WO2022036067A1

WO2022036067A1 - Combination therapies for use in treating cancer

Info

Publication number: WO2022036067A1
Application number: PCT/US2021/045702
Authority: WO
Inventors: Fu LI; Kevin Marks; Katya MARJON; Petar KALEV; Marc Lee HYER
Original assignee: Servier Pharmaceuticals LLC
Current assignee: Servier Pharmaceuticals LLC
Priority date: 2020-08-12
Filing date: 2021-08-12
Publication date: 2022-02-17
Anticipated expiration: 2023-02-12
Also published as: TW202227082A; WO2022036067A4; AR123227A1

Abstract

The compound of Formula (I), or pharmaceutically acceptable salts thereof, is useful in, among other things, the treatment of cancer and provides a therapeutic advantage when used in combination with other agents as herein described compared to treatment with each agent when administered alone.

Description

COMBINATION THERAPIES FOR USE IN TREATING CANCER

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of United States Provisional Patent Application No. 63/064,786, filed August 12, 2020, the entirety of which is incorporated by reference herein.

FIELD

[0002] The compound of Formula (I) and pharmaceutically acceptable salts thereof are useful in, among other things, the treatment of cancers and provide a therapeutic advantage when used in combination with one or more other agents, as herein described, compared to treatment with each agent when administered alone.

BACKGROUND

[0003] Methionine adenosyltransferase (MAT), which is also known as S- adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S- adenosyl methionine (SAM or AdoMet) from methionine and ATP; the catalysis is considered to be rate-limiting step of the methionine cycle. SAM is the propylamino donor in polyamine biosynthesis, the principal methyl donor for DNA methylation, and is involved in gene transcription and cellular proliferation as well as the production of secondary metabolites.

[0004] Two genes designated as MAT1A and MAT2A encode two distinct catalytic MAT isoforms, respectively. A third gene, MAT2B, encodes a MAT2A regulatory subunit. MAT1 A is specifically expressed in the adult liver, whereas MAT2A is widely distributed. Because MAT isoforms differ in catalytic kinetics and regulatory properties, MAT1A- expressing cells have considerably higher SAM levels than do MAT2A-expressing cells. It has been found that hypomethylation of the MAT2A promoter and histone acetylation causes upregulation of MAT2A expression.

[0005] In hepatocellular carcinoma (HCC), the downregulation of MAT1A and the up-regulation of MAT2A occur, which is known as the MAT1A:MAT2A switch. The switch, accompanied with up-regulation of MAT2B, results in lower SAM contents, which provide a growth advantage to hepatoma cells. Because MAT2A plays a crucial role in facilitating the growth of hepatoma cells, it is a target for antineoplastic therapy. Recent studies have shown that silencing by using small interfering RNA substantially suppresses growth and induces apoptosis in hepatoma cells. See, e.g., T. Li et al., J. Cancer 7(10) (2016) 1317-1327. [0006] Some cancer cell lines that are MTAP-deficient are particularly sensitive to inhibition of MAT2A. Maqon et al. (Cell Reports 15(3) (2016) 574-587). MTAP (methylthioadenosine phosphorylase) is an enzyme widely expressed in normal tissues that catalyzes the conversion of methylthioadenosine (MTA) into adenine and 5- methylthioribose-1 -phosphate. The adenine is salvaged to generate adenosine monophosphate, and the 5-methylthioribose-l -phosphate is converted to methionine and formate. Because of this salvage pathway, MTA can serve as an alternative purine source when de novo purine synthesis is blocked, e.g., with antimetabolites, such as L-alanosine.

[0007] MAT2A is dysregulated in additional cancers that lack MTAP-deletion, including hepatocellular carcinoma and leukemia. J. Cai et al., Cancer Res. 58 (1998) 1444- 1450; T. S. Jani et al., Cell. Res. 19 (2009) 358-369. Silencing of MAT2A expression via RNA-interference results in anti-proliferative effects in several cancer models. H. Chen et al., Gastroenterology 133 (2007) 207-218; Q. Liu et al. Hepatol. Res. 37 (2007) 376-388.

[0008] Many human and murine malignant cells lack MTAP activity. MTAP deficiency is found not only in tissue culture cells but the deficiency is also present in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSCLC), bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endometrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin lymphoma, and mesotheliomas. The gene encoding for human MTAP maps to region 9p21 on human chromosome 9p. This region also contains the tumor suppressor genes pl6INK4A (also known as CDKN2A) and pl5INK4B. These genes code for pl 6 and pl 5, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.

[0009] The pl6INK4A transcript can alternatively be alternative reading frame (ARF) spliced into a transcript encoding pl4ARF. pl4ARF binds to MDM2 and prevents degradation of p53 (Pomerantz et al. (1998) Cell 92:713-723). The 9p21 chromosomal region is of interest because it is frequently homozygously deleted in a variety of cancers, including leukemias, NSLC, pancreatic cancers, gliomas, melanomas, and mesothelioma. The deletions often inactivate more than one gene. For example, Cairns et al. ((1995) Nat. Gen. 11 :210-212) reported that after studying more than 500 primary tumors, almost all the deletions identified in such tumors involved a 170 kb region containing MTAP, pl4ARF and P16INK4A. Carson et al. (WO 99/67634) reported that a correlation exists between the stage of tumor development and loss of homozygosity of the gene encoding MTAP and the gene encoding pl6. For example, deletion of the MTAP gene, but not pl6INK4A was reported to be indicative of a cancer at an early stage of development, whereas deletion of the genes encoding for p!6 and MTAP was reported to be indicative of a cancer at a more advanced stage of tumor development. In some osteosarcoma patients, the MTAP gene was present at diagnosis but was deleted at a later time point (Garcia-Castellano et al., Clin. Cancer Res. 8(3) 2002 782-787).

[0010] International Application No. PCT/US2017/049439, which published as WO 2018/045071, describes novel MAT2A inhibitors, including 3 -(cyclohex- l-en-l-yl)-6-(4- methoxyphenyl)-2-phenyl-5-(pyridine-3-ylamino)pyrzolo[l,5-a]pyrimidin-7(4H)-one, as demonstrated by biochemical and cellular assays.

SUMMARY

[0011] In some aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a PARP inhibitor, a Chkl inhibitor, a MDM2 inhibitor, a hypomethylating agent, a mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL-2 inhibitor, a PRMT5 inhibitor, or a PRMT1 inhibitor. In some aspects the cancer is MTAP deficient. In other aspects the cancer is MTAP wild type. In yet other embodiments the cancer is a cancer that responds to a reduction in S-adenosylmethionine (SAM) as a result of the administration of a MAT2A inhibitor such as Compound I.

[0012] In other aspects, the disclosure is directed to methods for the treatment of a cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is an antimetabolite, an Aurora inhibitor, a DNA cross-linker, or a microtubule stabilizer;wherein the cancer is MTAP-wild type.

[0013] In yet other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein the cancer is AML.

[0014] In yet other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of a BCL-2 inhibitor, wherein the cancer is AML. [0015] In yet other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient (1) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; (2) a therapeutically effective amount of a BCL-2 inhibitor; and (3) therapeutically effective amount of a hypomethylating agent; wherein the cancer is AML.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figures 1A and IB show the chemical structures of exemplary PARP inhibitors that may be used in the methods described herein.

[0017] Figure 2 shows the chemical structures of exemplary Chkl inhibitors that may be used in the methods described herein.

[0018] Figure 3 shows the chemical structures of exemplary MDM2 inhibitors that may be used in the methods described herein.

[0019] Figures 4A and 4B show the chemical structures of exemplary hypomethylating agents that may be used in the methods described herein.

[0020] Figures 5A-5E show the chemical structures of exemplary mTOR inhibitors that may be used in the methods described herein.

[0021] Figure 6 shows the chemical structures of exemplary ATM inhibitors that may be used in the methods described herein.

[0022] Figures 7A and 7B show the chemical structures of exemplary CDK 4/6 inhibitors that may be used in the methods described herein.

[0023] Figure 8 shows the chemical structures of exemplary PRMT5 inhibitors that may be used in the methods described herein.

[0024] Figure 9 shows the chemical structures of exemplary PRMT1 inhibitors that may be used in the methods described herein.

[0025] Figures 10A and 10B show the chemical structures of exemplary BCL-2 inhibitors that may be used in the methods described herein.

[0026] Figure 11 shows the chemical structures of exemplary antimetabolites that may be used in the methods described herein.

[0027] Figures 12A-12C show the chemical structures of exemplary Aurora inhibitors that may be used in the methods described herein.

[0028] Figure 13 shows the chemical structures of exemplary a microtubule stabilizer that may be used in the methods described herein.

[0029] Figure 14 shows the chemical structures of exemplary DNA cross-linker that may be used in the methods described herein. [0030] Figure 15 shows synergy scores associated with combining Compound of Formula (I) with multiple cancer therapeutic agents in various cancer cell lines.

[0031] Figure 16 shows the synergy of the combination of Compound of Formula (I) and Pemetrexed in KP-4 cells.

[0032] Figure 17 shows whole genome bisulfite sequencing (WGBS) analysis in TF1 cells treated with Compound of Formula (I).

[0033] Figure 18 shows in-cell Western analysis demonstrating that the Compound of Formula (I) inhibits the expression of PRMT1 -dependent ADMA marks in TF1 cells.

[0034] Figure 19 shows cell growth inhibition analysis to assess the impact of Compound of Formula (I) in combination with a PRMT1 inhibitor on the growth of TF1 and MV4-11 cell lines.

[0035] Figure 20 shows tumor volume as a function of time for the Compound of Formula (I); ventoclax with Formula (I); and ventoclax/azacytidine/Formula (I).

DETAILED DESCRIPTION

[0036] The compound, 3-(cy clohex- 1 -en- 1 -y l)-6-(4-methoxy pheny l)-2-pheny 1-5 - (pyridine-3-ylamino)pyrzolo[l,5-a]pyrimidin-7(4H)-one may be referred to herein as a compound of Formula

Formula (I).

For ease of reference, the compound may also be referred to as Compound I. The present disclosure also includes pharmaceutically acceptable salts of the compound of Formula (I).

[0037] As used herein, the term ‘MTAP-deficient cancer’ refers to a cancer which lacks activity of the metabolic enzyme Methylthioadenosine Phosphorylase (MTAP). Thus, an MTAP-deficient cancer is a cancer that is associated with a failure to express the MTAP gene, which failure may be attributable to the absence of MTAP gene, the lack of MTAP protein expression, or accumulation of MTAP substrate MTA. In some embodiments the term ‘MTAP-deficient’ is referred to as ‘MTAP-deleted’ and/or ‘MTAP -null’ and thus the three terms may be used interchangeably. For example in some embodiments, ‘MTAP- deleted’ or ‘MT AP -null’ cancer refers to chromosomal loss of the MTAP gene, resulting in full or partial loss of MTAP DNA which prevents expression of functional, full length MTAP protein. In some embodiments a MTAP-deficient cancer is a cancer where the locus of the CDKN2A gene is absent or deleted. In some embodiments, an MTAP-deficient cancer is one in which the MTAP gene has been deleted, lost, or otherwise deactivated. In some embodiments, an MTAP-deficient cancer is a cancer in which the MTAP protein has a reduced function or is functionally impaired as compared to a wild type MTAP gene. Accordingly, in an embodiment of the present disclosure, there is provided a method for treating a MTAP-deficient cancer in a subject, wherein the cancer is characterized by at least one of (i) a reduction or absence of MTAP expression; (ii) absence of the MTAP gene; and (iii) reduced function of MTAP protein, as compared to the corresponding cancers where the MTAP gene and/or protein is present and fully functioning, or as compared to the corresponding cancers with the wild type MTAP gene.

[0038] As used herein, the term “wild type MTAP cancer” or “MTAP wild type cancer” refers to a cancer in which the activity of the metabolic enzyme Methylthioadenosine Phosphorylase (MTAP) is intact. Thus, a wild type MTAP cancer is a cancer that expresses the MTAP gene and the MTAP protein.

[0039] As used herein, the term “cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor” refers to a cancer in which growth is inhibited when S-adenosylmethionine (SAM) level is reduced upon administering a MAT2A inhibitor.

[0040] As used herein, a “pharmaceutically acceptable salt” is a pharmaceutically acceptable, organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, e.g., alkali metal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3- naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, poly galacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt can have more than one charged atom in its structure. In such instance, the pharmaceutically acceptable salt can have multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counterions.

[0041] The terms “treat,” “treating,” and “treatment” refer to the amelioration or eradication of a disease or symptoms associated with a disease. In certain embodiments, such terms refer to minimizing the spread (e.g., metastasis) or minimizing the worsening of the disease resulting from the administration of one or more prophylactic or therapeutic agents to a patient with such a disease.

[0042] The terms “prevent,” “preventing,” and “prevention” refer to the prevention of or the delay in the onset, recurrence, or spread of the disease in a patient resulting from the administration of a prophylactic or therapeutic agent.

[0043] The terms “effective amount” refer to an amount of a compound of Formula (I) or other active ingredient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease or to delay or minimize symptoms associated with a disease. Further, a therapeutically effective amount with respect to a compound of Formula (I) means that amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. The terms may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of or synergies with another therapeutic agent.

[0044] A “patient” or “subject” includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea pig. In accordance with some embodiments, the animal is a mammal such as a non-primate and a primate (e.g., monkey and human). In one embodiment, a patient is a human, such as a human neonate, infant, child, adolescent, or adult. In one embodiment, the patient is a pediatric patient, including a patient from birth to eighteen years of age. In one embodiment, the patient is an adolescent patient, where an adolescent is a patient between the ages of 12 to 17 years of age. In one embodiment, the patient is an adult patient. In yet another embodiment, the terms indicating patient age are used in accordance with applicable regulatory guidance, such as, for example, the guidance set forth by the US FDA, where neonates are birth to one month of age, infants are one month up to two years of age; children are two years up to twelve years of age; and adolescents are twelve years up to sixteen years of age. [0045] “Inhibitor” means a compound that prevents or reduces the activity of a given protein.

