WO2023201338A1

WO2023201338A1 - Combination therapy comprising a mat2a inhibitor and a parp inhibitor

Info

Publication number: WO2023201338A1
Application number: PCT/US2023/065780
Authority: WO
Inventors: Claire L. NEILAN; Marcus Michael FISCHER; Kelsey Elizabeth ANNEN; Jenny Leigh LARAIO; Anthony Mazurek
Original assignee: Ideaya Biosciences, Inc.; Tesaro, Inc.
Priority date: 2022-04-15
Filing date: 2023-04-14
Publication date: 2023-10-19

Abstract

Provided herein is a combination of a MAT2A inhibitor and a PARP inhibitor. Also provided are methods of using such combinations to treat diseases or disorders, for example, cancer.

Description

COMBINATION THERAPY COMPRISING A MAT2A INHIBITOR AND A PARP INHIBITOR

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 63/331 ,619, filed on April 15, 2022, the contents of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND

Cancer is a leading cause of death throughout the world. A limitation of prevailing therapeutic approaches, e.g. chemotherapy and immunotherapy, is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur within normal tissues.

Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosyl methionine (SAM). SAM is a primary methyl donor in cells used to methylate several substrates including DNA, RNA and proteins. One methylase that utilizes SAM as a methyl donor is protein arginine N- methyltransferase 5 (PRMT5). While SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5’methylthioadenosine (MTA). Since MTA is part of the methionine salvage pathway, cellular MTA levels stay low in a process initiated by methylthioadenosine phosphorylase (MTAP).

MTAP is in a locus on chromosome 9 that is often deleted in cells of patients with cancers from several tissues of origin including central nervous system, pancreas, esophageal, bladder and lung (cBioPortal database). Loss of MTAP results in the accumulation of MTA making MTAP-deleted cells more dependent on SAM production, and thus MAT2A activity, compared to cells that express MTAP. In an shRNA cell-line screen across approximately 400 cancer cell lines, MAT2A knockdown resulted in the loss of viability in a larger percentage of MTAP-deleted cells compare to MTAP WT cells (see McDonald et. al. 2017 Cell 170, 577-592). Furthermore, inducible knockdown of MAT2A protein decreased tumor growth in vivo (see Marjon et. al., 2016 Cell Reports 15(3), 574- 587). These results indicate that MAT2A inhibitors may provide a novel therapy for cancer patients including those with MTAP-deleted tumors.

Poly (ADP-ribose) polymerases (PARP) are a family of enzymes involved in DNA damage repair (DDR) by resolving single-strand breaks (SSBs) and double-strand breaks (DSBs), and by inducing base excision repair (BER). PARP inhibition leads to accumulation of single-strand breaks (SSBs) and which renders cells more dependent on other DNA repair pathways, namely, the homologous recombination (HR) repair pathway. Cancer cells with HR deficiencies are in turn susceptible to PARP impairment of the BER pathway. Poly (ADP- ribose) Polymerase (PARP) inhibitors are a class of compounds that act as inhibitors of Poly (ADP-ribose) polymerase. It is believed that PARP inhibitors are useful in the treatment of cancer by preventing cancer cells from repairing their DNA, leading to cellular death.

There are currently four approved PARP inhibitors (niraparib, olaparib, rucaparib and talazoparib), with many more currently in clinical trials.

Niraparib is approved as a PARP inhibitor for the maintenance treatment of adult patients with advanced or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy; and for the treatment of adult patients with advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD) status defined by either a deleterious or suspected deleterious BRCA mutation, or genomic instability and who have progressed more than six months after response to the last platinum-based chemotherapy.

Olaparib is approved as a PARP inhibitor for use in the treatment of ovarian cancer, breast cancer, pancreatic cancer and prostate cancer in certain patient subgroups. In ovarian cancer, olaparib is used for the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy; for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy; and for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

Rucaparib is approved as PARP inhibitor for use in the treatment of ovarian and prostate cancer in certain patient subgroups. Talazoparib is approved for use in the treatment of breast cancer in adult patients with deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced metastatic breast cancer.

Despite many recent advances in cancer therapies, there remains a need for more effective and/or enhanced treatment for those individuals suffering the effects of cancer.

SUMMARY

Provided herein is a combination comprising a methionine adenosyltransferase II alpha (MAT2A) inhibitor and a Poly (ADP-ribose) Polymerase (PARP) inhibitor. The combination is useful for the treatment of a variety of cancers, including solid tumors. The combination is also useful for the treatment of any number of MAT2A-associated diseases. The combination is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting MAT2A. The combination is useful for treating MTAP-deficient tumors. The combination is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting PARP.

Provided herein is a combination product comprising a methionine adenosyltransferase II alpha (MAT2A) inhibitor and a Poly (ADP-ribose)Polymerase (PARP) inhibitor. The combination product is useful for the treatment of a variety of cancers, including solid tumors. The combination product is also useful for the treatment of any number of MAT2A-associated diseases. The combination product is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting MAT2A. The combination product is useful for the treatment of MTAP-deficient tumors. The combination product is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting PARP.

In an embodiment, provided herein is a combination of a MAT2A inhibitor and a PARP inhibitor.

In an embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a PARP inhibitor.

In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and a PARP inhibitor, thereby treating the cancer in the subject.

In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and a PARP inhibitor together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

In still another embodiment, the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, absence of MTAP gene, reduced function of MTAP protein, reduced level or absence of MTAP protein, MTA accumulation, or combination thereof.

In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a MAT2A inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising a PARP inhibitor, thereby treating the cancer in the subject. In an embodiment, provided herein are methods of treating a disease or disorder treatable by inhibiting MAT2A in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and a PARP inhibitor, thereby treating the disease or disorder in the subject. In an embodiment, the disease or disorder is cancer.

