EP4719421A1 - Combination therapy comprising kit inhibitors for use in the treatment of cancer - Google Patents

Abstract

The present disclosure relates to methods and compositions for treating conditions associated with aberrant KIT activity (e.g., cancer). The methods and compositions described herein generally comprise a compound of Formula (I) and M4205 or THE-630.

Description

COMBINATION THERAPY COMPRISING KIT INHIBITORS FOR USE IN THE TREATMENT OF CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. Provisional Application No. 63/506,045, filed June 2, 2023, the contents of which are incorporated herein by reference in their entirety.

FIELD

The present disclosure relates to methods and compositions for treating conditions associated with aberrant KIT activity (e.g, cancer).

BACKGROUND

This disclosure relates to methods and compositions comprising N-(pyridin-2- yl)pyrimidine-4-amine compounds that inhibit mutant KIT protein kinases and M4205 or THE-630 for treating cancer (e.g., gastrointestinal stromal tumor (GIST)).

The enzyme KIT (also called CD1 17) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization, kinase domain activation and activation of downstream signaling pathways. KIT plays an important role in the occurrence of diseases, such as cancer, and mutations in KIT are found in several cancers (e.g., GIST).

Current therapies are inadequate for treatment of GIST that has become resistant to inhibitors of the primary activating KIT mutations. Accordingly, there is a need for therapies targeting resistant KIT mutations.

SUMMARY

Disclosed herein is a method of treating a cancer in a subject in need thereof, comprising administering to the subject: M4205: or a pharmaceutically acceptable salt thereof, and a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R^1A are each independently selected from H, halogen, and CH3, or R¹ and R^1A taken together with the carbon to which they are attached form cyclopropyk

R²is selected from Ci-salkyl, CD3, C3-6Cycloalkyl, bicyclo[ 1.1.1] pentane, and 4- to 6- membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen. CH3, C2- alkenyl, OH, CH2OH, C4- 6cycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said alkyl, cycloalkyl, heterocycle or phenyl is optionally substituted with OH or NH2, Ci-2alkyl, CH2NH2, or halogen; X₃ is N or CH;

R⁵ is selected from H, Ci-3alkyl, CDs, C3-4cycloalkyl and bicyclo[l . 1. 1] pentane, wherein said alkyl, cycloalkyl or bicyclofl. 1.1. ]pentane is optionally substituted with 1-2 R⁷; each R⁷ is independently selected from CN, NH2, OH, CH2OH, cyclopropyl, pyridinyl, and oxazolyl, or taken together two R⁷ attached to the same carbon atom form 4- membered heterocycle containing N;

R⁶ is independently selected from Ci-salkyl, CHF2, CF3. 4- or 5-membered heterocycle containing N or O, and C3-4Cycloalkyl, wherein said alkyl or heterocycle is optionally substituted wi th one R⁸;

R⁸ is independently selected from OH, NR⁹R⁹, OCH3, CH3 and 4-membered heterocycle containing N or O, wherein said alkyl or heterocycle is optionally substituted with one R¹⁰; each R⁹ is independently selected from H, CH3 and CH2CF3; and

R¹⁰ is selected from CH3 and CF3.

In some embodiments, the method comprises administering an effective amount of M4205, or a pharmaceutically acceptable salt thereof.

In some embodiments, M4205 is dosed at about 100 mg to about 2000 mg per administration.

In some embodiments, M4205 is dosed orally.

In some embodiments, M4205 and the compound of Formula (I) are administered simultaneously.

In some embodiments, M4205 and the compound of Formula (I) are administered sequentially.

In some embodiments, M4205 is administered to the subject daily.

In some embodiments, M4205 is administered to the subject once daily.

In some embodiments, M4205 is administered to the subject twice daily.

In some embodiments, administering M4205 and the compound of Formula (I) reduces tumor size relative to administering M4205.

In some embodiments, administering M4205 and the compound of Formula (I) reduces tumor size relative to administering e compound of Formula (I).

Disclosed herein is a method of treating a cancer in a subject in need thereof, comprising administering to the subject:

THE-630, or a pharmaceutically acceptable salt thereof, and a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R^1A are each independently selected from H, halogen, and CH3, or R¹ and R^1A taken together with the carbon to which they are attached form cyclopropyl;

R²is selected from Ci-salkyl, CD3, Cs-ecycloalkyl, bicyclofl.1.1] pentane, and 4- to 6- membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen, CH3, C2-3alkenyl, OH, CH2OH, C4- ecycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said alkyl, cycloalkyl, heterocycle or phenyl is optionally substituted with OH or NH2, Ci-2alkyl,

CH2NH2. or halogen;

Xi is NH or O;

X₂ is N or CH;

X₃ is N or CH;

R⁵ is selected from H, Ci-3alkyl, CDs, C3-4cycloalkyl and bicyclo[l . 1. 1] pentane, wherein said alkyl, cycloalkyl or bicyclofl. 1.1. ]pentane is optionally substituted with 1-2 R⁷; each R⁷ is independently selected from CN, NH2, OH, CH2OH, cyclopropyl, pyridinyl, and oxazolyl, or taken together two R⁷ attached to the same carbon atom form 4- membered heterocycle containing N; R⁶ is independently selected from Ci-salkyl, CHF2, CF3, 4- or 5-membered heterocycle containing N or O, and C3-4cycloalkyl, wherein said alkyl or heterocycle is optionally substituted with one R⁸;

R⁸ is independently selected from OH, NR⁹R⁹, OCH3, CH3 and 4-membered heterocycle containing N or O, wherein said alky l or heterocycle is optionally substituted with one R¹⁰: each R⁹ is independently selected from H, CH3 and CH2CF3; and

R¹⁰ is selected from CH3 and CF3.

In some embodiments, the method comprises administering an effective amount of THE-630, or a pharmaceutically acceptable salt thereof.

In some embodiments, THE-630 is dosed at about 0. 1 mg to about 200 mg per administration per administration

In some embodiments, THE-630 is dosed orally.

In some embodiments, THE-630 and the compound of Formula (I) are administered simultaneously.

In some embodiments. THE-630 and the compound of Formula (I) are administered sequentially.

In some embodiments, THE-630 is administered to the subject daily.

In some embodiments, THE-630 is administered to the subject once daily.

In some embodiments. THE-630 is administered to the subject twice daily.

In some embodiments, administering THE-630 and the compound of Formula (I) reduces tumor size relative to administering THE-630.

In some embodiments, administering THE-630 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

In some embodiments, the method comprises administering an effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is dosed at about 0.1 mg to about 200 mg per administration.

In some embodiments, the compound of Formula (I) is a dosed orally.

In some embodiments, the compound of Formula (I) is administered to the subject daily.

In some embodiments, the compound of Formula (I) is administered to the subject once daily. In some embodiments, the compound of Formula (I) is administered to the subject twice daily.

In some embodiments, administering M4205 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

In some embodiments, administering THE-630 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

In some embodiments, the compound of Formula (I) is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject is resistant or has acquired resistance to an anticancer therapy.

In some embodiments, the anti-cancer therapy is administering an anti-cancer agent.

In some embodiments, the anti-cancer agent is a KIT inhibitor.

In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, ripretinib. AZD3229. BLU-263, alvocidib. anlotinib. avapritinib, axitinib. bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib. regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the subject is resistant or has acquired resistance to one or more anti-cancer therapies.

In some embodiments, each of the anti-cancer therapies is administering an anticancer agent.

In some embodiments, each of the anti-cancer agents is a KIT inhibitor.

In some embodiments, each of the anti-cancer agents is independently selected from: imatinib. sunitinib. regorafenib, ripretinib. AZD3229. BLU-263, alvocidib. anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib. regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the subject is receiving an anti-cancer therapy.

In some embodiments, the anti-cancer therapy is administering an anti-cancer agent.

In some embodiments, the anti-cancer agent is a KIT inhibitor.

In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, AZD3229, BLU-263, alvocidib, anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab. pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, subject is in a fasting state.

In some embodiments, the compound of Formula (I) is administered with food.

In some embodiments, the compound of Formula (I) is administered about 30 minutes to about 1 hour after food.

In some embodiments. M4205 is administered with food.

In some embodiments, M4205 is administered about 30 minutes to about 1 hour after food.

In some embodiments, THE-630 is administered with food.

In some embodiments, THE-630 is administered about 30 minutes to about 1 hour after food.

In some embodiments, the cancer is selected from: gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer and mediastinal B-cell lymphoma.

In some embodiments, the cancer is gastrointestinal stromal tumor (GIST).

In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations.

In some embodiments, the tumor has a primary activating KIT mutation. In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation, and combinations thereof.

In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation and an exon 17 KIT mutation, and combinations thereof.

In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, K642E, V654A, and N655K, and combinations thereof.

In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, K642E, V654A, and N655K, and combinations thereof.

In some embodiments, the tumor has an exon 9 KIT mutation.

In some embodiments, the tumor has an exon 11 KIT mutation.

In some embodiments, the tumor has an exon 13 KIT mutation.

In some embodiments, the exon 13 KIT mutation is selected from K642E, V654A and N655K, and combinations thereof.

In some embodiments, the tumor has an exon 14 KIT mutation.

In some embodiments, the exon 14 KIT mutation is T670I.

In some embodiments, the tumor has an exon 17 KIT mutation.

In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P.

In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.

In some embodiments, the tumor is resistant or has acquired resistance to an anticancer therapy.

In some embodiments, the anti-cancer therapy is administering an anti-cancer agent.

In some embodiments, the anti-cancer agent is a KIT inhibitor.

In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, AZD3229, BLU-263, alvocidib, anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab. pazopanib. pexidartinib. ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the tumor resistant or has acquired resistance to one or more anti-cancer therapies.

In some embodiments, each of the anti-cancer therapies is administering an anticancer agent.

In some embodiments, the anti-cancer agent is a KIT inhibitor.

In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, ripretinib, AZD3229, BLU-263, alvocidib, anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. l is a graph illustrating the impact of various doses of M4205 on tumor size.

FIG. l is a graph illustrating the percentage change of various doses of M4205 on target lesions from baseline.

FIG. 3 is a Western Blot demonstrating the combination drug effect of M4205 (2.5 nM) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines.

FIG. 4 is a Western Blot demonstrating the combination drug effect of M4205 (8.3 nM) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines.

FIG. 5 is a Western Blot demonstrating the combination drug effect of M4205 (25 nM) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines. FIG. 6 is a Western Blot demonstrating the combination drug effect of M4205 (75 nM) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines.

