Methods of treating mat2a-associated diseases

Abstract

The present disclosure relates to the use of MAT2A inhibitors in the treatment and prevention of MAT2A-associated diseases (e.g., proliferative diseases). The present disclosure also relates to corresponding pharmaceutical formulations, uses, methods, compositions, and related disclosed embodiments.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 583,058, filed September 15, 2023; U.S. Provisional Application No. 63 / 605,124, filed December 1, 2023; and U.S. Provisional Application No. 63 / 665,869, filed June 28, 2024, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] Declaration of rights to inventions made under federally funded research and development not applicable.

[0003] References are made to the "serial list," table, or computer program list appendix submitted on the CD. not applicable. Background Technology

[0004] Cancer is a leading cause of death worldwide. A limitation of mainstream treatments (such as chemotherapy and immunotherapy) is that their cytotoxic effects are not limited to cancer cells and can produce adverse side effects in normal tissues. Therefore, new strategies are needed to better target cancer cells.

[0005] Synthetic lethality occurs when a combination of defective expression of two or more genes leads to cell death, while a defect in only one of these genes does not. The concept of synthetic lethality originates from studies in the Drosophila model system, where a combination of mutations in two or more independent genes leads to cell death (as opposed to survival when only one gene is mutated or deleted). Recently, numerous studies have explored maladaptive genetic alterations in cancer cells that make them susceptible to synthetic lethal pathways. These tumor-specific genetic defects necessitate the use of targeted agents that induce tumor cell death without harming normal cells.

[0006] Methionine adenosine transferase 2A (MAT2A) is an enzyme that uses methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosine methionine (SAM). SAM is a major methyl donor in cells used for methylation of a variety of substrates, including DNA, RNA, and proteins. One methyltransferase that uses SAM as a methyl donor is protein arginine N-methyltransferase 5 (PRMT5). Although SAM is essential for PRMT5 activity, PRMT5 is competitively inhibited by 5'-methionine (MTA). Because MTA is part of the methionine rescue pathway, cellular MTA levels remain low during the initiation of methionine phosphorylase (MTAP).

[0007] MTAP is located at a locus on chromosome 9 that is frequently deleted in cells from patients with cancers originating from several tissues, including the central nervous system, pancreas, esophagus, bladder, and lung (cBioPortal database). MTAP deletion leads to the accumulation of MTA, making MTAP-deficient cells more dependent on SAM production and therefore on MAT2A activity compared to MTAP-expressing cells. In a shRNA cell line screening of approximately 400 cancer cell lines, MAT2A knockdown resulted in a greater proportion of viability loss in MTAP-deficient cells compared to MTAP-expressing WT cells (see McDonald et al., 2017). Cell 170, 577-592). Furthermore, inducible knockdown of the MAT2A protein reduces tumor growth in vivo (see Marjon et al., 2016). Cell Reports 15(3), 574-587). These results suggest that MAT2A inhibitors could provide a useful therapy for cancer patients, including those with MTAP-deficient tumors.

[0008] Therefore, there is a need in the art to provide methods for treating MAT2A-related diseases. This disclosure satisfies these needs and also provides related advantages. Summary of the Invention

[0009] In one aspect, this disclosure is characterized by a method for treating or preventing proliferative diseases (e.g., cancer) in a subject with this need. The method includes administering a therapeutically effective amount of a methionine adenosine transferase 2A inhibitor (MAT2Ai) to the subject. The methods described herein may include one or more of the features described below.

[0010] In some embodiments, the MAT2A inhibitor is 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 1) or a pharmaceutically acceptable salt thereof.

[0011] In some implementations, the MAT2A inhibitor is administered orally.

[0012] In some respects, this article provides methods for treating MAT2A-related diseases, which include administering a therapeutically effective amount of compound 1 or its pharmaceutically acceptable salt.

[0013] In some respects, this article provides a method for treating cancer in subjects who require it, the method comprising administering to the subject a therapeutically effective amount of compound 1 or its pharmaceutically acceptable salt.

[0014] In some embodiments, the method includes administering to a subject in need a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 1) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1. In some embodiments, compound 1 is administered in free base form.

[0015] In some embodiments, the method described herein comprises administering a therapeutically effective amount of Compound 1 to a subject in need of the form of a free base at a total daily dose of about 50 mg to about 75 mg, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1. In some embodiments, a therapeutically effective amount of Compound 1 is a total daily dose of about 25 mg to about 50 mg of the free base form of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1. In some embodiments, a therapeutically effective amount of Compound 1 is a total daily dose of about 5 mg of the free base form of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1. In some embodiments, a therapeutically effective amount of Compound 1 is a total daily dose of about 10 mg of the free base form of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1. In some embodiments, a therapeutically effective amount of Compound 1 is a total daily dose of about 15 mg of the free base form of Compound 1, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 30 mg of the total daily dose in the free base form of compound 1, or an equivalent amount in the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 45 mg of the total daily dose in the free base form of compound 1, or an equivalent amount in the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 60 mg of the total daily dose in the free base form of compound 1, or an equivalent amount in the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 80 mg of the total daily dose in the free base form of compound 1, or an equivalent amount in the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 100 mg of the total daily dose in the free base form of compound 1, or an equivalent amount in the pharmaceutically acceptable salt form of compound 1.

[0016] In some embodiments, compound 1 in its free base form is administered at a dose of about 5 mg to about 60 mg QD once daily (QD) (e.g., 5 mg QD, 10 mg QD, 15 mg QD, 30 mg QD, 45 mg or 60 mg QD), or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form is administered.

[0017] In some embodiments, compound 1 in its free base form is administered at a dose of about 60 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, compound 1 in its free base form is administered at a dose of about 30 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, compound 1 in its free base form is administered at a dose of about 15 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered.

[0018] In some embodiments, compound 1 in its free base form is administered at a dose of about 60 mg QD. In some embodiments, compound 1 in its free base form is administered at a dose of about 45 mg QD. In some embodiments, compound 1 in its free base form is administered at a dose of about 30 mg QD. In some embodiments, compound 1 in its free base form is administered at a dose of about 15 mg QD. In some embodiments, compound 1 in its free base form is administered at a dose of about 10 mg QD. In some embodiments, compound 1 in its free base form is administered at a dose of about 5 mg QD.

[0019] In some embodiments, the MAT2A inhibitor is administered with food (i.e., the administration of the MAT2A inhibitor occurs 1 hour before a meal or 2 hours after a meal). In some embodiments, the MAT2A inhibitor is not administered with food (i.e., the administration of the MAT2A inhibitor occurs more than 1 hour before a meal or 2 hours after a meal).

[0020] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered orally.

[0021] In some implementations, the subject is a human being. In some implementations, the human being is an adult patient aged 18 years or older.

[0022] In some embodiments, the cancer is non-small cell lung cancer (squamous and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, or gastric cancer. In some embodiments, the cancer is non-small cell lung cancer (squamous). In some embodiments, the cancer is non-small cell lung cancer (adenocarcinoma). In some embodiments, the cancer is urothelial carcinoma (bladder). In some embodiments, the cancer is urothelial carcinoma (upper urinary tract).

[0023] In some implementations, the subject has non-small cell lung cancer (e.g., squamous or adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, or gastric cancer. In some implementations, the subject has squamous and adenocarcinoma of esophagus cancer, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0024] In some implementations, the cancer has the MTAP gene missing.

[0025] In some implementations, the cancer is refractory to at least one anticancer agent.

[0026] In some embodiments, subjects who have received Compound 1 or its pharmaceutically acceptable salts for at least 21 days have not exhibited any Grade 3 or 4 adverse events related to Compound 1 therapy. In some embodiments, subjects who have received Compound 1 or its pharmaceutically acceptable salts for at least 42 days have not exhibited any Grade 3 or 4 adverse events related to Compound 1 therapy. In some embodiments, subjects who have received Compound 1 or its pharmaceutically acceptable salts for at least 63 days have not exhibited any Grade 3 or 4 adverse events related to Compound 1 therapy. In some embodiments, subjects have at least demonstrated stable disease after receiving Compound 1 or its pharmaceutically acceptable salts. In some embodiments, subjects have at least demonstrated a partial response after receiving Compound 1 or its pharmaceutically acceptable salts.

[0027] In some embodiments, the methods described herein include administering at least one additional therapeutic agent. In some embodiments, the methods described herein include administering at least one additional therapeutic agent or diagnostic agent. In some embodiments, the at least one additional therapeutic agent is a signal transduction inhibitor (STI). In some embodiments, the at least one additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the at least one additional therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the at least one additional therapeutic agent is a PRMT5 inhibitor.

[0028] In some respects, this article provides unit dosage forms containing about 5 mg to about 100 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0029] In some aspects, this document provides kits comprising one or more unit dosage forms described herein. In some embodiments, the kits also comprise at least one additional therapeutic agent.

[0030] Any of the above aspects and implementation methods can be combined with any other aspect or implementation method.

[0031] Other objects, features and advantages of the present invention will become apparent to those skilled in the art from the following detailed description and accompanying drawings. Attached Figure Description

[0032] not applicable. Detailed Implementation

[0033] I. Overview Overexpression of the MAT2A enzyme has been shown to mediate certain cancers. Cancers characterized by reduced or absent expression of the methionine phosphorylase (MTAP) gene, MTAP gene deletion, reduced MTAP protein function, decreased MTAP protein levels, MTAP protein deficiency, MTA accumulation, or a combination thereof have been identified as synthetic lethal targets.

[0034] This article describes a method for treating MAT2A-related disease in subjects. The method includes a specific dosing regimen that has demonstrated significant efficacy and is well-tolerated by the subjects.