In an embodiment, provided herein are methods of treating a disease or disorder treatable by inhibiting MAT2A in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and a PARP inhibitor, together with at least a pharmaceutically acceptable carrier, thereby treating the disease or disorder in the subject. In an embodiment, the PARP inhibitor is niraparib, or a pharmaceutically acceptable salt thereof. In an embodiment, the disease or disorder is cancer.

In an embodiment, the MAT2A inhibitor is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein the variables of Formula I are defined below.

In another embodiment, the MAT2A inhibitor is Compound A having the following structural formula:

Compound A or a pharmaceutically acceptable salt thereof. Compound A, and methods of making Compound A are disclosed in PCT/US 19/65260 (WO 2020/123395).

In another embodiment, the MAT2A inhibitor is Compound A1 having the following structural formula:

Compound A1 or a pharmaceutically acceptable salt thereof. Compound A1 , and methods of making Compound A1 are disclosed in PCT/US 19/65260 (WO 2020/123395).

MAT2A inhibitors for use in the combination therapy described herein are described in WO 2020/123395 (PCT/US19/65260), the generic and specific compounds described in this application can be used to treats cancer as described herein.

In yet another embodiment, the PARP inhibitor is niraparib (Compound B) having the following structural formula:

Compound B or a pharmaceutically acceptable salt thereof. The chemical name for niraparib is (S)-

2-(4-(piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide (or alternatively 2-{4-[(3S)-piperidin-

3-yl]phenyl}-2H-indazole-7-carboxamide).

In still another embodiment, the PARP inhibitor is rucaparib (Compound C) having the following structural formula

Compound C or a pharmaceutically acceptable salt thereof. The chemical name for rucaparib is 8- fluoro-5-(4-((methylamino)methyl)phenyl)-2,3,4,6-tetrahydro-1H-azepino[5,4,3-cd]indol-1- one.

In another embodiment, the PARP inhibitor is olaparib (Compound D):

Compound D or a pharmaceutically acceptable salt thereof. The chemical name for olaparib is 4- (3-(4-(cyclopropanecarbonyl)piperazine-1 -carbonyl )-4-fluorobenzyl)phthalazin-1(2H)-one. In another embodiment, the PARP inhibitor is talazoparib (Compound E):

Compound E or a pharmaceutically acceptable salt thereof. The chemical name for talazoparib is (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1 H-1 ,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H- pyrido[4,3,2-de]phthalazin-3-one.

In another embodiment, the PARP inhibitor is veliparib (Compound F):

Compound F or a pharmaceutically acceptable salt thereof. The chemical name for veliparib is (R)-

2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-7-carboxamide.

In another embodiment, the PARP inhibitor is AZD5305:

or a pharmaceutically acceptable salt thereof. The chemical name for AZD5305 is 5- [4-[(7-ethyl-6-oxo-5H-1 ,5-napthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2- carboxamide.

In another embodiment, the PARP inhibitor is AZD9574:

or a pharmaceutically acceptable salt thereof. The chemical name for AZD9574 is 6- fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl- pyridine-2-carboxamide. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A-1C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in NCI-H838 cell line.

FIG. 2A-2C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in NCI-H2228 cell line.

FIG. 3A-3C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in RT112/84 cell line.

FIG. 4A-4C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in UMUC5 cell line.

FIG. 5A-5C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in Pane 03.27 MTAP CRISPR knock-out cell line (Clone 31).

FIG. 6A-6C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in Pane 03.27 MTAP wild type cell line.

FIG. 7A-7C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in NCI-H520 MTAP wild type cell line.

FIG. 8A-8C depict excess over Bliss synergy of Compound A and PARP inhibitor combinations in TCCSUP MTAP wild type cell line.

DETAILED DESCRIPTION

Provided herein is a combination therapy comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof. The combination therapy is useful for the treatment of a variety of cancers, including, for example, pancreatic cancer and lung cancer. In another aspect, the combination therapy is useful for the treatment of any number of MAT2A-associated diseases.

Administering a combination of a MAT2A inhibitor and a PARP inhibitor can provide beneficial effects for treating cancer, e.g., solid tumors, in a subject. Such an approach - combination or co-administration of the two types of agents - may offer an uninterrupted treatment to a subject in need over a clinically relevant treatment period. Definitions

Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used in the specification and in the claims, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.

It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.

The terms “combination,” “therapeutic combination,” “pharmaceutical combination,” or “combination product” as used herein refer to either a fixed combination in one dosage unit form, or non-fixed combination in separate dosage forms, or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently, at the same time or separately within time intervals.

The term “combination therapy” refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations (e.g., capsules and/or intravenous formulations) for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times. Regardless of whether the active ingredients are administered as a single formulation or in separate formulations, the drugs are administered to the same patient as part of the same course of therapy. In any case, the treatment regimen will provide beneficial effects in treating the conditions or disorders described herein.

As used herein, the term “treating” or “treatment” refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (j.e. , arresting further development of the pathology and/or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and/or symptomology) such as decreasing the severity of the disease.

As used herein, the term “patient,” “individual,” or “subject” refers to a human.

As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein a parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts described herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts discussed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. The phrase “pharmaceutically acceptable salt” is not limited to a mono, or 1 :1 , salt. For example, “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of a compound disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. Other additional ingredients that may be included in the pharmaceutical compositions are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

The term “single formulation” as used herein refers to a single carrier or vehicle formulated to deliver therapeutically effective amounts of both therapeutic agents to a patient. The single vehicle is designed to deliver a therapeutically effective amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients. In some embodiments, the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.