[0046] The “therapeutically effective amount” of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is administered may be governed by considerations such as the minimum amount necessary to exert a cytotoxic effect, or to inhibit MAT2A activity, or both. Such amount may be below the amount that is toxic to normal cells, or the patient as a whole. Generally, the initial therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to be administered is in the range of about 0.01 to about 200 mg/kg or about 0.1 to about 20 mg/kg of patient body weight per day, with the typical initial range being about 0.3 to about 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, may contain from about 1 mg to about 1000 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In another embodiment, such dosage forms may contain from about 20 mg to about 800 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In yet another embodiment, such dosage forms may contain about 20 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, or 800 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In still other embodiments such dosage forms may contain between about 100 mg to about 300 mg of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In yet further embodiments, such dosage forms may contain about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg. In further embodiments, such dosage forms may contain 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, or 300 mg. In another aspect, the dosage is measured as an amount corresponding to an amount of free form equivalent of the Compound of Formula (I). “Free-form equivalent,” as used herein, refers to that quantity of the Compound of Formula (I), whether present in free form (or free base form), or as a salt, that corresponds to a given quantity of free form compound of Formula (I). In a further aspect, administering a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt thereof includes circumstances wherein the combination, i.e. the compound of Formula (I) or a pharmaceutical salt thereof and one or more additional therapeutic agents, is administered within a specific period and for a duration of time. In some embodiments, the dosage form comprising the compound of Formula (I) or a pharmaceutical salt thereof is given once per day. In other embodiments, the dosage form is given twice a day. As used herein the term “daily dosing” means a particular dosing schedule for the compound of Formula (I) or a pharmaceutically acceptable salt thereof that takes place within a twenty -four period.

[0047] In some aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein the therapeutic agent is a PARP inhibitor, a Chkl inhibitor, a MDM2 inhibitor, a hypomethylating agent, a mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL-2 inhibitor, a PRMT5 inhibitor, or a PRMT1 inhibitor. It will be understood that the therapeutically effective amount of a therapeutic agent can be provided by one or more active pharmaceutical ingredients, for example, one or more PARP inhibitors or a PARP inhibitor and a Chkl inhibitor.

[0048] In some aspects, the disclosure is directed to methods for the treatment of cancer. In some embodiments, the cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, nonsmall cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0049] In some embodiments, the cancer is a MTAP-deficient cancer. In some embodiments, the MTAP-deficient cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, nonsmall cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0050] In other embodiments, the MTAP-deficient cancer is MTAP-deficient lung cancer, MTAP-deficient pancreatic cancer, MTAP-deficient esophageal cancer, MTAP- deficient colorectal cancer, MTAP-deficient kidney cancer, or MTAP-deficient leukemia, such as acute myeloid leukemia (AML).

[0051] In some embodiments, the MTAP-deficient cancer is MTAP-deficient lung cancer, such as NSCLC.

[0052] In other embodiments, the MTAP-deficient cancer is MTAP-deficient pancreatic cancer, such as PDAC. [0053] In other embodiments, the MTAP-deficient cancer is MTAP-deficient esophageal cancer.

[0054] In other embodiments, the MTAP-deficient cancer is MTAP-deficient colorectal cancer.

[0055] In other embodiments, the MTAP-deficient cancer is MTAP-deficient kidney cancer.

[0056] In some embodiments, the MTAP-deficient cancer is MTAP-deficient leukemia, such as acute myeloid leukemia (AML).

[0057] In other embodiments, the cancer is a MTAP wild type cancer. In some embodiments, the MTAP wild type cancer is a primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0058] In other embodiments, the MTAP wild type cancer is MTAP wild type lung cancer, MTAP wild type pancreatic cancer, MTAP wild type esophageal cancer, MTAP wild type colorectal cancer, MTAP wild type kidney cancer, or MTAP wild type leukemia, such as acute myeloid leukemia (AML).

[0059] In some embodiments, the MTAP wild type cancer is MTAP wild type lung cancer, such as NSCLC.

[0060] In other embodiments, the MTAP wild type cancer is MTAP wild type pancreatic cancer, such as PDAC.

[0061] In other embodiments, the MTAP wild type cancer is MTAP wild type esophageal cancer.

[0062] In other embodiments, the MTAP wild type cancer is MTAP wild type colorectal cancer.

[0063] In other embodiments, the MTAP wild type cancer is MTAP wild type kidney cancer.

[0064] In some embodiments, the MTAP wild type cancer is MTAP wild type leukemia, such as acute myeloid leukemia (AML).

[0065] In other embodiments, the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. In some embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is a primary leukemia, hematological malignancy, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[0066] In other embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is lung cancer, pancreatic cancer, esophageal cancer, colorectal cancer, kidney cancer, or leukemia, such as acute myeloid leukemia (AML).

[0067] In some embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is lung cancer, such as NSCLC.

[0068] In other embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is pancreatic cancer, such as PDAC.

[0069] In other embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is esophageal cancer.

[0070] In other embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is colorectal cancer.

[0071] In other embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is kidney cancer.

[0072] In some embodiments, the cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor is leukemia, such as acute myeloid leukemia (AML).

[0073] In some aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a PARP inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “PARP inhibitor” refers to a compound that inhibits the activity of the enzyme poly ADP ribose polymerase (PARP).

[0074] In some methods of the disclosure, the PARP inhibitor is Olaparib (AZD2281; available as LYNPARZA®), Veliparib (ABT-888), Rucaparib (AG-014699) phosphate, Rucaparib camsylate (available as RUBRACA®), Talazoparib (BMN 673), Talazoparib tosylate (available as TALZENNA®), AG-14361, INO-1001 (3 -Aminobenzamide), A- 966492, PJ34 HC1, Niraparib (MK-4827), UPF 1069, ME0328, RK-287107, Pamiparib (BGB-290), NMS-P118, E7449, Picolinamide, Benzamide, Niraparib (MK-4827) tosylate (available as available as ZEJULA®), NU1025, Iniparib (BSI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-Hydroxyquinazoline, NVP-TNKS656, MN 64, G007-LK, E7106, or CEP 9722; or a pharmaceutically acceptable salt of a listed compound.

[0075] In some embodiments, the PARP inhibitor is Olaparib, or a pharmaceutically acceptable salt thereof.

[0076] In other embodiments, the PARP inhibitor is Veliparib, or a pharmaceutically acceptable salt thereof.

[0077] In other embodiments, the PARP inhibitor is Rucaparib, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the phosphate salt. In other embodiments, the salt is the camsylate salt.

[0078] In other embodiments, the PARP inhibitor is Talazoparib (BMN 673), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the tosylate salt.

[0079] In other embodiments, the PARP inhibitor is AG-14361, or a pharmaceutically acceptable salt thereof.

[0080] In other embodiments, the PARP inhibitor is INO-1001 (3 -Aminobenzamide), or a pharmaceutically acceptable salt thereof.

[0081] In other embodiments, the PARP inhibitor is A-966492, or a pharmaceutically acceptable salt thereof.

[0082] In other embodiments, the PARP inhibitor is PJ34, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceuticaly acceptable salt is the HC1 salt, i.e., PJ34 HC1.

[0083] In other embodiments, the PARP inhibitor is Niraparib (MK-4827), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the tosylate salt.

[0084] In other embodiments, the PARP inhibitor is UPF 1069.

[0085] In other embodiments, the PARP inhibitor is ME0328, or a pharmaceutically acceptable salt thereof.

[0086] In other embodiments, the PARP inhibitor is RK-28710, or a pharmaceutically acceptable salt thereof. [0087] In other embodiments, the PARP inhibitor is Pamiparib (BGB-290), or a pharmaceutically acceptable salt thereof.

[0088] In other embodiments, the PARP inhibitor is NMS-P118, or a pharmaceutically acceptable salt thereof.

[0089] In other embodiments, the PARP inhibitor is E7449, or a pharmaceutically acceptable salt thereof.

[0090] In other embodiments, the PARP inhibitor is Picolinamide, or a pharmaceutically acceptable salt thereof.

[0091] In other embodiments, the PARP inhibitor is Benzamide.

[0092] In other embodiments, the PARP inhibitor is NU1025, or a pharmaceutically acceptable salt thereof.

[0093] In other embodiments, the PARP inhibitor is AZD2461, or a pharmaceutically acceptable salt thereof.

[0094] In other embodiments, the PARP inhibitor is BGP-15, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the 2HC1 salt, i.e., BGP-15 2HC1.

[0095] In other embodiments, the PARP inhibitor is XAV-939, or a pharmaceutically acceptable salt thereof.

[0096] In other embodiments, the PARP inhibitor is 4-Hydroxyquinazoline, or a pharmaceutically acceptable salt thereof.

[0097] In other embodiments, the PARP inhibitor is NVP-TNKS656, or a pharmaceutically acceptable salt thereof.

[0098] In other embodiments, the PARP inhibitor is MN 64.

[0099] In other embodiments, the PARP inhibitor is G007-LK, or a pharmaceutically acceptable salt thereof.

[00100] In other embodiments, the PARP inhibitor is CEP 9722, or a pharmaceutically acceptable salt thereof.

[00101] In other embodiments, the PARP inhibitor is E7016, or a pharmaceutically acceptable salt thereof.

[00102] In other embodiments, the PARP inhibitor is Iniparib.

[00103] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a Chkl inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “Chkl inhibitor” refers to a compound that inhibits the activity of the enzyme checkpoint kinase 1 (Chkl), a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene.

[00104] In some methods of the disclosure, the Chklinhibitor is AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC-0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, or Prexasertib HC1 (LY2606368), or a pharmaceutically acceptable salt of a listed compound.

[00105] In other embodiments, the Chkl inhibitor is AZD7762, or a pharmaceutically acceptable salt thereof.

[00106] In other embodiments, the Chkl inhibitor is Rabusertib (LY2603618), or a pharmaceutically acceptable salt thereof.

[00107] In other embodiments, the Chkl inhibitor is MK-8776 (SCH 900776), or a pharmaceutically acceptable salt thereof.

[00108] In other embodiments, the Chkl inhibitor is CHIR-124 or a pharmaceutically acceptable salt thereof.

[00109] In other embodiments, the Chkl inhibitor is PF-477736, or a pharmaceutically acceptable salt thereof.

[00110] In other embodiments, the Chkl inhibitor is VX-803 (M4344), or a pharmaceutically acceptable salt thereof.

[00111] In other embodiments, the Chkl inhibitor is GDC-0575 (ARRY-575), or a pharmaceutically acceptable salt thereof.

[00112] In other embodiments, the Chkl inhibitor is SAR-020106, or a pharmaceutically acceptable salt thereof.

[00113] In other embodiments, the Chkl inhibitor is CCT245737, or a pharmaceutically acceptable salt thereof.

[00114] In other embodiments, the Chkl inhibitor is PD0166285, or a pharmaceutically acceptable salt thereof.

[00115] In other embodiments, the Chkl inhibitor is Prexasertib, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt. [00116] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a MDM2 inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “MDM2 inhibitor” refers to a compound that inhibits the activity of the enzyme murine double minute 2 (MDM2), including by binding to MDM2 protein and preventing its binding to tumor suppressor protein p53.

[00117] In some methods of the disclosure, the MDM2 inhibitor is Nutlin-3, NSC 207895, Nutlin-3a, Nutlin-3b, MX69, NVP-CGM097, MI-773 (SAR405838), Idasanutlin (RG-7388), RG-7112, HDM201 (Siremadlin), YH239-EE, (-)-Parthenolide, or Serdemetan (JNJ-26854165); or a pharmaceutically acceptable salt of a listed compound.

[00118] In other embodiments, the MDM2 inhibitor is Nutlin-3, or a pharmaceutically acceptable salt thereof.

[00119] In other embodiments, the MDM2 inhibitor is NSC 207895, or a pharmaceutically acceptable salt thereof.

[00120] In other embodiments, the MDM2 inhibitor is Nutlin-3a, or a pharmaceutically acceptable salt thereof.

[00121] In other embodiments, the MDM2 inhibitor is Nutlin-3b, or a pharmaceutically acceptable salt thereof.

[00122] In other embodiments, the MDM2 inhibitor is MX69, or a pharmaceutically acceptable salt thereof.

[00123] In other embodiments, the MDM2 inhibitor is NVP-CGM097, or a pharmaceutically acceptable salt thereof.

[00124] In other embodiments, the MDM2 inhibitor is MI-773 (SAR405838), or a pharmaceutically acceptable salt thereof.

[00125] In other embodiments, the MDM2 inhibitor is Idasanutlin (RG-7388), or a pharmaceutically acceptable salt thereof.

[00126] In other embodiments, the MDM2 inhibitor is RG-7112, or a pharmaceutically acceptable salt thereof.

[00127] In other embodiments, the MDM2 inhibitor is HDM201 (Siremadlin), or a pharmaceutically acceptable salt thereof. [00128] In other embodiments, the MDM2 inhibitor is YH239-EE, or a pharmaceutically acceptable salt thereof.

[00129] In other embodiments, the MDM2 inhibitor is (-)-Parthenolide.

[00130] In other embodiments, the MDM2 inhibitor is Ser demetan (JNJ-

26854165), or a pharmaceutically acceptable salt thereof.

[00131] In other aspects, the disclosure is directed to methods for the treatment of MTAP-deficient cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a hypomethylating agent. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “a hypomethylating agent,” refers to a compound that inhibits methylation of DNA.

[00132] In some methods of the disclosure, the hypomethylating agent is Decitabine (available as DACOGEN®), Azacitidine (5 -Azacytidine; available as VID AZA®), Guadecitabine (SGI-110), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-Deoxy-5-Fluorocytidine, Procainamide HC1, Bobcat339 hydrochloride, Gamma-Oryzanol, P-thujaplicin, CP-4200, Nanaomycin A, or (-)-Epigallocatechin Gallate; or a pharmaceutically acceptable salt of a listed compound.

[00133] In other embodiments, the hypomethylating agent is Decitabine, or a pharmaceutically acceptable salt thereof.

[00134] In other embodiments, the hypomethylating agent is Azacitidine (5- Azacytidine), or a pharmaceutically acceptable salt thereof.

[00135] In other embodiments, the hypomethylating agent is Guadecitabine (SGI-110) or a pharmaceutically acceptable salt thereof.