FIG. 7 is a Western Blot demonstrating the combination drug effect of M4205 (250 nM) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines.

FIG. 8 is a Western Blot demonstrating the drug effect of M4205 and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines.

FIG. 9 is a dose-response matrix of M4205 and Compound 198 in GIST 430/654 (exon 11/13) mutant cell lines

FIG. 10 illustrates the synergy of M4205 and Compound 198 in GIST 430/654 (exon 11/13) mutant cell lines. ZIP synergy analysis was performed to generate synergy score.

FIG. 11 illustrates the synergy of M4205 and Compound 198 in GIST 430/654 (exon 11/13) mutant cell lines. HSA synergy analysis was performed to generate synergy score.

FIG. 12 illustrates the synergy of M4205 and Compound 198 in GIST 430/654 (exon 1 1/13) mutant cell lines. Loewe synergy analysis was performed to generate synergy score.

FIG. 13 illustrates the synergy' of M4205 and Compound 198 in GIST 430/654 (exon 11/13) mutant cell lines. Bliss synergy analysis was performed to generate synergy score.

FIG. 14 is a dose-response matrix of M4205 and Compound 198 in GIST Tl/654 (exon 1 1/13) mutant cell lines.

FIG. 15 illustrates the synergy' of M4205 and Compound 198 in GIST Tl/654 (exon 11/13) mutant cell lines. ZIP synergy analysis was performed to generate synergy score.

FIG. 16 illustrates the synergy of M4205 and Compound 198 in GIST Tl/654 (exon 1 1/13) mutant cell lines. HSA synergy analysis was performed to generate synergy score.

FIG. 17 illustrates the synergy of M4205 and Compound 198 in GIST Tl/654 (exon 11/13) mutant cell lines. Loewe synergy analysis was performed to generate synergy score.

FIG. 18 illustrates the synergy of M4205 and Compound 198 in GIST Tl/654 (exon 11/13) mutant cell lines. Bliss synergy analysis was performed to generate synergy score. DETAILED DESCRIPTION

As generally described herein, the present disclosure features methods and compositions useful for treating a KIT-dependent disorders or diseases, such as cancer.

Definitions

The following definitions apply to the terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the art to which it pertains. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.

The terms “a.” “an.” and “the” refer to one or to more than one. unless context indicates otherwise. Similarly, the term “or” is intended to include “and”, unless context indicates otherwise.

As used herein, the terms “about” and “approximately” refer to a value that is within 10% above or below the value being described. For example, the term “about 5 mg” indicates a range of from 4.5 mg to 5.5 mg.

The terms “disease,” “disorder,” and “condition” are used interchangeably herein.

The term “effective amount” means an amount when administered to the subject or patient 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). The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body w eight, 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 or antiviral 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 or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57^th ed., 2003).

As used herein, a “malignant disease” refers to a disease in which abnormal cells divide without control and can invade nearby tissues. Malignant cells can also spread to other parts of the body through the blood or lymph system. Examples of malignant diseases are carcinoma, sarcoma, leukemia, and lymphoma. Cancer is a malignant disease. Systemic mastocytosis is a malignant disease. Indolent systemic mastocytosis is a malignant disease.

Examples of cancer include, but are not limited to, gastrointestinal stomal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer and mediastinal B-cell lymphoma.

As used herein, an “inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that inhibits a protein e.g, an enzyme such that a reduction in activity of the protein can be observed e.g.. by biochemical assay. In certain embodiments, an inhibitor has an IC50 of less than 1 mM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, and less than 1 nM.

The term “KIT” refers to a human tyrosine kinase that may be referred to as mast/stem cell growth factor receptor (SCFR), proto-oncogene c-KIT, tyrosine-protein kinase Kit or CD1 17.

The term “KIT mutation”, as used herein, refers to a KIT gene, cDNA, mRNA, or protein whose sequence differs from the KIT gene sequence of human reference genome hgl9, or the corresponding cDNA, mRNA, or protein. In some embodiments, when discussing KIT mutations in a nucleotide sequence that encodes a KIT polypepride, mutations are described in terms of the change that is produced in the sequence of the polypeptide that is encoded by the nucleotide. In some embodiments the KIT mutation is V654A, N655K or K642E in exon 13. As used herein, the term “an exon 9 KIT mutation” refers to a mutation in exon 9 of KIT. As used herein, the term “an exon 11 KIT mutation” refers to a mutation in exon 11 of KIT. As used herein, the term “an exon 13 KIT mutation’' refers to a mutation in exon 13 of KIT. As used herein, the term “an exon 17 KIT mutation” refers to a mutation in exon 17 of KIT. As used herein, the term “an exon 18 KIT mutation” refers to a mutation in exon 18 of KIT. A829P is a mutation at the very start of exon 18 KIT but, in some embodiments, A829P is referred to as an “exon 17” KIT mutation. In some embodiments, the KIT mutation is N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E. D820Y and D823D in exon 17. In some embodiments, the KIT mutation is A829P in exon 18 or in exon 17.

As used herein, a “selective KIT inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that selectively inhibits KIT protein kinase over another protein kinase and exhibits at least a 2-fold selectivity’ for a KIT protein kinase over another kinase. For example, a selective KIT inhibitor exhibits at least a 10-fold selectivity; at least a 15-fold selectivity’; at least a 20-fold selectivity’; at least a 30-fold selectivity⁷; at least a 40-fold selectivity; at least a 50-fold selectivity⁷; at least a 60-fold selectivity⁷; at least a 70- fold selectivity; at least a 80-fold selectivity; at least a 90-fold selectivity; at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, or at least 200-fold selectivity for a KIT kinase over another kinase. In some embodiments, a selective KIT inhibitor exhibits at least 150-fold selectivity⁷ over another kinase, e.g., VEGFR2 (vascular endothelial growth factor receptor 2), SRC (Non-receptor protein tyrosine kinase), and FLT3 (Fms-Like Tyrosine kinase 3). See for example, Evans et al. (2017). In some embodiments, selectivity for a KIT kinase over another kinase is measured in a cellular assay (e.g, a cellular assay as provided herein). In other embodiments, selectivity for a KIT kinase or over another kinase is measured in a biochemical assay (e.g, a biochemical assay provided in Evans, et al. (2017)).

As used herein, the term “BID” refers to twice a day.

As used herein, the term “QD” refers to once a day.

As used herein, the term “pharmaceutical composition” refers to a formulation (e.g, medicinal formulation) that contains at least one active ingredient (e.g, a compound of Formula (I) or subclasses thereof, a compound of Table 1 or Table 2, M4205, or THE-630, or a pharmaceutically acceptable salt thereof) as well as one or more excipients or diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes pharmaceutically acceptable components that are compatible with compounds disclosed herein (e.g., compounds of Formula (I) and subclasses thereof, compounds of Table 1 and Table 2, M4205, and THE-630, and pharmaceutically acceptable salts thereof).

As used herein, the term '‘pharmaceutically acceptable” refers to compounds, compositions, dosage forms, or materials which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without excessive allergic response, irritation, toxicity, or other problem or complication, commensurate with a reasonable benefit/risk ratio. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

As used herein, the term “pharmaceutically acceptable excipient” refers to a substance or material other than the compounds disclosed herein (e.g., compounds of Formula (I) and subclasses thereof, compounds of Table 1 and Table 2, M4205, and THE-630, and pharmaceutically acceptable salts thereof) that is included in the compositions disclosed herein. Excipients are generally nontoxic to the subject and compatible with the other ingredients of the composition. Excipients include, but are not limited to. adjusting agents, adjuvants, anti adherents, antimicrobial agents, antioxidants, binders, buffers, carriers, coatings, compression aids, diluents, disintegrants, dispersing agents, dyes, emollients, emulsifiers, encapsulating materials, fillers, flavors, fragrances, glidants, lubricants, preservatives, salts, solvents, sorbents, stabilizers, surfactants, suspending agents, and sweeteners. For example, a pharmaceutically acceptable excipient may be a vehicle capable of suspending or dissolving a compound disclosed herein. Exemplary' excipients are found, e.g., in Remington’s Pharmaceutical Sciences, 15^th Ed., Mack Publ. Co., Easton, PA (1975).

A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g, companion animals (e.g, dogs, cats, and the like), farm animals (e.g, cows, sheep, pigs, horses, and the like) and laboratory⁷ animals (e.g, rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In one aspect, the patient is an adult human.

As used herein, the term “treat” or “treating” a disease or disorder refers to alleviating, ameliorating, delaying, inhibiting, preventing, reversing, slowing down, or stopping the aggravation, deterioration, onset, or progression of the disease or disorder, or a condition or symptom associated with the disease or disorder. In some embodiments, treatment slows the progression of the disease (e.g.. cancer), improves the subject's outcome, or eliminates the disease, or symptoms thereof. In some embodiments, treatment of a disease (e.g., cancer) in a subject alleviates or ameliorates one or more symptoms or conditions associated with the disease (e.g, cancer). In some embodiments, treatment of a disease (e.g., cancer) in a subject diminishes the extent of the disease. In some embodiments, treatment of a disease (e.g., cancer) in a subject stabilizes (z.e., not worsening) the state of the disease (e.g, cancer). In some embodiments, treatment of a disease (e.g, cancer) in a subject prevents the spread of the disease (e.g. cancer). In some embodiments, treatment of a disease (e.g. cancer) in a subject delays or slows the progress of the disease (e.g., cancer), as compared to the state or the condition of the disease (e.g., cancer) in the absence of the treatment.

Chemical Definitions

The following chemical definitions apply to the abbreviations and terms as used to describe the present disclosure, unless otherwise indicated or apparent from context. Unless explicitly indicated otherwise, or apparent from context, the terms below do not exclude the meaning that the term has acquired in the chemical arts. The definitions below are provided to facilitate the description of the disclosure, but they are not intended to limit the scope of the disclosure.

The abbreviations and terms used herein have their conventional meaning within the chemical arts. The structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

Definitions of select chemical terms and functional groups are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics. 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modem Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

The term “alkyd” used alone or as part of a larger moiety, such as “alkoxy”, “hydroxyalkyl” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms (Ci-6 alkyl), (z.e., 1, 2, 3, 4, 5 or 6) alternatively, 1 to 3 carbon atoms (C1-3 alkyl) (z.e., 1, 2 or 3). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, and the like.

The term "alkenyl" means an aliphatic straight-chain or branched monovalent hydrocarbon radical with one double bond. Unless otherwise specified, an alkenyl group typically has 1 to 6 carbon atoms (C1-3 alkenyl), alternatively, 1 to 3 carbon atoms (C1-3 alkenyl).

"Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 8 ring carbon atoms (Cs-s cycloalkyl), alternatively, 3 to 6 ring carbon atoms (Cs-6 cycloalkyl), alternatively, 3 to 5 carbon atoms (Cs-5 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term '‘halogen” or '‘halo” means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

The term “heterocycle” refers to a monocyclic non-aromatic ring radical containing unless otherwise specified. 3 to 8 ring atoms (/.e., “3, 4. 5, 6, 7, or 8 membered”) selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e g., NO); oxygen; and sulfur, including sulfoxide and sulfone. Representative heterocycles include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl. pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl. tetrahydropyranyl. tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

The term “hydroxyl” or “hydroxy” refers to the group OH.

The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).

If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 nonhydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions.

Compounds having one or more chiral centers can exist in various stereoisomeric forms, i. e. , each chiral center can have an R or S' configuration or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are non-superimposable mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “7?” or “S'”) or structure (e.g., the configuration is indicated by “wedge'’ bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.

“Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

When two or more stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer relative to the other is as indicated above.

When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S' configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S' configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “5” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched. diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.

Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well know n methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

“Peak I " or “first eluting isomer” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/punfication that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2” or “second eluting isomer”.

When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers. As used herein, the term “pharmaceutically acceptable salt’' refers to pharmaceutical salts that are. 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 are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66: 1-19. Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of this disclosure with acidic groups 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).

Compounds

The N-(pyridin-2-yl)pyrimidine-4-amine compounds described herein (e.g., compounds of Formula (I) and subclasses thereof and compounds of Table 1 and Table 2) and pharmaceutically acceptable salts thereof are useful as selective inhibitors of mutant KIT protein kinases and for use in compositions and methods of treating a disease (e g., cancer) characterized by KIT mutation. Compounds of Formula (I) include those described generally herein, and are further illustrated by the classes, subclasses, and species described herein (e.g., compounds of Formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X) and compounds of Table 1 and Table 2, and pharmaceutically acceptable salts thereof).

Example embodiments of compounds of Formula (I) include: First embodiment: a compound represented by Formula (I): (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are described in the summary above.

Second embodiment: a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R¹ and R^1A are each independently selected from H, halogen and CH31 R² is selected from Ci-salkyl, CD3. Cs-ecycloalkyl and 4- to 6-membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen, CHs, OH, NH2, C4- ecycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said cycloalkyl or phenyl is optionally substituted with OH or NH2; each R⁷ is independently selected from CN, OH, CH2OH, cyclopropyl, pyridinyl, and oxazolyl. or taken together two R⁷ attached to the same carbon atom form 4-membered heterocycle containing N; and R¹⁰ is CH3. The remainder of the variables in Formula (I) are described above in the first embodiment. In some second embodiments, each R⁴ is independently selected from halogen, CH3, OH, C4- ecycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said cycloalkyl or phenyl is optionally substituted with OH or NH2.

Third embodiment: a compound represented by Formula (II): or a pharmaceutically acceptable salt thereof. The variables in Formula (II) are described in the first and/or second embodiment.

Fourth embodiment: a compound represented by Formula (III): (Ill) or a pharmaceutically acceptable salt thereof. The variables in Formula (III) are described in the first and/or second embodiment.

Fifth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R¹ and R^1A are each independently selected from H, halogen and CH3; R²is selected from Ci-salkyl. CD3, C3-4cycloalkyl and 4- to 6- membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen, CH3 and phenyl; R⁵ is selected from H, Ci-salkyl, CD3, C3-4cycloalkyl and bicyclo[ 1.1.1] pentane, wherein said alkyl, cycloalkyl or bicyclofl. 1.1. ]pentane is optionally substituted with 1-2 R⁷; and each R⁷ is independently selected from CN. OH, CH2OH, cyclopropyl, pyridinyl and oxazolyl, or taken together two R⁷ attached to the same carbon atom form 4-membered heterocycle containing N. The remainder of the variables in Formula (I) are described above in the first or second embodiment.

Sixth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R² is selected from CH3, CD3, CH2CH3, CH2CH2CH3, CH(CHS)2, CH₂CH(CH₃)2, CH(CH₃)CH₂CH₃, cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-3 R⁴. The remainder of the variables in Formula (I). (II) and (III) are described above in the first, second and/or fifth embodiment.

Seventh embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R² is selected from:

Formula (I), (II) and (III) are described above in the first, second and/or fifth embodiment.

Eighth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein each R⁴ is independently selected from F, CH3, cyclobuty l and phenyl. The remainder of the variables in Formula (I), (II) and (III) are described above in the first, second, fifth, sixth and/or seventh embodiment. Ninth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from H, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH₃)₂, cyclobutyl, cyclopropyl and bicylo[l. l. l]pentanyl, wherein said CH3, CH2CH3, CH2CH2CH3, CH(CHS)2, cyclobutyl, cyclopropyl or bicylo[l.l.l]pentanyl are optionally substituted with 1-2 R⁷. The remainder of the variables in Formula (I), (II) and (III) are described above in the first, second, fifth, sixth, seventh and/or eighth embodiment.

Tenth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R⁵ is selected from: variables in Formula (I), (II) and (III) are described above in the first, second, fifth, sixth, seventh and/or eighth embodiment.

Eleventh embodiment: a compound represented by Formula (I). (II) or (III), or a pharmaceutically acceptable salt thereof, wherein each R⁷ is independently selected from CN,

CH2OH, cyclopropyl, or taken together two R⁷ attached to the same carbon atom form . The remainder of the variables in Formula (I). (II) and (II) are described above in the first, second, fifth, sixth, seventh, eighth, ninth and/or tenth embodiment.

Twelfth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R¹ and R^1A are each independently selected from H, F and CEE. The remainder of the variables in Formula (I), (II) and (II) are described above in the first, second, fifth, sixth, seventh, eighth, ninth, tenth and/or eleventh embodiment.

Thirteenth embodiment: a compound represented by Formula (IV), (V) or (VI):

or a pharmaceutically acceptable salt thereof. The variables in Formula (IV), (V) and (VI) are described above in the first and/or second embodiment.

Fourteenth embodiment: a compound represented by Formula (VII), (VII), (IX) or

(X): (VII) (VIII)

(IX) or a pharmaceutically acceptable salt thereof. The variables in Formula (VII). (VIII). (IX) and (X) are described above in the first and/or second embodiment.

Fifteenth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R¹ and R^1A are each independently selected from H. halogen, and CHs; R² is selected from Ci-salkyl, CDs. Cs-4cycloalkyl and 4- to 6-membered heterocycle containing one O, wherein said alkyl, cycloalkyl, or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen, OH, cyclopropyl, 4- to 6-membered heterocycle containing one O, and phenyl, wherein said cyclopropyl or phenyl is optionally substituted with OH or NH2; R⁶ is selected from Cwalkyl, CHF2, CF3. 4- or 5-membered heterocycle containing N or O. and Cs-4cycloalkyl, wherein said alkyl, heterocycle or cycloalkyl is optionally substituted with R⁸; R⁸ is selected from OH, NR⁹R⁹, OCHs, CHs and 4-membered heterocycle containing N or O, wherein said heterocycle is optionally substituted with CHs; and each R⁹ is independently- selected from H, CHs, and CH2CF3. The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first and/or second embodiment.

Sixteenth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R² is selected from CHs, CDs, CH2CH3, CH2CH2CH3. CH(CHS)2. cyclobutyl, cyclopropyl, oxetanyl. tetrahydrofuranyl, tetrahydrofuranyl and tetrahydropyranyl. each of which is optionally substituted with 1-3 R⁴. The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second and/or fifteenth embodiment. Seventeenth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R²is selected from: the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second and/or fifteenth embodiment.

Eighteenth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII). (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein each R⁴ is independently selected from F, OH, cyclobutyl, oxetanyl, phenyl, tetrahydrofuranyl and tetrahydropyranyl, wherein said cy clobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranyl or tetrahydropyranyl is optionally substituted with OH or NH2. The remainder of the variables in Formula (I), (IV), (V), (VI), (VII). (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth and/or seventeenth embodiment.

Nineteenth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein each R⁴ is independently selected from F, OH, wherein * — represents OH or NH2. The remainder of the variables in Formula (1), (IV), (V). (VI). (VII), (VIII). (IX) or (X) are described above in the first, second, fifteenth, sixteenth and/or seventeenth embodiment.

Twentieth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from CHs, CH2CH3, CH2CH2CH3. CH(CH₃)₂. CH₂CH(CH₃)2. C(CH₃)₃. CH₂CH₂CH(CH3)₂, CHF2, CF3, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, each of which is optionally substituted with R⁸. The remainder of the variables in Formula (I), (IV), (V). (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth and/or nineteenth embodiment. Twenty-first embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from:

(V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth. sixteenth, seventeenth, eighteenth and/or nineteenth embodiment.

Twenty-second embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from OH, OCH3, CH3, NH2, NHCH3, N(CH₃)₂, NHCH2CF3, N(CH₃)CH₂CF3, azetidinyl, azetidinyl and oxetanyl. The remainder of the variables in Formula (I), (IV), (V). (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth and/or twenty-first embodiment.

Twenty-third embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from: variables in Formula (I), (IV), (V), (VI). (VII), (VIII). (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth and/or twenty-first embodiment.

Twenty-fourth embodiment: a compound represented by Formula (I), (IV), (V), (VI). (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R¹ and R^1A are each independently selected from H, F and CH3. The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty- second and/or twenty -third embodiment.

Twenty-fifth embodiment: a compound represented by Formula (III) or (VII):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R^1A are each independently selected from H, F and CH3; R² is selected from Ci-salkyl, CD3, Cs-4cy cloalky I and 4-membered heterocycle containing one O, wherein said alkyl is optionally substituted with 1-3 halo; R⁵ is selected from CH?, CH2CH3 and cyclopropyl; R⁶ is selected from Cisalkyl, CHF2, CF? and 4- to 5-membered heterocycle containing O orN, wherein said alkyl or heterocycle is optionally substituted with R⁸; R⁸ is selected from OH, NR⁹R⁹, OCH3, CH3 and 4-membered heterocycle containing O or N; and each R⁹ is independently selected from H and CH3.

Twenty-sixth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R² is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH₃)2, CH(CH₃)CH₂F, CH(CH₃)CHF2, cyclobutyl, cyclopropyl and . The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth embodiment.

