFI PLISTRVSLRKTRQPPERIASGAITKGVVLDSTEALCLAISRNSEQMASHSAVLEAGKNLY TFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKEIS DIVQR

[0678] Combination of a BCR:ABL1 Inhibitor with a Tyrosine Kinase Inhibitor

[0679] Disclosed herein, in certain embodiments, are combinations comprising a BCR:ABL1 inhibitor (e.g., a compound of formula (I) or (I’), such as Compound 5 and / or 243), or a

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[0681] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 pharmaceutically acceptable salt thereof and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib).

[0682] Further disclosed herein, in certain embodiments, are pharmaceutical combinations comprising a BCR:ABL1 inhibitor (e.g., a compound of formula (I) or (I’), such as Compound 5 or 243), or a pharmaceutically acceptable salt thereof and a tyrosine kinase inhibitor (e.g., imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib).

[0683] Disclosed herein, in certain embodiments, are combinations comprising Compound 5 and / or 243 and a tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

[0684] Further disclosed herein, in certain embodiments, are pharmaceutical combinations comprising Compound 5 and / or 243 and a tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

[0685] In some embodiments, Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib are coadministered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.

[0686] In some embodiments, the co-administration of Compound 5 and / or 243 and the tyrosine- kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib increases the bioavailability of Compound 5 and / or 243. In some embodiments, the coadministration of Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib increases the Cmax of Compound 5 and / or 243. In some embodiments, the co-administration of Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib increases the AUC of Compound 5 and / or 243. In some embodiments, the co-administration of Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib increases the T1 / 2 of Compound 5 and / or 243.

[0687] Compositions or therapies disclosed herein may be administered individually to a subject or may be administered in combination (e.g. simultaneously, sequentially or separately). In some embodiments, Compound 5 and / or 243 is administered in advance of the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinibln some embodiments, the tyrosine-kinase inhibitor selected from asciminib, imatinib,

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[0689] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 nilotinib, dasatinib, bosutinib, ponatinib and bafetinib is administered before Compound 5 and / or 243.

[0690] In some embodiments, Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib are administered in temporal proximity (e.g., Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib can be initially administered simultaneously). Accordingly, the present disclosure provides a method of treating or preventing cancer comprising administering Compound 5 and / or 243 and a tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib in temporal proximity.

[0691] In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent.

[0692] In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the another therapeutic agent. “Temporal proximity” may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered. In some embodiments, “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks. In some embodiments, multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity may change during a treatment cycle or within a dosing regimen.

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[0695] In some embodiments, the disclosure provides a synergistic combination of Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib, wherein Compound 5 and / or 243 and the tyrosinekinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib come into contact with each other in the human body (e.g., only in the human body).

[0696] In some embodiments, Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib are coadministration concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.

[0697] In some embodiments, Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib are coadministered in separate dosage forms. In some embodiments, Compound 5 and / or 243 and the tyrosine-kinase inhibitor selected from asciminib, imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib are co-administered in combined dosage forms.

[0698] Methods of Administration and Dosage Forms

[0699] The precise amount of compound administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti-cancer agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure being used by following, for example, dosages reported in the literature and recommended in the Physician ’s Desk Reference (57th ed., 2003).

[0700] The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day).

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[0703] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0704] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, the particular treatment). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years. However, a person of ordinary skill in the art would immediately recognize appropriate and / or equivalent doses looking at dosages of approved compositions for treating cancer using a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure for guidance.

[0705] Compounds of the disclosure, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising a compound of the disclosure taught herein can be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0706] The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In some embodiments, the pharmaceutical composition is formulated for intravenous administration.

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[0709] Typically, for oral therapeutic administration, compounds of the disclosure, or pharmaceutically acceptable salts thereof may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0710] Typically for parenteral administration, solutions of compounds of the disclosure, or pharmaceutically acceptable salts thereof can generally be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0711] Typically, for injectable use, sterile aqueous solutions or dispersion of, and sterile powders of, a compound of the disclosure, or the pharmaceutically acceptable salt thereof for the extemporaneous preparation of sterile injectable solutions or dispersions are appropriate.

[0712] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 5 mg.

[0713] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 10 mg.

[0714] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 15 mg.

[0715] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 20 mg.

[0716] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 25 mg.

[0717] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 30 mg.

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[0720] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 35 mg.

[0721] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 40 mg.

[0722] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 45 mg.

[0723] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 50 mg.

[0724] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 55 mg.

[0725] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 60 mg.

[0726] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 65 mg.

[0727] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 70 mg.

[0728] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 75 mg.

[0729] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 80 mg.

[0730] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 85 mg.

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[0733] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 90 mg.

[0734] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 95 mg.

[0735] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 100 mg.

[0736] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 110 mg.

[0737] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 120 mg.

[0738] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 130 mg.

[0739] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 140 mg.

[0740] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 150 mg.

[0741] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 160 mg.

[0742] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 170 mg.

[0743] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 175 mg.

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[0746] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 180 mg.

[0747] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 190 mg.

[0748] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 200 mg.

[0749] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 220 mg.

[0750] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 240 mg.

[0751] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 250 mg.

[0752] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 260 mg.

[0753] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 280 mg.

[0754] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 300 mg.

[0755] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 320 mg.

[0756] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 340 mg.

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[0759] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 350 mg.

[0760] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 360 mg.

[0761] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 380 mg.

[0762] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 400 mg.

[0763] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 420 mg.

[0764] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 440 mg.

[0765] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 460 mg.

[0766] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 480 mg.

[0767] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 500 mg.

[0768] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 520 mg.

[0769] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 540 mg.

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[0772] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 560 mg.

[0773] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 580 mg.

[0774] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 600 mg.

[0775] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 620 mg.

[0776] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 640 mg.

[0777] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 660 mg.

[0778] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 680 mg.

[0779] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 700 mg.

[0780] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 20±2 mg, 20±1.8 mg, 20±1.6 mg, 20±1.5 mg, 20±1.4 mg, 15±1.3 mg, 20±1.2 mg, 20±l.l mg, 20±l mg, 20±0.9 mg, 20±0.8 mg, 20±0.7 mg, 20±0.6 mg, 20±0.5 mg, 20±0.4 mg, 20±0.3 mg, 20±0.2 mg, or 20±0.1 mg.

[0781] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 40±2 mg, 40±1.8 mg, 40±1.6 mg, 40±1.5 mg, 40±1.4 mg,

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[0784] 40±1.3 mg, 40±1.2 mg, 40±l.l mg, 40±l mg, 40±0.9 mg, 40±0.8 mg, 40±0.7 mg, 40±0.6 mg, 40±0.5 mg, 40±0.4 mg, 40±0.3 mg, 40±0.2 mg, or 40±0.1 mg.

[0785] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 50±2 mg, 50±1.8 mg, 50±1.6 mg, 50±1.5 mg, 50±1.4 mg, 50±1.3 mg, 50±1.2 mg, 50±l.l mg, 50±l mg, 50±0.9 mg, 50±0.8 mg, 50±0.7 mg, 50±0.6 mg, 50±0.5 mg, 50±0.4 mg, 50±0.3 mg, 50±0.2 mg, or 50±0.1 mg.

[0786] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 80±5 mg, 80±4.5 mg, 80±4 mg, 80±3.5 mg, 80±3 mg, 80±2.5 mg, 80±2 mg, 80±1.5 mg, 80±l mg, 80±0.9 mg, 80±0.8 mg, 80±0.7 mg, 80±0.6 mg, 80±0.5 mg, 80±0.4 mg, 80±0.3 mg, 80±0.2 mg, or 80±0.1 mg.

[0787] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 100±10 mg, 100±9 mg, 100±8 mg, 100±7 mg, 100±6 mg, 100±5 mg, 100±4.5 mg, 100±4.0 mg, 100±3.5 mg, 100±3.0 mg, 100±2.5 mg, 100±2.0 mg, 100±1.5 mg, 100±1.0 mg, 100±0.9 mg, 100±0.8 mg, 100±0.7 mg, 100±0.6 mg, 100±0.5 mg, 100±0.4 mg, 100±0.3 mg, 100±0.2 mg, or 100±0.1 mg.

[0788] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 160±10 mg, 160±9 mg, 160±8 mg, 160±7 mg, 160±6 mg, 160±5 mg, 160±4.5 mg, 160±4.0 mg, 160±3.5 mg, 160±3.0 mg, 160±2.5 mg, 160±2.0 mg, 160±1.5 mg, 160±1.0 mg, 160±0.9 mg, 160±0.8 mg, 160±0.7 mg, 160±0.6 mg, 160±0.5 mg, 160±0.4 mg, 160±0.3 mg, 160±0.2 mg, or 160±0.1 mg.

[0789] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 175±10 mg, 175±9 mg, 175±8 mg, 175±7 mg, 175±6 mg, 175±5 mg, 175±4.5 mg, 175±4.0 mg, 175±3.5 mg, 175±3.0 mg, 175±2.5 mg, 175±2.0 mg, 175±1.5 mg, 175±1.0 mg, 175±0.9 mg, 175±0.8 mg, 175±0.7 mg, 175±0.6 mg, 175±0.5 mg, 175±0.4 mg, 175±0.3 mg, 175±0.2 mg, or 175±0.1 mg.