[00136] In other embodiments, the hypomethylating agent is RG108, or a pharmaceutically acceptable salt thereof.

[00137] In other embodiments, the hypomethylating agent is Thioguanine, or a pharmaceutically acceptable salt thereof.

[00138] In other embodiments, the hypomethylating agent is Zebularine, or a pharmaceutically acceptable salt thereof.

[00139] In other embodiments, the hypomethylating agent is SGI-1027, or a pharmaceutically acceptable salt thereof. [00140] In other embodiments, the hypomethylating agent is CM272, or a pharmaceutically acceptable salt thereof.

[00141] In other embodiments, the hypomethylating agent is 2'-Deoxy-5- Fluorocytidine, or a pharmaceutically acceptable salt thereof.

[00142] In other embodiments, the hypomethylating agent is Procainamide , or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., Procainamide HC1.

[00143] In other embodiments, the hypomethylating agent is Bobcat339 hydrochloride, or a pharmaceutically acceptable salt thereof.

[00144] In other embodiments, the hypomethylating agent is Gamma-Oryzanol, or a pharmaceutically acceptable salt thereof.

[00145] In other embodiments, the hypomethylating agent is [3-thujaplicin, or a pharmaceutically acceptable salt thereof.

[00146] In other embodiments, the hypomethylating agent is CP-4200, or a pharmaceutically acceptable salt thereof.

[00147] In other embodiments, the hypomethylating agent is Nanaomycin A, or a pharmaceutically acceptable salt thereof.

[00148] In other embodiments, the hypomethylating agent is (-)- Epigallocatechin Gallate, or a pharmaceutically acceptable salt thereof.

[00149] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a mTOR inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “mTOR inhibitor” refers to a compound that inhibits the activity of the serine/threonine-specific protein kinase known as mammalian target of rapamycin (mTOR).

[00150] In some methods of the disclosure, the mTOR inhibitor is Dactolisib (BEZ235), Rapamycin (Sirolimus; available as RAPAMUNE®), Everolimus (RAD001), AZD8055, Temsirolimus (CCI-779), PI-103, KU-0063794, Torkinib (PP242), Ridaforolimus (Deforolimus, MK-8669), Sapanisertib (MLN0128), Voxtalisib (XL765) Analogue, Torin 1, Omipalisib (GSK2126458), OSI-027, PF-04691502, Apitolisib (GDC-0980), GSK1059615, Gedatolisib (PKI-587), WYE-354, Vistusertib (AZD2014), Torin 2, WYE-125132 (WYE- 132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib(CC 223), Voxtalisib (XL765), Zotarolimus(ABT-578), Tacrolimus (FK506), BGT226 maleate (NVP- BGT226 maleate), Palomid 529 (P529), LY3023414 (Samotolisib), or Chrysophanic Acid; or a pharmaceutically acceptable salt of a listed compound.

[00151] In some embodiments, the mTOR inhibitor is Everolimus.

[00152] In other embodiments, the mTOR inhibitor is Dactolisib (BEZ235), or a pharmaceutically acceptable salt thereof.

[00153] In other embodiments, the mTOR inhibitor is Rapamycin (Sirolimus), or a pharmaceutically acceptable salt thereof.

[00154] In other embodiments, the mTOR inhibitor is AZD8055, or a pharmaceutically acceptable salt thereof.

[00155] In other embodiments, the mTOR inhibitor is Temsirolimus (CCI-779), or a pharmaceutically acceptable salt thereof.

[00156] In other embodiments, the mTOR inhibitor is PI-103, or a pharmaceutically acceptable salt thereof.

[00157] In other embodiments, the mTOR inhibitor is KU-0063794, or a pharmaceutically acceptable salt thereof.

[00158] In other embodiments, the mTOR inhibitor is Torkinib (PP242), or a pharmaceutically acceptable salt thereof.

[00159] In other embodiments, the mTOR inhibitor is Ridaforolimus (Deforolimus, MK-8669), or a pharmaceutically acceptable salt thereof.

[00160] In other embodiments, the mTOR inhibitor is Sapanisertib (MLN0128), or a pharmaceutically acceptable salt thereof.

[00161] In other embodiments, the mTOR inhibitor is Voxtalisib (XL765) Analogue, or a pharmaceutically acceptable salt thereof.

[00162] In other embodiments, the mTOR inhibitor is Torin 1, or a pharmaceutically acceptable salt thereof.

[00163] In other embodiments, the mTOR inhibitor is Omipalisib (GSK2126458), or a pharmaceutically acceptable salt thereof.

[00164] In other embodiments, the mTOR inhibitor is OSI-027, or a pharmaceutically acceptable salt thereof. [00165] In other embodiments, the mTOR inhibitor is PF-04691502, or a pharmaceutically acceptable salt thereof.

[00166] In other embodiments, the mTOR inhibitor is Apitolisib (GDC-0980), or a pharmaceutically acceptable salt thereof.

[00167] In other embodiments, the mTOR inhibitor is GSK1059615, or a pharmaceutically acceptable salt thereof.

[00168] In other embodiments, the mTOR inhibitor is Gedatolisib (PKI-587), or a pharmaceutically acceptable salt thereof.

[00169] In other embodiments, the mTOR inhibitor is WYE-354, or a pharmaceutically acceptable salt thereof.

[00170] In other embodiments, the mTOR inhibitor is Vistusertib (AZD2014), or a pharmaceutically acceptable salt thereof.

[00171] In other embodiments, the mTOR inhibitor is Torin 2, or a pharmaceutically acceptable salt thereof.

[00172] In other embodiments, the mTOR inhibitor is WYE- 125132 (WYE- 132), or a pharmaceutically acceptable salt thereof.

[00173] In other embodiments, the mTOR inhibitor is PP121, or a pharmaceutically acceptable salt thereof.

[00174] In other embodiments, the mTOR inhibitor is WYE-687, or a pharmaceutically acceptable salt thereof.

[00175] In other embodiments, the mTOR inhibitor is WAY-600, or a pharmaceutically acceptable salt thereof.

[00176] In other embodiments, the mTOR inhibitor is ETP-46464, or a pharmaceutically acceptable salt thereof.

[00177] In other embodiments, the mTOR inhibitor is GDC-0349, or a pharmaceutically acceptable salt thereof.

[00178] In other embodiments, the mTOR inhibitor is XL388, or a pharmaceutically acceptable salt thereof.

[00179] In other embodiments, the mTOR inhibitor is GNE-477, or a pharmaceutically acceptable salt thereof.

[00180] In other embodiments, the mTOR inhibitor is Bimiralisib (PQR309),or a pharmaceutically acceptable salt thereof.

[00181] In other embodiments, the mTOR inhibitor is SF2523,or a pharmaceutically acceptable salt thereof. [00182] In other embodiments, the mTOR inhibitor is CZ415, or a pharmaceutically acceptable salt thereof.

[00183] In other embodiments, the mTOR inhibitor is Paxalisib (GDC-0084), or a pharmaceutically acceptable salt thereof.

[00184] In other embodiments, the mTOR inhibitor is CC-115, or a pharmaceutically acceptable salt thereof.

[00185] In other embodiments, the mTOR inhibitor is Onatasertib(CC 223), or a pharmaceutically acceptable salt thereof.

[00186] In other embodiments, the mTOR inhibitor is Voxtalisib (XL765), or a pharmaceutically acceptable salt thereof.

[00187] In other embodiments, the mTOR inhibitor is Zotarolimus(ABT-578), or a pharmaceutically acceptable salt thereof.

[00188] In other embodiments, the mTOR inhibitor is Tacrolimus (FK506), or a pharmaceutically acceptable salt thereof.

[00189] In other embodiments, the mTOR inhibitor is BGT226 maleate (NVP- BGT226 maleate), or a pharmaceutically acceptable salt thereof.

[00190] In other embodiments, the mTOR inhibitor is Palomid 529 (P529), or a pharmaceutically acceptable salt thereof.

[00191] In other embodiments, the mTOR inhibitor is LY3023414 (Samotolisib), or a pharmaceutically acceptable salt thereof.

[00192] In other embodiments, the mTOR inhibitor is Chrysophanic Acid or a pharmaceutically acceptable salt thereof.

[00193] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is an ATM inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “ATM inhibitor” refers to a compound that inhibits the activity of the serine/threonine protein kinase known as Ataxia-telangiectasia mutated (ATM) kinase.

[00194] In some methods of the disclosure, the ATM inhibitor is KU-55933, KU-60019, Wortmannin, Torin 2, CP-466722, ETP-46464, CGK 733, AZ32, AZD1390, AZ31, or AZD0156; or a pharmaceutically acceptable salt of a listed compound. [00195] In some embodiments, the ATM inhibitor is KU-55933, or a pharmaceutically acceptable salt thereof.

[00196] In other embodiments, the ATM inhibitor is KU-60019, or a pharmaceutically acceptable salt thereof.

[00197] In other embodiments, the ATM inhibitor is Wortmannin, or a pharmaceutically acceptable salt thereof.

[00198] In other embodiments, the ATM inhibitor is Torin 2, or a pharmaceutically acceptable salt thereof.

[00199] In other embodiments, the ATM inhibitor is CP-466722, or a pharmaceutically acceptable salt thereof.

[00200] In other embodiments, the ATM inhibitor is ETP-46464, or a pharmaceutically acceptable salt thereof.

[00201] In other embodiments, the ATM inhibitor is CGK 733, or a pharmaceutically acceptable salt thereof.

[00202] In other embodiments, the ATM inhibitor is AZ32, or a pharmaceutically acceptable salt thereof.

[00203] In other embodiments, the ATM inhibitor is AZDI 390, or a pharmaceutically acceptable salt thereof.

[00204] In other embodiments, the ATM inhibitor is AZ31, or a pharmaceutically acceptable salt thereof.

[00205] In other embodiments, the ATM inhibitor is AZD0156, or a pharmaceutically acceptable salt thereof.

[00206] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a CDK 4/6 inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “CDK 4/6 inhibitor” refers to a compound that inhibits the activity of cyclin-dependent kinase 4 and/or 6 (CDK4/6).

[00207] In some methods of the disclosure, the CDK 4/6 inhibitor is Palbociclib (PD-0332991; available as IBRANCE®), Palbociclib (PD-0332991) HC1, Flavopiridol (Alvocidib), AT7519, Flavopiridol HC1, JNJ-7706621, PHA-793887, Palbociclib (PD0332991) Isethionate, abemaciclib mesylate (LY2835219), BMS-265246, Milciclib (PHA-848125), R547, Riviciclib hydrochloride (P276-00), MCI 80295, G1T38, Abemaciclib (available as VERZENIO®), ON123300, AT7519 HC1, Purvalanol A, SU9516, Ribociclib (LEE011), or BSJ-03-123; or a pharmaceutically acceptable salt of a listed compound.

[00208] In other embodiments, the CDK 4/6 inhibitor is Palbociclib (PD- 0332991), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., Palbociclib HC1. In other embodiments, the pharmaceutically acceptable salt is the Isethionate salt, i.e., Palbociclib Isethionate.

[00209] In other embodiments, the CDK 4/6 inhibitor is Flavopiridol (Alvocidib), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., Flavopiridol HC1.

[00210] In other embodiments, the CDK 4/6 inhibitor is AT7519, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., AT7519 HC1.

[00211] In other embodiments, the CDK 4/6 inhibitor is JNJ-7706621, or a pharmaceutically acceptable salt thereof.

[00212] In other embodiments, the CDK 4/6 inhibitor is PHA-793887, or a pharmaceutically acceptable salt thereof.

[00213] In other embodiments, the CDK 4/6 inhibitor is Abemaciclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the mesylate salt, i.e., abemaciclib mesylate (LY2835219).

[00214] In other embodiments, the CDK 4/6 inhibitor is BMS-265246, or a pharmaceutically acceptable salt thereof.

[00215] In other embodiments, the CDK 4/6 inhibitor is Milciclib (PHA- 848125), or a pharmaceutically acceptable salt thereof.

[00216] In other embodiments, the CDK 4/6 inhibitor is R547, or a pharmaceutically acceptable salt thereof.

[00217] In other embodiments, the CDK 4/6 inhibitor is Riviciclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., Riviciclib hydrochloride (P276-00).

[00218] In other embodiments, the CDK 4/6 inhibitor is MCI 80295, or a pharmaceutically acceptable salt thereof. [00219] In other embodiments, the CDK 4/6 inhibitor is G1T38, or a pharmaceutically acceptable salt thereof.

[00220] In other embodiments, the CDK 4/6 inhibitor is ON123300, or a pharmaceutically acceptable salt thereof.

[00221] In other embodiments, the CDK 4/6 inhibitor is Purvalanol A, or a pharmaceutically acceptable salt thereof.

[00222] In other embodiments, the CDK 4/6 inhibitor is SU9516, or a pharmaceutically acceptable salt thereof.

[00223] In other embodiments, the CDK 4/6 inhibitor is Riboci clib (LEE011), or a pharmaceutically acceptable salt thereof.

[00224] In other embodiments, the CDK 4/6 inhibitor is BSJ-03-123, or a pharmaceutically acceptable salt thereof.

[00225] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a BCL-2 inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, the term “BCL-2” refers to the regulator protein that is encoded by the BCL2 gene.

[00226] In some embodiments, the BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, Venetoclax (ABT-199; available as VENCLEXTA®), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable salt of a listed compound.

[00227] In some embodiments, the BCL-2 inhibitor is ABT-737, or a pharmaceutically acceptable salt thereof.

[00228] In some embodiments, the BCL-2 inhibitor is Navitoclax (ABT-263), or a pharmaceutically acceptable salt thereof.

[00229] In some embodiments, the BCL-2 inhibitor is Obatoclax Mesylate (GX15-070), or a pharmaceutically acceptable salt thereof.

[00230] In some embodiments, the BCL-2 inhibitor is TW-37, or a pharmaceutically acceptable salt thereof. [00231] In some embodiments, the BCL-2 inhibitor is Venetoclax (ABT- 199), or a pharmaceutically acceptable salt thereof.

[00232] In some embodiments, the BCL-2 inhibitor is ATI 01, or a pharmaceutically acceptable salt thereof.