Twenty-seventh embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from CH3, CH2CH3, CH2CH2CH3, CH₂CH(CH3)2, CH₂CH₂CH(CH3)2, CHF2, azetidinyL oxetanyl, tetrahydrofuranyl and pyrrolidinyl, each of which is optionally substituted with one R⁸. The remainder of the variables in Formula (III) or (VII) are described above in the twenty -fifth and/or twenty-sixth embodiment. Twenty-eighth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from: . The remainder of the variables in Formula (III) or (VII) are described above in the twent -fifth and/or twenty-sixth embodiment.

Twenty-ninth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from OH, OCH3, NH2,

NHCH3, N(CH3)2, CH3, . The remainder of the variables in

Formula (III) or (VII) are described above in the twenty -fifth, twenty-sixth, twenty -seventh and/or twenty -eighth embodiment.

Thirtieth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from OH, OCH3, NH2, NHCH3, N(CH3)2, and CH3. The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth and/or twenty -ninth embodiment.

Thirty-first embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from CH3, CH2CH3, CH2CH2CH3, CH₂CH(CH3)₂, CH₂CH₂CH(CH3)2 and CHF2, each of which is optionally substituted with one R⁸. The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty -seventh, twenty-eighth, twenty -ninth and/or thirtieth embodiment. In some thirty-first embodiments, R⁶ is selected from CH3, CH2CH3, CH2CH2CH3, CH₂CH(CH3)₂, CH₂CH₂CH(CH3)2 and CHF2, each of which is optionally substituted with one R⁸. In some thirty-first embodiments, R⁶ is selected from CH3, CH2CH3, CH2CH2CH3, CH₂CH(CH₃)2, and CH2CH2CH(CHs)2, each of which is substituted with one R⁸.

Thirty-second embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R⁶ is selected from CH3, CH2CH2OH, CH₂CH₂N(CH3)2, CH2CH2NHCH3, CH2CH2NH2, CH₂CH(N(CH3)2)CH3. CH₂CH(NHCH3)CH3, CH₂C(NHCH3)(CH3)2, CH₂C(NH₂)(CH₃)₂, CH₂CH₂OCH₃, CH₂CH(OH)(CH3), CH₂C(OH)(CH3)₂, CH₂CH₂C(OH)(CH₃)₂, and C(CH3)₂CH₂OH. The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty -ninth, thirtieth and/or thirty-first embodiment.

Thirty-third embodiment: a compound represented by Formula (III), or a pharmaceutically acceptable salt thereof. The variables in Formula (III) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty -ninth, thirtieth, thirty-first and/or thirty-second embodiment.

Thirty-fourth embodiment: a compound represented by Formula (VII), or a pharmaceutically acceptable salt thereof. The variables in Formula (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty -ninth, thirtieth, thirty-first and/or thirty-second embodiment.

The N-(pyridin-2-yl)pyrimidine-4-amine compounds described herein also include compounds depicted in Table 1 and Table 2, and pharmaceutically acceptable salts thereof.

In one embodiment, the compounds in Table 2, and pharmaceutically acceptable salts thereof, are excluded from the N-(pyridin-2-yl)pyrimidine-4-amine compounds described herein.

In some embodiments, one or more hydrogen atoms is replaced with deuterium in a compound of Formulae (I), (II), (III), (IV), (V), (VI), (VII). (VIII), (IX) or (X). or a compound in Table 1 or Table 2, or a pharmaceutically acceptable salt of any of the foregoing. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%. Deuterium enrichment is a mole percent and is obtained by dividing the number of compounds with deuterium enrichment at the site of enrichment with the number of compounds having hydrogen or deuterium at the site of enrichment.

Table 1. Compounds of Formula (I)

M4205. also known as IDRX-42 and IDRX42, has the following structure:

M4205

M4205 inhibits primary' and secondary cKIT mutations. M4205 and is potent against Exons 9 and 11 and multiple mutants of exon 17. M4205 is somewhat less potent, though still active, against Exon 13.

THE-630, also known as THE630, is a pan-variant KIT inhibitor.

Pharmaceutical Compositions

Disclosed herein is a composition comprising M4205. or a pharmaceutically acceptable salt thereof; or aN-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof; or a combination thereof. Additionally disclosed herein is a composition comprising THE-630, or a pharmaceutically acceptable salt thereof; or a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g. , a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof; or a combination thereof.

Disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a composition comprising M4205. or a pharmaceutically acceptable salt thereof; or aN-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof; or a combination thereof. Additionally disclosed herein is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a composition comprising THE-630, or a pharmaceutically acceptable salt thereof; or aN-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2). or a pharmaceutically acceptable salt thereof; or a combination thereof.

While it is possible for a compound or a composition described herein (e.g, M4205 or a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a combination thereof, or THE- 630 or a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a combination thereof) to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound or the composition is combined with one or more pharmaceutically acceptable excipients or carriers. The compounds and compositions described herein or pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way for use in human or veterinary medicine. In some embodiments, the compound or composition included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.

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

Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (1 1) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules and the like) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

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

Suspensions, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of compound of the disclosure or pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

Dosage forms for the topical or transdermal administration of a compound of this disclosure or pharmaceutically acceptable salts thereof, include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

When the compounds of the disclosure or pharmaceutically acceptable salts thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally. intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

In some embodiments, the amount of M4205, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 20 mg to about 2000 mg (e.g., about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg. about 100 mg, about 110 mg, about 120 mg. about 130 mg. about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 115 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg).

In some embodiments, the amount of THE-630, or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition descnbed herein is about 0. 1 mg to about 200 mg (e.g. , about 0. 1 mg, about 0. 11 mg, about 0. 12 mg, about 0. 13 mg, about 0. 14 mg, about 0. 15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.30 mg, about 0.32 mg, about 0.34 mg, about 0.36 mg, about 0.38 mg, about 0.4 mg, about 0.42 mg, about 0.44 mg, about 0.46 mg, about 0.48 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about

1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.2 mg, about 2.4 mg. about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg. about 3.4 mg, about 3.6 mg. about 3.8 mg, about 4 mg. about

4.2 mg, about 4.4 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg. about 18 mg. about 19 mg. about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg. about 65 mg, about 70 mg, about 75 mg, about 80 mg. about 85 mg. about 90 mg, about 95 mg, about 100 mg. about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg).

In some embodiments, the amount of a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof, in a pharmaceutical composition described herein is about 0. 1 mg to about 200 mg (e.g. , about 0. 1 mg, about 0. 11 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.30 mg, about 0.32 mg. about 0.34 mg. about 0.36 mg. about 0.38 mg. about 0.4 mg. about 0.42 mg, about 0.44 mg, about 0.46 mg, about 0.48 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.2 mg, about 2.4 mg, about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg. about 3.8 mg, about 4 mg, about 4.2 mg, about 4.4 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg. about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg. about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg).

Dosages

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

The selected dosage level will depend upon a variety of factors including the activity of the particular active ingredient employed, the route of administration, the time of administration, the rate of excretion of the particular active ingredient being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular active ingredient employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

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, trans dermally, 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.; Pergamon; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

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, and whether the treatment is prophylactic). 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.

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 preferred embodiments, the pharmaceutical composition is formulated for intravenous administration.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” 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 excipients 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 activity⁷ of the compounds provided herein. One of ordinary⁷ skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

In some embodiments, M4205 is dosed at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, M4205 is dosed once a week. In some embodiments, M4205 is dosed twice a week. In some embodiments, M4205 is dosed three times a week.

In some embodiments, M4205 is administered to daily. In some embodiments, M4205 is administered once daily. In some embodiments, M4205 is administered twice daily.

In some embodiments, THE-630 is dosed at least once a week (e.g., once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments. THE-630 is dosed once a week. In some embodiments. THE-630 is dosed twice a week. In some embodiments, THE-630 is dosed three times a week.

In some embodiments, THE-630 is administered to daily. In some embodiments, THE-630 is administered once daily. In some embodiments, THE-630 is administered twice daily.

In some embodiments, a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), is dosed at least once a week (e.g, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week). In some embodiments, a N-(pyridin-2- yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), is dosed once a week. In some embodiments, a N- (pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), is dosed twice a week. In some embodiments, a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), is dosed three times a week.

In some embodiments, a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2) is administered to daily. In some embodiments, aN-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2) is administered once daily. In some embodiments, a N-(pyridin-2-yl)pyrimidine- 4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2) is administered twice daily.

In some embodiments, M4205 is dosed at about 20 mg to about 2000 mg (e.g, about 20 mg, about 22 mg, about 24 mg, about 25 mg. about 26 mg, about 28 mg, about 30 mg, about 32 mg. about 32 mg. about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg. about 850 mg. about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg) per administration. In some embodiments, M4205 is administered orally.

In some embodiments, THE-630 is dosed at about 0.1 mg to about 200 mg (e.g, about 0.1 mg, about 0.11 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.30 mg. about 0.32 mg. about 0.34 mg. about 0.36 mg, about 0.38 mg, about 0.4 mg, about 0.42 mg, about 0.44 mg, about 0.46 mg, about 0.48 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg. about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.2 mg, about 2.4 mg. about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg, about 3.8 mg, about 4 mg, about 4.2 mg, about 4.4 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg. about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg. about 20 mg, about 22 mg, about 24 mg, about 25 mg. about 26 mg. about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg. or about 200 mg) per administration. In some embodiments, THE-630 is administered orally.

In some embodiments, a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2) is dosed at about 0. 1 mg to about 200 mg (e.g., about 0. 1 mg, about 0. 11 mg, about 0. 12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.30 mg, about 0.32 mg, about 0.34 mg, about 0.36 mg, about 0.38 mg, about 0.4 mg, about 0.42 mg, about 0.44 mg. about 0.46 mg. about 0.48 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg. about 0.75 mg. about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.2 mg, about 2.4 mg, about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg, about 3.8 mg. about 4 mg, about 4.2 mg. about 4.4 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg. about 20 mg. about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. about 110 mg, about 120 mg, about 130 mg, about 140 mg. about 150 mg, about 160 mg, about 170 mg. about 180 mg. about 190 mg, or about 200 mg) per administration. In some embodiments, the N-(pyridin-2-yl)pyrimidine-4-amine compound e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2) is administered orally. Methods of Treatment

Disclosed herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject M4205, or a pharmaceutically acceptable salt thereof, and aN-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof.

Additionally disclosed herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject THE-630, or a pharmaceutically acceptable salt thereof, and a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease is characterized by a KIT mutation (e.g., an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, and exon 14 KIT mutation, or an exon 17 KIT mutation, or a combination thereof). In some embodiments, the disease a malignant disease. In some embodiments, the disease is a cancer. In some embodiments, the cancer is adjuvant. Examples of malignant diseases or cancers treatable bycompounds of the disclosure include gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer, and mediastinal B-cell lymphoma.