[0790] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 200±10 mg, 200±9 mg, 200±8 mg, 200±7 mg, 200±6 mg,

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[0793] 200±5 mg, 200±4.5 mg, 200±4.0 mg, 200±3.5 mg, 200±3.0 mg, 200±2.5 mg, 200±2.0 mg, 200±1.5 mg, 200±1.0 mg, 200±0.9 mg, 200±0.8 mg, 200±0.7 mg, 200±0.6 mg, 200±0.5 mg, 200±0.4 mg, 200±0.3 mg, 200±0.2 mg, or 200±0.1 mg.

[0794] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 250±10 mg, 250±9 mg, 250±8 mg, 250±7 mg, 250±6 mg, 250±5 mg, 250±4.5 mg, 250±4.0 mg, 250±3.5 mg, 250±3.0 mg, 250±2.5 mg, 250±2.0 mg, 250±1.5 mg, 250±1.0 mg, 250±0.9 mg, 250±0.8 mg, 250±0.7 mg, 250±0.6 mg, 250±0.5 mg, 250±0.4 mg, 250±0.3 mg, 250±0.2 mg, or 250±0.1 mg.

[0795] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 300±10 mg, 300±9 mg, 300±8 mg, 300±7 mg, 300±6 mg, 300±5 mg, 300±4.5 mg, 300±4.0 mg, 300±3.5 mg, 300±3.0 mg, 300±2.5 mg, 300±2.0 mg, 300±1.5 mg, 300±1.0 mg, 300±0.9 mg, 300±0.8 mg, 300±0.7 mg, 300±0.6 mg, 300±0.5 mg, 300±0.4 mg, 300±0.3 mg, 300±0.2 mg, or 300±0.1 mg.

[0796] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 320±10 mg, 320±9 mg, 320±8 mg, 320±7 mg, 320±6 mg, 320±5 mg, 320±4.5 mg, 320±4.0 mg, 320±3.5 mg, 320±3.0 mg, 320±2.5 mg, 320±2.0 mg, 320±1.5 mg, 320±1.0 mg, 320±0.9 mg, 320±0.8 mg, 320±0.7 mg, 320±0.6 mg, 320±0.5 mg, 320±0.4 mg, 320±0.3 mg, 320±0.2 mg, or 320±0.1 mg.

[0797] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 350±10 mg, 350±9 mg, 350±8 mg, 350±7 mg, 350±6 mg, 350±5 mg, 350±4.5 mg, 350±4.0 mg, 350±3.5 mg, 350±3.0 mg, 350±2.5 mg, 350±2.0 mg, 350±1.5 mg, 350±1.0 mg, 350±0.9 mg, 350±0.8 mg, 350±0.7 mg, 350±0.6 mg, 350±0.5 mg, 350±0.4 mg, 350±0.3 mg, 350±0.2 mg, or 350±0.1 mg.

[0798] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 400±10 mg, 400±9 mg, 400±8 mg, 400±7 mg, 400±6 mg, 400±5 mg, 400±4.5 mg, 400±4.0 mg, 400±3.5 mg, 400±3.0 mg, 400±2.5 mg, 400±2.0 mg, 400±1.5 mg, 400±1.0 mg, 400±0.9 mg, 400±0.8 mg, 400±0.7 mg, 400±0.6 mg, 400±0.5 mg, 400±0.4 mg, 400±0.3 mg, 400±0.2 mg, or 400±0.1 mg.

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[0801] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 500±10 mg, 500±9 mg, 500±8 mg, 500±7 mg, 500±6 mg, 500±5 mg, 500±4.5 mg, 500±4.0 mg, 500±3.5 mg, 500±3.0 mg, 500±2.5 mg, 500±2.0 mg, 500±1.5 mg, 500±1.0 mg, 500±0.9 mg, 500±0.8 mg, 500±0.7 mg, 500±0.6 mg, 500±0.5 mg, 500±0.4 mg, 500±0.3 mg, 500±0.2 mg, or 500±0.1 mg.

[0802] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg to about 700 mg, about 5 mg to about 650 mg, about 5 mg to about 600 mg, about 5 mg to about 550 mg, about 5 mg to about 500 mg, about 5 mg to about 450 mg, about 5 mg to about 400 mg, about 5 mg to about 350 mg, about 5 mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 140 mg, about 5 mg to about 130 mg, about 5 mg to about 120 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 45 mg, about 5 mg to about 40 mg, about 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, or about 5 mg to about 20 mg.

[0803] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 700 mg, about 25 mg to about 700 mg, about 30 mg to about 700 mg, about 35 mg to about 700 mg, about 40 mg to about 700 mg, about 45 mg to about 700 mg, about 50 mg to about 700 mg, about 60 mg to about 700 mg, about 70 mg to about 700 mg, about 80 mg to about 700 mg, about 90 mg to about 700 mg, about 100 mg to about 700 mg, about 110 mg to about 700 mg, about 120 mg to about 700 mg, about 130 mg to about 700 mg, about 140 mg to about 700 mg, about 150 mg to about 700 mg, about 200 mg to about 700 mg, about 250 mg to about 700 mg, about 300 mg to about 700 mg, about 350 mg to about 700 mg, about 400 mg to about 700 mg, about 450 mg to about 700 mg, about 500 mg to about 700 mg, about 550 mg to about 700 mg, about 600 mg to about 700 mg, or about 650 mg to about 700 mg.

[0804] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 600 mg, about 25 mg to about 600 mg, about 30 mg to about 600 mg, about 35 mg to about 600 mg, about 40 mg to about 600 mg,

[0805] 140

[0806] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 about 45 mg to about 600 mg, about 50 mg to about 600 mg, about 60 mg to about 600 mg, about 70 mg to about 600 mg, about 80 mg to about 600 mg, about 90 mg to about 600 mg, about 100 mg to about 600 mg, about 110 mg to about 600 mg, about 120 mg to about 600 mg, about 130 mg to about 600 mg, about 140 mg to about 600 mg, about 150 mg to about 600 mg, about 200 mg to about 600 mg, about 250 mg to about 600 mg, about 300 mg to about 600 mg, about 350 mg to about 600 mg, about 400 mg to about 600 mg, about 450 mg to about 600 mg, about 500 mg to about 600 mg, or about 550 mg to about 600 mg.

[0807] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 500 mg, about 25 mg to about 500 mg, about 30 mg to about 500 mg, about 35 mg to about 500 mg, about 40 mg to about 500 mg, about 45 mg to about 500 mg, about 50 mg to about 500 mg, about 60 mg to about 500 mg, about 70 mg to about 500 mg, about 80 mg to about 500 mg, about 90 mg to about 500 mg, about 100 mg to about 500 mg, about 110 mg to about 500 mg, about 120 mg to about 500 mg, about 130 mg to about 500 mg, about 140 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 350 mg to about 500 mg, about 400 mg to about 500 mg, or about 450 mg to about 500 mg.

[0808] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 400 mg, about 25 mg to about 400 mg, about 30 mg to about 400 mg, about 35 mg to about 400 mg, about 40 mg to about 400 mg, about 45 mg to about 400 mg, about 50 mg to about 400 mg, about 60 mg to about 400 mg, about 70 mg to about 400 mg, about 80 mg to about 400 mg, about 90 mg to about 400 mg, about 100 mg to about 400 mg, about 110 mg to about 400 mg, about 120 mg to about 400 mg, about 130 mg to about 400 mg, about 140 mg to about 400 mg, about 150 mg to about 400 mg, about 200 mg to about 400 mg, about 250 mg to about 400 mg, about 300 mg to about 400 mg, or about 350 mg to about 400 mg.

[0809] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 300 mg, about 25 mg to about 300 mg, about 30 mg to about 300 mg, about 35 mg to about 300 mg, about 40 mg to about 300 mg, about 45 mg to about 300 mg, about 50 mg to about 300 mg, about 60 mg to about 300 mg,

[0810] 141

[0811] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 about 70 mg to about 300 mg, about 80 mg to about 300 mg, about 90 mg to about 300 mg, about 100 mg to about 300 mg, about 110 mg to about 300 mg, about 120 mg to about 300 mg, about 130 mg to about 300 mg, about 140 mg to about 300 mg, about 150 mg to about 300 mg, about 200 mg to about 300 mg, or about 250 mg to about 300 mg.

[0812] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 30 mg to about 200 mg, about 35 mg to about 200 mg, about 40 mg to about 200 mg, about 45 mg to about 200 mg, about 50 mg to about 200 mg, about 60 mg to about 200 mg, about 70 mg to about 200 mg, about 80 mg to about 200 mg, about 90 mg to about 200 mg, about 100 mg to about 200 mg, about 110 mg to about 200 mg, about 120 mg to about 200 mg, about 130 mg to about 200 mg, about 140 mg to about 200 mg, about 150 mg to about 200 mg.

[0813] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 150 mg, about 25 mg to about 150 mg, about 30 mg to about 150 mg, about 35 mg to about 150 mg, about 40 mg to about 150 mg, about 45 mg to about 150 mg, about 50 mg to about 150 mg, about 60 mg to about 150 mg, about 70 mg to about 150 mg, about 80 mg to about 150 mg, about 90 mg to about 150 mg, about 100 mg to about 150 mg, about 110 mg to about 150 mg, about 120 mg to about 150 mg, about 130 mg to about 150 mg, or about 140 mg to about 150 mg.