[0035] II. Definition Although various embodiments and aspects of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments and aspects are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out the invention.

[0036] The chapter headings used herein are for organizational purposes only and should not be construed as limiting the subject matter. All documents or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are hereby expressly incorporated herein by reference in their entirety for any purpose.

[0037] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. See, for example, Singleton et al., Dictionary of Microbiology and Molecular Biology, 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, apparatus, and materials similar to or equivalent to those described herein may be used in the practice of this invention. The following definitions are provided for ease of understanding of certain terms frequently used herein and are not intended to limit the scope of this disclosure.

[0038] "Compound 1" refers to the chemical substance 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one, which has the following formula: (Compound 1).

[0039] In some embodiments, compound 1 is a pharmaceutically acceptable salt form. Compound 1 and its pharmaceutically acceptable salts are described in international publications WO2020 / 123395 and WO2024 / 118070. The entire contents of WO 2020 / 123395 and WO 2024 / 118070 are incorporated herein by reference for all purposes.

[0040] "Pharmaceutically acceptable salt" refers to a derivative of compound 1 in which the parent compound is modified by converting the existing base moiety into its salt form. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium compounds (methyl iodide, ethyl iodide, etc.). It should be understood that pharmaceutically acceptable salts are nontoxic. More information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 23rd edition, 2020, which is incorporated herein by reference.

[0041] Compound 1 can exist in a pharmaceutically acceptable isotopic form, wherein one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than those commonly found in nature. Examples of isotopes that can be incorporated into Compound 1 include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as... 2 H,3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O and 18 F. These radiolabeled compounds can be used to help determine or measure the effectiveness of compound 1, for example, by characterizing the site or mode of action, or binding affinity to pharmacologically important sites. Certain isotopic labeled forms of compound 1, such as those incorporating radioisotopes, can be used for drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) It is particularly suitable for this purpose due to its ease of incorporation and readily available detection methods.

[0042] When referring to the specific amount of Compound 1 administered to a patient, the application refers to the amount of the free base of Compound 1. Those skilled in the art will understand that minor adjustments to the overall amount administered are necessary to administer the same amount of Compound 1 in different salt forms.

[0043] As used herein, the term “a” or “an” refers to one or more.

[0044] The terms “contains,” “includes,” and “has,” and their derivatives, are used interchangeably in this document as comprehensive open-ended terms. For example, the use of “contains,” “includes,” or “has” implies that any element contained, having, or including is not the only element covered by the subject of the clause containing the verb.

[0045] As used herein, the term "about" refers to a range of values ​​that includes the specified value and is reasonably similar to the specified value as would be considered by one of ordinary skill in the art. In some embodiments, the term "about" refers to a standard deviation using measurements generally acceptable in the art. In some embodiments, "about" refers to a range extending to + / - 10% of the specified value. In some embodiments, "about" refers specifically to the specified value.

[0046] As used herein, the terms “treatment,” “cure,” “relief,” and “improvement” are used interchangeably. These terms refer to methods used to achieve beneficial or desired outcomes, including but not limited to therapeutic benefits. In the context of cancer treatment, therapeutic benefits are intended to include the eradication, improvement, and cessation of cancer. Furthermore, therapeutic benefits are achieved through the eradication, improvement, or cessation of one or more physiological symptoms associated with the underlying condition, resulting in observed improvement in the subject, although the subject may still have the underlying condition. Treatment includes slowing the development of clinical symptoms of the disease by administering a composition; suppressing the disease, i.e., alleviating the clinical symptoms of the disease; inhibiting the disease, i.e., preventing the development of clinical symptoms by administering a composition after the initial appearance of symptoms; and / or alleviating the disease, i.e., resolving the clinical symptoms by administering a composition after the initial appearance of symptoms.

[0047] An "effective amount" or "therapeutic effective amount" is a quantity sufficient to achieve a predetermined purpose (e.g., to achieve the effect of administration, to treat a disease, to reduce enzyme activity, to alleviate one or more symptoms of a disease or condition). An example of an "effective amount" is a quantity sufficient to help treat or alleviate one or more symptoms of a disease, which may also be referred to as a "therapeutic effective amount." "Ameliorating" one or more symptoms (and its grammatically equivalent expression) refers to reducing the severity or frequency of symptoms, or eliminating symptoms. Therapeutic efficacy can also be expressed as an increase or decrease of a "-fold." For example, a therapeutically effective amount may have an effect at least 1.2 times, 1.5 times, 2 times, 5 times, or more than the control. When treating cancer, an effective amount can produce tumor arrest, tumor reduction, reduced progression, tumor eradication, or improved overall survival.

[0048] "Patient," "subject," or "subject with need" means a living organism that suffers from or is susceptible to a disease or condition that can be treated using the methods provided herein. The term does not necessarily mean that a subject has been diagnosed with a specific disease, but generally refers to an individual under medical supervision. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, dairy cows, deer, and other non-mammals. In some embodiments, the patient, subject, or subject with need is a human.

[0049] A "partial response" or "PR" refers to a clinical outcome in which the target lesion size of a subject decreases but remains present after treatment with compound 1 or its pharmaceutically acceptable salt. A partial response is defined as a reduction of at least 30% in the total diameter of target lesions in a subject after treatment with compound 1 or its pharmaceutically acceptable salt, compared to the baseline total diameter of target lesions before treatment.

[0050] "Complete response" or "CR" refers to a clinical outcome in which all target lesions in a subject disappear and the short axis of any pathological lymph nodes shrinks to less than 10 mm after treatment with compound 1 or its pharmaceutically acceptable salt.

[0051] "Disease progression" or "PD" refers to a clinical outcome in which the size of the target lesion increases in a subject following treatment with compound 1 or its pharmaceutically acceptable salt. Disease progression is defined as an increase of at least 20% in the sum of the target lesion diameters, using the minimum sum in the study as a reference (including the baseline sum if it is the minimum sum in the study), and in addition to a relative increase of 20%, there must be an absolute increase of at least 5 mm. (Note: The presence of one or more new lesions is also considered progression.) "Stable disease" or "SD" refers to a clinical outcome in which, after treatment with compound 1 or its pharmaceutically acceptable salt, the target lesion in the subject does not achieve a sufficient reduction in PR or a sufficient increase in PD.

[0052] "Controlled disease state" is a state in which a subject may alternate between exhibiting stable disease and partial response.

[0053] As used in this article, “CAAP1” refers to the cysteine ​​activity and apoptosis inhibitor 1 gene.

[0054] As used in this article, "CDKN2A" refers to the cyclin-dependent kinase inhibitor 2A gene.

[0055] III. Detailed Description of Implementation Methods method MAT2A has been found to act in certain conditions in human or animal subjects. This disclosure relates to compounds, such as MAT2A inhibitors, that exhibit antiproliferative activity, preferably in cancer patients, when used alone or in combination. Suitably, the method relates to a method of treating proliferative diseases by administering or co-administering the compounds.

[0056] In some embodiments, the MAT2A inhibitor used herein is 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound 1), which has the following formula: (Compound 1).

[0057] In some embodiments, as used herein, the MAT2A inhibitor is a pharmaceutically acceptable salt of compound 1.

[0058] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered as a free base of compound 1 at a daily dose of about 5 mg to about 100 mg, or as an equivalent amount of a pharmaceutically acceptable salt of compound 1, for example, orally.

[0059] In some respects, this article provides a method for treating MAT2A-related disease comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0060] In some respects, this article provides a method for treating diseases mediated by MAT2A, comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0061] In some respects, this article provides a method for treating cancer comprising administering a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0062] In some embodiments, subjects who have received Compound 1 or its pharmaceutically acceptable salts for at least 21 days have not exhibited any Grade 3 or 4 adverse events related to Compound 1 therapy. In some embodiments, subjects who have received Compound 1 or its pharmaceutically acceptable salts for at least 42 days have not exhibited any Grade 3 or 4 adverse events related to Compound 1 therapy. In some embodiments, subjects who have received Compound 1 or its pharmaceutically acceptable salts for at least 63 days have not exhibited any Grade 3 or 4 adverse events related to Compound 1 therapy. In some embodiments, subjects have at least demonstrated stable disease after receiving Compound 1 or its pharmaceutically acceptable salts. In some embodiments, subjects have at least demonstrated a partial response after receiving Compound 1 or its pharmaceutically acceptable salts.

[0063] In some embodiments, the cancer is characterized by reduced or absent expression of the methionine phosphorylase (MTAP) gene, absence of the MTAP gene, reduced function of the MTAP protein, decreased MTAP protein level, absence of the MTAP protein, accumulation of MTA, or a combination thereof.

[0064] In some embodiments, this document provides a method of treating cancer in a subject, comprising administering to a patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1, wherein the cancer is characterized by reduced or absent expression of methionine phosphorylase (MTAP) gene, MTAP gene deletion, reduced MTAP protein function, reduced MTAP protein level, MTAP protein deletion, MTA accumulation, or a combination thereof.

[0065] In some embodiments, this document provides a method for treating MTAP-null cancer in a subject, comprising administering to a patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0066] In some embodiments, this document provides a method for treating cancer in subjects with MTAP gene deletion, comprising administering to the patient a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein said therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0067] In some implementations, compound 1 or its pharmaceutically acceptable salt is administered once daily (QD).

[0068] In some embodiments, a therapeutically effective amount of compound 1 is a free base form of compound 1 at a total daily dose of about 50 mg to about 75 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is a free base form of compound 1 at a total daily dose of about 25 mg to about 50 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0069] In some embodiments, a therapeutically effective amount of compound 1 is about 5 mg of the total daily dose of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 10 mg of the total daily dose of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 15 mg of the total daily dose of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 30 mg of the total daily dose of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 45 mg of the total daily dose of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 60 mg of the total daily dose of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 80 mg of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1. In some embodiments, a therapeutically effective amount of compound 1 is about 100 mg of the free base form of compound 1, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1.