[00233] In some embodiments, the BCL-2 inhibitor is HA14-1, or a pharmaceutically acceptable salt thereof.

[00234] In some embodiments, the BCL-2 inhibitor is Sabutoclax, or a pharmaceutically acceptable salt thereof.

[00235] In some embodiments, the BCL-2 inhibitor is S55746, or a pharmaceutically acceptable salt thereof.

[00236] In some embodiments, the BCL-2 inhibitor is Gambogic Acid, or a pharmaceutically acceptable salt thereof.

[00237] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a PRMT5 inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “PRMT5 inhibitor” refers to a compound that inhibits the activity of the enzyme protein arginine methyl transferase 5.

[00238] In some methods of the disclosure, the PRMT5 inhibitor is JNJ- 64619178 (AGI-931), HLCL-61, GSK591, EPZ015666(GSK3235025), GSK3326595 (EPZ015938; AGI-219), ; or a pharmaceutically acceptable salt of a listed compound.

[00239] In some embodiments, the PRMT5 inhibitor is JNJ-64619178, or a pharmaceutically acceptable salt thereof.

[00240] In some embodiments, the PRMT5 inhibitor is HLCL-61, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., HLCL-61 HCL.

[00241] In some embodiments, the PRMT5 inhibitor is GSK591, or a pharmaceutically acceptable salt thereof.

[00242] In some embodiments, the PRMT5 inhibitor is EPZ015666(GSK3235025), or a pharmaceutically acceptable salt thereof. [00243] In some embodiments, the PRMT5 inhibitor is GSK3326595 (EPZ015938), or a pharmaceutically acceptable salt thereof.

[00244] In some embodiments, the PRMT5 inhibitor is AGI-219, or a pharmaceutically acceptable salt thereof.

[00245] In some embodiments, the PRMT5 inhibitor is AGI-931, or a pharmaceutically acceptable salt thereof.

[00246] In other aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a PRMT1 inhibitor. In some embodiments the cancer is an MTAP-deficient cancer. In other embodiments the cancer is an MTAP wild type cancer. In still other embodiments the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, a “PRMT1 inhibitor” refers to a compound that inhibits the activity of the enzyme protein arginine methyl transferase 1.

[00247] In some methods of the disclosure, the PRMT1 inhibitor is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HC1, MS023, or AMI-1; or a pharmaceutically acceptable salt of a listed compound.

[00248] In some embodiments, the PRMT1 inhibitor is GSK3368715 (EPZ019997), or a pharmaceutically acceptable salt thereof.

[00249] In some embodiments, the PRMT1 inhibitor is C7280948, or a pharmaceutically acceptable salt thereof.

[00250] In some embodiments, the PRMT1 inhibitor is EPZ020411, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., EPZ020411 2HC1.

[00251] In some embodiments, the PRMT1 inhibitor is MS023, or a pharmaceutically acceptable salt thereof.

[00252] In some embodiments, the PRMT1 inhibitor is AMI-1, or a pharmaceutically acceptable salt thereof.

[00253] In other aspects, the disclosure is directed to methods for the treatment of a cancer in a patient comprising administering to the patient: (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is an antimetabolite, an Aurora inhibitor, a DNA crosslinker, or a microtubule stabilizer; wherein the cancer is MTAP wild type.

[00254] In some embodiments, the MTAP wild type cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[00255] In some embodiments, the therapeutic agent is an antimetabolite. As used herein, the term “antimetabolite” refers to a compound that inhibits DNA synthesis.

[00256] In some embodiments, the antimetabolite is 5-Fluorouracil (5-FU), 6- Mercaptopurine (6-MP), Capecitabine (Xeloda®), Cytarabine (Ara-C®), Floxuridine, Fludarabine, Gemcitabine (Gemzar®), Hydroxy carbamide, Methotrexate, Pemetrexed (Alimta®), or Phototrexate, or a pharmaceutically acceptable salt of a listed compound.

[00257] In some embodiments, the antimetabolite is Pemetrexed, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the disodium salt. Pemetrexed is (2S)-2-[[4-[2-(2-amino-4-oxido-7H- pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioc acid, having the following structure:

[00258] As used herein, the term “Pemetrexed” also includes pharmaceutically acceptable salts thereof such as pemetrexed disodium which is available as ALIMTA®.

[00259] In some embodiments, the antimetabolite is Methotrexate, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the disodium salt.

[00260] In some embodiments, the antimetabolite is Phototrexate, or a pharmaceutically acceptable salt thereof.

[00261] In some embodiments, the antimetabolite is 6-Mercaptopurine (6-MP), or a pharmaceutically acceptable salt thereof. [00262] In some embodiments, the antimetabolite is 5-fluorouracil, or a pharmaceutically acceptable salt thereof.

[00263] In some embodiments, the antimetabolite is capecitabine, or a pharmaceutically acceptable salt thereof.

[00264] In some embodiments, the antimetabolite is Gemcitabine, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt.

[00265] In some embodiments, the antimetabolite is fludarabine, or a pharmaceutically acceptable salt thereof.

[00266] In some embodiments, the antimetabolite is Floxuridine, or a pharmaceutically acceptable salt thereof.

[00267] In some embodiments, the antimetabolite is Hydroxycarbamide, or a pharmaceutically acceptable salt thereof.

[00268] In some embodiments, the antimetabolite is Cytarabine, or a pharmaceutically acceptable salt thereof.

[00269] In other embodiments, the therapeutic agent is an Aurora inhibitor. As used herein, the term “Aurora inhibitor” refers to a compound that inhibits the enzyme Aurora kinase.

[00270] In some embodiments, the Aurora inhibitor is Alisertib (MLN8237), Tozasertib (VX-680, MK-0457), Barasertib (AZD1152-HQPA), ZM 447439, MLN8054, Danusertib (PHA-739358), AT9283, JNJ-7706621, Hesperadin, Aurora A Inhibitor I (TC-S 7010), KW-2449, SNS-314, ENMD-2076, PHA-680632, MK-5108 (VX-689), CYC116, AMG-900, PF-03814735, CCT129202, GSK1070916, TAK-901, CCT137690, MK-8745, ENMD-2076 L-(+)-Tartaric acid, Aurora Kinase Inhibitor III, SNS-314 Mesylate, BI- 847325, Reversine, or ABT-348, or pharmaceutically acceptable salts of the listed compounds.

[00271] In some embodiments, the Aurora inhibitor is Alisertib (MLN8237), or a pharmaceutically acceptable salt thereof.

[00272] In some embodiments, the Aurora inhibitor is Tozasertib (VX-680, MK-0457), or a pharmaceutically acceptable salt thereof.

[00273] In some embodiments, the Aurora inhibitor is Barasertib (AZDI 152- HQPA), or a pharmaceutically acceptable salt thereof.

[00274] In some embodiments, the Aurora inhibitor is ZM 447439, or a pharmaceutically acceptable salt thereof. [00275] In some embodiments, the Aurora inhibitor is MLN8054), or a pharmaceutically acceptable salt thereof.

[00276] In some embodiments, the Aurora inhibitor is Danusertib (PHA- 739358), or a pharmaceutically acceptable salt thereof.

[00277] In some embodiments, the Aurora inhibitor is AT9283, or a pharmaceutically acceptable salt thereof.

[00278] In some embodiments, the Aurora inhibitor is JNJ-7706621, or a pharmaceutically acceptable salt thereof.

[00279] In some embodiments, the Aurora inhibitor is Hesperadin, or a pharmaceutically acceptable salt thereof.

[00280] In some embodiments, the Aurora inhibitor is Aurora A Inhibitor I (TC-S 7010), or a pharmaceutically acceptable salt thereof.

[00281] In some embodiments, the Aurora inhibitor is KW-2449, or a pharmaceutically acceptable salt thereof.

[00282] In some embodiments, the Aurora inhibitor is SNS-314, or a pharmaceutically acceptable salt thereof.

[00283] In some embodiments, the Aurora inhibitor is ENMD-2076, or a pharmaceutically acceptable salt thereof.

[00284] In some embodiments, the Aurora inhibitor is PHA-680632, or a pharmaceutically acceptable salt thereof.

[00285] In some embodiments, the Aurora inhibitor is MK-5108 (VX-689), or a pharmaceutically acceptable salt thereof.

[00286] In some embodiments, the Aurora inhibitor is CYC116, or a pharmaceutically acceptable salt thereof.

[00287] In some embodiments, the Aurora inhibitor is AMG-900, or a pharmaceutically acceptable salt thereof.

[00288] In some embodiments, the Aurora inhibitor is PF-03814735, or a pharmaceutically acceptable salt thereof.

[00289] In some embodiments, the Aurora inhibitor is CCT 129202, or a pharmaceutically acceptable salt thereof.

[00290] In some embodiments, the Aurora inhibitor is GSK1070916, or a pharmaceutically acceptable salt thereof.

[00291] In some embodiments, the Aurora inhibitor is TAK-901, or a pharmaceutically acceptable salt thereof. [00292] In some embodiments, the Aurora inhibitor is CCT137690, or a pharmaceutically acceptable salt thereof.

[00293] In some embodiments, the Aurora inhibitor is MK-8745, or a pharmaceutically acceptable salt thereof.

[00294] In some embodiments, the Aurora inhibitor is ENMD-2076 L-(+)- Tartaric acid, or a pharmaceutically acceptable salt thereof.

[00295] In some embodiments, the Aurora inhibitor is Aurora Kinase Inhibitor III, or a pharmaceutically acceptable salt thereof.

[00296] In some embodiments, the Aurora inhibitor is SNS-314 Mesylate, or a pharmaceutically acceptable salt thereof.

[00297] In some embodiments, the Aurora inhibitor is BI-847325, or a pharmaceutically acceptable salt thereof.

[00298] In some embodiments, the Aurora inhibitor is Reversine, or a pharmaceutically acceptable salt thereof.

[00299] In some embodiments, the Aurora inhibitor is ABT-348, or a pharmaceutically acceptable salt thereof.

[00300] In other embodiments, the therapeutic agent is microtubule stabilizer. As used herein, the term “microtubule stabilizer” refers to a compound that promotes polymerization of tubulin, stabilizes tubulin, and /or prevents depolymerization of tubulin.

[00301] In some embodiments, the microtubule stabilizer is paclitaxel, nab- paclitaxel, docetaxel, Epothilone A, or Epothilone B.

[00302] In some embodiments, the microtubule stabilizer is paclitaxel.

[00303] In other embodiments, the microtubule stabilizer is nab-paclitaxel.

[00304] In some embodiments, the microtubule stabilizer is docetaxel.

[00305] In some embodiments, the microtubule stabilizer is Epothilone A.

[00306] In some embodiments, the microtubule stabilizer is Epothilone B.

[00307] In other embodiments, the therapeutic agent is a DNA crosslinker. As used herein, the term “DNA crosslinker” refers to a compound that crosslink DNA strands.

[00308] In some embodiments, the DNA crosslinker is cisplatin.

[00309] In some embodiments, the DNA crosslinker is carboplatin.

[00310] In other embodiments, the DNA crosslinker is oxaliplatin.

[00311] In some methods of the disclosure, the MTAP wild type cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

[00312] In some embodiments, the MTAP wild type cancer is lung cancer, pancreatic cancer, esophageal cancer, colorectal cancer, kidney cancer, leukemia, or myeloid leukemia (AML).

[00313] In some aspects, the disclosure is directed to methods for the treatment of cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein the cancer is acute myeloid leukemia (AML). In some embodiments the AML is MTAP- deficient. In other embodiments the AML is MTAP wild type. In still other embodiments the AML responds to a reduction in SAM as a result of administering an MAT2A inhibitor.

[00314] In some embodiments, the methods of treating cancer in a patient comprise treating acute myeloid leukemia (AML) by administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and further comprise administering to the patient a BCL-2 inhibitor. In some embodiments the AML is MTAP-deficient. In other embodiments the AML is MTAP wild type. In still other embodiments the AML responds to a reduction in SAM as a result of administering an MAT2A inhibitor. As used herein, the term “BCL-2” refers to the regulator protein that is encoded by the BCL2 gene.

[00315] In some embodiments, the BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, Venetoclax (ABT-199; available as VENCLEXTA®), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable salt of a listed compound.

[00316] In some embodiments, the BCL-2 inhibitor is ABT-737, or a pharmaceutically acceptable salt thereof.

[00317] In some embodiments, the BCL-2 inhibitor is Navitoclax (ABT-263), or a pharmaceutically acceptable salt thereof.

[00318] In some embodiments, the BCL-2 inhibitor is Obatoclax Mesylate (GX15-070), or a pharmaceutically acceptable salt thereof.

[00319] In some embodiments, the BCL-2 inhibitor is TW-37, or a pharmaceutically acceptable salt thereof.

[00320] In some embodiments, the BCL-2 inhibitor is Venetoclax (ABT- 199), or a pharmaceutically acceptable salt thereof. [00321] In some embodiments, the BCL-2 inhibitor is ATI 01, or a pharmaceutically acceptable salt thereof.

[00322] In some embodiments, the BCL-2 inhibitor is HA14-1, or a pharmaceutically acceptable salt thereof.

[00323] In some embodiments, the BCL-2 inhibitor is Sabutoclax, or a pharmaceutically acceptable salt thereof.

[00324] In some embodiments, the BCL-2 inhibitor is S55746, or a pharmaceutically acceptable salt thereof.

[00325] In some embodiments, the BCL-2 inhibitor is Gambogic Acid, or a pharmaceutically acceptable salt thereof.

[00326] In some embodiments, the methods of treating acute myeloid leukemia (AML) comprise administering to the patient a therapeutically effective amount of: (1) a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (2) a therapeutically effective amount of a BCL-2 inhibitor, and (3) a hypomethylating agent. In some embodiments the AML is MTAP-deficient. In other embodiments the AML is MTAP wild type. In still other embodiments the AML responds to a reduction in SAM as a result of administering an MAT2A inhibitor.

[00327] In some embodiments of these methods, the hypomethylating agent is Decitabine, Azacitidine (5 -Azacytidine), Guadecitabine (SGI-110), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-Deoxy-5-Fluorocytidine, Procainamide HC1, Bobcat339 hydrochloride, Gamma-Oryzanol, P-thujaplicin, CP-4200, Nanaomycin A, or (-)- Epigallocatechin Gallate; or a pharmaceutically acceptable salt of a listed compound.