[0814] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg to about 100 mg, about 25 mg to about 100 mg, about 30 mg to about 100 mg, about 35 mg to about 100 mg, about 40 mg to about 100 mg, about 45 mg to about 100 mg, about 50 mg to about 100 mg, about 60 mg to about 100 mg, about 70 mg to about 100 mg, about 80 mg to about 100 mg, or about 90 mg to about 100 mg.

[0815] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 5 mg / day.

[0816] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 10 mg / day.

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[0819] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 15 mg / day.

[0820] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 20 mg / day.

[0821] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 25 mg / day.

[0822] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 30 mg / day.

[0823] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 35 mg / day.

[0824] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 40 mg / day.

[0825] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 45 mg / day.

[0826] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 50 mg / day.

[0827] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 55 mg / day.

[0828] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 60 mg / day.

[0829] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 65 mg / day.

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[0832] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 70 mg / day.

[0833] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 75 mg / day.

[0834] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 80 mg / day.

[0835] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 85 mg / day.

[0836] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 90 mg / day.

[0837] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 95 mg / day.

[0838] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 100 mg / day.

[0839] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 110 mg / day.

[0840] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 120 mg / day.

[0841] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 130 mg / day.

[0842] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 140 mg / day.

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[0845] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 150 mg / day.

[0846] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 160 mg / day.

[0847] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 170 mg / day.

[0848] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 175 mg / day.

[0849] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 180 mg / day.

[0850] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 190 mg / day.

[0851] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 200 mg / day.

[0852] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 220 mg / day.

[0853] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 240 mg / day.

[0854] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 250 mg / day.

[0855] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 260 mg / day.

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[0858] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 280 mg / day.

[0859] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 300 mg / day.

[0860] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 320 mg / day.

[0861] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 340 mg / day.

[0862] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 350 mg / day.

[0863] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 360 mg / day.

[0864] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 380 mg / day.

[0865] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 400 mg / day.

[0866] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 420 mg / day.

[0867] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 440 mg / day.

[0868] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 460 mg / day.

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[0871] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 480 mg / day.

[0872] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 500 mg / day.

[0873] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 520 mg / day.

[0874] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 540 mg / day.

[0875] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 560 mg / day.

[0876] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 580 mg / day.

[0877] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 600 mg / day.

[0878] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 620 mg / day.

[0879] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 640 mg / day.

[0880] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 660 mg / day.

[0881] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 680 mg / day.

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[0884] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage of about 700 mg / day.

[0885] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 700 mg / day.

[0886] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 600 mg / day.

[0887] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 500 mg / day.

[0888] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 400 mg / day.

[0889] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 300 mg / day.

[0890] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 200 mg / day.

[0891] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 100 mg / day.

[0892] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 95 mg / day.

[0893] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 90 mg / day.

[0894] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 85 mg / day.

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[0897] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 80 mg / day.

[0898] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 75 mg / day.

[0899] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 70 mg / day.

[0900] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 65 mg / day.

[0901] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 60 mg / day.

[0902] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 55 mg / day.

[0903] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 50 mg / day.

[0904] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 45 mg / day.

[0905] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 40 mg / day.

[0906] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 35 mg / day.

[0907] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 30 mg / day.

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[0910] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 25 mg / day.

[0911] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 5 mg / day to about 20 mg / day.

[0912] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 10 mg / day to about 700 mg / day.

[0913] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 15 mg / day to about 700 mg / day.

[0914] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 20 mg / day to about 700 mg / day.

[0915] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 25 mg / day to about 700 mg / day.

[0916] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 30 mg / day to about 700 mg / day.

[0917] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 35 mg / day to about 700 mg / day.

[0918] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 40 mg / day to about 700 mg / day.

[0919] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 45 mg / day to about 700 mg / day.

[0920] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 50 mg / day to about 700 mg / day.

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[0923] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 55 mg / day to about 700 mg / day.

[0924] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 60 mg / day to about 700 mg / day.

[0925] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 65 mg / day to about 700 mg / day.

[0926] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 70 mg / day to about 700 mg / day.

[0927] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 75 mg / day to about 700 mg / day.

[0928] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 80 mg / day to about 700 mg / day.

[0929] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 85 mg / day to about 700 mg / day.

[0930] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 90 mg / day to about 700 mg / day.

[0931] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 95 mg / day to about 700 mg / day.

[0932] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 100 mg / day to about 700 mg / day.

[0933] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 200 mg / day to about 700 mg / day.

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[0936] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 300 mg / day to about 700 mg / day.

[0937] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 400 mg / day to about 700 mg / day.

[0938] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 500 mg / day to about 700 mg / day.

[0939] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered at a dosage ranging from about 600 mg / day to about 700 mg / day.

[0940] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered orally.

[0941] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily.

[0942] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 700 mg.

[0943] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 600 mg.

[0944] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 500 mg.

[0945] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 400 mg.

[0946] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 350 mg.

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[0949] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 320 mg.

[0950] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 300 mg.

[0951] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 250 mg.

[0952] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 200 mg.

[0953] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 180 mg.

[0954] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 175 mg.

[0955] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 160 mg.

[0956] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 140 mg.

[0957] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 120 mg.

[0958] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 100 mg.

[0959] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 80 mg.

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[0962] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 60 mg.

[0963] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 50 mg.

[0964] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 40 mg.

[0965] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily at a dosage of about 20 mg.

[0966] In some embodiments of the methods provided by the present disclosure, the compound is administered to the subject at a dose of 5 mg to 700 mg. In some embodiments, the compound is administered at a dose of 5 mg to 100 mg. In some embodiments, the compound is administered at a dose of 40 mg to 140 mg. In some embodiments, the compound is administered at a dose of 100 mg to 200 mg. In some embodiments, the compound is administered at a dose of 150 mg to 250 mg. In some embodiments, the compound is administered at a dose of 200 mg to 300 mg. In some embodiments, the compound is administered at a dose of 250 mg to 350 mg. In some embodiments, the compound is administered at a dose of 300 mg to 400 mg. In some embodiments, the compound is administered at a dose of 350 mg to 450 mg. In some embodiments, the compound is administered at a dose of 400 mg to 500 mg. In some embodiments, the compound is administered at a dose of 450 mg to 550 mg. In some embodiments, the compound is administered at a dose of 500 mg to 600 mg. In some embodiments, the compound is administered at a dose of 600 mg to 700 mg. In some embodiments, the compound is administered at a dose of 140 mg to 180 mg. In some embodiments, the compound is administered at a dose of 150 mg to 170 mg. In some embodiments, the compound is administered at a dose of 300 mg to 340 mg. In some embodiments, the compound is administered at a dose of 310 mg to 330 mg. In some embodiments, the compound is administered at a dose of 380 mg to 420 mg. In some embodiments, the compound is administered at a dose of 390 mg to 410 mg. In some embodiments, the compound is administered at a dose of 480 mg to 520 mg. In some embodiments, the compound is

[0967] 154

[0968] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 administered at a dose of 490 mg to 510 mg. In some embodiments, the compound is administered at a dose of 50 mg. In some embodiments, the compound is administered at a dose of 100 mg. In some embodiments, the compound is administered at a dose of 120 mg. In some embodiments, the compound is administered at a dose of 140 mg. In some embodiments, the compound is administered at a dose of 160 mg. In some embodiments, the compound is administered at a dose of 175 mg. In some embodiments, the compound is administered at a dose of 180 mg. In some embodiments, the compound is administered at a dose of 200 mg. In some embodiments, the compound is administered at a dose of 220 mg. In some embodiments, the compound is administered at a dose of 240 mg. In some embodiments, the compound is administered at a dose of 250 mg. In some embodiments, the compound is administered at a dose of 260 mg. In some embodiments, the compound is administered at a dose of 280 mg. In some embodiments, the compound is administered at a dose of 300 mg. In some embodiments, the compound is administered at a dose of 320 mg. In some embodiments, the compound is administered at a dose of 340 mg. In some embodiments, the compound is administered at a dose of 350 mg. In some embodiments, the compound is administered at a dose of 360 mg. In some embodiments, the compound is administered at a dose of 380 mg. In some embodiments, the compound is administered at a dose of 400 mg. In some embodiments, the compound is administered at a dose of 420 mg. In some embodiments, the compound is administered at a dose of 440 mg. In some embodiments, the compound is administered at a dose of 460 mg. In some embodiments, the compound is administered at a dose of 480 mg. In some embodiments, the compound is administered at a dose of 500 mg. In some embodiments, the compound is administered at a dose of 520 mg. In some embodiments, the compound is administered at a dose of 540 mg. In some embodiments, the compound is administered at a dose of 560 mg. In some embodiments, the compound is administered at a dose of 580 mg. In some embodiments, the compound is administered at a dose of 600 mg. In some embodiments, the compound is administered at a dose of 620 mg. In some embodiments, the compound is administered at a dose of 640 mg. In some embodiments, the compound is administered at a dose of 660 mg. In some embodiments, the compound is administered at a dose of 680 mg. In some embodiments, the compound is administered at a dose of 700 mg.