In some embodiments, the malignant disease or cancer is selected from: gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer, and mediastinal B-cell lymphoma. In some embodiments, the malignant disease or cancer is gastrointestinal stromal tumor (GIST).

M4205, or a pharmaceutically acceptable salt thereof, in combination with a N- (pyri din-2 -yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof, is contemplated to be useful in treating cancers including, but not limited to, gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer and mediastinal B-cell lymphoma. THE-630, or a pharmaceutically acceptable salt thereof, in combination with a N- (pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof, is contemplated to be useful in treating cancers including, but not limited to, gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer and mediastinal B-cell lymphoma.

In some embodiments, the subject received an anti-cancer therapy for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the anti-cancer therapy. In some embodiments, the subject is receiving an anti-cancer therapy for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the anti-cancer therapy. In some embodiments, the subject is resistant or has acquired resistance to an anti-cancer therapy.

In some embodiments, the anti-cancer therapy is administering an anti-cancer agent. In some embodiments, the anti-cancer agent is a KIT inhibitor. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib. ripretinib, AZD3229, BLU-263, alvocidib, anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib, ribocliclib, sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the subject received one or more anti-cancer therapies for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the one or more anti-cancer therapies. In some embodiments, the subject is receiving one or more anti-cancer therapies for the malignant disease or cancer. In some embodiments, the malignant disease or cancer progressed after the one or more anti-cancer therapies. In some embodiments, the subject is resistant or has acquired resistance to one or more anti-cancer therapies.

In some embodiments, each of the anti-cancer therapies is administering an anticancer agent. In some embodiments, each of the anti-cancer agents is a KIT inhibitor. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib. regorafenib, ripretinib. AZD3229. BLU-263, alvocidib. anlotinib, avapritinib, axitinib, bezuclastinib, binimetinib, cabozantinib, crenolanib, dasatinib, everolimus, famitinib, larotrectinib, nilotinib, olaratumab, pazopanib, pexidartinib, ponatinib. ribocliclib. sorafenib, and vandetanib, and pharmaceutically acceptable salts thereof, and combinations thereof. In some embodiments, each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the malignant disease or cancer is characterized by a primary activating KIT mutation. A "primary activating mutation’’ is an initial mutation that converts or contributes to the conversion of a normal cell to a cancer cell (/. e. a primary' activating mutation is responsible for initiating tumorigenesis and/or driving the cancer). In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation or an exon 11 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. In some embodiments, the primary' activating KIT mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation. In some embodiments, the primary activating KIT mutation is selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, and an exon 17 KIT mutation.

In some embodiments, the primary' activating KIT mutation is an exon 17 KIT mutation, (e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E. D820Y and D823D). In one embodiment, the exon 17 KIT mutation is D816V. In some embodiments, the primary activating mutation is A829P. A829P is a mutation at the very start of exon 18 KIT but is commonly referred to as an ”exon 17” mutation. In some embodiments, the primary' activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V. D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P. In some embodiments, the primary’ activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D. In some embodiments the primary’ activating KIT mutation is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation such as V654A. N655K or K642E. In some embodiments, the tumor is resistant or has acquired resistance to an anticancer therapy. For example, the tumor is or has acquired mutation resistance to the anticancer therapy because a mutation is present in the tumor that renders the tumor resistant or refractory to the anti-cancer therapy (e.g., administering an anti-cancer agent). For example, the tumor may have become mutation resistance to a Primary KIT Inhibitor. In some embodiments, the tumor has a mutation that is resistant to an exon 9 KIT inhibitor or an exon 11 KIT inhibitor, or a combination thereof. In some embodiments, the tumor has a mutation that is resistant to an exon 9 KIT inhibitor, an exon 11 KIT inhibitor, an exon 13 KIT mutation, an exon 17 KIT mutation, or an exon 14 KIT mutation, or a combination thereof. In some embodiments, the prior agent is imatinib and the mutation is an imatinib-resistant mutation. In one embodiment, the tumor has a mutation that is resistant to a prior agent. In one embodiment, the mutation that is resistant to the prior agent is selected from an exon 13 KIT mutation, an exon 17 KIT mutation, an exon 18 KIT mutation, and an exon 14 KIT mutation, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K and K642E. and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K, and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V. D816E, D816F, D816H. D816I. D816Y, D820E, D820Y, D823D and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D, and combinations thereof. In some embodiments, the exon 17 KIT mutation is A829P. In some embodiments, the exon 18 KIT mutation is A829P. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P. and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g, an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 14 KIT mutation, e.g. an exon 14 KIT mutation such as N680K. In some embodiments, the tumor is or has become resistant to the prior agent has one or more mutations.

In some embodiments, administering an effective amount of M4205, or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 20 mg to about 2000 mg (e.g., about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg. about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg. about 240 mg, about 260 mg, about 280 mg, about 300 mg. about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg. about 975 mg. about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg) of M4205, or a pharmaceutically acceptable salt thereof.

In some embodiments, administering an effective amount of THE-630, or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 0. 1 mg to about 200 mg (e.g. , about 0.1 mg, about 0. 11 mg, about 0. 12 mg, about 0. 13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg. about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.30 mg, about 0.32 mg, about 0.34 mg, about 0.36 mg, about 0.38 mg, about 0.4 mg, about 0.42 mg, about 0.44 mg, about 0.46 mg, about 0.48 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1 mg, about 1.2 mg. about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg. about 2.2 mg, about 2.4 mg, about 2.6 mg, about 2.8 mg, about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg, about 3.8 mg, about 4 mg, about 4.2 mg, about 4.4 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg. about 10 mg. about 11 mg, about 12 mg about 13 mg. about 14 mg, about 15 mg. about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg. about 180 mg, about 190 mg, or about 200 mg) of THE-630, or a pharmaceutically acceptable salt thereof.

In some embodiments, administering an effective amount of aN-(pyridin-2- yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof, comprises administering to the subject about 0.1 mg to about 200 mg (e.g, about 0.1 mg, about 0.1 1 mg, about 0.12 mg, about 0.13 mg, about 0.14 mg, about 0.15 mg, about 0.16 mg, about 0.17 mg, about 0.18 mg, about 0.19 mg, about 0.2 mg, about 0.22 mg, about 0.24 mg, about 0.26 mg, about 0.28 mg, about 0.30 mg, about 0.32 mg, about 0.34 mg, about 0.36 mg, about 0.38 mg, about 0.4 mg, about 0.42 mg, about 0.44 mg. about 0.46 mg. about 0.48 mg. about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.2 mg, about 2.4 mg, about 2.6 mg, about 2.8 mg. about 3 mg, about 3.2 mg, about 3.4 mg, about 3.6 mg, about 3.8 mg, about 4 mg, about 4.2 mg, about 4.4 mg, about 4.6 mg, about 4.8 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg about 13 mg, about 14 mg, about 15 mg, about 16 mg. about 17 mg. about 18 mg, about 19 mg, about 20 mg, about 22 mg, about 24 mg, about 25 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 55 mg, about 60 mg. about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. about 110 mg. about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg) of the N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof. In some embodiments, M4205, or a pharmaceutically acceptable salt thereof, and aN- (pyridin-2-yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof are administered simultaneously.

In some embodiments, M4205, or a pharmaceutically acceptable salt thereof, and aN- (pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof are administered sequentially.

In some embodiments, THE-630, or a pharmaceutically acceptable salt thereof, and a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g, a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2). or a pharmaceutically acceptable salt thereof are administered simultaneously.

In some embodiments, THE-630, or a pharmaceutically acceptable salt thereof, and a N-(pyridin-2-yl)pyrimidine-4-amine compound (e.g., a compound of Formula (I), or a subclass thereof, or a compound of Table 1 or Table 2), or a pharmaceutically acceptable salt thereof are administered sequentially.

EXAMPLES

The disclosure is further illustrated by the following examples, which serve as exemplary modes of making and practicing the methods and compositions of the disclosure. The scope of the disclosure is not to be construed as limited to specific embodiments described in these examples, which are illustrative only.

EXAMPLE 1. First-in-human Study of M4205 in Subjects with GIST

This study is designed to evaluate the safety, tolerability, PK, and preliminary’ antitumor activity of M4205 in adult participants with advanced (metastatic and/or surgically unresectable) GIST.

This is a Phase 1/lb, first-in-human (FIH) study of M4205, an orally administered small molecule t rosine kinase inhibitor. Eligible participants have metastatic and/or surgically unresectable GIST, after failure of at least imatinib due to progression of GIST. The study consists of 2 parts. Phase 1 comprises dose escalation to assess clinical and pharmacologic profile, safety, /tolerability, and support choice of the recommended phase 2 dose and schedule (RP2DS). Phase lb expansion will enroll separate cohorts of participants defined by numbers of lines of prior GIST therapy at the selected RP2DS to assess the preliminary' antitumor effect of M4205 and further characterize the safety profile of M4205 at the RP2DS.

Studies with further elevated dose levels are ongoing.

Cohort 1 consisted of subjects who have progressed on imatinib only (n = 29). Cohort 2 consisted of subjects who have progressed on both imatinib and sunitinib or progressed on imatinib, sunitinib, and an additional agent (e.g., regorafenib or ripretinib). Cohort 3 consisted of subjects who have progressed on imatinib, sunitinib, regorafenib, and ripretinib. Cohort 3 400 mg QD dose confirmed to be safe and tolerable.

M4205 has a half-life (ti/2) of about 150 hours, and a 5-7 fold accumulation was observed at steady state. Dose-related increase in exposure was observed from 120 mg to 600 mg QD.

The impact on tumor size for a few of the subjects at varying dose levels is shown in FIG. 1. The change of target lesions for a few of the subjects at varying dose levels is shown in FIG. 2

EXAMPLE 2. Combination of M4205 and Compounds of Formula (I)

This study investigated the combination effects of M4205 and compounds of Formula (I)

Western Blots demonstrated the combination drug effect of M4205 (also know n as IDRX-42) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines (see FIG. 3, Fig. 4, FIG. 5, FIG. 6, FIG. 7, and FIG. 8)

Synergy Matrices demonstrated combination drug effect of M4205 (also known as IDRX-42) and Compound 198 in the inhibition of cKIT phosphorylation in the GIST 430/654 (exon 11/13) and GIST Tl/654 (exon 11/13) mutant cell lines, including the potential for Compound 198 to facilitate synergistic enhancement of the efficacy of M4205 at clinically relevant dosing concentrations (see FIG. 9, FIG. 10, FIG. 11, FIG. 12, FIG. 13, FIG. 14, FIG. 15, FIG. 16, FIG. 17, and FIG. 18). This synergy indicates the potential to facilitate dose reduction of M4205 to improve tolerability and/or enhance antitumor activity.