As used herein “methionine adenosyltransferase II alpha inhibitor” or “MAT2A inhibitor” means an agent that modulates the activity of MAT2A or inhibits the production of S-adenosylmethionine (SAM) by methionine adenosyltransferase 2A (MAT2A).

As used herein, “Poly (ADP-ribose) Polymerase (PARP) inhibitor” refers to an agent that inhibits, PARP activity, including PARP1 and PARP2. Examples of PARP inhibitors include, but are not limited to, niraparib, rucaparib, olaparib, talazoparib, veliparib, AZD5305, and AZD9574, and pharmaceutically acceptable salts thereof.

The combination of agents described herein may display a synergistic effect. The term “synergistic effect” or “synergy” as used herein, refers to action of two agents such as, for example, a MAT2A inhibitor and a PARP inhibitor producing an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves. A synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981)), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, T. C. and Talalay, P., Adv. Enzyme Regul. 22: 27-55 (1984)). Each equation referred to above can be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

In an embodiment, provided herein is a combination therapy comprising a therapeutically effective amount of a MAT2A inhibitor and a PARP inhibitor. A “therapeutically effective amount” of a combination of agents (i.e., a MAT2A inhibitor and a PARP inhibitor) is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorders treated with the combination. Observable improvements include those that can be visually ascertained by a clinician and biological tests, biopsies, and assays.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon (i.e. C1-6 means one to six carbons) atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms (i.e. C3-6 means three to six carbons). Alkyl can include any number of carbons, such as C1.2, C1-3, C1-4, C1-5, C1-6, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6. Example of alkyl groups inlcude methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term “alkyl” may include “alkylene” groups.

“Amino” means a -NH2.

“Cycloalkyl” means a monocyclic monovalent hydrocarbon radical of three to six carbon atoms (e.g., C3-6 cycloalkyl) which may be saturated or contains one double bond. Cycloalkyl can include any number of carbons, such as C3-6, C4-6, and C5-6. Partially unsaturated cycloalkyl groups have one or more double in the ring, but cycloalkyl groups are not aromatic. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

“Haloalkyl” means alkyl radical as defined above, which is substituted with one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, and the like. When the alkyl is substituted with only fluoro, it can be referred to as fluoroalkyl. As for alkyl group, haloalkyl groups can have any suitable number of carbon atoms, such as Ci-e.

Combination Product

Provided herein is a combination product comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof. The combination product is useful for the treatment of a variety of cancers, including solid tumors. In another aspect, the combination product is useful for the treatment of any number of MAT2A-associated diseases. In another aspect, the combination product is useful for the treatment of a disease or disorder treatable by inhibiting MAT2A. In another aspect, the combination product is useful for the treatment of MTAP-deficient tumors.

As used herein, the term “combination product” includes embodiments in which the MAT2A inhibitor and PARP inhibitor are formulated together into a single pharmaceutical composition (e.g. tablet or capsule), and alternative embodiments in which each therapeutic agent in the combination is individually formulated into its own pharmaceutical composition and each of the pharmaceutical compositions are administered in the same medical treatment (for example, the same medical treatment of cancer). In this embodiment, each of the pharmaceutical compositions may have the same or different carriers, diluents or excipients. The carrier(s), diluent(s) or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof.

In one embodiment, the combination product comprises first and second pharmaceutical compositions, wherein the first pharmaceutical composition contains a PARP inhibitor (suitably selected from compounds B, C, D, E, F, AZD5305, or AZD9574 or pharmaceutically acceptable salts thereof), the second pharmaceutical composition contains Compound A or Compound A1 (or a pharmaceutically acceptable salt thereof), and the first and second pharmaceutical compositions are both administered to treat cancer. The first and second pharmaceutical compositions may be administered simultaneously, separately or sequentially and in any order. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

MAT2A inhibitors

The disclosure provides MAT2A inhibitors. In an embodiment, the MAT2A inhibitor is a compound of Formula I:

(I) or a pharmaceutically acceptable salt thereof; wherein

X is CH or N;

R³ is halo, C1-6 haloalkyl or C3-6 cycloalkyl;

R² is -NR⁴R⁵;

R⁴ is hydrogen or C1-6 alkyl;

R⁵ is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and

R¹ is phenyl, wherein phenyl is substituted with 0-2 halo.

In an embodiment, X in Formula (I) and subembodiments thereof is CH. In an embodiment, X in Formula (I) and subembodiments thereof is N.

In still another embodiment, R³ in formula (I) and subembodiments thereof is halo or C1-6 haloalkyl. In an embodiment, R³ in formula (I) and subembodiments thereof is halo. In an embodiment, R³ in formula (I) and subembodiments thereof is C1-6 haloalkyl. In an embodiment, R³ in formula (I) and subembodiments thereof is C3-6 cycloalkyl. In an embodiment, R³ in formula (I) and subembodiments thereof is chloro, fluoro, bromo, -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, or -CF(CH₃)₂. In an embodiment, R³ in formula (I) and subembodiments thereof is chloro or -CF3. In an embodiment, R³ in formula (I) and subembodiments thereof is chloro. In an embodiment, R³ in formula (I) and subembodiments thereof is -CF3.

In still another embodiment, R⁴ in formula (I) and subembodiments thereof is H. In an embodiment, R⁴ in formula (I) and subembodiments thereof is Cvsalkyl . In an embodiment, R⁴ in formula (I) and subembodiments thereof is methyl, ethyl, propyl, or isopropyl.