[0969] In some embodiments of methods provided by the present disclosure, the compound is administered to about the subject at a dose of about 5 mg to about 700 mg. In some embodiments, the compound is administered at a dose of about 5 mg to about 100 mg. In some embodiments, the compound is administered at a dose of about 40 mg to about 140 mg. In some

[0970] 155

[0971] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 embodiments, the compound is administered at a dose of about 100 mg to about 200 mg. In some embodiments, the compound is administered at a dose of about 150 mg to about 250 mg. In some embodiments, the compound is administered at a dose of about 200 mg to about 300 mg. In some embodiments, the compound is administered at a dose of about 250 mg to about 350 mg. In some embodiments, the compound is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the compound is administered at a dose of about 350 mg to about 450 mg. In some embodiments, the compound is administered at a dose of about 400 mg to about 500 mg. In some embodiments, the compound is administered at a dose of about 450 mg to about 550 mg. In some embodiments, the compound is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the compound is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the compound is administered at a dose of about 140 mg to about 180 mg. In some embodiments, the compound is administered at a dose of about 150 mg to about 170 mg. In some embodiments, the compound is administered at a dose of about 300 mg to about 340 mg. In some embodiments, the compound is administered at a dose of about 310 mg to about 330 mg. In some embodiments, the compound is administered at a dose of about 380 mg to about 420 mg. In some embodiments, the compound is administered at a dose of about 390 mg to about 410 mg. In some embodiments, the compound is administered at a dose of about 480 mg to about 520 mg. In some embodiments, the compound is administered at a dose of about 490 mg to about 510 mg. In some embodiments, the compound is administered at a dose of about 50 mg. In some embodiments, the compound is administered at a dose of about 100 mg. In some embodiments, the compound is administered at a dose of about 120 mg. In some embodiments, the compound is administered at a dose of about 140 mg. In some embodiments, the compound is administered at a dose of about 160 mg. In some embodiments, the compound is administered at a dose of about 175 mg. In some embodiments, the compound is administered at a dose of about 180 mg. In some embodiments, the compound is administered at a dose of about 200 mg. In some embodiments, the compound is administered at a dose of about 220 mg. In some embodiments, the compound is administered at a dose of about 240 mg. In some embodiments, the compound is administered at a dose of about 250 mg. In some embodiments, the compound is administered at a dose of about 260 mg. In some embodiments, the compound is administered at a dose of about 280 mg. In some embodiments, the compound is administered at a dose of about 300 mg. In some embodiments, the compound is administered at a dose of about 320 mg. In some embodiments, the compound is administered at a dose of about 340 mg. In some embodiments, the compound is administered at a dose of about 350 mg. In some embodiments, the compound is administered

[0972] 156

[0973] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 at a dose of about 360 mg. In some embodiments, the compound is administered at a dose of about 380 mg. In some embodiments, the compound is administered at a dose of about 400 mg. In some embodiments, the compound is administered at a dose of about 420 mg. In some embodiments, the compound is administered at a dose of about 440 mg. In some embodiments, the compound is administered at a dose of about 460 mg. In some embodiments, the compound is administered at a dose of about 480 mg. In some embodiments, the compound is administered at a dose of about 500 mg. In some embodiments, the compound is administered at a dose of about 520 mg. In some embodiments, the compound is administered at a dose of about 540 mg. In some embodiments, the compound is administered at a dose of about 560 mg. In some embodiments, the compound is administered at a dose of about 580 mg. In some embodiments, the compound is administered at a dose of about 600 mg. In some embodiments, the compound is administered at a dose of about 620 mg. In some embodiments, the compound is administered at a dose of about 640 mg. In some embodiments, the compound is administered at a dose of about 660 mg. In some embodiments, the compound is administered at a dose of about 680 mg. In some embodiments, the compound is administered at a dose of about 700 mg.

[0974] In some embodiments of the methods provided by the present disclosure, the compound, or salt thereof, is administered to the subject at a dose of 5 mg to 700 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 5 mg to 100 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 40 mg to 140 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 100 mg to 200 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 150 mg to 250 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 200 mg to 300 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 250 mg to 350 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 300 mg to 400 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 350 mg to 450 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 400 mg to 500 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 450 mg to 550 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 500 mg to 600 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 600 mg to 700 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 140 mg to 180 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 150 mg to 170 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 300 mg to 340

[0975] 157

[0976] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 310 mg to 330 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 380 mg to 420 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 390 mg to 410 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 480 mg to 520 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 490 mg to 510 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 50 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 100 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 120 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 140 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 160 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 175 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 180 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 200 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 220 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 240 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 250 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 260 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 280 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 300 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 320 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 340 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 350 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 360 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 380 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 400 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 420 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 440 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 460 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 480 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 500 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 520 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 540 mg. In some embodiments, the compound, or salt thereof, is

[0977] 158

[0978] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 administered at a dose of 560 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 580 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 600 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 620 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 640 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 660 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 680 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of 700 mg.

[0979] In some embodiments of the methods provided by the present disclosure, the compound, or salt thereof, is administered to about the subject at a dose of about 5 mg to about 700 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 5 mg to about 100 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 40 mg to about 140 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 100 mg to about 200 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 150 mg to about 250 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 200 mg to about 300 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 250 mg to about 350 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 350 mg to about 450 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 400 mg to about 500 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 450 mg to about 550 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 140 mg to about 180 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 150 mg to about 170 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 300 mg to about 340 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 310 mg to about 330 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 380 mg to about 420 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 390 mg to about 410 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 480 mg to about 520 mg. In some

[0980] 159

[0981] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 embodiments, the compound, or salt thereof, is administered at a dose of about 490 mg to about 510 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 50 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about

[0982] 100 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 120 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 140 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 160 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 175 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 180 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 200 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 220 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 240 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 250 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 260 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 280 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 300 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 320 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 340 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 350 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 360 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 380 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 400 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 420 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 440 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 460 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 480 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 500 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 520 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 540 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 560 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 580 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 600 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about 620 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about

[0983] 160

[0984] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[0985] 640 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about

[0986] 660 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about

[0987] 680 mg. In some embodiments, the compound, or salt thereof, is administered at a dose of about

[0988] 700 mg.

[0989] In some embodiments of the methods provided by the present disclosure, the salt of the compound is administered to the subject at a dose of 5 mg to 700 mg. In some embodiments, the salt of the compound is administered at a dose of 5 mg to 100 mg. In some embodiments, the salt of the compound is administered at a dose of 40 mg to 140 mg. In some embodiments, the salt of the compound is administered at a dose of 100 mg to 200 mg. In some embodiments, the salt of the compound is administered at a dose of 150 mg to 250 mg. In some embodiments, the salt of the compound is administered at a dose of 200 mg to 300 mg. In some embodiments, the salt of the compound is administered at a dose of 250 mg to 350 mg. In some embodiments, the salt of the compound is administered at a dose of 300 mg to 400 mg. In some embodiments, the salt of the compound is administered at a dose of 350 mg to 450 mg. In some embodiments, the salt of the compound is administered at a dose of 400 mg to 500 mg. In some embodiments, the salt of the compound is administered at a dose of 450 mg to 550 mg. In some embodiments, the salt of the compound is administered at a dose of 500 mg to 600 mg. In some embodiments, the salt of the compound is administered at a dose of 600 mg to 700 mg. In some embodiments, the salt of the compound is administered at a dose of 140 mg to 180 mg. In some embodiments, the salt of the compound is administered at a dose of 150 mg to 170 mg. In some embodiments, the salt of the compound is administered at a dose of 300 mg to 340 mg. In some embodiments, the salt of the compound is administered at a dose of 310 mg to 330 mg. In some embodiments, the salt of the compound is administered at a dose of 380 mg to 420 mg. In some embodiments, the salt of the compound is administered at a dose of 390 mg to 410 mg. In some embodiments, the salt of the compound is administered at a dose of 480 mg to 520 mg. In some embodiments, the salt of the compound is administered at a dose of 490 mg to 510 mg. In some embodiments, the salt of the compound is administered at a dose of 50 mg. In some embodiments, the salt of the compound is administered at a dose of 100 mg. In some embodiments, the salt of the compound is administered at a dose of 160 mg. In some embodiments, the salt of the compound is administered at a dose of 120 mg. In some embodiments, the salt of the compound is administered at a dose of 140 mg. In some embodiments, the salt of the compound is administered at a dose of 160 mg. In some embodiments, the salt of the compound is administered at a dose of 175 mg. In some embodiments, the salt of the compound is

[0990] 161

[0991] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 administered at a dose of 180 mg. In some embodiments, the salt of the compound is administered at a dose of 200 mg. In some embodiments, the salt of the compound is administered at a dose of 220 mg. In some embodiments, the salt of the compound is administered at a dose of 240 mg. In some embodiments, the salt of the compound is administered at a dose of 250 mg. In some embodiments, the salt of the compound is administered at a dose of 260 mg. In some embodiments, the salt of the compound is administered at a dose of 280 mg. In some embodiments, the salt of the compound is administered at a dose of 300 mg. In some embodiments, the salt of the compound is administered at a dose of 320 mg. In some embodiments, the salt of the compound is administered at a dose of 340 mg. In some embodiments, the salt of the compound is administered at a dose of 350 mg. In some embodiments, the salt of the compound is administered at a dose of 360 mg. In some embodiments, the salt of the compound is administered at a dose of 380 mg. In some embodiments, the salt of the compound is administered at a dose of 400 mg. In some embodiments, the salt of the compound is administered at a dose of 420 mg. In some embodiments, the salt of the compound is administered at a dose of 440 mg. In some embodiments, the salt of the compound is administered at a dose of 460 mg. In some embodiments, the salt of the compound is administered at a dose of 480 mg. In some embodiments, the salt of the compound is administered at a dose of 500 mg. In some embodiments, the salt of the compound is administered at a dose of 520 mg. In some embodiments, the salt of the compound is administered at a dose of 540 mg. In some embodiments, the salt of the compound is administered at a dose of 560 mg. In some embodiments, the salt of the compound is administered at a dose of 580 mg. In some embodiments, the salt of the compound is administered at a dose of 600 mg. In some embodiments, the salt of the compound is administered at a dose of 620 mg. In some embodiments, the salt of the compound is administered at a dose of 640 mg. In some embodiments, the salt of the compound is administered at a dose of 660 mg. In some embodiments, the salt of the compound is administered at a dose of 680 mg. In some embodiments, the salt of the compound is administered at a dose of 700 mg.