EXAMPLE 3. In Vivo Efficacy Study of M4205 and Compounds of Formula (I) as Single Agents

This study investigated the therapeutic efficacy of M4205 and compounds of Formula (I) (e.g., Compound 198) as single test agents in GS 11331 gastrointestinal stromal tumor PDX model in female BALB/c nude mice.

Methods: Tumor inoculation was conducted as follows. Fresh tumor tissues from stock mice were harvested and used for inoculation into mice. Each mouse was inoculated subcutaneously in the right front flank with primary human tumor xenograft model tumor fragments (approximately 2-3 mm in diameter) for tumor development.

The randomization started when the mean tumor size reached approximately 147- 148 mm³. 42 mice were enrolled in the study. All animals were randomly allocated to 7 study groups based on the tumor volume, 6 mice in each group. Randomization was performed based on '‘Matched distribution” method/ “Stratified” method (Study Director™ software). The date of randomization was denoted as day 0.

The treatment was initiated on the same day of randomization (day 0) per studydesign.

Observations and Data Collection: After tumor cells inoculation, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and w ater consumption, body weight gain/loss (body weights were measured twice per w eek after randomization), eye/hair matting and any other abnormalities. Mortality and observed clinical signs were recorded for individual animals in detail.

Tumor volumes were measured twice per week after randomization in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: “V = (L x W x W)/2, where V was tumor volume, L was tumor length (the longest tumor dimension) and W was tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements w ere conducted in a Laminar Flow Cabinet. The body weights and tumor volumes w ere measured by scale and caliper, the data was recorded by using Study-Director™ software.

Criteria for Dosing Holiday and Supplemental Gel Administration: No dosing holiday. Treatment resumed when the BWL recovered. Sacrificed the individual mouse when BWL>15% for 72 hours. Supplemental gels were administered to the individual mouse with BWL > 15%. BWL was calculated based in the BW of mouse on the day of randomization.

Endpoints: The body weight of all animals was monitored throughout the study and animals were euthanized if they lost over 20% of their body weight relative to the weight on the first day of treatment. The individual mouse was euthanized if its tumor volume exceeded 3000 mm³. To deter cannibalization, any animal exhibiting an ulcerated or necrotic tumor were separated immediately and singly housed and monitored daily before the animal was euthanized or until tumor regression was completed. The mouse was euthanized rapidly if: tumor ulcerates, and the ulceration diameter was greater than 5 mm, or pus or necrosis observed; or tumor burden, including metastasis, compromises animal’s normal physiologic performances, e.g., orientation, access to food or water. The mouse was euthanized rapidly if the animal was: emaciated - skeletal structure extremely prominent, little or no flesh cover, vertebrae distinctly segmented; persistent hypothermia; blood stained or mucopurulent discharge from any orifice; labored breathing, particularly accompanied by nasal discharge or cyanosis; hind limb paralysis or weakness (cannot reach food and water); severe anemia, mainly indicated by pale feet or ears; severe infection; incontinence or diarrhea over 48 hours; or severe dehydration.

Study Termination: The treatments were performed for 57 days. The study was terminated on day 57. Tumors were not collected for euthanized mice before termination of the study. No sampling for mice found dead.

Table 3 Table 4

Statistical Analysis: Test of homogeneity of variance by Bartlet's test: if the p-value of Bartlet's test is greater than 0.05, it indicates that there is not enough evidence to reject the null hypothesis of homogeneity of variance, which is one of the assumptions of ANOVA. Therefore, an ANOVA test was conducted to determine whether there exists any pair of groups with different group means and run the post hoc Tukey HSD for all pairwise comparisons or Dunnet's t test for each treatment against one control.

If p-value of Bartlet's test is less than or equal to 0.05, it indicates that there is some evidence that variances may not be equal or data do not follow normal distribution. Then a Kruskal-Wallis test was conducted to determine if there exists any pair of groups with different group medians and run the post hoc Conover's non-parametric all-pairs comparison test for all pairwise comparisons, or Conover's non-parametric many-to-one comparison test for each treatment against one control.

Both tests use single-step p-value adjustment. In addition, pairwise comparisons were performed without multiple comparison correction and report nominal/uncorrected p-values directly from Welch's t-test or Mann-Whitney U test. The criterion of choosing Welch’s t-test or Mann-Whitney U test is the same as the two-group comparison method mentioned above. All statistical analyses had been done in R language and environment for statistical computing and graphics (version 3.6.0). All tests were two-sided unless otherwise specified, and p-values of <0.05 are regarded as statistically significant. For survival analysis, Kaplan- Meier model with Log-rank method was applied.

Results: In this study, no mouse was euthanized due to the body weight loss. The tumor growth inhibition of test agents in the treatment of subcutaneous GS11331 PDX model is summarized in the table below. Table 5. Antitumor Activity of Test Agents in the Treatment Model GS11331 a. Mean ± SEM (mice number); b. TGI% = [1-T/C] x 100%; c. ns: P > 0.05 and ***: PO.OOl

Group 1 was vehicle group (10 pL/g, p.o.QD x 30 days). In this study, the mean tumor volume of vehicle group reached 1745.47 mm³ on day 56 post treatment.

Group 2 was treated with Compound 198 (3 mg/kg, 10 pL/g, p.o.QD x 30 days) and had TGI value of 36.77 % on day 56.

Group 3 was treated with Compound 198 (10 mg/kg, 10 pL/g, p.o.QD x 30 days) and had TGI value of 95.04 % on day 56.

Group 4 was treated with Compound 198 (30 mg/kg, 10 pL/g, p.o.QD x 30 days) and had TGI value of 98.58 % on day 56.

Group 5 was treated with M4205 (1 mg/kg, 10 pL/g, p.o.QD x 30 days) and had TGI value of 7.65 % on day 56.

Group 6 was treated with M4205 (2.5 mg/kg, 10 pL/g, p.o.QD x 30 days) and had TGI value of 86. 16 % on day 56.

Group 7 was treated with M4205 (10 mg/kg, 10 pL/g, p.o.QD x 30 days) and TGI value of 98.18 % on day 56.

Compared with vehicle group, the mid-dose and high-dose single treatment of M4205 showed statistically significant anti -tumor efficacy in GS 11331 PDX model. Similarly, the mid-dose and high-dose single treatment of Compound 198 also showed statistically significant anti-tumor efficacy in GS 11331 PDX model. In this study, there was no significant body weight loss in test compounds M4205 and Compound 198 treatment groups, which indicated that test compounds M4205 and Compound 198 were well-tolerated. EXAMPLE 4. In Vivo Combination Efficacy Study of M4205 and Compounds of

Formula (I)

This study investigated the combination efficacy of M4205 and compounds of Formula (I) (e g., Compound 198) in GS11331 gastrointestinal stromal tumor PDX model in female BALB/c nude mice.

Methods: Fresh tumor tissues from stock mice were harvested and used for inoculation into mice. Each mouse was inoculated subcutaneously in the right front flank with primary human tumor xenograft model tumor fragments (approximately 2-3 mm in diameter) for tumor development.

The randomization started when the mean tumor size reached approximately 184 mm³. 56 mice were enrolled in the study. All animals were randomly allocated to 7 study groups based on the tumor volume, 8 mice in each group. Randomization was performed based on “Matched distribution” method/ “Stratified” method (StudyDirector™ software). The date of randomization was denoted as day 0.

The treatment was initiated on the same day of randomization (day 1) per study design.

Observations and Data Collection: After tumor cells inoculation, the animals were checked daily for morbidity and mortality⁷. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain/loss (body weights were measured twice per week after randomization), eye/hair matting and any other abnormalities. Mortality and observed clinical signs were recorded for individual animals in detail.

Tumor volumes were measured twice per week after randomization in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: “V = (L x W x W)/2, where V was tumor volume, L was tumor length (the longest tumor dimension) and W was tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements were conducted in a Laminar Flow Cabinet. The body weights and tumor volumes were measured by scale and caliper, the data was recorded by using StudyDirector™ software.

Criteria for Dosing Holiday and Supplemental Gel Administration: No dosing holiday. Treatment resumed when the BWL recovered. Sacrificed the individual mouse when BWL>15% for 72 hours. Supplemental gels were administered to the individual mouse with BWL > 15%. BWL was calculated based in the BW of mouse on the day of randomization.

Endpoints: The body weight of all animals was monitored throughout the study and animals were euthanized if they lost over 20% of their body weight relative to the weight on the first day of treatment. The individual mouse was euthanized if its tumor volume exceeded 3000 mm³. To deter cannibalization, any animal exhibiting an ulcerated or necrotic tumor were separated immediately and singly housed and monitored daily before the animal was euthanized or until tumor regression was completed. The mouse was euthanized rapidly if: tumor ulcerates, and the ulceration diameter was greater than 5 mm, or pus or necrosis observed; or tumor burden, including metastasis, compromises animal’s normal physiologic performances, e.g.. orientation, access to food or water. The mouse was euthanized rapidly if the animal was: emaciated - skeletal structure extremely prominent, little or no flesh cover, vertebrae distinctly segmented; persistent hypothermia; blood stained or mucopurulent discharge from any orifice; labored breathing, particularly accompanied by nasal discharge or cyanosis; hind limb paralysis or weakness (cannot reach food and water); severe anemia, mainly indicated by pale feet or ears; severe infection; incontinence or diarrhea over 48 hours; or severe dehydration.

Study Termination: The treatments were performed for 28 days. The study was terminated on day 29. Tumors were not collected for euthanized mice before termination of the study. No sampling for mice found dead.

Table 6

Table 7

Statistical Analysis: Test of homogeneity of variance by Bartlet's test: if the p-value of Bartlet's test is greater than 0.05, it indicates that there is not enough evidence to reject the null hypothesis of homogeneity of variance, which is one of the assumptions of ANOVA. Therefore, an ANOVA test was conducted to determine whether there exists any pair of groups with different group means and run the post hoc Tukey HSD for all pairwise comparisons or Dunnet's t test for each treatment against one control.

If p-value of Bartlet's test is less than or equal to 0.05, it indicates that there is some evidence that variances may not be equal or data do not follow normal distribution. Then a Kruskal-Wallis test was conducted to determine if there exists any pair of groups with different group medians and run the post hoc Conover's non-parametric all-pairs comparison test for all pairwise comparisons, or Conover's non-parametric many-to-one comparison test for each treatment against one control.