[00328] In other embodiments, the hypomethylating agent is Decitabine, or a pharmaceutically acceptable salt thereof.

[00329] In other embodiments, the hypomethylating agent is Azacitidine (5- Azacytidine), or a pharmaceutically acceptable salt thereof.

[00330] In other embodiments, the hypomethylating agent is Guadecitabine (SGI-110) or a pharmaceutically acceptable salt thereof.

[00331] In other embodiments, the hypomethylating agent is RG108, or a pharmaceutically acceptable salt thereof.

[00332] In other embodiments, the hypomethylating agent is Thioguanine, or a pharmaceutically acceptable salt thereof.

[00333] In other embodiments, the hypomethylating agent is Zebularine, or a pharmaceutically acceptable salt thereof. [00334] In other embodiments, the hypomethylating agent is SGI-1027, or a pharmaceutically acceptable salt thereof.

[00335] In other embodiments, the hypomethylating agent is CM272, or a pharmaceutically acceptable salt thereof.

[00336] In other embodiments, the hypomethylating agent is 2'-Deoxy-5- Fluorocytidine, or a pharmaceutically acceptable salt thereof.

[00337] In other embodiments, the hypomethylating agent is Procainamide , or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is the HC1 salt, i.e., Procainamide HC1.

[00338] In other embodiments, the hypomethylating agent is Bobcat339 hydrochloride, or a pharmaceutically acceptable salt thereof.

[00339] In other embodiments, the hypomethylating agent is Gamma-Oryzanol, or a pharmaceutically acceptable salt thereof.

[00340] In other embodiments, the hypomethylating agent is [3-thujaplicin, or a pharmaceutically acceptable salt thereof.

[00341] In other embodiments, the hypomethylating agent is CP-4200, or a pharmaceutically acceptable salt thereof.

[00342] In other embodiments, the hypomethylating agent is Nanaomycin A, or a pharmaceutically acceptable salt thereof.

[00343] In other embodiments, the hypomethylating agent is (-)- Epigallocatechin Gallate, or a pharmaceutically acceptable salt thereof.

[00344] In some embodiments, the disclosure is directed to methods of treating acute myeloid leukemia (AML) by administering (a) a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; (b) a therapeutically effective amount of venetoclax or a pharmaceutically acceptable salt thereof; and (c) a therapeutically effective amount of azacitidine or a pharmaceutically acceptable salt thereof. In some embodiments the AML is MTAP-deficient. In other embodiments the AML is MTAP wild type. In still other embodiments the AML responds to a reduction in SAM as a result of administering an MAT2A inhibitor.

[00345] In any of the methods of treatment described above the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered concurrently or sequentially with one or more therapeutic agents described above. In some embodiments of any of the foregoing methods of treatment the patient is administered (a) compound of Formula (I) or a pharmaceutically acceptable salt thereof and (b) one or more therapeutic agents concurrently. In other embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more therapeutic agent may be administered sequentially. In still other embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered concurrently or sequentially with one or more therapeutic agents.

[00346] In still other embodiments of any of the foregoing methods of treatment, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered orally. In further embodiments of any of the foregoing methods of treatment, the compound of Formula (I) a pharmaceutically acceptable salt thereof is administered once or twice daily.

[00347] Positive therapeutic effects in cancer can be measured in a number of ways. The administration of a therapeutically effective amount of the combinations herein described are therapeutically advantageous over the individual component compounds. As used herein “therapeutically advantageous” combinations are those combinations that provide at least one of the following improved properties when compared to the individual administration of a therapeutically effective amount of a component compounds: i) a greater anticancer effect than the most active single agent, alone; ii) synergistic anticancer effect; or iii) additive activity.

[00348] In embodiments of the present disclosure in which a patient is administered a therapeutically effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a therapeutic agent, the combination is therapeutically advantageous.

[00349] In some embodiments, synergy is determined using at least one of the models described herein. Combination effects may be characterized by comparing each data point to that of a combination reference model that was derived from the single agent curves. Three models are generally used: (1) the Highest Single Agent, which is a simple reference model where the expected combination effect is the maximum of the single agent responses at corresponding concentrations; (2) the Bliss Independence model, which represents the statistical expectation for independent competing inhibitors; (3) the Loewe Additivity model, which represents the expected response if both agents are actually the same compound; (4) the Chou-Talalay model, which estimates from dose-effect data of single and combined treatments and is represented as a Combination Index (CI) score; or a combination of one or more models. [00350] The Loewe Additivity model is the most generally accepted reference for synergy, and, therefore, the Loewe Additivity model was used, and a metric was derived from it, which is characterized herein as the “Loewe Synergy Score.” Loewe Additivity Model

[00351] The Loewe additivity model is dose-based and applies only to the activity levels achieved by the single agents. Loewe Volume is used to assess the overall magnitude of the combination interaction in excess of the Loewe additivity model. Loewe Volume is particularly useful when distinguishing synergistic increases in a phenotypic activity (positive Loewe Volume) versus synergistic antagonisms (negative Loewe Volume). When antagonisms are observed, the Loewe Volume should be assessed to examine if there is any correlation between antagonism and a particular drug target-activity or cellular genotype. This model defines additivity as a non-synergistic combination interaction where the combination dose matrix surface should be indistinguishable from either drug crossed with itself. The calculation for Loewe additivity is:

Aoewe that satisfies ( 7Ai) + (T/Ti) = 1 where Aj and Ti are the single agent effective concentrations for the observed combination effect/. For example, if 50% inhibition is achieved separately by IpM of drug A or IpM of drug B, a combination of 0.5pM of A and 0.5pM of B should also inhibit by 50%.

[00352] Activity observed in excess of Loewe additivity identifies a potential synergistic interaction. For the present analysis, empirically derived combination matrices were compared to their respective Loewe additivity models constructed from experimentally collected single agent dose response curves. Summation of this excess additivity across the dose response matrix is referred to as Loewe Volume. Positive Loewe volume suggests potential synergy, while negative Loewe Volume suggests potential antagonism.

Loewe Synergy Score

[00353] To measure combination effects in excess of Loewe additivity, a scalar measure was devised to characterize the strength of synergistic interaction, which is herein termed the “Loewe Synergy Score.” The Loewe Synergy Score is calculated as:

Loewe Synergy Score = log /x log/y X max(0,Idata)(Idata - Eoewe)

[00354] The fractional inhibition for each component agent and combination point in the matrix is calculated relative to the median of all untreated/vehicle-treated control wells. The Loewe Synergy Score equation integrates the experimentally-observed activity volume at each point in the matrix in excess of a model surface numerically derived from the activity of the component agents using the Loewe model for additivity. Additional terms in the Loewe Synergy Score equation (above) are used to normalize for various dilution factors used for individual agents and to allow for comparison of synergy scores across an entire experiment. The inclusion of positive inhibition gating or an Idata multiplier removes noise near the zero effect level, and biases results for synergistic interactions at that occur at high activity levels. Combinations with higher maximum Growth Inhibition (GI) effects or those that are synergistic at low concentrations will have higher Loewe Synergy Scores.

[00355] As will be shown in the examples below, a further modified combination statistical analysis was performed to determine if the compound of Formula (I), when combined with an antimitotic agent or a DNA synthesis inhibitor, yielded anti-tumor combination benefit. The synergy score may be referred to as an “in vivo Synergy Score.”

[00356] In greater detail, in vivo methodology for this combination analysis is as follows: the input data consists of tumor volumes from each animal at successive time points. For each tumor volume, add 1 and take the log to base 10. For each animal, subtract the log(tumor volume + 1) at the earliest time point from the log(tumor volume + 1) at each time point. Use the resulting difference versus time data to calculate an area under the curve (AUC) value for each animal using the trapezoid rule. Calculate the mean AUC for each group. In vivo Synergy Score = 100 x (meanAUCAB - meanAUCA - meanAUCB + meanAUCV) / meanAUCV, where meanAUCAB, meanAUCA, meanAUCB and meanAUCV are the mean AUC values for the combination group, the A single agent group, the B single agent group and the vehicle/control group, respectively. Using the AUC values for the individual animals, carry out an ANOVA statistical test for whether the In vivo Synergy Score is not zero, obtaining a p value. For the combination to be considered synergistic the in vivo Synergy Score must be <0; an in vivo Synergy Score of 0 is exact additivity. As the in vivo Synergy Score increases above 0, the score moves away from additivity towards antagonism. If the p-value is above 0.05, the combination is considered to be additive. If the p-value is below 0.05 and the in vivo Synergy Score is less than zero, the combination is considered to be synergistic. If the p-value is below 0.05, the in vivo Synergy Score is greater than zero and the mean AUC for the combination is lower than the lowest mean AUC for the single agents, the combination is considered to be sub-additive. If the p- value is below 0.05, the in vivo Synergy Score is greater than zero and the mean AUC for the combination is greater than the mean AUC for at least one of the single agents, the combination is considered to be antagonistic. Chou-Talalay Model

[00357] An alternative model of synergy is the assessment of drug interactions using the Chou-Talalay model, which was introduced in 1983, and which allows an estimate the interactions between two drugs in combination studies, herein referred to as the “Combination Index (CI) Score.” According this model the interactions are estimated from dose-effect data of single and combined treatments and are represented as a Combination Index (CI) score. The CI is defined as (Dl/EDxl) + (D2/EDx2), where EDxl (or EDx2) is the dose of single agent drug 1 (or drug 2) which produces a selected effect x (such as 50% growth inhibition), and DI and D2 are doses of drugs 1 and 2 which also produce the effect x when given in combination. For a given pair of compounds, multiple dose combinations were explored (in a matrix design) to identify the D1/D2 pair that give the lowest CI.

[00358] If CI < 1, the two drugs have a synergistic effect, and if CI > 1, the drugs have an antagonistic effect. Lastly, a CI = 1 suggests that the drugs have an additive effect. Reference is made to Chou, T. C. & Talalay, P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 22, 27-55 (1984).

PHARMACEUTICAL COMPOSITIONS

[00359] The disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable carrier. In some embodiments, the composition further contains, in accordance with accepted practices of pharmaceutical compounding, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.

[00360] The pharmaceutical composition of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular patient being treated, the clinical condition of the patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[00361] The pharmaceutical compositions may be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, or intrastemal injections, or infusion techniques.

[00362] Suitable oral compositions in accordance with the disclosure include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, syrups, or elixirs.

[00363] The pharmaceutical compositions may be suitable for single unit dosages that comprise a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00364] The pharmaceutical compositions suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. For instance, liquid formulations may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically suitable and/or palatable preparations.

[00365] For tablet compositions, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be formulated in admixture with non-toxic pharmaceutically acceptable excipients is used for the manufacture of tablets. Examples of such excipients include, without limitation, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thereby to provide a sustained therapeutic action over a desired time period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[00366] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [00367] For aqueous suspensions, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, may be admixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include, without limitation, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia.

[00368] Oral suspensions can also contain dispersing or wetting agents, such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[00369] Oily suspensions may be formulated by suspending a compound of the present disclosure in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol.

[00370] Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[00371] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide a compound of the present disclosure in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[00372] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation reaction products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[00373] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, or flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable, an aqueous suspension, or an oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may find use in the preparation of injectables.

[00374] The compound of Formula (I), or a pharmaceutically acceptable salt thereof, may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

[00375] Compositions for parenteral administrations are administered in a sterile medium. Depending on the vehicle used and concentration the concentration of the drug in the formulation, the parenteral formulation can either be a suspension or a solution containing dissolved drug. Adjuvants such as local anesthetics, preservatives and buffering agents can also be added to parenteral compositions.

Solid Dispersions

[00376] The solid dispersions described below are also described in, for example, U.S. Provisional Patent Application No. 63/064,866 the disclosure of which is expressly incorporated herein for all purposes. [00377] The term "dispersion" refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g, colloidal particles of nanometer dimension, to multiple microns in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include a crystalline therapeutically active compound (dispersed phase) in an amorphous polymer(s) (continuous phase), or alternatively, an amorphous therapeutically active compound (dispersed phase) in an amorphous polymer (continuous phase).

[00378] The term "amorphous solid dispersion" generally refers to a solid dispersion of two or more components, usually a therapeutically active compound and polymer (or plurality of polymers), but possibly containing other components such as surfactants or other pharmaceutical excipients, where the therapeutically active compound is in the amorphous phase, and the physical stability and/or dissolution and/or solubility of the amorphous therapeutically active compound is enhanced by the other components. In some embodiments, an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the dispersed phase, and the therapeutically active compound constitutes the continuous phase. In some embodiments, an amorphous solid dispersion includes the polymer(s) (and optionally a surfactant) constituting the continuous phase, and the therapeutically active compound constitutes the dispersed phase.

[00379] An exemplary solid dispersion is a co-precipitate or a co-melt of a particular therapeutically active compound with one or more polymer(s). A "co-precipitate" is produced after dissolving a therapeutically active compound and one or more polymer(s) in a solvent or solvent mixture followed by the removal of the solvent or solvent mixture. Sometimes the one or more polymer(s) can be suspended in the solvent or solvent mixture. The solvent or solvent mixture includes organic solvents and supercritical fluids. The solvent or solvent mixture can also contain anon-volatile solvent. A "co-melt" is produced after heating a therapeutically active compound and one or more polymer(s) to melt, optionally in the presence of a solvent or solvent mixture, followed by mixing, removal of at least a portion of the solvent if applicable, and cooling to room temperature at a selected rate. In some cases, solid dispersions are prepared by adding a solution of a therapeutically active compound and solid polymers followed by mixing and removal of the solvent or solvent mixture. To remove the solvent or solvent mixture, vacuum drying, spray drying, tray drying, lyophilization, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this disclosure, would provide the particular therapeutically active compound in an amorphous state in the final solid dispersion product.

Processes for preparing solid dispersions

[00380] In some embodiments, the solid dispersion may be prepared according to a process described herein. In some embodiments, a solid state form as described herein may be used as the starting material in a process to prepare the solid dispersion. In some embodiments, the solid state form used as a starting material in the process to prepare the solid dispersion is one of the crystalline forms described herein. In some embodiments, where the solid state form is a basic salt, the process to prepare the solid state dispersion includes an optional de-salting step, whereby the basic salt is converted to the free base or neutral form prior to preparing the dispersion.