[0992] In some embodiments of the methods provided by the present disclosure, the salt of the compound is administered to the subject at a dose of about 5 mg to about 700 mg. In some embodiments, the salt of the compound is administered at a dose of about 5 mg to about 100 mg. In some embodiments, the salt of the compound is administered at a dose of about 40 mg to

[0993] 162

[0994] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 about 140 mg. In some embodiments, the salt of the compound is administered at a dose of about 100 mg to about 200 mg. In some embodiments, the salt of the compound is administered at a dose of about 150 mg to about 250 mg. In some embodiments, the salt of the compound is administered at a dose of about 200 mg to about 300 mg. In some embodiments, the salt of the compound is administered at a dose of about 250 mg to about 350 mg. In some embodiments, the salt of the compound is administered at a dose of about 300 mg to about 400 mg. In some embodiments, the salt of the compound is administered at a dose of about 350 mg to about 450 mg. In some embodiments, the salt of the compound is administered at a dose of about 400 mg to about 500 mg. In some embodiments, the salt of the compound is administered at a dose of about 450 mg to about 550 mg. In some embodiments, the salt of the compound is administered at a dose of about 500 mg to about 600 mg. In some embodiments, the salt of the compound is administered at a dose of about 600 mg to about 700 mg. In some embodiments, the salt of the compound is administered at a dose of about 140 mg to about 180 mg. In some embodiments, the salt of the compound is administered at a dose of about 150 mg to about 170 mg. In some embodiments, the salt of the compound is administered at a dose of about 300 mg to about 340 mg. In some embodiments, the salt of the compound is administered at a dose of about 310 mg to about 330 mg. In some embodiments, the salt of the compound is administered at a dose of about 380 mg to about 420 mg. In some embodiments, the salt of the compound is administered at a dose of about 390 mg to about 410 mg. In some embodiments, the salt of the compound is administered at a dose of about 480 mg to about 520 mg. In some embodiments, the salt of the compound is administered at a dose of about 490 mg to about 510 mg. In some embodiments, the salt of the compound is administered at a dose of about 50 mg. In some embodiments, the salt of the compound is administered at a dose of about 100 mg. In some embodiments, the salt of the compound is administered at a dose of about 120 mg. In some embodiments, the salt of the compound is administered at a dose of about 140 mg. In some embodiments, the salt of the compound is administered at a dose of about 160 mg. In some embodiments, the salt of the compound is administered at a dose of about 175 mg. In some embodiments, the salt of the compound is administered at a dose of about 180 mg. In some embodiments, the salt of the compound is administered at a dose of about 200 mg. In some embodiments, the salt of the compound is administered at a dose of about 220 mg. In some embodiments, the salt of the compound is administered at a dose of about 240 mg. In some embodiments, the salt of the compound is administered at a dose of about 250 mg. In some embodiments, the salt of the compound is administered at a dose of about 260 mg. In some embodiments, the salt of the

[0995] 163

[0996] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 compound is administered at a dose of about 280 mg. In some embodiments, the salt of the compound is administered at a dose of about 300 mg. In some embodiments, the salt of the compound is administered at a dose of about 320 mg. In some embodiments, the salt of the compound is administered at a dose of about 340 mg. In some embodiments, the salt of the compound is administered at a dose of about 350 mg. In some embodiments, the salt of the compound is administered at a dose of about 360 mg. In some embodiments, the salt of the compound is administered at a dose of about 380 mg. In some embodiments, the salt of the compound is administered at a dose of about 400 mg. In some embodiments, the salt of the compound is administered at a dose of about 420 mg. In some embodiments, the salt of the compound is administered at a dose of about 440 mg. In some embodiments, the salt of the compound is administered at a dose of about 460 mg. In some embodiments, the salt of the compound is administered at a dose of about 480 mg. In some embodiments, the salt of the compound is administered at a dose of about 500 mg. In some embodiments, the salt of the compound is administered at a dose of about 520 mg. In some embodiments, the salt of the compound is administered at a dose of about 540 mg. In some embodiments, the salt of the compound is administered at a dose of about 560 mg. In some embodiments, the salt of the compound is administered at a dose of about 580 mg. In some embodiments, the salt of the compound is administered at a dose of about 600 mg. In some embodiments, the salt of the compound is administered at a dose of about 620 mg. In some embodiments, the salt of the compound is administered at a dose of about 640 mg. In some embodiments, the salt of the compound is administered at a dose of about 660 mg. In some embodiments, the salt of the compound is administered at a dose of about 680 mg. In some embodiments, the salt of the compound is administered at a dose of about 700 mg.

[0997] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fed conditions, wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, or less than about 45%.

[0998] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fed

[0999] 164

[1000] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 conditions, wherein the difference between AUCinf of the compound if administered under fed conditions and AUCmf of the compound if administered under fasted conditions is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, or about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, or about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, or about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%.

[1001] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fasted conditions, wherein the difference between AUCmf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, or less than about 45%.

[1002] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fasted conditions, wherein the difference between AUCinf of the compound if administered under fed conditions and AUCmf of the compound if administered under fasted conditions is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, or about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, or about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, or about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45%.

[1003] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fed conditions, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 35%, less than about 38%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, or less than about 60%.

[1004] 165

[1005] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[1006] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fed conditions, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, or about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, or about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, or about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, or about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, or about 57%, about 58%, about 59%, or about 60%.

[1007] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fasted conditions, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 35%, less than about 38%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, or less than about 60%.

[1008] In some embodiments, a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure is administered once daily, for example, at any of the dosage described herein, under fasted conditions, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, or about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, or about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, or about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, or about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, or about 57%, about 58%, about 59%, or about 60%.

[1009] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the

[1010] 166

[1011] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 40%.

[1012] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 35%.

[1013] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 30%.

[1014] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 25%.

[1015] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 20%.

[1016] 167

[1017] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[1018] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 15%.

[1019] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is about 5%, about 10%, about 11%, about 15%, about 20%, about 25%, about 30%, about 35%, or about 40%.

[1020] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 60%.

[1021] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 55%.

[1022] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of

[1023] 168

[1024] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 50%.

[1025] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 45%.

[1026] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 40%.

[1027] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is administered at a dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is about 35%, about 38%, about 40%, about 45%, about 50%, about 55%, or about 60%.

[1028] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 200 ng*h / mL to about 1,500 ng*h / mL.

[1029] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the

[1030] 169

[1031] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 250 ng*h / mL to about 1,300 ng*h / mL.

[1032] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCmi of the compound is from about 300 ng*h / mL to about 1,100 ng*h / mL.

[1033] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 350 ng*h / mL to about 900 ng*h / mL.

[1034] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 400 ng*h / mL to about 800 ng*h / mL.

[1035] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCmf of the compound is from about 450 ng*h / mL to about 700 ng*h / mL.

[1036] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a

[1037] 170

[1038] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 500 ng*h / mL to about 650 ng*h / mL.

[1039] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 500 ng*h / mL to about 600 ng*h / mL.

[1040] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 100 ng*h / mL to about 1,500 ng*h / mL.

[1041] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 250 ng*h / mL to about 1,300 ng*h / mL.

[1042] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 300 ng*h / mL to about 1,100 ng*h / mL.

[1043] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 350 ng*h / mL to about 900 ng*h / mL.

[1044] 171

[1045] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[1046] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 400 ng*h / mL to about 800 ng*h / mL.

[1047] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 450 ng*h / mL to about 700 ng*h / mL.

[1048] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 500 ng*h / mL to about 650 ng*h / mL.

[1049] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 20 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 500 ng*h / mL to about 600 ng*h / mL.

[1050] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 1,500 ng*h / mL to about 2,800 ng*h / mL.

[1051] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition

[1052] 172

[1053] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957 comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 1,600 ng*h / mL to about 2,700 ng*h / mL.

[1054] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 1,700 ng*h / mL to about 2,600 ng*h / mL.

[1055] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 1,800 ng*h / mL to about 2,500 ng*h / mL.