Both tests use single-step p-value adjustment. In addition, pairwise comparisons were performed without multiple comparison correction and report nominal/uncorrected p-values directly from Welch's t-test or Mann-Whitney U test. The criterion of choosing Welch’s t-test or Mann-Whitney U test is the same as the two-group comparison method mentioned above. All statistical analyses had been done in R language and environment for statistical computing and graphics (version 3.6.0). All tests were two-sided unless otherwise specified, and p-values of <0.05 are regarded as statistically significant. For survival analysis, Kaplan- Meier model with Log-rank method was applied.

Results: In this study, 1 mouse in Group 1 (vehicle group) was euthanized due to the body weight loss exceeding 20% on Day 12. The tumor growth inhibition of test agents in the treatment of subcutaneous GS11331 PDX model is summarized in the table below. Table 8. Antitumor Activity of Test Agents in the Treatment Model GS11331 a. Mean ± SEM (mice number); b. TGI% = [1-T/C] x 100%; c. *: P < 0.05 and ***: PO.OOl

In this study, the mean tumor volume of Group 1 (vehicle group; 10 pL/g, p.o.QD x 28 days) reached 695.04 mm³ on day 24 post treatment.

Group 2 was treated with sunitinib (10 mg/kg, 10 pL/g, p.o.QD x 28 days) and had TGI value of 51.65 % on day 24.

Group 3 was treated with combination of Compound 198 (3 mg/kg, 5 pL/g, p.o.QD x 28 days) and M4205 (1 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 61.39 % on day 24.

Group 4 was treated with combination of Compound 198 (3 mg/kg, 5 pL/g, p.o.QD x 28 days) and M4205 (2.5 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 92.36 % on day 24.

Group 5 was treated with combination of Compound 198 (3 mg/kg, 5 pL/g, p.o.QD x 28 days) and M4205 (10 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 94.40 % on day 24.

Group 6 was treated with combination of Compound 198 (10 mg/kg, 5 pL/g, p.o.QD x 28 days) and M4205 (1 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 94.97 % on day 24.

Group 7 was treated with combination of Compound 198 (10 mg/kg, 5 pL/g, p.o.QD x 28 days) and M4205 (2.5 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 95.60 % on day 24.

Compared with vehicle group, the combined administration of M4205 and Compound 198 (M4205 1 mg/kg combined with Compound 198 3 mg/kg, M4205 2.5 mg/kg combined with Compound 198 3 mg/kg, M4205 10 mg/kg combined with Compound 198 3 mg/kg, M4205 1 mg/kg combined with Compound 198 10 mg/kg, and M4205 2.5 mg/kg combined with Compound 198 10 mg/kg) showed statistically significant anti-tumor efficacy in GS11331 PDX model. In this study, there was no significant body weight loss in test compounds M4205 and Compound 198 treatment groups which indicated that test compounds M4205 and Compound 198 were well-tolerated. The positive control sunitinib resulted in the expected anti-tumor efficacy.

EXAMPLE 5. In Vivo Efficacy Study of M4205 and Compounds of Formula (I) (Alone and in Combination)

This study investigated the therapeutic efficacy of M4205 and compounds of Formula (I) (e g., Compound 198) as single test agents and in combination in GS1 1331 gastrointestinal stromal tumor PDX model in female BALB/c nude mice.

Methods: Fresh tumor tissues from stock mice were harvested and used for inoculation into mice. Each mouse was inoculated subcutaneously in the right front flank with primary human tumor xenograft model tumor fragments (approximately 2-3 mm in diameter) for tumor development.

The randomization started when the mean tumor size reached approximately 176 -178 mm³. 54 mice were enrolled in the study. All animals were randomly allocated to 9 study groups based on the tumor volume, 6 mice in each group. Randomization was performed based on “Matched distribution” method/ “Stratified” method (StudyDirector^1M software). The date of randomization was denoted as day 0.

The treatment was initiated on the same day of randomization (day 0) per study design.

Observations and Data Collection: After tumor cells inoculation, the animals were checked daily for morbidity and mortality. During routine monitoring, the animals were checked for any effects of tumor growth and treatments on behavior such as mobility, food and water consumption, body weight gain/loss (body weights were measured twice per week after randomization), eye/hair matting and any other abnormalities. Mortality and observed clinical signs were recorded for individual animals in detail.

Tumor volumes were measured twice per week after randomization in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: “V = (L x W x W)/2, where V was tumor volume, L was tumor length (the longest tumor dimension) and W was tumor width (the longest tumor dimension perpendicular to L). Dosing as well as tumor and body weight measurements were conducted in a Laminar Flow Cabinet. The body weights and tumor volumes were measured by scale and caliper, the data was recorded by using Study Director™ software.

Criteria for Dosing Holiday and Supplemental Gel Administration: No dosing holiday. Treatment resumed when the BWL recovered. Sacrificed the individual mouse when BWL>15% for 72 hours. Supplemental gels were administered to the individual mouse with BWL > 15%. BWL was calculated based in the BW of mouse on the day of randomization.

Endpoints: The body weight of all animals was monitored throughout the study and animals were euthanized if they lost over 20% of their body weight relative to the weight on the first day of treatment. The individual mouse was euthanized if its tumor volume exceeded 3000 mm³. To deter cannibalization, any animal exhibiting an ulcerated or necrotic tumor were separated immediately and singly housed and monitored daily before the animal was euthanized or until tumor regression was completed. The mouse was euthanized rapidly if: tumor ulcerates, and the ulceration diameter was greater than 5 mm, or pus or necrosis observed; or tumor burden, including metastasis, compromises animal’s normal physiologic performances, e.g., orientation, access to food or water. The mouse was euthanized rapidly if the animal was: emaciated - skeletal structure extremely prominent, little or no flesh cover, vertebrae distinctly segmented; persistent hypothermia; blood stained or mucopurulent discharge from any orifice; labored breathing, particularly accompanied by nasal discharge or cyanosis; hind limb paralysis or weakness (cannot reach food and water); severe anemia, mainly indicated by pale feet or ears; severe infection; incontinence or diarrhea over 48 hours; or severe dehydration.

Study Termination: The treatments were performed for 28 days. The study was terminated on day 28. Tumors were not collected for euthanized mice before termination of the study. No sampling for mice found dead.

Table 9 Table 10

Statistical Analysis: Test of homogeneity of variance by Bartlet's test: if the p-value of Bartlet's test is greater than 0.05, it indicates that there is not enough evidence to reject the null hypothesis of homogeneity of variance, which is one of the assumptions of ANOVA. Therefore, an ANOVA test was conducted to determine whether there exists any pair of groups w ith different group means and run the post hoc Tukey HSD for all pairw ise comparisons or Dunnetf s t test for each treatment against one control.

If p-value of Bartlet's test is less than or equal to 0.05, it indicates that there is some evidence that variances may not be equal or data do not follow normal distribution. Then a Kruskal-Wallis test was conducted to determine if there exists any pair of groups with different group medians and run the post hoc Conover's non-parametric all-pairs comparison test for all pairwise comparisons, or Conover's non-parametric many-to-one comparison test for each treatment against one control.

Both tests use single-step p-value adjustment. In addition, pairwise comparisons were performed without multiple comparison correction and report nominal/uncorrected p-values directly from Welch's t-test or Mann-Whitney U test. The criterion of choosing Welch's t-test or Mann-Whitney U test is the same as the two-group comparison method mentioned above. All statistical analyses had been done in R language and environment for statistical computing and graphics (version 3.6.0). All tests were two-sided unless otherwise specified, and p-values of <0.05 are regarded as statistically significant. For survival analysis, Kaplan- Meier model with Log-rank method was applied.

Results: In this study, no mouse was euthanized due to the body weight loss. The tumor growth inhibition of test agents in the treatment of subcutaneous GS11331 PDX model is summarized in the table below. Table 11. Antitumor Activity of Test Agents in the Treatment Model GS11331 a. Mean ± SEM (mice number); b. TGI% = [1-T/C] x 100%; c. ns: non-significant, **: P < 0.01 , and ***: P<0.001

In this study, the mean tumor volume of Group 1 (vehicle group; 10 pL/g, p.o.QD x 28 days) reached 517.24 mm³ on day 25 post treatment.

Group 2 was treated with M4205 (1 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 35.95 % on day 25.

Group 3 treated with M4205 (2.5 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 74.54 % on day 25.

Group 4 treated with Compound 198 (3 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 17.21 % on day 25.

Group 5 treated with Compound 198 (10 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 84.99 % on day 25.

Group 6 was treated with combination of Compound 198 (3 mg/kg. 5 pL/g, p.o.QD x 28 days) and M4205 (1 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 68.21 % on day 25.

Group 7 was treated with combination of Compound 198 (10 mg/kg, 5 pL/g, p.o.QD x 28 days) and M4205 (1 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 88.87 % on day 25. Group 8 was treated with combination of Compound 198 (3 mg/kg, 5 pL/g. p.o.QD x 28 days) and M4205 (2.5 mg/kg, 5 pL/g, p.o.QD x 28 days) and had TGI value of 83.45 % on day 25.

Group 9 was treated with sunitinib (20 mg/kg, 10 pL/g, p.o.QD x 28 days) and had TGI value of 76.69 % on day 25.

Compared with vehicle group, the mid-dose single treatment of M4205 and Compound 198 showed significant anti -tumor efficacy in GS I 1331 PDX model. The combination administration of M4205 and Compound 198 (M4205 1 mg/kg combined with Compound 198 3 mg/kg, M4205 1 mg/kg combined with Compound 198 10 mg/kg, M4205 2.5 mg/kg combined with Compound 198 3 mg/kg) showed additive anti-tumor efficacy in GS11331 PDX model. In this study, there was no significant body weight loss in test compounds M4205 and Compound 198 treatment groups which indicated that test compounds M4205 and Compound 198 were well-tolerated. The positive control sunitinib resulted in the expected anti-tumor efficacy.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. Such equivalents are intended to be within the scope of the following claims.