[00381] In general, methods that could be used include those that involve rapid removal of solvent or solvent mixture from a mixture or cooling a molten sample. See, e.g., International Patent Publication Nos. WO-2019/090059 and WO-2015/138837, which are incorporated herein by reference. Such methods include, but are not limited to, rotational evaporation, freeze-drying (i.e., lyophilization), vacuum drying, melt congealing, and melt extrusion. One embodiment of this disclosure involves solid dispersion obtained by spraydrying. In one embodiment, the product obtained by spray drying is dried to remove the solvent or solvent mixture.

[00382] Preparations disclosed herein, e.g., a pharmaceutical composition, can be obtained by spray-drying a mixture comprising Compound I, or a pharmaceutically acceptable salt thereof, one or more polymer(s), and an appropriate solvent or solvent mixture. Spray drying involves atomization of a liquid mixture containing, e.g., a solid and a solvent or solvent mixture, and removal of the solvent or solvent mixture. The solvent or solvent mixture can also contain a non-volatile solvent. Atomization may be done, for example, through a two-fluid or pressure or electrosonic nozzle or on a rotating disk.

[00383] Spray drying converts a liquid feed to a dried particulate form. Spray drying generally involves the atomization of a liquid feed solution into a spray of droplets and contacting the droplets with hot air or gas in a drying chamber. The sprays are generally produced by either rotary (wheel) or nozzle atomizers. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled temperature and airflow conditions. [00384] Optionally, a secondary drying process such as fluidized bed drying or vacuum drying, may be used to reduce residual solvents (and other additives, such as glacial acetic acid) to pharmaceutically acceptable levels. Typically, spray-drying involves contacting a highly dispersed liquid suspension or solution (e.g., atomized solution), and a sufficient volume of hot air or gas (e.g., nitrogen, e.g, pure nitrogen) to produce evaporation and drying of the liquid droplets. The preparation to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that may be atomized using the selected spray-drying apparatus. In a standard procedure, the preparation is sprayed into a current of warm filtered air (or into gas, e.g, nitrogen) that evaporates the solvent and conveys the dried product to a collector (e.g, a cyclone). The spent air or gas is then exhausted with the solvent (or solvent mixture including any additives such as glacial acetic acid), (e.g, then filtered) or alternatively the spent air or gas is sent to a condenser to capture and potentially recycle the solvent or solvent mixture. For example, if a gas (e.g, nitrogen) is used, the gas is then optionally recycled, heated again and returned to the unit in a closed loop system. Commercially available types of apparatus may be used to conduct the spraydrying. For example, commercial spray dryers are manufactured by Buchi Ltd. and Niro (e.g, the PSD line of spray driers manufactured by Niro).

[00385] Spray-drying typically employs solids loads of material from about 1% to about 30% or up to about 50% (i.e., therapeutically active compound plus and excipients), preferably at least about 10%. In some embodiments, solids loads of less than 10% may result in poor yields and unacceptably long run-times. In general, the upper limit of solids loads is governed by the viscosity of (e.g, the ability to pump) the resulting solution and the solubility of the components in the solution. Generally, the viscosity of the solution can determine the size of the particle in the resulting powder product.

[00386] Techniques and methods for spray-drying may be found in Perry's Chemical Engineering Handbook, 6th Ed., R. H. Perry, D. W. Green & J. O. Maloney, eds., McGraw-Hill Book Co. (1984); and Marshall "Atomization and Spray -Drying" 50, Chem. Eng. Prog. Monogr. Series 2 (1954). In general, the spray-drying is conducted with an inlet temperature of from about 40°C to about 200°C, for example, from about 70°C to about 150°C, preferably from about 40°C to about 60°C, about 50°C to about 55°C, or about 80°C to about 110°C, e.g, about 90°C. The spray-drying is generally conducted with an outlet temperature of from about 20 °C to about 100°C, for example from about 25°C to about 30°C (e.g, about 26°C), about 40°C to about 50°C, about 50°C to about 65°C, e.g, about 56°C to about 58°C. [00387] Removal of the solvent or solvent mixture may require a subsequent drying step, such as tray drying, fluid bed drying (e.g., from about room temperature to about 100°C), vacuum drying, microwave drying, rotary drum drying or biconical vacuum drying (e.g, from about room temperature to about 200°C).

[00388] In one embodiment, the spray-drying is fluidized spray drying (FSD). The steps in FSD can include, for example: preparing a liquid feed solution (e.g., containing Compound I or a pharmaceutically acceptable salt thereof, and optionally a polymer(s) and/or surfactant(s), dissolved or suspended in solvent(s)); atomizing (e.g, with a pressure nozzle, a rotary atomizer or disk, two-fluid nozzle or other atomizing methods) the feed solution upon delivery into the drying chamber of a spray dryer, e.g., operating in FSD mode; drying the feed solution in the drying chamber with heated air or a heated gas (e.g. , nitrogen) to obtain a product, wherein larger particles of product separate out, e.g., drop out, while fines are carried by a stream of air or gas up to the top of the drying chamber (e.g., by natural convection) and to a cyclone, and re-introducing (e.g., at the top of the drying chamber or axially to the middle of the chamber) the fines into the drying chamber, wherein the reintroduced fines can agglomerate with newly formed product to generate an agglomerated product, wherein if the agglomerated product is large enough, it will separate out, if it is not large enough to separate out, the agglomerated product will be carried by convection to the top of the chamber and to the cyclone and re-introduced into the chamber. This process repeats until an agglomerated product that is large enough to drop out is formed. The fines can be re-introduced from the cyclone to the drying chamber via a feed pipe.

[00389] In some embodiments, the process includes an optional step of desalting the pharmaceutically acceptable salt of Compound I (so as to form the free base of Compound I) prior to preparing the liquid feed solution.

[00390] In some embodiments, rather than drying the feed solution with heated air or a heated gas, the feed solution can instead be spray congealed, e.g., the chamber is at room temperature (e.g, 21 ± 4 °C) or is cooled, e.g., cooled gas (e.g., nitrogen) is used for the process.

[00391] FSD can further include collecting the agglomerated product in a first fluidizing chamber; which can be followed by discharging the agglomerated product from the first fluidizing chamber to a second fluidizing chamber, wherein a post-drying process can occur.

[00392] The agglomerated product (e.g. , that separates out in the drying chamber) can then be transferred from the second fluidizing chamber to a third fluidizing chamber, where the agglomerated product is cooled. The agglomerated product (e.g., a solid dispersion of an amorphous compound) can then be further processed. For example, the product can be directly compressed. The product can optionally be blended with a surfactant, excipient, or pharmaceutically acceptable carrier, e.g., prior to direct compression. The product can optionally be further processed, e.g., milled, granulated, blended, and/or mixed with a melt granulate, surfactant, excipient, and/or pharmaceutically acceptable carrier.

[00393] FSD can be performed in a commercial spray dryer operating in fluidized spray dryer mode (FSD mode). FSD can be accomplished in either open cycle mode or closed cycle mode (e.g., the drying gas, e.g., nitrogen, is recycled). Examples of suitable spray dryers for use in FSD include dryers from Niro (e.g., the PSD line of spray driers manufactured by Niro: PHARMASD™; Chemical or SD line dryers). FSD can essentially be performed in any spray dryer that is configured to allow for the re-introduction of fines into the drying chamber.

[00394] Additional post drying, e.g. , in a vacuum or fluidized bed dryer or a double cone or biconical post-dryer or a tumble dryer, can be performed if needed/applicable to remove further solvents. In some embodiments, a post-drying step is performed.

[00395] To remove the solvent or solvent mixture, vacuum drying, spray drying, fluidized spray drying, tray drying, lyophilization, rotovapping, and other drying procedures may be applied. Applying any of these methods using appropriate processing parameters, according to this disclosure, would provide Compound I, or a pharmaceutically acceptable salt thereof in an amorphous state in the final solid dispersion product. Upon use of appropriate conditions (e.g., low outlet temperatures in the spray dryer, use of low boiling point solvents, use of heated gas) that result in a dispersion, e.g., powder, with desirable properties (e.g., median particle size (dso) of 40-200 microns, e.g., 40-150 microns), powder bulk density of >0.2 g/ml (e.g., 0.2 to 0.5 g/ml), or > 0.25 g/ml, improved powder flowability (e.g., low cohesion forces, low interparticle internal friction); and/or dry powder with low OVIs (Organic Volatile Impurities), e.g., below ICH limits and/or user specifications), the dispersion can be directly compressed into a dosage form.

[00396] In some embodiments, the inlet temperature is about 50°C to about 200°C, e.g., about 60°C to about 150°C, about 70°C to about 100°C, about 60°C to about 95°C, about 65°C to about 85°C, about 70°C to about 90°C, about 85°C to about 95°C, or about 70°C to about 85°C.

[00397] In some embodiments, the outlet temperature is about room temperature (e.g., USP room temperature (e.g., 21 ± 4°C)) to about 80°C, e.g., about 25°C to about 75°C, about 30°C to about 65°C, about 35°C to about 70°C, about 40°C to about 65°C, about 45°C to about 60°C, about 35°C to about 45°C, about 35°C to about 40°C, or about 37°C to about 40°C.

[00398] In some embodiments, the temperature set points of the fluidized beds (the temperature for each bed being selected independently from the temperature selected for another bed) is about room temperature (e.g, USP room temperature (e.g, 21±4°C)) to about 100°C, e.g, about 30°C to about 95°C, about 40°C to about 90°C, about 50°C to about 80°C, about 60°C to about 85°C, about 65°C to about 95°C, or about 80°C to about 95°C.

[00399] FSD can be performed on a mixture containing a compound of interest (e.g, a therapeutically active compound or API such as Compound I, or a pharmaceutically acceptable salt thereof). For example, FSD can be performed on a mixture containing Compound I, or a pharmaceutically acceptable salt thereof and one or more polymer(s), and optionally one or more surfactant(s), and optionally one or more additional excipients(s)) to obtain a solid dispersion of amorphous Compound I, or a pharmaceutically acceptable salt thereof that can be directly compressed into an oral dosage form (e.g, tablet). Alternatively, the dispersion can be blended with one or more excipients prior to compression.

[00400] In one embodiment, the process for preparing a solid dispersion of compound I comprises:

[00401] a) forming a mixture of Compound I, or a pharmaceutically acceptable salt thereof, one or more polymer(s), and one or more solvent(s); and

[00402] b) rapidly removing the solvent(s) from the solution to form a solid amorphous dispersion comprising Compound I, or a pharmaceutically acceptable salt thereof, and the one or more polymer(s). The one or more polymer(s) and one or more solvent(s) may be any of those disclosed herein.

[00403] In some embodiments, the process includes an optional step of desalting the pharmaceutically acceptable salt of Compound I (so as to form the free base of Compound I) prior to the process for preparing a solid dispersion.

[00404] In some embodiments, the solvent is removed by spray drying. In other embodiments the solid dispersion is tray dried using a convection tray dryer. In further embodiments, the solid dispersion is screened.

[00405] In one embodiment, Compound I, or a pharmaceutically acceptable salt thereof, is crystalline. In another embodiment, Compound I, or a pharmaceutically acceptable salt thereof, is amorphous. [00406] As would be appreciated by one of skill in the art, spray drying may be done and is often done in the presence of an inert gas such as nitrogen. In certain embodiments, processes that involve spray drying may be done in the presence of a supercritical fluid involving carbon dioxide or a mixture including carbon dioxide.

[00407] In another embodiment, the process for preparing a solid dispersion of Compound I, or a pharmaceutically acceptable salt thereof, comprises:

[00408] a) forming a mixture of Compound I, or a pharmaceutically acceptable salt thereof, at least one polymer, and a solvent; and

[00409] b) spray-drying the mixture to form a solid dispersion comprising Compound I, or a pharmaceutically acceptable salt thereof, and the polymer.

[00410] In some embodiments the process for preparing a solid dispersion of a pharmaceutically acceptable salt of Compound I optionally includes a step of de-salting the pharmaceutically acceptable salt of Compound I (so as to form the free base of Compound I) prior to the step of forming a mixture with the at least one polymer and the solvent.

[00411] Post-drying and/or polishing the wet spray dried dispersion to below ICH or given specifications for residual solvents can optionally be performed.

[00412] These processes may be used to prepare the pharmaceutical compositions disclosed herein. The amounts and the features of the components used in the processes may be as disclosed herein.

[00413] In some embodiments, the solvent comprises one or more volatile solvent(s) to dissolve or suspend Compound I, or a pharmaceutically acceptable salt thereof, and the polymer(s). In other embodiments, the one or more solvent(s) completely dissolves Compound I, or a pharmaceutically acceptable salt thereof, and the polymer(s). Solvents suitable for use in spray-drying processes will tend to be those that are volatile at the temperature and pressure of the drying process to facilitate removal of the solvent from the dispersion.

[00414] In some embodiments, the solvent is a volatile solvent. In other embodiments the solvent is a mixture of two or more volatile solvents. Examples of suitable volatile solvents include those that dissolve or suspend the therapeutically active compound either alone or in combination with another co-solvent. In other embodiments, the solvent(s) completely dissolves the therapeutically active compound.

[00415] In some embodiments, the solvent is a non-volatile solvent. In other embodiments the non-volatile solvent is water. In other embodiments, a non-volatile solvent is a component in a mixture comprising two or more solvents in any ratio. For example the non-volatile solvent may be present as a component in a mixture of solvents from about 1% to about 20% w/w (e.g, from about 3% w/w to about 15% w/w, from about 4% w/w to about 12% w/w, or from about 5% w/w to about 10% w/w).

[00416] In some embodiments, the solvent is a mixture of solvents. For example, the solvent mixture can include from about 0% to about 30% of solvent A and from about 70% to about 100% of solvent B, or the solvent mixture can include from about 0% to about 40% solvent A and from about 60% to about 100% solvent B. Other exemplary ratios of various solvents may include 80:20, 75:25, 70:30, 60:40, 55:45, and 50:50.