[1056] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 1,900 ng*h / mL to about 2,400 ng*h / mL.

[1057] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 1,950 ng*h / mL to about 2,300 ng*h / mL.

[1058] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound of the disclosure, or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising a compound of the disclosure, wherein the compound is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about 2,000 ng*h / mL to about 2,200 ng*h / mL.

[1059] 173

[1060] 327684990 Attorney Docket No.: TRPH-063 / 001WO 346923-2957

[1061] In some embodiments, the method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, comprises administering to the subject a compound o...

Claims

1. Attorney Docket No.: TRPH-063 / 001WO 346923-2957CLAIMSWhat is claimed is:

1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound of Formula (I):or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof, wherein:L is -NH-CO-, -CO-NH-, -NH-SO2-, or -SO2-NH-;R1is optionally substituted Ce-Cio aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocycle, C(O)NR6R7, S(O)2NR6R7, NR6COR7, or NR6SO2R7, or C(O)OR6;R2is H, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl;R3is H, optionally substituted Ci-Ce alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, OR6, or NR6R7; orR2and R3together with the intervening atoms form cycloalkyl or heterocycloalkyl, preferably an optionally substituted Cs-Cs cycloalkyl or an optionally substituted 4-10 membered heterocycloalkyl;R4is optionally substituted Ci-Ce alkyl, preferably C1-C3 haloalkyl, such as CF3 or CF2CI, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl;X is O or S;Y is CH, C-(Ci-C2 alkyl), or C-halo or N;Z is CR5or N;R5is H or halogen;414327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957R6is H, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl; andR7is H, optionally substituted Ci-Ce alkyl, optionally substituted Cs-Cs cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted Ce-Cio aryl, or optionally substituted 5-10 membered heteroaryl; orR6and R7together with the nitrogen to which they are attached form an optionally substituted 4-7 membered heterocycle; or administering to the subject a compound of Formula (I’):(I’), or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof, wherein: ring A’ is selected from C3-6 cycloalkyl, 4-7-membered heterocyclyl, Ce-io aryl or 5-7- membered heteroaryl;Ri’ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 haloalkoxy;Mi is selected from N or CRa;M2 is selected from NRa or C(Ra)2;M3 is selected from N or CRa; each Ra is independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio or C1-6 haloalkoxy;R2’ and R3’ are each independently selected from hydrogen, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, C3-6 cycloalkyl, 4-7-membered heterocyclyl, Ce-io aryl or 5-7-membered heteroaryl; and n is 0, 1 or 2.415327684990Attorney Docket No.: TRPH-063 / 001WO 346923-29572. The method of claim 1, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 50 mg.

3. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 175 mg.

4. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 350 mg.

5. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 400 mg.

6. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 500 mg.

7. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 50 mg to about 700 mg.

8. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 50 mg to about 500 mg.

9. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 160 mg to about 500 mg.

10. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 160 mg to about 400 mg.416327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295711. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 350 mg to about 500 mg.

12. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered at a daily dosage of about 400 mg to about 500 mg.

13. The method of any one of the previous claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered to a fed subject at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 40%.

14. The method of any one of the preceding claims, wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 35%.

15. The method of any one of the preceding claims, wherein the difference between / AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 30%.

16. The method of any one of the preceding claims, wherein the difference between AUCinf the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 25%.

17. The method of any one of the preceding claims, wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 20%.

18. The method of any one of the preceding claims, wherein the difference between AUCinf of the compound if administered under fed conditions and AUCinf of the compound if administered under fasted conditions is less than about 15%.417327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295719. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is administered to a fed subject at a daily dosage of between about 5 mg and about 700 mg, and wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 60%.

20. The method of any one of the preceding claims, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 55%.

21. The method of any one of the preceding claims, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 50%.

22. The method of any one of the preceding claims, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 45%.

23. The method of any one of the preceding claims, wherein the difference between Cmax of the compound if administered under fed conditions and Cmax of the compound if administered under fasted conditions is less than about 40%.

24. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound is administered once daily.

25. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound is administered orally.418327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295726. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound is administered with food.

27. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound is administered without food.

28. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the AUCmf of the compound is from about 500 ng*h / mL to about 600 ng*h / mL.

29. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the compound, is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the AUCmf of the compound is from about 2,000 ng*h / mL to about 2,200 ng*h / mL.

30. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fasted conditions, wherein after administration the AUCinf of the compound is from about2.500 ng*h / mL to about 2,600 ng*h / mL.

31. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fed conditions, wherein after administration the AUCinf of the compound is from about 2,200 ng*h / mL to about 2,300 ng*h / mL.

32. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 160 mg at fasted conditions, wherein after administration the AUCmf of the compound is from about6.500 ng*h / mL to about 6,700 ng*h / mL.419327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295733. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 20 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 70 ng / mL to about 150 ng / mL.

34. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 40 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 250 ng / mL to about 350 ng / mL.

35. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 350 ng / mL to about 460 ng / mL.

36. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 80 mg at fed conditions, wherein after administration the Cmax of the compound is from about 200 ng / mL to about 330 ng / mL.

37. The method of any one of the preceding claims, wherein the compound, or pharmaceutically acceptable salt thereof, is orally administered at a daily dosage of about 160 mg at fasted conditions, wherein after administration the Cmax of the compound is from about 800 ng / mL to about 950 ng / mL.

38. The method of any one of the preceding claims, wherein the subject has previously been administered at least one tyrosine kinase inhibitor (TKI).

39. The method of any one of the preceding claims, wherein the subject has previously been administered asciminib.420327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295740. The method of any one of the preceding claims, wherein the subject has previously been administered a combination of asciminib and a second TKI.

41. The method of any one of the previous claims, wherein the second TKI binds to the active site of the BCR:ABL-1.

42. The method of any one of the preceding claims, wherein the second TKI is selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

43. The method of any one of the preceding claims, wherein the second TKI is selected from ponatinib and dasatinib.

44. The method of any one of the preceding claims, wherein the subject has previously been administered dasatinib, ponatinib, asciminib, imatinib, nilotinib, bosutinib, olverembatinib, ELVN-001, and / or bafetinib.

45. The method of any one of the preceding claims, wherein the subject has previously been administered with a TKI for at least one year.

46. The method of any one of the preceding claims, wherein the subject has previously been administered a TKI for at least five years.

47. The method of any one of the preceding claims, wherein the subject has previously been administered with a TKI for at least ten years.

48. The method of any one of the preceding claims, wherein the subject had treatment failure with a previously-administered TKI.

49. The method of any one of the preceding claims, wherein the subject had intolerance to one or more prior TKI treatments.

50. The method of any one of the preceding claims, wherein the subject had intolerance to asciminib.421327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295751. The method of any one of the preceding claims, wherein the subject had a suboptimal response to a previously-administered TKI.

52. The method of any one of the preceding claims, wherein the suboptimal response is defined by BCR::ABL1 transcript levels in the subject.

53. The method of any one of the previous claims, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 0.1% (IS).

54. The method of any one of the previous claims, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 0.1 % (IS) to about 1% (IS).

55. The method of any one of the previous claims, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 1% (IS).

56. The method of any one of the previous claims, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 1 % (IS) to about 10% (IS).

57. The method of any one of the previous claims, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of about 10% (IS).

58. The method of any one of the previous claims, wherein administration of the previously-administered TKI effectuated BCR::ABL1 transcript levels in the subject of greater than 10% (IS).422327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295759. The method of any one of the preceding claims, wherein the subject had loss of response to a previously-administered TKI before the initiation of treatment with a compound of the present disclosure.

60. The method of any one of the preceding claims, wherein the loss of response is defined by BCR::ABL1 transcript levels in the subject.

61. The method of any one of the preceding claims, wherein the BCR: :ABL-1 transcript levels in the subject increased during the course of treatment with the previously- administered TKI.

62. The method of any one of the preceding claims, wherein the BCR: :ABL-1 transcript levels in the subject increased to about 0.1% (IS) during the course of treatment with the previously-administered TKI.

63. The method of any one of the preceding claims, wherein the BCR::ABL-1 transcript levels in the subject increased to a level from about 0.1 % (IS) to about 1% (IS) during the course of treatment with the previously-administered TKI.

64. The method of any one of the preceding claims, wherein the BCR: :ABL-1 transcript levels in the subject increased to about 1% (IS) during the course of treatment with the previously-administered TKI.

65. The method of any one of the preceding claims, wherein the BCR::ABL-1 transcript levels in the subject increased to a level from about 1 % (IS) to about 10% (IS) during the course of treatment with the previously-administered TKI.

66. The method of any one of the preceding claims, wherein the BCR: :ABL-1 transcript levels in the subject increased to a level greater than about 10% (IS) during the course of treatment with the previously-administered TKI.

67. The method of any one of the preceding claims, wherein the previously- administered TKI was a second-generation TKI.423327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295768. The method of any one of the preceding claims, wherein the previously- administered TKI was a third-generation TKI.

69. The method of any one of the preceding claims, wherein the previously- administered TKI binds to the ATP -binding site of BCR::ABL1.

70. The method of any one of the preceding claims, wherein the previously- administered TKI binds to the myristoyl pocket of BCR::ABL1.