In still another embodiment, R⁵ in formula (I) and subembodiments thereof is H. In an embodiment, R⁵ in formula (I) and subembodiments thereof is Cvsalkyl . In an embodiment, R⁵ in formula (I) and subembodiments thereof is methyl, ethyl, propyl, or isopropyl. In an embodiment, R⁵ in formula (I) and subembodiments thereof is C3-6 cycloalkyl.

In still another embodiment, R² in formula (I) and subembodiments thereof is -NH2, - NHCi-salkyl, or -N(Ci-3alkyl)2. In an embodiment, R² in formula (I) and subembodiments thereof is NH2, -NHMe, or -N(Me)2. In an embodiment, R² in formula (I) and subembodiments thereof is NH2. In an embodiment, R² in formula (I) and subembodiments thereof is -NHMe.

In still another embodiment, R¹ in formula (I) and subembodiments thereof is unsubstituted phenyl. In an embodiment, R¹ in formula (I) and subembodiments thereof is phenyl substituted with 1 halo. In an embodiment, R¹ in formula (I) and subembodiments thereof is phenyl substituted 1 halo selected fluoro and chloro. In an embodiment, R¹ in formula (I) and subembodiments thereof is phenyl substituted chloro. In an embodiment, R¹ in formula (I) and subembodiments thereof is phenyl substituted 2 halo.

In yet another embodiment, MAT2A inhibitor is selected from the group consisting of a compound from Table 1, or a pharmaceutically acceptable salt thereof.

Table 1.

or a pharmaceutically acceptable salt thereof.

In another embodiment, the MAT2A inhibitor is Compound A:

Compound A or a pharmaceutically acceptable salt thereof.

Compound A1 or a pharmaceutically acceptable salt thereof.

The preparation and activity of the MAT2A inhibitors provided herein are disclosed in PCT/US2019/065260 (WO 2020/123395), the entire contents of which are hereby incorporated by reference in their entirety.

It should be noted that reference to a MAT2A inhibitor also includes reference to their pharmaceutically acceptable salts. In other words, “MAT2A inhibitor” is synonymous with “MAT2A inhibitor or a pharmaceutically acceptable salt thereof’. PARP Inhibitors

The disclosure provides PARP inhibitors for use with a MAT2A inhibitor. A number of agents with PARP inhibitory activity and methods of making the same are known in the art. Each of these is embraced by this disclosure. In an embodiment the PARP inhibitor is selected from the group consisting of the compounds in Table 2, or a pharmaceutically acceptable salt or hydrate thereof.

Table 2

In other embodiments, the PARP inhibitor may be selected from the group consisting of AZD5305, AZD9574, THG-008, RBN-2397, TSL-1502, NMS-03305293, HWH-340, STP06-1002, JPI-547, ABT-767, simmiparib, stenoparib, IDX-1197, SC-10914, AMXI-5001 , amelparib dihydrochloride dihydrate, CK-102, IMP-4297, pamiparib, and fluzoparib or a pharmaceutically acceptable salt thereof.

AZD5305 is described in WO 2021/013735 and is known to be 5-[4-[(7-ethyl-6-oxo- 5H-1 ,5-napthyridine-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide and has the following structure:

AZD9574 is described in WO2021260092 and is known to be 6-fluoro-5-[4-[(5-fluoro- 2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide and has the following structure:

In some cases, the PARP inhibitor is selected from the group consisting of AZD5305, AZD9574 and the compounds in Table 2.

The preparation and activity of niraparib are described in US 8,071 ,579; US 8,071623; US 8,143,241; US 8,426,185; US 8,859,562; and US 11 ,091 ,459, the entire contents of which are hereby incorporated by reference in their entirety. The preparation and activity of rucaparib are described in US 6,495,541 ; US 7,351 ,701 ; and US 7,531 ,530, the entire contents of which are hereby incorporated by reference in their entirety.

The preparation and activity of olaparib are described in US 7, 151 , 102; US 7,449,464; US 7,981 ,889; and US 8,071 ,579, the entire contents of which are hereby incorporated by reference in their entirety.

The preparation and activity of talazoparib are described in US 8,012,976; US 8,420,650; and US 8,735,392, the entire contents of which are hereby incorporated by reference in their entirety.

In an embodiment, the PARP inhibitor is selected from the group consisting of niraparib, olaparib, talazoparib and rucaparib or a pharmaceutically acceptable salt thereof.

In a further embodiment, the PARP inhibitor is selected from the group consisting of niraparib, talazoparib and rucaparib or a pharmaceutically acceptable salt thereof.

In an embodiment, the PARP inhibitor is selective for PARP1 over PARP2.

In an embodiment, the PARP inhibitor is AZD5305 or a pharmaceutically acceptable salt thereof, as defined above.

In an embodiment, the PARP inhibitor is AZD9574 or a pharmaceutically acceptable salt thereof, as defined above.

It should be noted that reference to a PARP inhibitor also includes reference to their pharmaceutically acceptable salts. In other words, “PARP inhibitor” is synonymous with “PARP inhibitor or a pharmaceutically acceptable salt thereof”.

In one embodiment, the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof, in particular niraparib tosylate monohydrate. Reference to niraparib is intended to include all versions of niraparib, for example salts including pharmaceutically acceptable salts, polymorphs and solvates, including the tosylate monohydrate.

In another embodiment, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. Reference to olaparib is intended to include all versions of olaparib, for example salts including pharmaceutically acceptable salts, polymorphs and solvates.

In another embodiment, the PARP inhibitor is rucaparib or a pharmaceutically acceptable salt thereof, in particular rucaparib camsylate. Reference to rucaparib is intended to include all versions of rucaparib, for example salts including pharmaceutically acceptable salts, polymorphs and solvates.