[0070] In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 50 mg once daily (QD) to about 75 mg once daily (QD), or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 25 mg QD to about 50 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered.

[0071] In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 5 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 10 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 15 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 30 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 45 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 60 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 80 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered. In some embodiments, a therapeutically effective amount of the free base form of compound 1 is administered at a dose of about 100 mg QD, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered.

[0072] In some implementations, cancer is a solid tumor. In some implementations, cancer is a solid malignant tumor.

[0073] In some implementations, the cancer is neuroblastoma, colorectal cancer (such as rectal cancer, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, and brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors). Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder cancer, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0074] In some implementations, the cancer is lung cancer, non-small cell lung cancer (NSLC), bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, or gastric cancer. Cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, mesothelioma, hepatocellular carcinoma, bile duct cancer, chronic or acute leukemia, lymphocytic lymphoma, central nervous system (CNS) tumors, spinal axis tumors, brainstem glioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenoma, including refractory forms of any of the above cancers, or combinations of one or more of the above cancers.

[0075] In some implementations, the cancer is selected from the group consisting of: leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, esophageal and gastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

[0076] In some embodiments, the cancer is selected from the group consisting of: non-small cell lung cancer (squamous and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer. In some embodiments, the cancer is non-small cell lung cancer (squamous). In some embodiments, the cancer is non-small cell lung cancer (adenocarcinoma). In some embodiments, the cancer is urothelial carcinoma (bladder and upper urinary tract). In some embodiments, the cancer is urothelial carcinoma (bladder). In some embodiments, the cancer is urothelial carcinoma (upper urinary tract). In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is squamous and adenocarcinoma of the esophagus, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0077] In some embodiments, this document provides a method for treating cancer in a subject, wherein the cancer is characterized by reduced or absent MTAP gene expression, MTAP gene deletion, decreased MTAP protein levels, decreased MTAP protein function, MTAP protein deletion, MTA accumulation, or a combination thereof, compared to cancer in which the MATP gene is present and fully functional. The method comprises administering to the subject in need a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a free base form of Compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1. In one embodiment, MTAP-null cancer is leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, or mesothelioma. In another embodiment, MTAP-null cancer is pancreatic cancer. In yet another embodiment, MTAP null cancer is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B-cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), or mantle cell lymphoma (MCL). In yet another embodiment, MTAP null cancer is stomach cancer. In yet another embodiment, cancer is colon cancer. In yet another embodiment, MTAP null cancer is liver cancer. In yet another embodiment, MTAP null cancer is glioblastoma multiforme (GBM). In yet another embodiment, MTAP null cancer is bladder cancer. In yet another embodiment, MTAP null cancer is esophageal cancer. In yet another embodiment, MTAP null cancer is breast cancer. In yet another embodiment, MTAP null cancer is NSLCC. In yet another embodiment, MTAP null cancer is MCL. In yet another embodiment, MTAP null cancer is DLBCL. In yet another embodiment, MTAP null cancer is ALL. In some embodiments, MTAP null cancer is selected from the group consisting of: non-small cell lung cancer (squamous and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer. In some embodiments, MTAP null cancer is squamous and adenocarcinoma of the esophagus, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0078] In yet another embodiment, the cancer is selected from the group consisting of: leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, anal cancer, gastric cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, gastric cancer, esophageal cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma. In one embodiment, the cancer is mesothelioma. In one embodiment, the cancer is non-small cell lung cancer. In another embodiment, the cancer is non-squamous non-small cell lung cancer. In one embodiment, the cancer is colon or rectal cancer. In one embodiment, the cancer is adenocarcinoma of the colon or rectum. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is adenocarcinoma of the breast. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is gastric adenocarcinoma. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is pancreatic adenocarcinoma. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is characterized by MTAP-null. In one embodiment, the cancer is characterized by MTAP deficiency. In one embodiment, the cancer is characterized by CAAP1-null. In one embodiment, the cancer is characterized by CAAP1 deficiency. In one embodiment, the cancer is characterized by CDKN2A deficiency. In yet another embodiment, the cancer is a solid tumor. In yet another embodiment, the cancer is a solid tumor lacking MTAP. In yet another embodiment, the cancer is a metastatic solid tumor lacking MTAP. In yet another embodiment, the cancer is metastatic. In yet another embodiment, the cancer is a solid malignancy. In yet another embodiment, the cancer is MTAP-deficient lung cancer or MTAP-deficient pancreatic cancer, including MTAP-deficient NSCLC or MTAP-deficient pancreatic ductal adenocarcinoma (PDAC) or MTAP-deficient esophageal cancer. In another embodiment, the cancer is a tumor with MTAP gene deletion. In any of the embodiments herein, the cancer is a solid tumor or a hematologic malignancy. In one embodiment, the tumor is MTAP-deficient. In another embodiment, the tumor has normal MTAP expression. In yet another embodiment, the cancer is NSCLC, mesothelioma, head and neck squamous cell carcinoma, salivary gland tumor, urothelial carcinoma, sarcoma, or ovarian cancer. In yet another embodiment, the cancer is NSCLC, esophageal or gastric cancer, or pancreatic cancer. In yet another embodiment, the cancer is characterized by reduced or absent MTAP gene expression. In yet another embodiment, the cancer is characterized by decreased MTAP protein function. In yet another embodiment, the cancer is characterized by reduced or absent MTAP protein levels. In yet another embodiment, the cancer is characterized by MTA accumulation.

[0079] Genomic analysis of MTAP null cell lines showed that cell lines containing KRAS or p53 mutations were sensitive to MAT2A inhibition.

[0080] In some embodiments, a method of treating cancer in a subject is provided, wherein the cancer is characterized by reduced or absent MTAP expression, or MTAP gene deletion, reduced MTAP protein levels, reduced MTAP protein function, MTAP protein deletion, or a combination thereof, and is further characterized by the presence of mutated KRAS and / or mutated p53. The method comprises administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1. In some embodiments, the cancer is MTAP null and KRAS mutant. In some embodiments, the cancer is MTAP null and p53 mutant. In some embodiments, the cancer is MTAP null, KRAS mutant, and p53 mutant.

[0081] The term "mutated KRAS" or "KRAS mutant" refers to a KRAS protein (or the gene encoding the protein) containing an activating mutation that alters its normal function. For example, a mutant KRAS protein may have a single amino acid substitution at position 12 or 13. In a particular embodiment, the KRAS mutant has a G12X or G13X substitution, where X represents any amino acid change at the indicated position. In a particular embodiment, the substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substitution is G13D. "Mutated p53" or "p53 mutation" refers to a p53 protein (or the gene encoding the protein) containing a mutation that inhibits or eliminates its tumor-suppressive function. In one embodiment, the p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, or R196. The following are optional inclusion codes: C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splicing, R267P, R273C, R282W, A159V, or R280K. In one embodiment, the aforementioned cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer.

[0082] In some implementations, the cancer is selected from the group consisting of: leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, and mesothelioma.

[0083] In some embodiments, the cancer is refractory to at least one anticancer agent. That is, the subject receiving treatment has been given a previous anticancer agent, but the patient has not responded to this treatment, or the medical professional responsible for the subject's care believes that the subject's response is insufficient. In some embodiments, a MAT2A inhibitor in combination with said at least one anticancer agent is administered to the subject who is refractory to at least one anticancer agent. In some embodiments, said at least one anticancer agent is no longer administered to the subject who is refractory to at least one anticancer agent.

[0084] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective dose with little or no adverse effects.

[0085] In some embodiments, the MAT2A inhibitor is administered with food (i.e., the administration of the MAT2A inhibitor occurs 1 hour before a meal or 2 hours after a meal). In some embodiments, the MAT2A inhibitor is not administered with food (i.e., the administration of the MAT2A inhibitor occurs more than 1 hour before a meal or 2 hours after a meal).

[0086] In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 5 mg to 100 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 5 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 10 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 15 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 30 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 45 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 60 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer is provided, wherein 100 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0087] In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 5 mg to 100 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg, or 100 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 5 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 10 mg of compound 1 in its free base form, or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form, is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 15 mg of compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 30 mg of compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 45 mg of compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 60 mg of compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form is administered daily. In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof for treating cancer is provided, wherein 100 mg of compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form is administered daily.

[0088] In some implementations, compound 1 or its pharmaceutically acceptable salt is administered as a single therapy.

[0089] Exemplary durations of treatment related to the course of the treatment methods disclosed herein include: approximately one week; approximately two weeks; approximately three weeks; approximately four weeks; approximately five weeks; approximately six weeks; approximately seven weeks; approximately eight weeks; approximately nine weeks; approximately ten weeks; approximately eleven weeks; approximately twelve weeks; approximately thirteen weeks; approximately fourteen weeks; approximately fifteen weeks; approximately sixteen weeks; approximately seventeen weeks; approximately eighteen weeks; approximately nineteen weeks; approximately twenty weeks; approximately twenty-one weeks; approximately twenty-two weeks; approximately twenty-three weeks; approximately twenty-four weeks; approximately four months; approximately seven months; approximately eight months; approximately nine months; approximately ten months; approximately eleven months; approximately 10 months; approximately 11 months; approximately 15 weeks; approximately 16 weeks; approximately 17 weeks; approximately 18 weeks; approximately 19 weeks; approximately 20 weeks; approximately 21 weeks; approximately 22 weeks; approximately 23 weeks; approximately 24 weeks; approximately 4 months; approximately seven months; approximately eight months; approximately nine months; approximately ten months; approximately 11 months; approximately 12 weeks; approximately 13 weeks; approximately 14 weeks; approximately 15 weeks; approximately 16 weeks; approximately 17 weeks; approximately 18 weeks; approximately 19 weeks; approximately 10 weeks; approximately 11 weeks ... Months; approximately twelve months; approximately thirteen months; fourteen months; approximately fifteen months; approximately sixteen months; approximately seventeen months; approximately eighteen months; approximately nineteen months; approximately twenty months; approximately twenty-one months; approximately twenty-two months; approximately twenty-three months; approximately twenty-four months; approximately thirty months; approximately three years; approximately four years and approximately five years, etc.; or any number of days, weeks, months or years therein; for example, a treatment cycle may include 5 months and additional weeks and / or days; or one year and additional months, weeks and / or days, etc.