71. The method of any one of the preceding claims, wherein the cancer is lymphoma or leukemia.

72. The method of any one of the preceding claims, wherein the lymphoma or leukemia is chronic myeloid leukemia (CML) or chronic lymphocytic leukemia (CLL).

73. The method of any one of the preceding claims, wherein the lymphoma or leukemia is CML.

74. The method of any one of the preceding claims, wherein the method further comprises the step of: determining the DNA sequence of the BCR:ABL1 gene expressed by the subject; and / or determining the amino acid sequence of the BCR:ABL1 protein expressed by the subject.

75. The method of any one of the preceding claims, wherein the subject expresses wild-type BCR:ABL-1.

76. The method of any one of the preceding claims, wherein the wild-type form of BCR:ABL-1 has the amino acid sequence of SEQ ID NO: 1.

77. The method of any one of the preceding claims, wherein the subject expresses a mutant form of BCR:ABL-1.424327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295778. The method of any one of the preceding claims, wherein the mutant form of BCR:ABL-1 contains an amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F.

79. The method of any one of the preceding claims, wherein the mutant form ofBCR:ABL-1 contains multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T3151, (iii) E255V and T3151, (iv) H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T315I, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

80. The method of any one of the preceding claims, wherein the mutant form ofBCR:ABL-1 has the amino acid sequence of any one of SEQ ID NOs 2-22.

81. The method of any one of the previous claims, wherein the compound ofFormula (I) is Compound 5a:or a pharmaceutically acceptable salt thereof.

82. The method of any one of the previous claims, wherein the compound ofFormula (I) is Compound 5:425327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957 or a pharmaceutically acceptable salt thereof.

83. The method of any one of the previous claims, wherein the compound ofFormula (F) is Compound 234.or a pharmaceutically acceptable salt thereof.

84. The method of any one of the previous claims, wherein the compound of Formula (T) is Compound 243.or a pharmaceutically acceptable salt thereof.

85. A pharmaceutical composition comprising:(i) Compound 5a:or a pharmaceutically acceptable salt thereof; and (ii) an excipient.

86. A pharmaceutical composition comprising:(i) Compound 5 :426327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957or a pharmaceutically acceptable salt thereof; and(ii) an excipient.

87. The pharmaceutical composition of any one of the previous claims, wherein about 50 mg of Compound 5 or about 50 mg of Compound 5a is present in the pharmaceutical composition.

88. The pharmaceutical composition of any one of the previous claims, wherein about 175 mg of Compound 5 or about 175 mg of Compound 5a is present in the pharmaceutical composition.

89. The pharmaceutical composition of any one of the previous claims, wherein about 350 mg of Compound 5 or about 350 mg of Compound 5a is present in the pharmaceutical composition.

90. The pharmaceutical composition of any one of the previous claims, wherein about 400 mg of Compound 5 or about 400 mg of Compound 5a is present in the pharmaceutical composition.

91. The pharmaceutical composition of any one of the previous claims, wherein about 500 mg of Compound 5 or about 500 mg of Compound 5a is present in the pharmaceutical composition.

92. The pharmaceutical composition of any one of the previous claims, wherein compound 5 or compound 5a is present as a salt.

93. A pharmaceutical composition comprising:(i) Compound 234:427327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957(Compound 234) or a pharmaceutically acceptable salt thereof; and(ii) an excipient.

94. A pharmaceutical composition comprising:(i) Compound 243 :(Compound 243) or a pharmaceutically acceptable salt thereof; and (ii) an excipient.

95. The pharmaceutical composition of any one of the previous claims, wherein about 50 mg of Compound 243 or about 50 mg of Compound 234 is present in the pharmaceutical composition.

96. The pharmaceutical composition of any one of the previous claims, wherein about 175 mg of Compound 243 or about 175 mg of Compound 234 is present in the pharmaceutical composition.

97. The pharmaceutical composition of any one of the previous claims, wherein about 350 mg of Compound 243 or about 350 mg of Compound 234 is present in the pharmaceutical composition.428327684990Attorney Docket No.: TRPH-063 / 001WO 346923-295798. The pharmaceutical composition of any one of the previous claims, wherein about 400 mg of Compound 243 or about 400 mg of Compound 234 is present in the pharmaceutical composition.

99. The pharmaceutical composition of any one of the previous claims, wherein about 500 mg of Compound 243 or about 500 mg of Compound 234 is present in the pharmaceutical composition.

100. The pharmaceutical composition of any one of the previous claims, wherein compound 243 or compound 234 is present as a salt.

101. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5a, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 5 a) wherein: the subject was previously administered asciminib; during the course of the administration of asciminib to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 5a to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

102. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject:429327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957(Compound 5) wherein: the subject was previously administered asciminib; during the course of the administration of asciminib to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 5 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

103. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 234, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 234) wherein: the subject was previously administered asciminib; during the course of the administration of asciminib to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 234 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

104. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject:430327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957(Compound 243) wherein: the subject was previously administered asciminib; during the course of the administration of asciminib to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 243 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

105. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5a, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 5 a) wherein: the subject was previously administered a tyrosine kinase inhibitor (TKI) that binds to the ATP -binding site of the BCR::ABL1 protein;(ii) during the course of the administration of the previously-administered TKI to the subject, BCR::ABL-1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 5a to the subject, BCR::ABL-1 transcript levels in the subject decreased to less than 0.1% (IS).

106. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject:431327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957(Compound 5) wherein: the subject was previously administered a tyrosine kinase inhibitor (TKI) that binds to the ATP -binding site of the BCR::ABL1 protein;(ii) during the course of the administration of the previously-administered TKI to the subject, BCR: : ABL-1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 5 to the subject, BCR:: ABL-1 transcript levels in the subject decreased to less than 0.1% (IS).

107. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 234, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 234) wherein: the subject was previously administered a tyrosine kinase inhibitor (TKI) that binds to the ATP -binding site of the BCR::ABL1 protein; during the course of the administration of the previously-administered TKI to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 234 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).432327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957108. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 243) wherein: the subject was previously administered a tyrosine kinase inhibitor (TKI) that binds to the ATP -binding site of the BCR::ABL1 protein; during the course of the administration of the previously-administered TKI to the subject, BCR::ABL1 transcript levels in the subject rose to greater than 0.1% (IS); and following the administration of Compound 243 to the subject, BCR::ABL1 transcript levels in the subject decreased to less than 0.1% (IS).

109. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5a, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 5 a) wherein: the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject expresses a mutant form of BCR:ABL1 containing (ii-a) a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F; or (ii-b) multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv)433327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T3151, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

110. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 5) wherein: the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject expresses a mutant form of BCR:ABL1 containing (ii-a) a single amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F; or (ii-b) multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv) H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T3151, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

111. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 234, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 234) wherein: the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and434327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957 the subject expresses a mutant form of BCR:ABL1 containing (ii-a) an amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F; or (ii-b) multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv) H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T3151, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

112. A method of treating chronic myeloid leukemia (CML) in a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, to the subject:(Compound 243) wherein: the subject was previously administered at least one tyrosine kinase inhibitor (TKI); and the subject expresses a mutant form of BCR:ABL1 containing (ii-a) an amino acid mutation selected from F359V, F359C, F359I, H396R, E255V, T315I, A337V, A344P, P465S, T315M, V468F, M244V, F317L, Y253F, E255K, V299L, G250H, E549K, E355G, M351T, L384M, V379I, Q252H, E459K, I502L, P465S, and V468F; or (ii-b) multiple amino acid mutations selected from (i) G250E and T315I, (ii) Y253H and T315I, (iii) E255V and T315I, (iv) H396R and T3151, (v) E255V and V299L, (vi) Y253H and F317L, (vii) A337V and T3151, (viii) A344P and T315I, (ix) P465S and T315I, and (x) V468F and T315I.

113. The method of any one of the previous claims, wherein Compound 5 or Compound 5a is administered at a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg.

114. The method of any one of the previous claims, wherein Compound 243 or Compound 234 is administered at a daily dosage of about 50 mg, about 80 mg, about 100 mg,435327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957 about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg.

115. The method of any one of the previous claims, wherein Compound 5, Compound 5a, Compound 234, or Compound 243 is administered as a pharmaceutically acceptable salt.

116. The method of any one of the previous claims, wherein a pharmaceutically acceptable salt of Compound 5a is administered in an amount such that a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg of Compound 5a is provided.

117. The method of any one of the previous claims, wherein a pharmaceutically acceptable salt of Compound 5 is administered in an amount such that a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg of Compound 5 is provided.

118. The method of any one of the previous claims, wherein a pharmaceutically acceptable salt of Compound 234 is administered in an amount such that a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg of Compound 234 is provided.

119. The method of any one of the previous claims, wherein a pharmaceutically acceptable salt of Compound 243 is administered in an amount such that a daily dosage of about 50 mg, about 80 mg, about 100 mg, about 160 mg, about 175 mg, about 250 mg, about 320 mg, about 350 mg, about 400 mg, or about 500 mg of Compound 243 is provided.

120. The method of any one of the previous claims, wherein the subject is able to receive a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or OATP1B1 / 3.436327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957121. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or OATP1B1 / 3.

122. The method of any one of the previous claims further comprising, advising the subject that the administration according to a method of any one of the previous claims does not alter a concurrent treatment with a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or 0ATP1B1 / 3.