In another embodiment, the PARP inhibitor is talazoparib or a pharmaceutically acceptable salt thereof, in particular talazoparib tosylate. Reference to talozaparib is intended to include all versions of talazoparib, for example salts including pharmaceutically acceptable salts, polymorphs and solvates. Combinations of MAT2A inhibitors and PARP Inhibitors

In another aspect, provided herein is a combination product comprising Compound A or a pharmaceutically acceptable salt thereof, and Compounds B, C, D, E, or F or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a combination product comprising Compound A

Compound A or a pharmaceutically acceptable salt thereof, and Compound B:

Compound B or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a combination product comprising Compound A:

Compound A or a pharmaceutically acceptable salt thereof, and Compound C

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a combination product comprising Compound

A:

Compound A or a pharmaceutically acceptable salt thereof, and Compound D:

Compound D or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a combination product comprising Compound

A:

Compound A or a pharmaceutically acceptable salt thereof, and Compound E:

Compound E or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a combination product comprising Compound

A:

Compound A or a pharmaceutically acceptable salt thereof, and Compound F:

Compound F or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a combination product comprising Compound A1 or a pharmaceutically acceptable salt thereof, and Compounds B, C, D, E, or F or a pharmaceutically acceptable salt thereof. In further embodiments, the combination product comprises Compound A or Compound A1 or a pharmaceutically acceptable salt thereof, and AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof.

In further embodiments, the combination product comprises Compound A or a pharmaceutically acceptable salt thereof, and AZD5305 or a pharmaceutically acceptable salt thereof.

In further embodiments, the combination product comprises Compound A or a pharmaceutically acceptable salt thereof, and AZD9574 or a pharmaceutically acceptable salt thereof.

The administration of a pharmaceutical combination provided herein may result in a beneficial effect, e.g. a synergistic therapeutic effect, e.g., with regard to alleviating, delaying progression of or inhibiting the symptoms, and may also result in further surprising beneficial effects, e.g., fewer side-effects, an improved quality of life or a decreased morbidity, compared with a monotherapy applying only one of the pharmaceutically active ingredients used in the combination of the invention.

Methods of Treatment

In an embodiment, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a MAT2A inhibitor and administering to the subject a therapeutically effective amount of a PARP inhibitor, thereby treating the cancer in the subject. In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and a PARP inhibitor, together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.

In an embodiment, provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a MAT2A inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising a PARP inhibitor, thereby treating the cancer in the subject.

In an embodiment, use of a combination of a MAT2A inhibitor and a PARP inhibitor for the manufacture of a medicament is provided. In one embodiment, the MAT2A inhibitor is Compound A. In one embodiment, the MAT2A inhibitor is Compound A1. In one embodiment, provided is a combination of Compound A and Compound B for the manufacture of a medicament. In one embodiment, provided is a combination of Compound A and Compound C for the manufacture of a medicament. In one embodiment, provided is a combination of Compound A and Compound D for manufacture of a medicament. In one embodiment, provided is a combination of Compound A and Compound E for manufacture of a medicament. In one embodiment, provided is a combination of Compound A and Compound F for manufacture of a medicament. In one embodiment, provided is a combination of Compound A1 and Compound B for the manufacture of a medicament. In one embodiment, provided is a combination of Compound A1 and Compound C for the manufacture of a medicament. In one embodiment, provided is a combination of Compound A1 and Compound D for manufacture of a medicament. In one embodiment, provided is a combination of Compound A1 and Compound E for manufacture of a medicament. In one embodiment, provided is a combination of Compound A1 and Compound F for manufacture of a medicament. In further embodiemnts, provided is a combination of Compound A or Compound A1 and AZD5305 or AZD9574 for manufacture of a medicament. In further embodiemnts, provided is a combination of Compound A and AZD5305 for manufacture of a medicament. In further embodiemnts, provided is a combination of Compound A and AZD9574 for manufacture of a medicament.

In another embodiment, use of a combination of a MAT2A inhibitor and a PARP inhibitor for the treatment of cancer is provided. In one embodiment, the MAT2A inhibitor is a compound of Formula I. In one embodiment, the MAT2A inhibitor is Compound A. In one embodiment, the MAT2A inhibitor is Compound A1. In one embodiment, provided is a combination of Compound A and Compound B for the treatment of cancer. In one embodiment, provided is a combination of Compound A and Compound C for the treatment of cancer. In one embodiment, provided is a combination of Compound A and Compound D for the the treatment of cancer. In one embodiment, provided is a combination of Compound A and Compound E for the treatment of cancer. In one embodiment, provided is a combination of Compound A and Compound F for the treatment of cancer. In one embodiment, provided is a combination of Compound A1 and Compound B for the treatment of cancer. In one embodiment, provided is a combination of Compound A1 and Compound C for the treatment of cancer. In one embodiment, provided is a combination of Compound A1 and Compound D for the treatment of cancer. In one embodiment, provided is a combination of Compound A1 and Compound E for the treatment of cancer. In one embodiment, provided is a combination of Compound A1 and Compound F for the treatment of cancer.

In further embodiments, the provided is a combination of Compound A or Compound A1 or a pharmaceutically acceptable salt thereof, and AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof for the treatment of cancer.

In further embodiments, the provided is a combination of Compound A or a pharmaceutically acceptable salt thereof, and AZD5305 or a pharmaceutically acceptable salt thereof for the treatment of cancer. In further embodiments, the provided is a combination of Compound A or a pharmaceutically acceptable salt thereof, and AZD9574 or a pharmaceutically acceptable salt thereof for the treatment of cancer.

In an embodiment, the MAT2A inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein the variables are defined supra.