[0090] Exemplary durations of treatment associated with the course of treatment may be approximately 5 years, approximately 4 years, approximately 3 years, approximately 2 years, approximately 1 year, approximately 11 months, approximately 10 months, approximately 9 months, approximately 8 months, approximately 7 months, approximately 6 months, approximately 5 months, approximately 4 months, approximately 3 months, approximately 2 months, or approximately 1 month.

[0091] In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered together with one or more other therapeutic agents (e.g., anticancer agents).

[0092] Pharmaceutical Composition Compound 1, or a pharmaceutically acceptable salt thereof, may be in a compositional form suitable for administration to a subject. Typically, such compositions are pharmaceutical compositions comprising compound 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically or physiologically acceptable excipients. The pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, the pharmaceutical compositions may be administered to a subject ex vivo or in vivo to perform the treatment methods and uses described herein.

[0093] Pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration; exemplary routes of administration are shown herein. Furthermore, pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds as described herein to treat the diseases, symptoms, and conditions considered in this disclosure.

[0094] Pharmaceutical compositions containing an active ingredient (e.g., compound 1 or its pharmaceutically acceptable salt) can be in forms suitable for oral administration, such as tablets, capsules, lozenges, sugar tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method of preparing pharmaceutical compositions known in the art, and these compositions can contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically aesthetically pleasing and palatable formulation. Tablets, capsules, etc., contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for preparing tablets, capsules, etc. These excipients can be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants, such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0095] Tablets, capsules, etc., suitable for oral administration can be uncoated or coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action. For example, delay-release materials such as glyceryl monostearate or glyceryl distearate can be used. Tablets can also be coated using techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particulate or polymeric substances such as polyesters, polyamines, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethyl cellulose, protamine sulfate, or copolymers of lactide and glycolide, polylactic acid and glycolide, or ethylene-vinyl acetate copolymers, to control the delivery of the administered composition. For example, oral medications can be encapsulated in microcapsules prepared by coagulation techniques or interfacial polymerization, either by using hydroxymethyl cellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, or encapsulated in colloidal drug delivery systems. Colloidal dispersion systems include macromolecular complexes, nanocapsules, microspheres, microbeads, and lipid-based systems, including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the formulations described above are known in the art.

[0096] Formulations intended for oral use may also be presented in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose), or in the form of soft gelatin capsules, wherein the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0097] Aqueous suspensions contain active materials mixed with excipients suitable for their preparation. Such excipients can be suspending agents, such as sodium carboxymethyl cellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersing or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of ethylene oxide and fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptdecaethyleneoxycetanol), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyvinyl sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0098] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oils (e.g., liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings, as described above, can be added to provide a palatable oral formulation.

[0099] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide active ingredients that can be mixed with dispersants or wetting agents, suspending agents, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are illustrated herein.

[0100] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean, lecithin, and fatty acid-derived esters or metaesters; hexitanic anhydrides, such as sorbitan monooleate; and condensation products of metaesters and ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0101] Pharmaceutical compositions typically comprise a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethylparaben, or n-propylparaben), emulsifiers, suspending agents, dispersants, solvents, fillers, building agents, detergents, buffers, mediators, diluents, and / or adjuvants. For example, a suitable mediator may be an aqueous solution of physiological saline or a citrate-buffered saline solution, possibly supplemented with other materials commonly found in pharmaceutical compositions intended for parenteral administration. Neutral buffered saline or saline mixed with serum albumin is a further exemplary mediator. Those skilled in the art will readily recognize the variety of buffers that can be used in the pharmaceutical compositions and dosage forms described herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer component can be a water-soluble substance such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), sodium 2-(N-morpholino)ethanesulfonate (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0102] After formulation, the pharmaceutical composition can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations can be stored in ready-to-use form, lyophilized form requiring reconstitution before use, liquid form requiring dilution before use, or other acceptable forms. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or auto-injector (similar to, for example, EpiPen®)), or in other embodiments in a reusable container (e.g., a reusable vial).

[0103] The pharmaceutical composition may also include a carrier to protect the composition from rapid degradation or elimination from the body, such as controlled-release formulations, including liposomes, hydrogels, prodrugs, and microencapsulation delivery systems. For example, delayed-release materials, such as glyceryl monostearate or glyceryl stearate alone, or in combination with waxes, may be used. Any drug delivery device may be used to deliver compound 1 or its pharmaceutically acceptable salts, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps, and devices, all well known to those skilled in the art.

[0104] combination therapy The present invention is intended to use compound 1 or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

[0105] As used herein, “combination” is intended to include therapies that can be administered alone, such as those formulated separately for single administration (e.g., those that may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., “co-formulation”).

[0106] In some embodiments, compound 1 or its pharmaceutically acceptable salt is administered or applied sequentially, for example, one agent is administered before one or more other agents. In other embodiments, compound 1 or its pharmaceutically acceptable salt is administered simultaneously, for example, two or more agents are administered simultaneously or approximately simultaneously; said two or more agents may be present in two or more individual formulations or combined into a single formulation (i.e., a co-formulation). Whether the two or more formulations are administered sequentially or simultaneously, for the purposes of this disclosure, they are considered to be administered in combination. In such combination therapies, the various active agents typically have different complementary mechanisms of action. Such combination therapies may be particularly advantageous by allowing for reductions in the dosage of one or more agents, thereby reducing or eliminating adverse reactions associated with one or more agents. Furthermore, such combination therapies may have synergistic therapeutic or preventative effects on underlying diseases, symptoms, or conditions.

[0107] This disclosure provides a method for treating cancer using compound 1 or a pharmaceutically acceptable salt thereof in the dosage amounts described herein, along with at least one other therapeutic or diagnostic agent. This disclosure also provides a method for treating cancer using compound 1 or a pharmaceutically acceptable salt thereof in the dosage amounts described herein, along with at least one other therapeutic agent.

[0108] In some embodiments, at least one additional therapeutic agent is temozolomide, pemetrexed, pegylated liposomal doxorubicin (Doxil), eribulin (Halaven), ixaprilone (Ixempra), protein-bound paclitaxel (Abraxane), oxaliplatin, irinotecan, veneclax (a bcl2 inhibitor), 5-azacytidine, anti-CD20 therapeutic agents such as rituximab (Rituxan) and obbinutuzumab, hormonal therapeutic agents (anastrozole, exemestane, letrozole, naledox, lupon eligard), CDK4 / 6 inhibitors, palbociclib, abemaciclib, and CPIs (avelumab, cimiplimab-rwlc, or bevacizumab).

[0109] In some embodiments, at least one additional therapeutic agent is a signal transduction inhibitor (STI). In some embodiments, STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) HER-2 / neu receptor inhibitors (e.g., HERCEPTIN); (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopiridol); and (vi) phosphatidylinositol kinase inhibitors.

[0110] In some embodiments, at least one additional therapeutic agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent includes, but is not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphamide, triethylenethiophosphamide, and trihydroxymethylmelamine; nitrogen mustards such as chiorambucil, chlornaphazine, cholophosphamide, estradiol, ifosfamide, mechlorethamine, and mechlorethamine oxide. Hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics, such as aclarubicin, actinomycin, autramycin, diazoserine, bleomycin, cactinomycin C, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, and mycophenolic acid. The following are listed as potential drug names: nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); and folic acid analogues such as demofolate, methotrexate, and pteroxate. ropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine, 5-FU; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone.Anti-adrenergic agents, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate); etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; methylbenzylhydrazine; razoxane; sizofiran; spirogermanium; tenuazonic acid acid); triaziquone; 2,2',2''-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipebroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and its coordination complexes, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C;Mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitors; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and any of the above pharmaceutically acceptable salts, acids, or derivatives. In some embodiments, at least one additional therapeutic agent is cisplatin, doxorubicin, taxol, taxotere, or mitomycin C.

[0111] Chemotherapy agents also include anti-hormonal agents used to modulate or inhibit the effects of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone, and toremifene; and anti-androgens, such as flutamide, nilutamide, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprolide, and goserelin; and any pharmaceutically acceptable salts, acids, or derivatives thereof. In some embodiments, at least one additional therapeutic agent is a hormone or a related hormonal agent.

[0112] In some embodiments, at least one additional therapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor targets CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, IDO1, TDO2, arginase, B7-H3, or B7-H4. In some embodiments, the immune checkpoint inhibitor is ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, or durvalumab.

[0113] In some embodiments, at least one additional therapeutic agent is radiotherapy, a monoclonal antibody against a tumor antigen, a complex of a monoclonal antibody and a toxin, a T-cell adjuvant, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy).

[0114] In some implementations, at least one additional therapeutic agent is radiation and / or temozolomide (TMZ), avastin, or lomustine.