Claims

CLAIMS What is claimed is:

1 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject:

M4205: or a pharmaceutically acceptable salt thereof, and a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R^1A are each independently selected from H, halogen, and CH3, or R¹ and R^1A taken together with the carbon to which they are attached form cyclopropyl;

R²is selected from Ci-salkyl, CD3, Cs-ecycloalkyl, bicyclo[ 1.1.1] pentane, and 4- to 6- membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen, CH3, C2-3alkenyl, OH, CH2OH, C4- ecycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said alkyl, cycloalkyl, heterocycle or phenyl is optionally substituted with OH or NH2, Ci-2alkyl,

CH2NH2. or halogen;

Xi is NH or O;

X₂ is N or CH;

X3 is N or CH;

R⁵ is selected from H, Ci-3alkyl, CD3, C3-4cycloalkyl and bicyclo[l. l. l] pentane, wherein said alkyl, cycloalkyl or bicyclo[l . l . l .]pentane is optionally substituted with 1 -2 R⁷; each R⁷ is independently selected from CN, NH2, OH, CH2OH, cyclopropyl, pyridinyl, and oxazolyl, or taken together two R⁷ attached to the same carbon atom form 4- membered heterocycle containing N;

R⁶ is independently selected from Ci-salkyl, CHF2, CF3, 4- or 5-membered heterocycle containing N or O, and Cs-4cycloalkyl, wherein said alkyl or heterocycle is optionally substituted with one R⁸;

R⁸ is independently selected from OH. NR⁹R⁹, OCH3. CH3 and 4-membered heterocycle containing N or O, wherein said alkyl or heterocycle is optionally substituted with one R¹⁰; each R⁹ is independently selected from H, CH3 and CH2CF3; and R¹⁰ is selected from CH3 and CF3.

2. The method of claim 1, wherein the method comprises administering an effective amount of M4205, or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein M4205 is dosed at about 100 mg to about 2000 mg per administration.

4. The method of any one of claims 1 to 3, wherein M4205 is dosed orally.

5. The method of any one of claims 1 to 4, wherein M4205 and the compound of Formula (I) are administered simultaneously.

6. The method of any one of claims 1 to 4. wherein M4205 and the compound of Formula (T) are administered sequentially.

7. The method of any one of claims 1 to 6, wherein M4205 is administered to the subject daily.

8. The method of any one of claims 1 to 7, wherein M4205 is administered to the subject once daily.

9. The method of any one of claims 1 to 7, wherein M4205 is administered to the subject twice daily.

10. The method of any one of claims 1 to 9, wherein administering M4205 and the compound of Formula (I) reduces tumor size relative to administering M4205.

11. The method of any one of claims 1 to 9, wherein administering M4205 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

12. A method of treating a cancer in a subject in need thereof, comprising administering to the subject:

THE-630 or a pharmaceutically acceptable salt thereof, and a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R^1A are each independently selected from H, halogen, and CH3, or R¹ and R^1A taken together with the carbon to which they are attached form cyclopropyl;

R²is selected from Ci-salkyl. CD3. Cs-scycloalkyl. bicyclo[ 1.1.1] pentane, and 4- to 6- membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R⁴; each R⁴ is independently selected from halogen, CH3, C2-3alkenyl, OH, CH2OH, C4- ecycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said alky l, cycloalkyl, heterocycle or phenyl is optionally substituted with OH or NH2, Ci-2alkyl,

CH2NH2, or halogen;

Xi is NH or O;

X₂ is N or CH;

X3 is N or CH;

R⁵ is selected from H, Ci-salkyl, CD3, C3-4Cycloalkyl and bicyclofl.1.1] pentane, wherein said alkyl, cycloalkyl or bicyclofl. 1.1. ]pentane is optionally substituted with 1-2 R⁷; each R⁷ is independently selected from CN, NH2, OH. CH2OH, cyclopropyl, pyridinyL and oxazolyl, or taken together two R⁷ attached to the same carbon atom form 4- membered heterocycle containing N;

R⁶ is independently selected from Ci-salkyl, CHF2, CF3, 4- or 5-membered heterocycle containing N or O, and C3-4cycloalkyl, wherein said alkyl or heterocycle is optionally substituted with one R⁸;

R⁸ is independently selected from OH, NR⁹R⁹, OCH3, CH3 and 4-membered heterocycle containing N or O, wherein said alk l or heterocycle is optionally substituted with one R¹⁰; each R⁹ is independently selected from H, CH3 and CH2CF3; and R¹⁰ is selected from CH3 and CF3.

13. The method of claim 12, wherein the method comprises administering an effective amount of THE-630. or a pharmaceutically acceptable salt thereof.

14. The method of claim 12 or 13, wherein THE-630 is dosed at about 0. 1 mg to about 200 mg per administration per administration

15. The method of any one of claims 12 to 14, wherein THE-630 is dosed orally.

16. The method of any one of claims 12 to 15, wherein THE-630 and the compound of Formula (I) are administered simultaneously.

17. The method of any one of claims 12 to 15, w herein THE-630 and the compound of Formula (I) are administered sequentially.

18. The method of any one of claims 12 to 17, wherein THE-630 is administered to the subject daily.

19. The method of any one of claims 12 to 18, wherein THE-630 is administered to the subject once daily.

20. The method of any one of claims 12 to 18. wherein THE-630 is administered to the subject twice daily.

21. The method of any one of claims 12 to 20, wherein administering THE-630 and the compound of Formula (I) reduces tumor size relative to administering THE-630.

22. The method of any one of claims 12 to 20, wherein administering THE-630 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

23. The method of any one of claims 1 to 22, wherein the method comprises administering an effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 1 to 22, wherein the compound of Formula (I) is dosed at about 0.1 mg to about 200 mg per administration.

25. The method of any one of claims 1 to 22, wherein the compound of Formula (I) is a dosed orally.

26. The method of any one of claims 1 to 22, wherein the compound of Formula (I) is administered to the subject daily.

27. The method of any one of claims 1 to 22, wherein the compound of Formula (I) is administered to the subject once daily.

28. The method of any one of claims 1 to 22, wherein the compound of Formula (I) is administered to the subject twice daily.

29. The method of any one of claims 1 to 11 and 23 to 28. wherein administering M4205 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

30. The method of any one of claims 12 to 28, wherein administering THE-630 and the compound of Formula (I) reduces tumor size relative to administering the compound of Formula (I).

31. The method of any one of claims 1 to 30, wherein the compound of Formula (I) is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

32. The method of any one of claims 1 to 30, wherein the compound of Formula (I) is a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

33. The method of any one of claims 1 to 32, wherein the subject is resistant or has acquired resistance to an anti-cancer therapy.

34. The method of claim 33, wherein the anti-cancer therapy is administering an anticancer agent.

35. The method of claim 34, wherein the anti-cancer agent is a KIT inhibitor.

36. The method of claim 34 or 35, wherein the anti-cancer agent is selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutical salts thereof, and combinations thereof.

37. The method of any one of claims 1 to 32, wherein the subject is resistant or has acquired resistance to one or more anti-cancer therapies.

38. The method of claim 37, wherein each of the anti-cancer therapies is administering an anti-cancer agent.

39. The method of claim 38, wherein the anti-cancer agent is a KIT inhibitor.

40. The method of claim 38 or 39, wherein each of the anti -cancer agents is independently selected from: imatinib, sunitinib, regorafenib, and ripretinib, and combinations thereof.

41. The method of any one of claims 1 to 40, wherein the subject is receiving an anticancer therapy.

42. The method of claim 41, wherein the anti-cancer therapy is administering an anticancer agent.

43. The method of claim 42, wherein the anti-cancer agent is a KIT inhibitor.

44. The method of claim 42 or 43, wherein the anti-cancer agent is selected from: imatinib, sunitinib. regorafenib, and ripretinib, and pharmaceutical salts thereof, and combinations thereof.

45. The method of any one of claims 1 to 44, wherein subject is in a fasting state.

46. The method of any one of claims 1 to 44, wherein the compound of Formula (I) is administered with food.

47. The method of any one of claims 1 to 44, wherein the compound of Formula (I) is administered about 30 minutes to about 1 hour after food.

48. The method of any one of claims 1 to 11 and 23 to 47, wherein M4205 is administered with food.

49. The method of any one of claims 1 to 11 and 23 to 47, wherein M4205 is administered about 30 minutes to about 1 hour after food.

50. The method of any one of claims 12 to 47, wherein THE-630 is administered with food.

51. The method of any one of claims 12 to 47. wherein THE-630 is administered about 30 minutes to about 1 hour after food.

52. The method of any one of claims 1 to 51, wherein the compound of Formula (I) is a compound of Table 1, or a pharmaceutically acceptable salt thereof

53. The method of any one of claims 1 to 51, wherein the compound of Formula (I) is a compound of Table 2, or a pharmaceutically acceptable salt thereof.

54. The method of any one of claims 1 to 53, wherein the cancer is selected from: gastrointestinal stromal tumor (GIST). AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

55. The method of any one of claims 1 to 53, wherein the cancer is gastrointestinal stromal tumor (GIST).

56. The method of claim 54 or 55, wherein the GIST is characterized by a tumor with one or more KIT mutations.

57. The method of claim 56, wherein the tumor has a primary activating KIT mutation.

58. The method of claim 56 or 57, wherein the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon

1 1 KIT mutation, an exon 13 KIT mutation, an exon 14 KIT mutation, and an exon 17 KIT mutation, and combinations thereof.

59. The method of claim 58. wherein each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, K642E, V654A, and N655K, and combinations thereof.

60. The method of claim 58. wherein the tumor has an exon 9 KIT mutation.

61. The method of claim 58, wherein the tumor has an exon 11 KIT mutation.

62. The method of claim 58, wherein the tumor has an exon 13 KIT mutation.

63. The method of claim 62, wherein the exon 13 KIT mutation is selected from K642E,

V654A and N655K, and combinations thereof.

64. The method of claim 58, wherein the tumor has an exon 14 KIT mutation.

65. The method of claim 64, wherein the exon 14 KIT mutation is T670I.

66. The method of claim 58, wherein the tumor has an exon 17 KIT mutation.

67. The method of claim 66, wherein the exon 17 KIT mutation is selected from N822K.

D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.

68. The method of any one of claims 57 to 67, w herein the tumor is resistant or has acquired resistance to an anti-cancer therapy.

69. The method of claim 68, wherein the anti-cancer therapy is administering an anticancer agent.

70. The method of claim 69, wherein the anti-cancer agent is a KIT inhibitor.

71. The method of claim 69, wherein the anti-cancer agent is selected from: imatinib, sunitinib. regorafenib, and ripretinib, and pharmaceutical salts thereof, and combinations thereof.

72. The method of any one of claims 57 to 67, wherein the tumor resistant or has acquired resistance to one or more anti-cancer therapies.

73. The method of claim 72, wherein each of the anti-cancer therapies is administering an anti-cancer agent.

74. The method of claim 73, w herein the anti-cancer agent is a KIT inhibitor.

75. The method of claim 73, wherein each of the anti-cancer agents is independently selected from: imatinib, sunitinib, regorafenib, and ripretinib, and pharmaceutical salts thereof, and combinations thereof.