In another embodiment, the MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof. In an embodiment, the PARP inhibitor is selected from the group consisting of the compounds in Table 2, or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the PARP inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is Compound C or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is Compound D or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is Compound E or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is Compound F or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is AZD5305 or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is AZD9574 or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof.

In yet another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound C or a pharmaceutically acceptable salt thereof.

In still another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound D or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound E or a pharmaceutically acceptable salt thereof. In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound F or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound B, Compound C, Compound D, Compound E, or Compound F, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of AZD5305 or AZD9574, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided is a product containing a MAT2A inhibitor and a PARP inhibitor as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, the MAT2A inhibitor is a compound of Formula I. In one embodiment, the MAT2A inhibitor is Compound A. In one embodiment, the MAT2A inhibitor is Compound A1. In one embodiment, provided is a product containing Compound A and Compound B as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, provided is a product containing Compound A and Compound C as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, provided is a product containing Compound A and Compound D as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, provided is a product containing Compound A and Compound E as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, provided is a product containing Compound A and Compound F as a combination product for simultaneous, separate, or sequential use in medicine. In one embodiment, provided is a product containing Compound A and AZD5305 or AZD9574 as a combination product for simultaneous, separate, or sequential use in medicine.

In another embodiment, provided is a product containing a MAT2A inhibitor and a PARP inhibitor as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, the MAT2A inhibitor is a compound of Formula I. In one embodiment, the MAT2A inhibitor is Compound A. In one embodiment, the MAT2A inhibitor is Compound A1. In one embodiment, provided is a product containing Compound A and Compound B as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product containing Compound A and Compound C as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product containing Compound A and Compound D as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product containing Compound A and Compound E as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product containing Compound A and Compound F as a combination product for simultaneous, separate, or sequential use in treating cancer in a subject. In one embodiment, provided is a product containing Compound A and AZD5305 or AZD9574 as a combination product for simultaneous, separate, or sequential treating cancer in a subject.

In yet another embodiment, the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastric cancer, esophagogastric cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

In an embodiment, the cancer is mesothelioma. In an embodiment, the cancer is non-small cell lung cancer. In another embodiment, the cancer is nonsquamous non-small cell lung cancer. In one embodiment, the cancer is cancer of the colon or rectum. In an embodiment, the cancer is adenocarcinoma of the colon or rectum. In an embodiment, the cancer is breast cancer. In an embodiment, the cancer is adenocarcinoma of the breast. In an embodiment, the cancer is gastric cancer. In an embodiment, the cancer is gastric adenocarcinoma. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is pancreatic adenocarcinoma. In an embodiment, the cancer is bladder cancer.

In an embodiment, the cancer is characterized as being MTAP-null. In an embodiment, the cancer is characterized as being MTAP-deficient.

In still another embodiment, the cancer is a solid tumor. In still another embodiment, the cancer is a MTAP-deleted solid tumor, n still another embodiment, the cancer is a metastatic MTAP-deleted solid tumor.

In still another embodiment, the cancer is metastatic.

In still another embodiment, the cancer is a solid malignant tumor. In still another embodiment, the cancer is MTAP-deficient lung or MTAP- deficient pancreatic cancer, including MTAP-deficient NSCLC or MTAP-deficient pancreatic ductal adenocarcinoma (PDAC) or MTAP-deficient esophageal cancer.

In another embodiment, the cancer is a tumor having an MTAP gene deletion.

In any one of the embodiments herein, the cancer is a solid tumor or a haematological cancer. In one embodiment, the tumor is deficient in MTAP. In another embodiment, the tumor is normal in its expression of MTAP.

In still another embodiment, the cancer is NSCLC, mesothelioma, squamous carcinoma of the head and neck, salivary gland tumors, urothelial cancers, sarcomas, or ovarian cancer. In still another embodiment, the cancer is NSCLC, esophagogastric cancer, or pancreatic cancers.

In still another embodiment, the cancer is characterized by a reduction or absence of MTAP gene expression, absence of MTAP gene, reduced function of MTAP protein, reduced level or absence of MTAP protein, MTA accumulation, or combination thereof.

In still another embodiment, the cancer is characterized by a reduction or absence of MTAP gene expression.

In still another embodiment, the cancer is characterized by reduced function of MTAP protein.

In still another embodiment, the cancer is characterized by reduced level or absence of MTAP protein.

In still another embodiment, the cancer is characterized by MTA accumulation.

In an embodiment, the MAT2A inhibitor and the PARP inhibitor are in separate dosage forms.

In another embodiment, the MAT2A inhibitor and the PARP inhibitor are in the same dosage form.

In another embodiment, the treatment comprises administering the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, at substantially the same time. In yet another embodiment, the treatment comprises administering the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, at different times.

In still another embodiment, the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject, followed by administration of the PARP inhibitor, or a pharmaceutically acceptable salt thereof. In an embodiment, the PARP inhibitor, or a pharmaceutically acceptable salt thereof, is administered to the subject, followed by administration of MAT2A inhibitor, or a pharmaceutically acceptable salt thereof. In an embodiment, the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, are administered orally.

In another embodiment, the cancer to be treated is selected from the group consisting of lung cancer, colon and rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, glioma, glioblastoma, neuroblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemia, lymphomas, myelomas, retinoblastoma, cervical cancer, melanoma and/or skin cancer, bladder cancer, uterine cancer, testicular cancer, esophageal cancer, thymic cancer, adenoid cystic carcinoma, gastroesophageal cancer, malignant peripheral nerve sheath tumor (MPNST), and cholangiocarcinoma. In some embodiments, the cancer is lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, and lymphomas. In other embodiments, the cancer is lung cancer, colon cancer, breast cancer, neuroblastoma, leukemia, or lymphoma. In a further embodiment, the cancer is non-small cell lung cancer (NSCLC) or small cell lung cancer. In yet another embodiment, the cancer is selected from the group consisting of NSCLC, pancreatic cancer, malignant peripheral nerve sheath tumor (MPNST), and esophagogastric cancer. In yet another embodiment, the cancer is selected from the group consisting of NSCLC and pancreatic cancer. In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is pancreatic cancer.