[00417] In some embodiments, the solvent is a mixture of solvents including at least one non-volatile solvent. For example, the solvent is a combination of components that includes both a volatile solvent and a non-volatile solvent.

[00418] In some embodiments, the solvent is a mixture of two or more volatile solvents and a non-volatile solvent such as water. For example, the solvent mixture may comprise from about 40% to about 80% of a first volatile solvent, from about 20% to about 35% of a second volatile solvent, and from about 0.1% to about 15% of a non-volatile solvent (e.g, from about 50% to about 70% of a volatile solvent, from about 25% to about 30% of another, different volatile solvent, and from about 1% to about 5% of a non-volatile solvent).

METHODS OF USE

[00419] In some embodiments, the methods of treatment set forth in the present disclosure may be used in treating a patient who has failed to respond, ceased responding, or experienced disease progression after one or more prior lines of therapy. In other embodiments, the methods of treatment set forth in the present disclosure may used in newly diagnosed patients (e.g. as a first line therapy).

[00420] In one embodiment, the methods of treatment set forth in the present disclosure may be used as a second line of therapy for the treatment of the cancer.

[00421] In another embodiment, the methods of treatment set forth in the present disclosure may be used as a third line of therapy for the treatment of the cancer.

[00422] In some embodiments, the dosage of the compounds used in the methods of treatment set forth in the present disclosure are administered by once or twice daily dosing.

[00423] In some embodiments, the dosage of the compounds used in the methods of treatment set forth in the present disclosure are administered orally. [00424] In embodiments in which the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the dosage is measured as an amount corresponding to an amount of free form equivalent of the Compound of Formula (I).

[00425] For each of the embodiments and aspects of the methods of the disclosure, the method may further comprise administering radiation therapy to the patient.

[00426] One or more aspects and embodiments may be incorporated in a different embodiment although not specifically described. That is, all aspects and embodiments described herein may be combined in any way or combination.

EXAMPLES

[00427] The present disclosure will be more fully understood by reference to the following examples. The examples should not, however, be construed as limiting the scope of the present disclosure.

[00428] The compound of Formula (I), which, as noted above, may also be referred to as Compound I, or Cmpd I, may be synthesized as set forth in International Application No. PCT/US2017/049439, which published as WO 2018/045071, and herein incorporated by reference in its entirety.

Example 1. Synergy Screen of MAT2A inhibitor and cancer therapeutic agents

[00429] A synergy screen was performed to evaluate potential synergistic effects of combining MAT2A inhibitor with other therapeutic agents for the treatment of cancer. These agents included those that Aurora kinase (e.g. ABT-348, AZD-1152), PARP (e.g. olaparib, BMN673), DNA cross-linking agents (e.g. oxaliplatin, cisplatin), cell cycle checkpoint inhibitor (e.g. AZD 7762, LY2603618), MDM2 pathway (e.g. JNJ 26854165, nutlin-3), antimetabolites (e.g. gemcitabine, pemetrexed), DNA hypomethylating agents (e.g. azacytidine, decitabine), mTOR pathway (e.g. everolimus), microtubule stabilization (e.g. paclitaxel), ATM pathway (e.g. KU-60019), CDK4/6 pathway (e.g. PD-0332991), and PRMT5 inhibitors (AGI-219 and AGI-931). Serial dilutions were prepared of MAT2A inhibitor (Compound I) and the combination agent in a dose matrix and treated a panel of 37 cancer cell lines (Table I) to assess for possible synergistic effects on cell growth inhibition. Table I. Cancer cell lines used to evaluate potential synergy between Compound I and other cancer therapeutic agents

[00430] Cells were seeded in appropriate growth media in black 384-well tissue culture-treated plates at 500 to 1,500 cells per well. Cells were equilibrated in assay plates via centrifugation and placed in incubators at 37°C for 24 hours before treatment. At the time of treatment, a set of untreated assay plates was collected and analyzed for ATP levels using CellTiter-Glo 2.0. These plates were designated TO and were read using ultra-sensitive luminescence on Envision plate readers (Perkin Elmer). Assay plates were then incubated for 96 hours with Compound I and combination agents, then analyzed using CellTiter-Glo (Promega). All datapoints were collected, processed, and analyzed using Horizon Discovery’s proprietary software. All summary data, including Synergy Scores, were fitted using linear interpolation. Chalice Analyzer software was used for data analysis.

Determination of combination benefit

[00431] The Loewe Additivity model is dose based and applies only to the activity levels achieved by the single agents. Loewe Volume is used to assess the overall magnitude of the combination interaction in excess of the Loewe Additivity model. Loewe Volume is particularly useful when distinguishing synergistic increases in a phenotypic activity (positive Loewe Volume) versus synergistic antagonisms (negative Loewe Volume). When antagonisms are observed, the Loewe Volume should be assessed to examine if there is any correlation between antagonism and a drug target-activity or cellular genotype. This model defines additivity as a nonsynergistic combination interaction, where the combination dose matrix surface should be indistinguishable from either drug crossed with itself. The equation used for Loewe additivity is:

Aoewe that satisfies (X/Xi)+(Y/Yi)=l Where Xi and Yi are the single-agent effective concentrations for the observed combination effect /. For example, if 50% inhibition is achieved separately by 1-pM Drug A or 1-pM Drug B, a combination of 0.5-pM Drug A and 0.5-pM Drug B should also inhibit by 50%.

[00432] Activity observed in excess of Loewe Additivity identifies potential synergistic interaction. For the analysis in this study, empirically derived combination matrices were compared to their respective Loewe Additivity models constructed from experimentally collected single-agent dose-response curves. Summation of this excess additivity across the dose-response matrix is referred to as Loewe Volume. Positive Loewe Volume suggests potential synergy, while negative Loewe Volume suggests potential antagonism.

[00433] To measure combination effects in excess of Loewe additivity, a scalar measure devised by the Horizon Discovery was used to characterize the strength of synergistic interaction, termed the Synergy Score. The Synergy Score was calculated as:

Synergy Score=log/x log/y X max(0,Idata)(Idata-lLoewe) [00434] The fractional inhibition for each component agent and combination point in the matrix was calculated relative to the median of all untreated/vehicle-treated control wells. The Synergy Score equation integrated the experimentally observed activity volume at each point in the matrix in excess of a model surface numerically derived from the activity of the component agents using the Loewe Additivity model. Additional terms in the Synergy Score equation were used to normalize for various dilution factors used for individual agents and to allow for comparison of Synergy Scores across an entire experiment. The inclusion of positive inhibition gating or an Idata multiplier removed noise near the zeroeffect level, and biases results for synergistic interactions that occurr at high activity levels. Combinations with higher maximum growth inhibition effects or those which were synergistic at low concentrations had higher Synergy Scores.

[00435] Potency shifting was evaluated using an isobologram, which demonstrated how much less drug was required in combination to achieve a desired effect level when compared to the single-agent doses needed to reach that effect. The isobologram was drawn by identifying the locus of concentrations that corresponded to crossing the indicated inhibition level. This was done by finding the crossing point for each single-agent concentration in a dose matrix across the concentrations of the other single agent. Practically, each vertical concentration (CY) was held fixed while a bisection algorithm was used to identify the horizontal concentration (Cx) in combination with that vertical dose that gave the chosen effect level in the response surface Z(CX,CY). These concentrations were then connected by linear interpolation to generate the isobologram display. For synergistic interactions, the isobologram contour would fall below the additivity threshold and approach the origin, and an antagonistic interaction would he above the additivity threshold. The error bars represent the uncertainty arising from the individual data points used to generate the isobologram. The uncertainty for each crossing point was estimated from the response errors using bisection to find the concentrations where Z-OZ(CX,CY) and Z+OZ(CX,CY) crossed /cut, where oZ was the standard deviation of the residual error on the effect scale.

[00436] The Combination of Compound I and several agents demonstrated a therapeutic advantage. (Figure 15).

Example 2. Combination with Pemetrexed

[00437] Methionine metabolism is intersected with folic acid metabolism. Concordantly, the synergy score analysis suggested potential combination benefit of pemetrexed and Compound I combination in some cancer cell lines (Figure 15). To further evaluate the combination of pemetrexed and Compound I, KP-4 cells were treated with Compound I and pemetrexed using a similar method described in the synergy screen experiment (Example 1). The combination indexes (CI) was determined across multiple dosing levels using Chou-Talalay method. The minimal CI observed was 0.05, indicating strong synergy between MAT2A inhibitor Compound I and pemetrexed (Figure 16).

[00438] Notably, the combination benefit between Compound I and pemetrexed was also observed in cell lines carrying wildtype MTAP gene. For example, the min CI was 0.45 in HCT-116 cells, while the minimal CI was 0.15 in NCI-H2122 cells (Figure 16).

Example 3. DNA methylation reduction by MAT2A inhibitor

[00439] Whole genome bisulfite sequencing (WGBS) of TF1 leukemia cells treated either with DMSO or Compound I for 6 days was performed to assess whether MAT2A inhibition by Compound I has an impact on DNA methylation. The result of WGBS revealed a significant reduction (~8%) in the CpG sites upon treatment with Compound I, indicating that MAT2A inhibition by Compound I reduces DNA methylation and may be beneficial in combination with DNA hypomethylating agents. The results are shown in Fig. 12.

Example 4: In-cell Western (ICW) assay/ Combination with PRMT inhibitors

[00440] The TF1 cells (5000cells) were plated in 96 well tissue culture plates pretreated with Cell-Tak and allowed to attach overnight at 37°C in 5% CO2. Compound I was added in a dose-response format in 3 rows to generate a 9 point dose-response curve in triplicate. Doses started at a 2 pM top concentration with 1:3 serial dilution. Compound I was diluted in DMSO to a final concentration of 0.2% DMSO in media. One column on each plate was designated for the 0.2% DMSO control. Cells were incubated with Compound I for 96 hours. After this treatment period, media was removed and cells stained with antibodies against SDMA protein marks (Cell Signaling Technology #13222), ADMA (Cell Signaling Technology #13522) as well as with nonspecific cell stain CellTag 700 (Cell Signaling Technology #926-41090). The change in SDMA level for each compound dose and the DMSO control was calculated by normalizing the SDMA/ ADMA signal in each well to the CellTag 700 signal in order to adjust for the effect of compound treatment on cell number. The SDMA level change was then plotted as SDMA Inhibition (%) (normalized to each cell line DMSO control sample) against loglO of compound concentration in molar (M) units. Curve fitting was performed using a four parameter logistic regression. The percentage of SDMA/ADMA inhibition was calculated as follows: SDMA Inhibition (%) =100*(l- SDMA/ADMAdose/SDMA/ADMADMSO control).

[00441] To assess whether MAT2A inhibition changes the enzymatic activity of protein arginine methyl transferases PRMT5 and PRMT1, TF1 cells were cultured for 96h in the presence of DMSO or with increasing doses of Compound I. The cells were then fixed and stained with antibodies, which recognize either PRMT5-dependent SDMA or PRMT1- dependent ADMA. The staining intensity for ADMA and SDMA was analyzed quantified using a LI- COR imaging system (Figure 18). This analysis revealed that Compound I treatment reduced the level of ADMA in a dose-dependent manner, without altering the level of SDMA.

Example 5: Combination between Compound I and PRMT1 inhibitor

[00442] To assess whether MAT2A inhibitor can combine with PRMT1 inhibitor and enhance its in vitro potency, cell growth inhibition analysis on TF1 and MV4- 11 cell lines was performed. These cells were plated in 96-well plate and incubated for 96 hours with increasing concentrations of PRMT1 inhibitor (GSK3368715), in the presence of either DMSO or 1 pmol/L Compound I. Cell growth inhibition was measured using Cell Titer Gio assay. This analysis demonstrated that MAT2A inhibitor can enhance the ability of PRMT1 inhibitor to delay the growth of TF1 and MV4-11 cells (Figure 19).

Example 6: Combination of compound of Formula (I) and Venetoclax/ Azacitidine in an AML THP-1 Xenograft Model

[00443] Study Objective: The objectives of this study were to evaluate the potential efficacy of 1) the compound of Formula (I) given once daily (PO), alone, 2) the combination of compound of Formula (I) in combination with Venetoclax/ Azaciti dine, 3) replacing Azacitidine with compound of Formula (I) in the Venetoclax/ Azaciti dine combination doublet, all in established MTAP-deficient AML xenograft tumors (THP-1), in female NOD SCID mice.

[00444] Study Design: 20-22 gram female, NOD SCID mice were subcutaneously inoculated with 5x10⁶ THP-1 cells in serum free media + Matrigel (1: 1). The mice were randomized on Day 14 once tumors averaged 144 mm³, into treatment groups and dosed as outlined in Table 2.

[00445] Materials and Methods: Tumor volumes were measured twice weekly in two dimensions using a caliper, and the volume was expressed in mm³ using the formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (perpendicular to L). Body weights were measured twice per week.

[00446] The compound of Formula (I) was supplied as a formulation comprising amorphous Formula (I). The compound was stored at 4°C protected from light. The compound of Formula (I) was formulated daily in a vehicle consisting of 2.86% w/w polymer A, 1% w/w Polymer B, 2% w/w surfactant, and 0.1% excipient. Formulated, the compound of Formula (I) is stable for 24 hours when stored at 4°C protected from light.

[00447] The compound of Formula (I) was dosed orally at 100 mg/kg, daily, for Groups 2, 6 and 7.

[00448] Azacitidine was purchased from Selleck (China, Cat. No. SI 782) and formulated in sterile saline. Azacitidine was dosed IP using 3 mg/kg for Groups 3, 5 and 7.

[00449] Venetoclax was purchased from Selleck (China, Cat. No. 8048) and formulated in 5%DMSO+50%PEG300+5%Tween80+40%H20. Venetoclax was dosed PO using 50 mg/kg for Groups 4, 5, 6 and 7. [00450] Vehicle preparation for Group 1 (vehicle only) matched that of the compound of Formula (I) formulation, Azacitidine and Venetoclax vehicles, respectively. Results:

[00451] Treatment with the vehicle was well tolerated with 0% body weight loss (BWL) during the study. Tumor volume reach a median of 1571.95 mm³ on day 17 of treatment (Table 2), last tumor measurement for this group.