123. The method of any one of the previous claims further comprising, advising the subject that administration of a substrate of CYP3A4, CYP2C19, CYP2D6, CYP2C8, CYP3A, CYP2C9, BCRP, and / or 0ATP1B1 / 3 does not alter the concurrent administration according to the method of any one of the previous claims.

124. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP3 A4.

125. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP2C19.

126. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP2D6.

127. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP2C8.

128. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP3 A.

129. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP2C9.437327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957130. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of BCRP.

131. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of OATP1B1 / 3.

132. The method of any one of the previous claims, wherein the subject concurrently receives a substrate of CYP3A4, and / or CYP2C19.

133. A method of treating a subject in need thereof, the method comprising administering Compound 5a, or a pharmaceutically acceptable salt thereof, and a statin to the subject in need thereof.

134. A method of treating a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, and a statin to the subject in need thereof.

135. A method of treating a subject in need thereof, the method comprising administering Compound 234, or a pharmaceutically acceptable salt thereof, and a statin to the subject in need thereof.

136. A method of treating a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, and a statin to the subject in need thereof.

137. The method of any one of claims 133-136, wherein the subject is treated for cancer.

138. The method of any one of claims 133-137, wherein the subject is treated for a cardiovascular disease.

139. The method of claim 138, wherein the cardiovascular disease is hypercholesterolemia or atherosclerosis.438327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957140. The method of any one of claims 133-139, where the statin is atorvastatin, rosuvastatin, simvastatin, pitavastatin, pravastratin, fluvastatin, or lovastatin.

141. The method of any one of claims 133-140, wherein the subject was receiving daily dosages of the statin before the administering of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, and the daily dosages of the statin are not modified upon the administering of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.

142. The method of any one of claims 133-140, wherein the subject was receiving daily dosages of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, before the administering of the statin and the daily dosages of Compound 5 a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, are not modified upon the administering of the statin.

143. A method of treating a subject in need thereof, the method comprising administering Compound 5a, or a pharmaceutically acceptable salt thereof, and a substrate of CYP3A4 to the subject in need thereof.

144. A method of treating a subject in need thereof, the method comprising administering Compound 5, or a pharmaceutically acceptable salt thereof, and a substrate of CYP3A4 to the subject in need thereof.

145. A method of treating a subject in need thereof, the method comprising administering Compound 234, or a pharmaceutically acceptable salt thereof, and a substrate of CYP3 A4 in need thereof.

146. A method of treating a subject in need thereof, the method comprising administering Compound 243, or a pharmaceutically acceptable salt thereof, and a substrate of CYP3 A4 in need thereof.439327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957147. The method of any one of claims 143-146, wherein the substrate of CYP3A4 is atorvastatin, simvastatin, lovastatin, cyclosporine, tacrolimus, sirolimus, amlodipine, diltiazem, verapamil, felodipine, midazolam, triazolam, alprazolam, diazepam, trazodone, quetiapine, aripiprazole, sertraline, erythromycin, clarithromycin, ritonavir, lopinavir, saquinavir, sildenafil, tadalafil, or vardenafil.

148. The method of any one of claims 143-147, wherein the subject was receiving daily dosages of the substrate of CYP3 A4 before the administering of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, and the daily dosages of the statin are not modified upon the administering of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.

149. The method of any one of claims 143-147, wherein the subject was receiving daily dosages of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, before the administering of the substrate of CYP3 A4 and the daily dosages of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, are not modified upon the administering of the substrate of CYP3 A4.

150. A method of co-administrating pharmaceutically active compounds, comprising:(a) administering to a subject Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof; and(b) administering to the subject a statin.

151. The method of claim 150, wherein the administering step (a) and the administering step (b) are performed within 24-72 hours of each other.

152. The method of claim 150 or claim 151, wherein the subject has been identified as being amenable to co-administration of a statin and Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.440327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957153. The method any one of claims 150-152, wherein the subject has been advised that co-administration of a statin and Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof would not cause adverse effects.

154. The method of any of claims 150-153, wherein the administering step (b) takes place prior to any administration of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.

155. The method of claim 154, wherein the quantity of statin administered subsequent to the administering step (a) is identical to the amount of statin administered to said subject prior to any administration of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.

156. The method of any one of claims 150-153, wherein the administering step (a) takes place prior to any administration of statin.

157. The method of claim 156, wherein the quantity of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof administered subsequent to the administering step (b) is identical to the amount of Compound 5a, Compound 5, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof administered to said subject prior to any administration of statin.

158. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, wherein said subject has received administration of a statin for more than 1 week prior to administering to the subject Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.

159. The method of claim 158, wherein the subject continues to receive the statin after administering to the subject Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.441327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957160. The method of claim 159, wherein the quantity of the statin administered prior to any administering to the subject Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof is the same as the quantity of statin administered subsequent to administering to the subject Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof.

161. A method of treating a cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a statin, wherein said subject has received administration of Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof for more than 1 week prior to administering to the subject the statin.

162. The method of claim 161, wherein the subject continues to receive Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof after administering to the subject the statin.

163. The method of claim 162, wherein the quantity of Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof administered prior to any administering to the statin is the same as the quantity of Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof administered subsequent to administering to the statin.

164. A method of treating, preventing, or reducing the severity of a cancer in a subject in need thereof, the method comprises administering Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94, to the subject, wherein the cancer is a leukemia.

165. A kit comprising Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94, and printed instructions for use in treatment of leukemia in a subject.442327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957166. A method of inhibiting tyrosine kinase enzymatic activity of a protein selected from the group consisting of Abelson protein (ABL1), Ab el son-related protein (ABL2), and a chimeric protein BCR::ABL1, the method comprises administering to the subject Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94, wherein Compound 5, Compound 5a, Compound 234, or Compound 243, or the pharmaceutically acceptable salt thereof, is administered at a daily dosage of between about 5 mg and about 700 mg.

167. The pharmaceutical composition of any one of claims 85, 86, 93, and 94, for use in treating a cancer in a subject in need thereof.

168. Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94, for use in treating a cancer in a subject in need thereof.

169. Compound 5, Compound 5 a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94, for use in treating leukemia in a subject in need thereof.

170. Use of Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94 in the manufacture of a medicament for the treatment of a cancer in a subject in need thereof.

171. Use of Compound 5, Compound 5a, Compound 234, or Compound 243, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 85, 86, 93, and 94 in the manufacture of a medicament for the treatment of leukemia in a subject in need thereof.

172. The method of any one of claims 1-80, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.443327684990Attorney Docket No.: TRPH-063 / 001WO 346923-2957173. The method of any one of claims 1-80, wherein the compound of Formula (I) is Compound 1, 2a, 3, 4, 5a, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24a, 25, 26, 27, 28a, 29, 30, 31, 32a, 33a, 34a, 35a, 36a, 37, 38a, 39a, 40a, 41a, 42a, 43a, 44a, 45a, 46a, 47a, 48a, 49a, 50, 51, 52, 53, 54, 55, 56a, 57a, 58a, 59a, 61a, 63, 64a, 66a, 67a, 68, 70a, 71a, 72, 76a, 77a, 80, 81, 82, 83a, 85, 86, 87a, 89, 90a, 91, 92, 93, 94, 96a, 97, 99a, 100, 102a, 104, 105a, 107, 108, 109, 110a, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123a, 125a, 127, 128, 130, 131a, 132a, 133a, 134, 136, 139, 140, 141a, 142a, 143, 144a, 145, 146a, 147, 148a, 149a, 150a, 151, 152a, 153a, 154a, 155a, 156a, 157a, 158a, 159a, 160a, 161a, 162a, 163a, 164a, 165a, 166a, 167a, 168a, 169a, 170a, 170, 171a, 173a, 174a, 175a, 176a, 177a, 178a, 179a, 182a, 184, 185a, 186, 187a, 189a, 190, 192a, 193, 194, 195a, 196a, 197a, 198a, 199a, 200a, 201, 202a, 203a, 204a, 205a, 206a, 207a, 208a, 210a, 212, 213, 214a, 215a, 216a, 217a, 218, 219a, 220a, 221a, 222a, 223a, 224a, 226a, 227a, 228a, 229a, 230a, 232a, 233, 234, 235, 236, 237, 238, 239, 240, or 241, or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof.

174. The method of any one of claims 1-80, wherein the compound of Formula (I) is Compound 2, 5, 24, 28, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 56, 57, 58, 59, 60, 61, 62, 64, 65, 66, 67, 69, 70, 71, 73, 74, 75, 76, 77, 78, 79, 83, 84, 87, 88, 90, 95, 96, 98, 99, 101, 102, 103, 105, 106, 110, 123, 124, 125, 126, 129, 131, 132, 133, 135, 137, 138, 141, 142, 144, 146, 148, 149, 150, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164,165, 166, 167, 168, 169, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 185,187, 188, 189, 191, 192, 195, 196, 197, 198, 199, 200, 202, 203, 204, 205, 206, 207, 208, 209,210, 211, 214, 215, 216, 217, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231,232, 242, 243, 244, 245, 246, 247, 248, 249, or 250, or a tautomer, N-oxide, isotopomer, prodrug, stereoisomer, pharmaceutically acceptable salt, and / or solvate thereof.444327684990

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