In an embodiment, the cancer is a hematologic cancer, such as leukemia or lymphoma. In a certain embodiment, lymphoma is Hodgkin’s lymphoma or Non-Hodgkin’s lymphoma. In certain embodiments, leukemia is myeloid, lymphocytic, myelocytic, lymphoblastic, or megakaryotic leukemia.

In an aspect, provided herein is a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof, for use in therapy.

In an embodiment, the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the PARP inhibitor, or a pharmaceutically acceptable salt thereof, are for use in the treatment of cancer in a subject in need thereof.

In an embodiment of the methods, the method involves the administration of a therapeutically effective amount of a combination or composition comprising compounds provided herein, or pharmaceutically acceptable salts thereof, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need).

In another embodiment of the methods, the treatment includes co-administering the amount of the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the amount of the PARP inhibitor, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of the MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of PARP inhibitor or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of PARP inhibitor or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In the foregoing methods, the treatment can include administering the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of a PARP or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and/or the amount of PARP inhibitor or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when either of MAT2A inhibitor or a pharmaceutically acceptable salt thereof, or PARP inhibitor or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound B or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound B or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound C, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound C or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound C or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound D, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound D or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound D or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound E, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound E or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound E or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound F, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound F or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound F or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In another embodiment of the methods, the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of AZD5305 or AZD9574, or a pharmaceutically acceptable salt thereof. In an embodiment, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form. In still other embodiments, the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.

In the foregoing methods, the treatment can include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound B or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound B or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and/or the amount of Compound B or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and Compound B or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

In the foregoing methods, the treatment can include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound C or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound C or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and/or the amount of Compound C or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and Compound C or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

In the foregoing methods, the treatment can include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound D or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound D or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and/or the amount of Compound D or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and Compound D or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

In the foregoing methods, the treatment can include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound E or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound E or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and/or the amount of Compound E or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and Compound E or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

In the foregoing methods, the treatment can include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound F or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of Compound F or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and/or the amount of Compound F or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and Compound F or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

In the foregoing methods, the treatment can include administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of Compound A or a pharmaceutically acceptable salt thereof and the amount of AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof at different times. In some embodiments of the foregoing methods, the amount of Compound A or a pharmaceutically acceptable salt thereof and/or the amount of AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A or a pharmaceutically acceptable salt thereof and AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.

Non-Limiting Exemplary Embodiments:

In further embodiments 1 to 96 below, the present disclosure includes:

1 . In embodiment 1 , provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a methionine adenosyltransferase II alpha (MAT2A) inhibitor and administering to the subject a therapeutically effective amount of a Poly (ADP-Ribose) Polymerase (PARP) inhibitor.

2. In embodiment 2, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a MAT2A inhibitor and administering to the subject a therapeutically effective amount of a PARP inhibitor, wherein the MAT2A inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is CH or N;

R³ is halo, C1-6 haloalkyl or C3-6 cycloalkyl;

R² is -NR⁴R⁵;

R⁴ is hydrogen or C1-6 alkyl;

R⁵ is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and

R¹ is phenyl, wherein phenyl is substituted with 0-2 halo.

3. In embodiment 3, provided is the method of embodiment 2, wherein X is N.

4. In embodiment 4, provided is the method of embodiment 2, wherein X is CH.

5. In embodiment 5, provided is the method of any one of embodiments 2 to 4, wherein

R⁴ is hydrogen and R⁵ is hydrogen or C1-3 alkyl.

6. In embodiment 6, provided is the method of any one of embodiments 2 to 5, wherein R⁵ is hydrogen or methyl.

7. In embodiment 7, provided is the method of any one of embodiments 2 to 6, wherein R¹ is phenyl substituted with chloro.

8. In embodiment 8, provided is the method of any one of embodiments 2 to 7, wherein R³ is C1-3 haloalkyl or halo.

9. In embodiment 9, provided is the method of any one of embodiments 2 to 8, wherein R³ is trifl uromethyl or chloro.

10. In embodiment 10, provided is the method of any one of embodiments 2 to 7, wherein R³ is cyclopropyl.

11. In embodiment 11 , provided is the method of any one of embodiments 1 to 10, wherein the MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof. 12. In embodiment 12, provided is the method of any one of embodiments 1 to 11 , wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof.

13. In embodiment 13, provided is the method of any one of embodiments 1 to 11 , wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof.

14. In embodiment 14, provided is the method of any one of embodiments 1 to 13, wherein the PARP inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F, AZD5305, and AZD9574, or a pharmaceutically acceptable salt thereof.

15. In embodiment 15, provided is the method of any one of embodiments 1 to 14, wherein the PARP inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

16. In embodiment 16, provided is the method of any one of embodiments 1 to 14, wherein the PARP inhibitor is Compound C or a pharmaceutically acceptable salt thereof.

17. In embodiment 17, provided is the method of any one of embodiments 1 to 14, wherein the PARP inhibitor is Compound D or a pharmaceutically acceptable salt thereof.

18. In embodiment 18, provided is the method of any one of embodiments 1 to 14, wherein the PARP inhibitor is Compound E or a pharmaceutically acceptable salt thereof.