[0115] In some embodiments, at least one additional therapeutic agent is a PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is an MTA-synergistic PRMT5 inhibitor. In some embodiments, the PRMT5 inhibitor is a compound having the following structure: Or its pharmaceutically acceptable salt.

[0116] In one implementation, the PRMT5 inhibitor is selected from: Or its pharmaceutically acceptable salt.

[0117] In one implementation, the PRMT5 inhibitor is: Or its pharmaceutically acceptable salt.

[0118] In one implementation, the PRMT5 inhibitor is: Or its pharmaceutically acceptable salt.

[0119] In one implementation, the PRMT5 inhibitor is: Or its pharmaceutically acceptable salt.

[0120] In one embodiment, the PRMT5 inhibitor is MRTX-1719 or a pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is TNG462 or a pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is TNG908 or a pharmaceutically acceptable salt thereof. In one embodiment, the PRMT5 inhibitor is AZD3470 or a pharmaceutically acceptable salt thereof.

[0121] Other PRMT5 inhibitors may include those described in WO2022 / 026892, WO2021 / 086879, WO2021 / 050915 and WO2023 / 036974, the entire contents of each of which are incorporated herein by reference.

[0122] Drug dosage form This disclosure includes pharmaceutical dosage forms of Compound 1 or its pharmaceutically acceptable form. The unit dosage forms described herein are suitable for oral administration to a subject. The unit dosage form can be any form suitable for oral administration, including but not limited to capsules, tablets, and powders. The phrase "unit dosage form" refers to physically discrete units, each containing a predetermined amount of Compound 1 or its pharmaceutically acceptable form, alone or in combination with one or more other pharmaceutical agents, sufficient to produce the desired effect.

[0123] In some embodiments, this disclosure provides a single-unit dose capsule or tablet form containing about 5 mg to 100 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0124] In some embodiments, the unit dosage form of compound 1 in its free base form is about 5 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 10 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 15 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 30 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 45 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 60 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 80 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in the free base form is about 100 mg, or an equivalent amount of compound 1 in the pharmaceutically acceptable salt form.

[0125] In some embodiments, the unit dosage form of compound 1 or its pharmaceutically acceptable salt is a tablet.

[0126] In some embodiments, the single-unit dosage form of compound 1 or its pharmaceutically acceptable salt is a powder.

[0127] In some embodiments, the single-unit dosage form of compound 1 or its pharmaceutically acceptable salt is a capsule.

[0128] In some embodiments, the single-unit dosage form is a capsule of strength #0, #1, #2, #3, #4, or #5. In some embodiments, the single-unit dosage form is a capsule of strength #0. In some embodiments, the single-unit dosage form is a capsule of strength #1. In some embodiments, the single-unit dosage form is a capsule of strength #2. In some embodiments, the single-unit dosage form is a capsule of strength #3. In some embodiments, the single-unit dosage form is a capsule of strength #4. In some embodiments, the single-unit dosage form is a capsule of strength #5.

[0129] Reagent test kit This disclosure also covers kits that contain pharmaceutical compositions and unit dosage forms as described herein. As described below, kits are generally in the form of a physical structure that accommodates various components and, for example, can be used to carry out the methods described herein.

[0130] The kit may contain one or more of Compound 1 or its pharmaceutically acceptable salts (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. Compound 1 or its pharmaceutically acceptable salts may be provided in a ready-to-use form (e.g., tablets or capsules) or in a form that requires reconstitution or dilution prior to administration (e.g., powder). When Compound 1 or its pharmaceutically acceptable salts are in a form that requires reconstitution or dilution by the user, the kit may also include a diluent (e.g., sterile water), a buffer, pharmaceutically acceptable excipients, etc., packaged together with or separately from Compound 1 or its pharmaceutically acceptable salts. When combination therapy is involved, the kit may contain several agents individually, or these may already be combined in the kit. Each component of the kit may be encapsulated in a single container, and all the various different containers may be in a single package. The kit of the present invention may be designed to maintain the necessary conditions (e.g., refrigeration or freezing) for the components contained therein.

[0131] The kit may include a label or packaging insert containing identification information for its components and instructions for use (e.g., dosing parameters, clinical pharmacology of the active ingredient, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse reactions, contraindications, etc.). The label or insert may include manufacturer information, such as batch number and expiration date. The label or packaging insert may be integrated into the physical structure containing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampoule, tube, or vial).

[0132] Labels or inserts may be additionally included or incorporated into computer-readable media such as disks (e.g., hard drives, cards, storage disks), optical discs such as CD-ROMs or DVD-ROMs / RAMs, DVDs, MP3s, magnetic tapes, or electrical storage media such as RAM and ROMs, or hybrid forms of these media such as magnetic / optical storage media, FLASH media, or memory cards. In some embodiments, the actual instructions for use are not present in the kit, but rather a method for obtaining the instructions from a remote source (e.g., via the Internet) is provided.

[0133] Some of the kits described herein include labels describing methods of administering compound 1 or its pharmaceutically acceptable salts. Some of the kits described herein include labels describing methods of treating cancer. In some embodiments, the cancer is characterized by reduced or absent expression of the methionine phosphorylase (MTAP) gene, MTAP gene deletion, reduced MTAP protein function, reduced or absent MTAP protein levels, MTA accumulation, or a combination thereof. In some embodiments, the cancer is MTAP-null cancer. In some embodiments, the subject with cancer has MTAP gene deletion.

[0134] The compositions of the present invention, including but not limited to, compositions comprising compound 1 or a pharmaceutically acceptable salt thereof in bottles, jars, vials, ampoules, tubes, blister packs, or other container closure systems approved by the U.S. Food and Drug Administration (FDA) or other regulatory agencies, may provide one or more unit doses comprising compound 1 or a pharmaceutically acceptable salt thereof. The packaging or dispenser may also be accompanied by notification in the form prescribed by a government agency regulating the manufacture, use, or sale of the drug in relation to the container, indicating agency approval. In some aspects, a kit may include a formulation or composition as described herein, a container closure system comprising the formulation or one or more unit dosage forms comprising the formulation, and notification or instructions describing the method of use as described herein.

[0135] Packaging systems (such as blister packs) include thermoformed rigid film or PVC suitable for pharmaceutical packaging, and a retractable cap. The cap may comprise foil made of a primer / aluminum / heat-sealable coating, or may be paper-based. Those skilled in the art will readily prepare blister packs containing Compound 1. The bottle systems described herein can be manufactured in various sizes (e.g., 75cc, 100cc, 200cc, etc.) and typically include child-protective caps made of polypropylene. In some embodiments, a pharmaceutical dosage form of Compound 1 or its pharmaceutically acceptable salt is packaged in a 75cc bottle with a child-protective cap. Those skilled in the art will readily prepare the bottle systems described herein.

[0136] In some embodiments, this disclosure provides kits for once-daily administration. These kits provide one or more unit dosage forms for each administration, said unit dosage form comprising compound 1 or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the unit dosage form of compound 1 in its free base form is about 5 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 10 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 15 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 30 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 45 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 60 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in its free base form is about 80 mg, or an equivalent amount of pharmaceutically acceptable salt form of compound 1. In some embodiments, the unit dosage form of compound 1 in the free base form is about 100 mg, or an equivalent amount of compound 1 in the pharmaceutically acceptable salt form.

[0138] Non-limiting exemplary implementation In further embodiments 1 to 92 described below, this disclosure includes: 1. Embodiment 1 is a method of treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is a free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of a pharmaceutically acceptable salt form of compound 1.

[0139] 2. Embodiment 2 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 of about 15 mg to about 85 mg of total daily dose, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0140] 3. Embodiment 3 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 50 mg to about 75 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0141] 4. Embodiment 4 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 25 mg to about 50 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0142] 5. Embodiment 5 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 at a total daily dose of about 5 mg to about 60 mg, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0143] 6. Embodiment 6 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 10 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0144] 7. Embodiment 7 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 15 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0145] 8. Embodiment 8 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 30 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0146] 9. Embodiment 9 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 at a total daily dose of about 45 mg to about 60 mg, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0147] 10. Embodiment 10 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 of about 5 mg to about 30 mg of total daily dose, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0148] 11. Embodiment 11 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 10 mg to about 30 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0149] 12. Embodiment 12 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 of about 15 mg to about 30 mg of total daily dose, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0150] 13. Embodiment 13 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 of about 5 mg to about 45 mg of total daily dose, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0151] 14. Embodiment 14 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 of about 10 mg to about 45 mg of total daily dose, or an equivalent amount of a pharmaceutically acceptable salt form of Compound 1.

[0152] 15. Embodiment 15 is the method of Embodiment 1, wherein the therapeutically effective amount is a free base form of Compound 1 in a total daily dose of about 15 mg to about 45 mg, or an equivalent amount in a pharmaceutically acceptable salt form of Compound 1.

[0153] 16. Embodiment 16 is the method of Embodiment 1, wherein the therapeutically effective amount is the free base form of Compound 1 in a total daily dose of about 30 mg to about 45 mg, or an equivalent amount in a pharmaceutically acceptable salt form.

[0154] 17. Embodiment 17 is the method of Embodiment 1, wherein the therapeutically effective amount is about 5 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0155] 18. Embodiment 18 is the method of Embodiment 1, wherein the therapeutically effective amount is about 10 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0156] 19. Embodiment 19 is the method of Embodiment 1, wherein the therapeutically effective amount is about 15 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0157] 20. Embodiment 20 is the method of Embodiment 1, wherein the therapeutically effective amount is about 30 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0158] 21. Embodiment 21 is the method of Embodiment 1, wherein the therapeutically effective amount is about 45 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0159] 22. Embodiment 22 is the method of Embodiment 1, wherein the therapeutically effective amount is about 60 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0160] 23. Embodiment 23 is the method of Embodiment 1, wherein the therapeutically effective amount is about 80 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0161] 24. Embodiment 24 is the method of Embodiment 1, wherein the therapeutically effective amount is about 100 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

[0162] 25. Embodiment 25 is the method of any one of Embodiments 1 to 24, wherein the cancer is a solid tumor.