[00452] Treatment with 100 mg/kg of the compound of Formula (I) alone (Group 2) was well tolerated with maximal median BWL of 2% on day 14 of treatment. Tumor volume reached a median of 1123.94 mm³ on day 28 of treatment, last tumor measurement for this group.

[00453] Treatment with 3 mg/kg Azacitidine alone (Group 3) was well tolerated with 0% BWL during the study. Tumor volume reached a median of 1319.61 mm³ on day 17 of treatment, last tumor measurement for this group.

[00454] Treatment with 50 mg/kg Venetoclax alone (Group 4) was well tolerated with maximal mean BWL of 2% on day 3 of treatment. Tumor volume reached a median of 1319.61 mm³ on day 17 of treatment, last tumor measurement for this group.

[00455] Treatment with the combination of 50 mg/kg Venetoclax and 3 mg/kg Azacitidine (Group 5) was well tolerated with a median BWL of 2% on day 14 of treatment. Tumor volume reached a median of 925.92 mm³ on day 21 of treatment, last tumor measurement for this group.

[00456] Treatment with the combination of 50 mg/kg Venetoclax and 100 mg/kg of the compound of Formula (I) (Group 6) was well tolerated with a median BWL of 6% on day 17 of treatment. Tumor volume reached a median of 478.03 mm³ on day 34 of treatment, last tumor measurement for this group.

[00457] Treatment with the combination of 50 mg/kg Venetoclax + 3 mg/kg Azacitidine + 100 mg/kg of the compound of Formula (I) (Group 7) was well tolerated with a median BWL of 13% on day 34 of treatment. Tumor volume reached a median of 119.84 mm³ on day 34 of treatment, last tumor measurement for this group.

[00458] The tumor volumes from each group are shown in Table 3 and are illustrated graphically in Figure 20, and the results by Group are shown in Table 3. Combination therapy using Compound I, Venetoclax and Azaciditine demonstrated additive anti-tumor activity and the combination of Venetoclax and the compound of Formula (I) demonstrated synergy.

[00459] All publications, patents and patent applications cited in this specification are incorporated herein by reference for the teaching to which such citation is used. [00460] The specific responses observed may vary according to and depending on the dosing of the particular active compound or combination selected, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with practice of the present invention.

[00461] Although specific embodiments of the present application are herein illustrated and described in detail, the application is not limited thereto. The above detailed descriptions are provided as exemplary and should not be construed as limiting. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the application are intended to be included with the scope of the appended claims.

Claims

What is claimed is:

1. A method for the treatment of cancer in a patient in need thereof, comprising administering to said patient:

(a) a therapeutically effective amount of a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof; and

(b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is a PARP inhibitor, a Chkl inhibitor, a MDM2 inhibitor, a hypomethylating agent, a mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a BCL-2 inhibitor, a PRMT5 inhibitor, or a PRMT1 inhibitor.

2. The method of claim 1, wherein said therapeutic agent is a PARP inhibitor.

3. The method of claim 2, wherein said PARP inhibitor is Olaparib (AZD2281), Veliparib (ABT-888), Rucaparib (AG-014699) phosphate, Talazoparib (BMN 673), AG- 14361, INO-1001 (3-Aminobenzamide), A-966492, PJ34 HC1, Niraparib (MK-4827), UPF 1069, ME0328, RK-287107, Pamiparib (BGB-290), NMS-P118, E7449, Picolinamide, Benzamide, Niraparib (MK-4827) tosylate, NU1025, Iniparib (B SI-201), AZD2461, BGP-15 2HC1, XAV-939, 4-Hydroxyquinazoline, NVP-TNKS656, MN 64, or G007-LK; or a pharmaceutically acceptable salt thereof.

4. The method of claim 3, wherein said PARP inhibitor is Olaparib (AZD2281), or Talazoparib (BMN 673); or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein said PARP inhibitor is Olaparib (AZD2281), or a pharmaceutically acceptable salt thereof.

6. The method of claim 4, wherein said PARP inhibitor is Talazoparib (BMN 673); or a pharmaceutically acceptable salt thereof.

7. The method of claim 1, wherein said therapeutic agent is a Chkl inhibitor.

8. The method of claim 7, wherein said Chkl inhibitor is AZD7762, Rabusertib (LY2603618), MK-8776 (SCH 900776), CHIR-124, PF-477736, VX-803 (M4344), GDC- 0575 (ARRY-575), SAR-020106, CCT245737, PD0166285, or Prexasertib HC1 (LY2606368); or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein said Chkl inhibitor is AZD7762 or

Rabusertib (LY2603618), or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein said Chkl inhibitor is AZD7762 or a pharmaceutically acceptable salt thereof.

11. The method of claim 9, wherein said Chkl inhibitor is Rabusertib (LY2603618) or a pharmaceutically acceptable salt thereof.

12. The method of claim 1, wherein said therapeutic agent is a MDM2 inhibitor.

13. The method of claim 12, wherein said MDM2 inhibitor is Nutlin-3, NSC 207895, Nutlin-3a, Nutlin-3b, MX69, NVP-CGM097, MI-773 (SAR405838), Idasanutlin (RG-7388), RG-7112, HDM201 (Siremadlin), YH239-EE, (-)-Parthenolide, or Serdemetan (JNJ-26854165); or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein said MDM2 inhibitor is Nutlin-3 or Serdemetan (JNJ-26854165), or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein said MDM2 inhibitor is Nutlin-3 or a pharmaceutically acceptable salt thereof.

16. The method of claim 14, wherein said MDM2 inhibitor is Serdemetan (JNJ- 26854165) or a pharmaceutically acceptable salt thereof.

17. The method of claim 1, wherein said therapeutic agent is a hypomethylating agent.

18. The method of claim 17, wherein said a hypomethylating agent is Decitabine, Azacitidine (5-Azacytidine), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-Deoxy- 5-Fluorocytidine, Procainamide HC1, Bobcat339 hydrochloride, Gamma-Oryzanol, - thujaplicin, or (-)-Epigallocatechin Gallate; or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein said a hypomethylating agent is Decitabine or Azacitidine (5-Azacytidine), or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein said a hypomethylating agent is Decitabine or a pharmaceutically acceptable salt thereof.

21. The method of claim 19, wherein said a hypomethylating agent is Azacitidine (5-Azacytidine) or a pharmaceutically acceptable salt thereof.

22. The method of claim 1, wherein said therapeutic agent is a mTOR inhibitor.

23. The method of claim 22, wherein said mTOR inhibitor is Dactolisib (BEZ235), Rapamycin (Sirolimus), Everolimus (RAD001), AZD8055, Temsirolimus (CCI- 779), PI- 103, KU-0063794, Torkinib (PP242), Ridaforolimus (Deforolimus, MK-8669),

59 Sapanisertib (MLN0128), Voxtalisib (XL765) Analogue, Torin 1, Omipalisib (GSK2126458), OSI-027, PF-04691502, Apitolisib (GDC-0980), GSK1059615, Gedatolisib (PKI-587), WYE-354, Vistusertib (AZD2014), Torin 2, WYE-125132 (WYE-132), PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, GNE-477, Bimiralisib (PQR309), SF2523, CZ415, Paxalisib (GDC-0084), CC-115, Onatasertib(CC 223), Voxtalisib (XL765), Zotarolimus(ABT-578), Tacrolimus (FK506), BGT226 maleate (NVP-BGT226 maleate), Palomid 529 (P529), LY3023414(Samotolisib), or Chrysophanic Acid; or a pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein said mTOR inhibitor is Everolimus (RAD001) or a pharmaceutically acceptable salt thereof.

25. The method of claim 1, wherein said therapeutic agent is an ATM inhibitor.

26. The method of claim 25, wherein said ATM inhibitor is KU-55933, KU- 60019, Wortmannin, Torin 2, CP-466722, ETP-46464, CGK 733, AZ32, AZD1390, AZ31, or AZD0156; or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein said ATM inhibitor is KU-60019 or a pharmaceutically acceptable salt thereof.

28. The method of claim 1, wherein said therapeutic agent is a CDK 4/6 inhibitor.

29. The method of claim 28, wherein said CDK 4/6 inhibitor is Palbociclib (PD- 0332991), Palbociclib (PD-0332991) HC1, Flavopiridol (Alvocidib), AT7519, Flavopiridol HC1, JNJ-7706621, PHA-793887, Palbociclib (PD0332991) Isethionate, abemaciclib mesylate (LY2835219), BMS-265246, Milciclib (PHA-848125), R547, Riviciclib hydrochloride (P276-00), MC180295, G1T38, Abemaciclib, ON123300, AT7519 HC1, Purvalanol A, SU9516, Ribociclib (LEE011), or BSJ-03-123; or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein said CDK 4/6 inhibitor is Palbociclib (PD- 0332991) or a pharmaceutically acceptable salt thereof.

31. The method of claim 1, wherein said therapeutic agent is a BCL-2 inhibitor.

32. The method of claim 31, wherein said BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, Venetoclax (ABT-199), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable salt thereof.

33. The method of claim 32, wherein said BCL-2 inhibitor is Venetoclax (ABT-

199), or a pharmaceutically acceptable salt thereof.

34. The method of claim 1, wherein said therapeutic agent is a PRMT5 inhibitor.

60

35. The method of claim 34, wherein said PRMT5 inhibitor is JNJ-64619178 (AGI-931), HLCL-61, GSK591, EPZ015666(GSK3235025), GSK3326595 (EPZ015938; AGI-219); or a pharmaceutically acceptable salt thereof.

36. The method of claim 35, wherein said PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or JNJ-64619178 (AGI-931); or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein said PRMT5 inhibitor is GSK3326595 (EPZ015938; AGI-219) or a pharmaceutically acceptable salt thereof.

38. The method of claim 36, wherein said PRMT5 inhibitor is JNJ-64619178 (AGI-931), or a pharmaceutically acceptable salt thereof.

39. The method of claim 1, wherein said therapeutic agent is a PRMT1 inhibitor.

40. The method of claim 39, wherein said PRMT1 inhibitor is GSK3368715 (EPZ019997), C7280948, EPZ020411 2HC1, MS023, or AMI-1; or a pharmaceutically acceptable salt of a listed compound.

41. The method of claim 40, wherein said PRMT1 inhibitor is GSK3368715 (EPZ019997), or a pharmaceutically acceptable salt thereof.

42. The method of any one of claims 1 to 41, further comprising administering to said patient a further therapeutic agent.

43. The method of claim 42, wherein said further therapeutic agent is a PARP inhibitor, a Chkl inhibitor, a MDM2 inhibitor, a hypomethylating agent, a mTOR inhibitor, an ATM inhibitor, a CDK 4/6 inhibitor, a PRMT5 inhibitor, a PRMT1 inhibitor, an antimetabolite, an Aurora inhibitor, a microtubule stabilizer, a DNA cross-linker, or a BCL-2 inhibitor.

44. The method of any one of claims 1 to 43, wherein the cancer is an MTAP- deficient cancer.

45. The method of any one of claims 1 to 43, wherein the cancer is an MTAP wild type cancer.

46. The method of any one of claims 1 to 45, wherein the cancer is a cancer that responds to a reduction in SAM as a result of administering an MAT2A inhibitor.

47. The method of any one of claims 1 to 46, wherein said cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer,

61 myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, or mesothelioma.

48. A method for the treatment of a cancer in a patient in need thereof, comprising administering to said patient:

(a) a therapeutically effective amount of a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof; and

(b) a therapeutically effective amount of a therapeutic agent, wherein said therapeutic agent is an antimetabolite, an Aurora inhibitor, a DNA-crosslinker, or a microtubule stabilizer; wherein said cancer is a MTAP wild type cancer.

49. The method of claim 48, wherein said cancer is a primary leukemia, hematological malignancies, acute myeloid leukemia (AML), glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, kidney cancer, colorectal cancer, esophageal cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, nonHodgkin lymphoma, or mesothelioma.

50. The method of claim 48 or claim 49, wherein said therapeutic agent is an antimetabolite.

51. The method of claim 50, wherein said antimetabolite is pemetrexed.

52. The method of claim 50, wherein said antimetabolite is gemcitabine, or a pharmaceutically acceptable salt thereof.

53. The method of claim 48 or claim 49, wherein said therapeutic agent is an Aurora inhibitor.

54. The method of claim 48 or claim 49, wherein said therapeutic agent is a microtubule stabilizer.

55. The method of claim 48 or claim 49, wherein said therapeutic agent is a DNA cross-linker.

56. A method for the treatment of cancer in a patient in need thereof, comprising administering to said patient: a therapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein said cancer is acute myeloid leukemia (AML).

57. The method of claim 56, wherein the AML is MTAP-deficient.

58. The method of claim 56, wherein the AML is MTAP wild type.

59. The method of any one of claims 56 to 58, wherein the AML responds to a reduction in SAM as a result of administering an MAT2A inhibitor.

60. The method of any one of claims 56 to 59, further comprising administering to said patient a therapeutically effective amount of a BCL-2 inhibitor.

61. The method of claim 60, wherein said BCL-2 inhibitor is ABT-737, Navitoclax (ABT-263), Obatoclax Mesylate (GX15-070), TW-37, Venetoclax (ABT-199), AT101, HA14-1, Sabutoclax, S55746, or Gambogic Acid; or a pharmaceutically acceptable salt thereof.

62. The method of claim 61, wherein said BCL-2 inhibitor is venetoclax, or a pharmaceutically acceptable salt thereof.

63. The method of any one of claims 60 to 62, further comprising administering to said patient a therapeutically effective amount of a hypomethylating agent.

64. The method of claim 63, wherein said a hypomethylating agent is Decitabine, Azacitidine (5-Azacytidine), RG108, Thioguanine, Zebularine, SGI-1027, CM272, 2'-Deoxy- 5-Fluorocytidine, Procainamide HC1, Bobcat339 hydrochloride, Gamma-Oryzanol, - thujaplicin, or (-)-Epigallocatechin Gallate; or a pharmaceutically acceptable salt thereof.

65. The method of claim 64, wherein said hypomethylating agent is Azacitidine (5-Azacytidine), or a pharmaceutically acceptable salt thereof.