[0163] 26. Embodiment 26 is the method of any one of Embodiments 1 to 25, wherein the cancer is a solid malignant tumor.

[0164] 27. Embodiment 27 is the method of any one of Embodiments 1 to 26, wherein the cancer is characterized by reduced or absent expression of methionine phosphorylase (MTAP) gene, absence of MTAP gene, reduced function of MTAP protein, decreased MTAP protein level, absence of MTA protein, accumulation of MTA, or a combination thereof.

[0165] 28. Embodiment 28 is the method of any one of Embodiments 1 to 27, wherein the cancer is MTAP-null cancer.

[0166] 29. Embodiment 29 is the method of any one of Embodiments 1 to 28, wherein the cancer has a deletion of the MTAP gene.

[0167] 30. Embodiment 30 is the method of any one of Embodiments 1 to 29, wherein the cancer is refractory to at least one anticancer agent.

[0168] 31. Embodiment 31 is the method of any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of: leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophageal and gastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

[0169] 32. Embodiment 32 is the method of any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of: non-small cell lung cancer (squamous and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

[0170] 33. Embodiment 33 is the method of any one of Embodiments 1 to 30, wherein the cancer is selected from the group consisting of: non-small cell lung cancer (squamous and adenocarcinoma) and urothelial carcinoma (bladder and upper urinary tract).

[0171] 34. Embodiment 34 is the method of any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (squamous and adenocarcinoma).

[0172] 35. Embodiment 35 is the method of any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (squamous).

[0173] 36. Embodiment 36 is the method of any one of Embodiments 1 to 30, wherein the cancer is non-small cell lung cancer (adenocarcinoma).

[0174] 37. Embodiment 37 is the method of any one of Embodiments 1 to 30, wherein the cancer is urothelial carcinoma (bladder and upper urinary tract).

[0175] 38. Embodiment 38 is the method of any one of Embodiments 1 to 30, wherein the cancer is urothelial carcinoma (bladder).

[0176] 39. Embodiment 39 is the method of any one of Embodiments 1 to 30, wherein the cancer is urothelial carcinoma (upper urinary tract).

[0177] 40. Embodiment 40 is the method of any one of Embodiments 1 to 30, wherein the cancer is squamous and adenocarcinoma of the esophagus, gastric adenocarcinoma, or gastroesophageal junction cancer.

[0178] 41. Embodiment 41 is the method of any one of Embodiments 1 to 40, wherein Compound 1 in the form of a free base or in the form of a pharmaceutically acceptable salt of Compound 1 is administered orally.

[0179] 42. Embodiment 42 is the method of any one of Embodiments 1 to 41, wherein Compound 1 in the form of a free base or in the form of a pharmaceutically acceptable salt of Compound 1 is administered once daily (QD).

[0180] 43. Embodiment 43 is the method of any one of Embodiments 1 to 41, wherein Compound 1 in the form of a free base or in the form of a pharmaceutically acceptable salt of Compound 1 is administered twice daily (BID).

[0181] 44. Embodiment 44 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form for at least one 7-day dosing cycle, two 7-day dosing cycles, three 7-day dosing cycles, four 7-day dosing cycles, five 7-day dosing cycles, six 7-day dosing cycles, seven 7-day dosing cycles, or eight 7-day dosing cycles.

[0182] 45. Embodiment 45 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of Compound 1 in its pharmaceutically acceptable salt form for at least three 7-day dosing cycles.

[0183] 46. ​​Embodiment 46 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of Compound 1 in its pharmaceutically acceptable salt form for at least nine 7-day dosing cycles.

[0184] 47. Embodiment 47 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of the pharmaceutically acceptable salt form of Compound 1 for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks.

[0185] 48. Embodiment 48 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of Compound 1 in its pharmaceutically acceptable salt form for at least 3 weeks.

[0186] 49. Embodiment 49 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of the pharmaceutically acceptable salt form of Compound 1 for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 16 months, 20 months, 24 months, 28 months, 32 months, 36 months, 40 months, 44 months or 48 months.

[0187] 50. Embodiment 50 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of Compound 1 in its pharmaceutically acceptable salt form for at least one month.

[0188] 51. Embodiment 51 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of Compound 1 in its pharmaceutically acceptable salt form for at least 3 months.

[0189] 52. Embodiment 52 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising administering Compound 1 in its free base form or an equivalent amount of Compound 1 in its pharmaceutically acceptable salt form for at least 6 months.

[0190] 53. Embodiment 53 is the method of any one of Embodiments 1 to 43, wherein Compound 1 or a pharmaceutically acceptable salt thereof is administered according to a dosing regimen comprising two 7-day dosing cycles of administering Compound 1 in its free base form or an equivalent amount of its pharmaceutically acceptable salt form, followed by a 7-day dosing period, and optionally the dosing regimen is subsequently repeated for at least 3, 6, 9, 12, 15, 18, 21, 24, 27, 31, 34, 37, 40, 43, 46, 49, or 52 weeks.

[0191] 54. Embodiment 54 is the method of any one of Embodiments 1 to 53, wherein after administration of Compound 1 in the form of a free base or in the form of an equivalent amount of a pharmaceutically acceptable salt of Compound 1, the subject exhibits at least stable disease (SD).

[0192] 55. Embodiment 55 is the method of any one of Embodiments 1 to 53, wherein after administration of Compound 1 in the form of a free base or in the form of an equivalent amount of a pharmaceutically acceptable salt of Compound 1, the subject exhibits at least a partial response (PR).

[0193] 56. Embodiment 56 is the method of Embodiment 55, wherein the partial response (PR) is characterized in that the total diameter of the target lesions is reduced by at least 30% compared with the total diameter of the target lesions at the baseline before treatment.

[0194] 57. Embodiment 57 is the method of any one of Embodiments 1 to 56, wherein the subject does not exhibit dose-limiting toxicity (DLT).

[0195] 58. Embodiment 58 is the method of any one of Embodiments 1 to 57, which includes the application of at least one additional therapeutic agent.

[0196] 59. Embodiment 59 is the method of any one of Embodiments 1 to 58, wherein compound 1 is in the form of a free base.

[0197] 60. Embodiment 60 is the method of any one of Embodiments 1 to 59, wherein the compound 1 is administered in tablet form.

[0198] 61. Embodiment 61 is the method of any one of Embodiments 1 to 60, wherein the subject is an adult.

[0199] 62. Embodiment 62 is the method of any one of Embodiments 1 to 61, wherein the subject is a human.

[0200] 63. Embodiment 63 is a unit dosage form containing about 5 mg to about 100 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt.

[0201] 64. Embodiment 64 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 5 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0202] 65. Embodiment 65 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 10 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0203] 66. Embodiment 66 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 15 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0204] 67. Embodiment 67 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 30 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0205] 68. Embodiment 68 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 45 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0206] 69. Embodiment 69 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 60 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0207] 70. Embodiment 70 is the unit dosage form described in Embodiment 63, wherein the unit dosage form comprises about 100 mg of Compound 1 in the form of a free base, or an equivalent amount of Compound 1 in the form of a pharmaceutically acceptable salt.

[0208] 71. Embodiment 71 is a kit comprising one or more unit dosage forms as described in any one of Embodiments 63 to 70.

[0209] 72. Embodiment 72 is the kit described in Embodiment 71, which further includes a label with instructions for administering Compound 1 in its free base form or in an equivalent amount of its pharmaceutically acceptable salt form.

[0210] 73. Embodiment 73 is the kit described in Embodiment 71 or Embodiment 72, which further includes at least one additional therapeutic agent.

[0211] 74. Embodiment 74 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 5 mg to 100 mg of compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form is administered daily.

[0212] 75. Embodiment 75 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg or 100 mg of compound 1 in the form of a free base, or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt, is administered daily.

[0213] 76. Embodiment 76 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 5 mg of compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form is administered daily.

[0214] 77. Embodiment 77 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 10 mg of compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form is administered daily.

[0215] 78. Embodiment 78 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 15 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0216] 79. Embodiment 79 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 30 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0217] 80. Embodiment 80 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 45 mg of compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form is administered daily.

[0218] 81. Embodiment 81 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 60 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0219] 82. Embodiment 82 is the use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer, wherein 100 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0220] 83. Embodiment 83 is the use of compound 1 or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein 5 mg to 100 mg of compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form is administered daily.

[0221] 84. Embodiment 84 is compound 1 for treating cancer or a pharmaceutically acceptable salt thereof, wherein 5 mg, 10 mg, 15 mg, 30 mg, 45 mg, 60 mg or 100 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0222] 85. Embodiment 85 is compound 1 or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein 5 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0223] 86. Embodiment 86 is compound 1 or a pharmaceutically acceptable salt thereof for treating cancer, wherein 10 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0224] 87. Embodiment 87 is compound 1 or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein 15 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0225] 88. Embodiment 88 is compound 1 or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein 30 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0226] 89. Embodiment 89 is compound 1 or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein 45 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0227] 90. Embodiment 90 is compound 1 or a pharmaceutically acceptable salt thereof for treating cancer, wherein 60 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

[0228] 91. Embodiment 91 is a compound 1 or a pharmaceutically acceptable salt thereof for treating cancer, wherein 100 mg of the free base form of compound 1 or an equivalent amount of the pharmaceutically acceptable salt form of compound 1 is administered daily.

[0229] 92. Embodiment 92 is any one of Embodiments 1 to 91, including the method, unit dosage form, kit, use, or compound, wherein compound 1 is in the form of a free base.

[0230] IV. Examples The following embodiments are provided to illustrate, rather than limit, the claimed invention.

[0231] Example 1: Phase I clinical trial of compound 1 (a selective MAT2A inhibitor) for the treatment of advanced solid tumors A phase 1, multicenter, open-label study of compound 1 is underway in adult patients with advanced solid tumors carrying MTAP genomic deletions or omissions (NCT04794699). A Bayesian logistic regression model was used to guide dose escalation and estimate the maximum tolerated dose (MTD) / recommended extended dose (RDE). Safety was described by the incidence of AEs based on their relevance and severity according to the Common Criteria for AEs (CTCAE, v5.0). In the evaluable patient population, the overall response rate was defined according to the Response Evaluation Criteria in Solid Tumor (RECIST, v1.1). See, Eisenhauer et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan; 45(2):228-47. Tumor size reduction in patients was defined as a reduction in tumor size as measured using RECIST 1.1 criteria.

[0232] Tumor size can be measured using methods such as radiographic scanning, MRI (magnetic resonance imaging), CT scan (also known as CAT scan or computed tomography), PET scan (positron emission tomography), X-ray, ultrasound, or a combination thereof.

[0233] Participants eligible for inclusion in this study must meet all of the following key criteria: • A confirmed advanced or metastatic solid tumor that has progressed after at least one prior line of therapy and for which additional effective standard therapy is not available or is intolerable to the participant.

[0234] • There is evidence of loss of homozygosity of MTAP or absence of MATP.

[0235] • Willing to undergo paired fresh tissue biopsies (before and after treatment) during the study period.

[0236] • Measurable disease is defined as at least, for example, a non-lymph node lesion that can be accurately measured by MRI or CT in at least one dimension (longest dimension) of ≥10 mm when the thickness of the scanned slice is no more than 5 mm; ≥10 mm by calipers / ruler measurement or medical photography during clinical examination; or ≥20 mm by chest X-ray measurement.

[0237] • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1.

[0238] • Sufficient organ function.

[0239] • Research treatments that can be swallowed and maintained during oral administration.

[0240] • Recovering from the acute effects of previous treatments.

[0241] • Able to comply with contraceptive / barrier requirements.

[0242] Participants with any of the following conditions are ineligible to participate in this study: • Symptomatic brain metastases requiring treatment with supraphysiological doses of systemic corticosteroids or anticonvulsants.

[0243] • Primary CNS malignancies.

[0244] • Current active liver or gallbladder disease.

[0245] • Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of compound 1 (e.g., any unresolved nausea, vomiting, or diarrhea graded >1 according to the National Cancer Institute (NCI) CTCAE version 5.0).

[0246] • Active, uncontrolled infection.

[0247] • Clinically significant cardiac abnormalities • Previous treatment with MAT2A inhibitors and / or PRMT inhibitors.

[0248] • Systemic anticancer therapy or major surgery within 4 weeks prior to enrollment in the study.

[0249] • Radiation therapy within 2 weeks prior to enrollment in the study.

[0250] •Previously >25% of bone marrow was irradiated.

[0251] • Foods or drugs that are currently in use or are expected to be used or are known to be strong CYP3A4 / 5 inhibitors or inducers.

[0252] • Currently undergoing treatment with another investigational drug.

[0253] • Known or suspected allergy to compound 1 / excipients or components.

[0254] Safety Summary: As of August 15, 2023, 40 patients received Compound 1 in its free base form at doses ranging from 5 mg to 100 mg once daily (QD). The most common treatment-associated adverse events (AEs, all grades, regardless of relevance, and reported in ≥20% of subjects) were nausea (47%), decreased appetite (37%), constipation (32%), hypoglycemia (22%), vomiting (30%), diarrhea (22%), dehydration (20%), and hearing loss (37%). Most AEs were Grade 1 and 2. Three subjects experienced dose-limiting toxicities (DLTs) at the 100 mg QT level, namely myalgia, hypocalcemia, and maculopapular rash in one subject each. DLTs were managed by interrupting Compound 1 administration, which improved the DLT event grades in subjects with hypocalcemia and rash. Based on overall tolerability, 60 mg daily was considered the maximum tolerated dose (MTD) and recommended dose extension (RDE).

[0255] Pharmacokinetic data showed that exposure increased dose-proportionately with increasing dose from 5 mg to 100 mg QD. The median Tmax for compound 1 at each dose ranged from 2 to 5 hours post-dose. The estimated half-life was approximately 4 days.

[0256] Exposure at doses equal to or greater than 15 mg QD was within the preclinically predicted effective range. Plasma SAM levels were assessed across the tested dose range (5 mg to 100 mg QD). All cohorts showed target engagement, with compound 1 showing a significant reduction in plasma SAM levels after treatment compared to pre-treatment levels.

[0257] Of the 32 evaluable subjects who had measurable disease at baseline and had tumor evaluation in at least one study, 15 patients had stable disease (SD) within the tested dose range (5 mg to 100 mg QD) as the best overall response. Of these 15 subjects with SD, 3 were treated with a 10 mg QD, 1 with a 15 mg QD, 2 with a 30 mg QD, 5 with a 60 mg QD, and 4 with a 100 mg QD.

[0258] Furthermore, a 50% or greater reduction in cfDNA (molecular response) was observed in nine subjects, including four NSCLC subjects (three with a 60 mg QD dose and one with a 10 mg QD dose) and one bladder cancer subject with a 100 mg QD dose. Additional tumor types showing molecular response included two pancreatic cancer subjects and one esophageal cancer subject with a 60 mg QD dose, and one phyllodes tumor subject with a 100 mg QD dose.

[0259] In addition, measured according to RECIST v1.1 criteria, one subject showed a partial response (PR) with a tumor shrinkage of -47% after the initial dose was reduced from 100 mg QD to 60 mg QD.

[0260] Compound 1 was well tolerated as a monotherapy with manageable toxicity and showed pharmacodynamic activity at an extended dose of 60 mg daily, and early signs of clinical efficacy in patients with advanced solid tumors.

[0261] Example 1A: An Update to Example 1 Safety Summary: As of November 21, 2023, 47 patients received compound 1 in its free base form at doses ranging from 5 mg to 100 mg once daily (QD). The most common treatment-associated adverse events (AEs, all grades, regardless of relevance, and reported in ≥20% of subjects) were decreased appetite (40%), nausea (40%), constipation (38%), hearing loss (36%), peripheral neuropathy (30%), elevated serum creatinine (23%), hypocalcemia (23%), diarrhea (21%), and vomiting (21%). Most AEs were Grade 1 and 2. Three subjects experienced dose-limiting toxicities (DLTs) at the 100 mg QD level, namely myalgia, hypocalcemia, and maculopapular rash in one subject each. Managing DLTs by discontinuing compound 1 administration improved the DLT event grades in subjects with hypocalcemia and rash. Based on overall tolerability, 60 mg daily is considered the maximum tolerated dose (MTD) and recommended extension dose (RDE).

[0262] Pharmacokinetic data showed that exposure increased dose-proportionately with increasing dose from 5 mg to 100 mg QD. The median Tmax for compound 1 at each dose ranged from 2 to 5 hours after administration. The estimated half-life was approximately 4 days.

[0263] Of the 31 evaluable subjects who had measurable disease at baseline and tumor evaluation in at least one study, 17 patients had stable disease (SD) within the tested dose range (5 mg to 100 mg QD) as the best overall response. Of these 17 SD subjects, 3 were treated with a 10 mg QD, 1 with a 15 mg QD, 1 with a 30 mg QD, 8 with a 60 mg QD, and 4 with a 100 mg QD.

[0264] In addition, a 50% or greater reduction in cfDNA (molecular remission) was observed in 13 subjects (out of 26 subjects with evaluable samples), including 6 subjects with NSCLC (4 subjects with a 60 mg QD dose and 2 subjects with a 100 mg QD dose), and 3 subjects with bladder cancer with 60 and 100 mg QD doses. Additional tumor types showing molecular remission included 1 subject with pancreatic cancer with a 60 mg QD dose, 1 subject with esophageal cancer, and 1 subject with melanoma, and 1 subject with phyllodes tumor with a 100 mg QD dose. Five other subjects showed a measurable reduction in ctDNA from baseline, but did not meet the criteria for molecular remission (3 subjects with pancreatic cancer with 5 to 60 mg QD doses and 2 subjects with cholangiocarcinoma with a 60 mg QD dose).

[0265] In addition, according to RECIST v1.1 criteria, one subject showed confirmed CR (target lymph node mass reduced to short axis <10 mm), despite being reduced from an initial dose of 100 mg QD to 30 mg QD after two dose reductions.

[0266] Compound 1 was well tolerated as a monotherapy with manageable toxicity and showed pharmacodynamic activity at an extended daily dose of 60 mg, and early signs of clinical efficacy in patients with advanced solid tumors.

[0267] Example 1B: An update to Example 1 and Example 1A Safety Summary: As of February 2, 2024, 56 patients received compound 1 in its free base form at doses ranging from 5 mg to 100 mg once daily (QD). The most common treatment-associated adverse events (TEAEs, all grades, regardless of relevance, and reported in ≥20% of subjects) were nausea (42.9%), decreased appetite (41.1%), constipation (39.3%), hearing loss (35.7%), peripheral neuropathy (28.6%), diarrhea (23.2%), hypocalcemia (23.2%), vomiting (21.4%), elevated serum creatinine (21.4%), and weight loss (21.4%). Regardless of relevance to the study drug / intervention, the most frequently reported ≥3 grade TEAEs (reported in ≥5% of subjects) were peripheral neuropathy (7.1%), followed by anemia, anemia of malignant disease, hypokalemia, and myasthenia (5.4% each). Three subjects experienced dose-limiting toxicities (DLTs) at the 100 mg QD level, namely myalgia, hypocalcemia, and maculopapular rash in one subject each. DLTs were managed by interrupting compound 1 administration, which improved the DLT event grade in the subjects with hypocalcemia and rash. Based on overall tolerability, 60 mg daily (QD) was considered the maximum tolerated dose (MTD).

[0268] As of June 12, 2024, 18 patients received an initial dose of 30 mg QD. The most common TEAEs (all grades, regardless of relevance, and reported in ≥15% of subjects) were nausea (27.8%), decreased appetite (22.2%), asthenia, elevated serum creatinine, constipation, and peripheral neuropathy (each 16.7%). Most of these adverse events were grade 1 and 2. The most common ≥ grade 3 TEAEs (regardless of relevance to the study drug / intervention, and reported in ≥5% of subjects) were asthenia, anemia, and hypokalemia (each 5.6%). Two patients (11.1%) each experienced one serious adverse event, neither of which was related to compound 1. Based on the overall safety profile of the 30 mg QD, this dose is the recommended extended dose (RDE).

[0269] Of the 18 subjects who received at least one cycle (21 days) of treatment with compound 1 at a time and underwent a post-baseline scan for tumor evaluation, 6 subjects experienced a partial response (PR) as the best overall response, and 1 subject experienced a complete response (CR). Two partial responses and 1 complete response were observed in subjects with urothelial carcinoma, while 4 subjects with NSCLC had partial responses. Furthermore, 10 patients with NSCLC or urothelial carcinoma experienced stable disease (SD) as the best overall response to treatment with compound 1.

[0270] Furthermore, among subjects treated with 30 mg QD compound 1, a reduction of ctDNA of 50% or more (molecular remission) was observed in 9 out of 12 evaluable subjects with NSCLC (N=5) or urothelial carcinoma (N=4).

[0271] Example 1C: An update to Examples 1, 1A, and 1B Additional inclusion criteria for the studies described in this embodiment and in embodiments 1, 1A, and 1B above include: • At enrollment, any acute effects of prior treatment (including surgery, chemotherapy, and radiotherapy) had regressed to baseline severity or (CTCAE version 5.0) ≤ grade 1, except for adverse events (AEs) that did not pose a safety risk.

[0272] Additional exclusion criteria for the studies described in this embodiment and in embodiments 1, 1A, and 1B above include: • A history of an active second malignancy or another malignancy within the past 2 years, except for well-treated non-melanoma skin cancer, cervical cancer in situ, or breast cancer in situ.

[0273] • Other acute or chronic medical or psychiatric conditions.

[0274] • Major surgery performed within 4 weeks prior to enrollment in the study.

[0275] • Current radiation-related toxicity or radiotherapy within 2 weeks prior to enrollment in the study.

[0276] • Systemic cytotoxic chemotherapy within 4 weeks prior to enrollment in the study.

[0277] • Received radioimmunotherapy within 6 weeks prior to administration of compound 1.

[0278] • Received therapeutic antibody therapy less than 4 weeks prior to the first dose of compound 1, or small molecule therapy less than 2 weeks prior.

[0279] As of August 8, 2024, 24 subjects received an initial dose of 30 mg QD. The most common TEAEs (all grades, regardless of relevance, and reported in ≥15% of subjects) were constipation (25%), decreased appetite (25%), asthenia, elevated serum creatinine, fatigue, insomnia, and nausea (20.8% each). Most of these adverse events were Grade 1 and 2. ≥Grade 3 TEAEs (regardless of relevance to the study drug / intervention) were uncommon. Asthenia, hyponatremia, chronic obstructive pulmonary disease, hypokalemia, positive human rhinovirus test, iron deficiency anemia, pernicious anemia, and muscle fatigue were reported in one subject each. Six patients (25%) each experienced one serious adverse event, none of which were related to compound 1. Based on the overall safety profile of the 30 mg QD, this dose is the recommended extended dose (RDE).

[0280] Pharmacokinetic data showed that exposure increased dose-proportionately from 5 mg to 100 mg. The median Tmax for compound 1 at all doses ranged from 2 to 8 hours after administration. The estimated half-life was approximately 4 days.

[0281] Single-therapy exposure at doses above 15 mg QD was considered a non-clinically predicted effective range. Plasma SAM levels were assessed within the tested dose range (5 mg to 100 mg QD).

[0282] Twenty-seven subjects were treated with compound 1 at a dose of 30 mg QD for at least 21 days and underwent a post-baseline scan for tumor evaluation (subjects with a higher initial dose of compound 1 and subsequently reduced to a dose of 30 mg QC were included in this analysis if they were treated with compound 1 at a dose of 30 mg QD for at least 21 days prior to the subsequent tumor evaluation scan). Of these 27 subjects, eight experienced a partial response (PR) as the best overall response, and one experienced a complete response (CR), resulting in an overall response rate (ORR) of approximately 33%. Three partial responses and one complete response were observed in the urothelial carcinoma subjects, while five subjects in NSCLC had partial responses. In addition, 16 patients with NSCLC or urothelial carcinoma (59%) experienced stable disease (SD) as the best overall response to treatment with compound 1.

[0283] Furthermore, among subjects treated with 30 mg QD compound 1, a reduction of ctDNA of 50% or more (molecular remission) was observed in 13 out of 16 evaluable subjects (those with NSCLC (N=8) or urothelial carcinoma (N=5)).

[0284] Although the invention has been described in considerable detail through illustration and examples for clarity, those skilled in the art will recognize that certain changes and modifications can be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated herein by reference in its entirety, and its effect is equivalent to that of each reference individually incorporated herein by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A method of treating cancer in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2(1H)-one (compound 1): (Compound 1), Or its pharmaceutically acceptable salt, wherein the therapeutically effective amount is the free base form of compound 1 at a total daily dose of about 5 mg to about 100 mg, or an equivalent amount of the pharmaceutically acceptable salt form of compound 1.

2. The method according to claim 1, wherein the therapeutically effective amount is a free base form of compound 1 in a total daily dose of about 5 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of compound 1.

3. The method of claim 1, wherein the therapeutically effective amount is a free base form of compound 1 in a total daily dose of about 10 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of compound 1.

4. The method of claim 1, wherein the therapeutically effective amount is a free base form of compound 1 in a total daily dose of about 15 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of compound 1.

5. The method of claim 1, wherein the therapeutically effective amount is a free base form of compound 1 in a total daily dose of about 30 mg to about 60 mg, or an equivalent amount in a pharmaceutically acceptable salt form of compound 1.

6. The method of claim 1, wherein the therapeutically effective amount is about 15 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

7. The method of claim 1, wherein the therapeutically effective amount is about 30 mg of the total dose of the compound 1 in the form of a free base, or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

8. The method of claim 1, wherein the therapeutically effective amount is about 45 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

9. The method of claim 1, wherein the therapeutically effective amount is about 60 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

10. The method of claim 1, wherein the therapeutically effective amount is about 100 mg of the compound 1 in the form of a free base or an equivalent amount of the compound 1 in the form of a pharmaceutically acceptable salt.

11. The method according to any one of claims 1 to 10, wherein the cancer is a solid tumor.

12. The method according to any one of claims 1 to 11, wherein the cancer is a solid malignant tumor.

13. The method according to any one of claims 1 to 12, wherein the cancer is characterized by reduced or absent expression of methionine phosphorylase (MTAP) gene, absence of MTAP gene, reduced function of MTAP protein, decreased MTAP protein level, absence of MTA protein, accumulation of MTA, or a combination thereof.

14. The method according to any one of claims 1 to 12, wherein the cancer is MTAP-null cancer.

15. The method according to any one of claims 1 to 12, wherein the cancer has a deletion of the MTAP gene.

16. The method according to any one of claims 1 to 15, wherein the cancer is refractory to at least one anticancer agent.

17. The method according to any one of claims 1 to 16, wherein the cancer is selected from the group consisting of: leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophageal and gastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

18. The method according to any one of claims 1 to 17, wherein the cancer is selected from the group consisting of: non-small cell lung cancer (squamous and adenocarcinoma), urothelial carcinoma (bladder and upper urinary tract), esophageal cancer, and gastric cancer.

19. The method according to any one of claims 1 to 18, wherein compound 1 is administered orally.

20. The method according to any one of claims 1 to 19, wherein compound 1 is administered once daily (QD).

21. The method according to any one of claims 1 to 20, further comprising administering at least one additional therapeutic agent.

22. The method according to any one of claims 1 to 21, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof is according to a dosing regimen comprising administering compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 24 weeks, 48 ​​weeks or 52 weeks.

23. The method according to any one of claims 1 to 21, wherein the administration of compound 1 or a pharmaceutically acceptable salt thereof is based on a dosing regimen comprising administering compound 1 in its free base form or an equivalent amount of compound 1 in its pharmaceutically acceptable salt form for at least 3 weeks.

24. The method according to any one of claims 1 to 23, wherein compound 1 is in the form of a free base represented by the following formula: 。 25. Use of compound 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of cancer, wherein 5 mg to 100 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

26. Compound 1 or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein 5 mg to 100 mg of compound 1 in the form of a free base or an equivalent amount of compound 1 in the form of a pharmaceutically acceptable salt is administered daily.

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