19. In embodiment 19, provided is the method of any one of embodiments 1 to 14, wherein the PARP inhibitor is Compound F or a pharmaceutically acceptable salt thereof.

20. In embodiment 20, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt thereof.

21. In embodiment 21 , provided is the method of any one of claims 1-20, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophagogastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma. 22. In embodiment 22, provided is the method of any one of claims 1-21 , wherein the cancer is a solid tumor.

23. In embodiment 23, provided is the method of any one of claims 1-22, wherein the cancer is a solid malignant tumor.

24. In embodiment 24, provided is the method of any one of claims 1-23, wherein the tumor has an MTAP gene deletion.

25. In embodiment 25, provided is the method of any one of claims 1-24, wherein the MAT2A inhibitor and the PARP inhibitor are in separate dosage forms.

26. In embodiment 26, provided is a combination product comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

27. In embodiment 27, the MAT2A inhibitor of embodiment 26 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

28. In embodiment 28, the MAT2A inhibitor of embodiment 26 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 2 to 10.

29. In embodiment 29, the MAT2A inhibitor of any one of embodiments 26 to 28 is selected from the group consisting of the compounds in Table 1 , or a pharmaceutically acceptable salt thereof.

30. In embodiment 30, the MAT2A inhibitor of any one of embodiments 26 to 29 is Compound A or a pharmaceutically acceptable salt thereof.

31. In embodiment 31 , the MAT2A inhibitor of any one of embodiments 26 to 29 is Compound A1 or a pharmaceutically acceptable salt thereof.

32. In embodiment 32, the PARP inhibitor of any one of embodiments 26 to 31 is selected from the group consisting of the compounds in Table 2, AZD5305, and AZD9574, or a pharmaceutically acceptable salt thereof.

33. In embodiment 33, the PARP inhibitor of any of embodiments 26 to 32 is Compound B or a pharmaceutically acceptable salt thereof. 34. In embodiment 34, the PARP inhibitor of any of embodiments 26 to 32 is Compound C or a pharmaceutically acceptable salt thereof.

35. In embodiment 35, the PARP inhibitor of any of embodiments 26 to 32 is Compound D or a pharmaceutically acceptable salt thereof.

36. In embodiment 36, the PARP inhibitor of any of embodiments 26 to 32 is Compound E or a pharmaceutically acceptable salt thereof.

37. In embodiment 37, the PARP inhibitor of any of embodiments 26 to 32 is Compound F or a pharmaceutically acceptable salt thereof.

38. In embodiment 38, the PARP inhibitor of any of embodiments 26 to 32 is AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

39. In embodiment 39, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a PARP inhibitor.

40. In embodiment 40, the MAT2A inhibitor of embodiment 39 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

41. In embodiment 41 , the MAT2A inhibitor of embodiment 40 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 2 to 10.

42. In embodiment 42, the MAT2A inhibitor of any one of embodiments 39 to 41 is selected from the group consisting of the compounds in Table 1 , or a pharmaceutically acceptable salt thereof.

43. In embodiment 43, the PARP inhibitor of any of embodiments 39 to 42 is selected from the group consisting of the compounds in Table 2, AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

44. In embodiment 44, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof.

45 In embodiment 45, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound C or a pharmaceutically acceptable salt thereof.

46. In embodiment 47, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound D or a pharmaceutically acceptable salt thereof.

47. In embodiment 47, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound E or a pharmaceutically acceptable salt thereof.

48. In embodiment48, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound F or a pharmaceutically acceptable salt thereof.

49. In embodiment 49, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

50. In embodiment 50, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof. 51. In embodiment 51 , provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound C or a pharmaceutically acceptable salt thereof.

52. In embodiment 52, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound D or a pharmaceutically acceptable salt thereof.

53. In embodiment 53, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound E or a pharmaceutically acceptable salt thereof.

54. In embodiment 54, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of Compound F or a pharmaceutically acceptable salt thereof.

55. In embodiment 55, provided is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

56. In embodiment 56, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor.

57. In embodiment 57, the MAT2A inhibitor of embodiment 56 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. 58. In embodiment 58, the MAT2A inhibitor of embodiment 57 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 2 to 10.

59. In embodiment 59, the MAT2A inhibitor of any one of embodiments 56 to 58 is selected from the group consisting of the compounds in Table 1 , or a pharmaceutically acceptable salt thereof.

60. In embodiment 60, the PARP inhibitor of any of embodiments 56 to 59 is selected from the group consisting of the compounds in Table 2, AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

61. In embodiment 61 , provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

62. In embodiment 62, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound C or a pharmaceutically acceptable salt thereof.

63. In embodiment 63, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound D or a pharmaceutically acceptable salt thereof.

64. In embodiment 64, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound E or a pharmaceutically acceptable salt thereof.

65. In embodiment 65, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound F or a pharmaceutically acceptable salt thereof.

66. In embodiment 66, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is AZD5305, AXD9574, or a pharmaceutically acceptable salt thereof.

67. In embodiment 67, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

68. In embodiment 68, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1or a pharmaceutically acceptable salt thereof; and the PARP inhibitor Compound C or a pharmaceutically acceptable salt thereof.

69. In embodiment 69, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound D or a pharmaceutically acceptable salt thereof.

70. In embodiment 70, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound E or a pharmaceutically acceptable salt thereof.

71. In embodiment 71 , provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound F or a pharmaceutically acceptable salt thereof. 72. In embodiment 72, provided is a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is AZD5305, AXD9574, or a pharmaceutically acceptable salt thereof.

73. In embodiment 73, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor.

74. In embodiment 74, the MAT2A inhibitor of embodiment 73 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

75. In embodiment 75, the MAT2A inhibitor of embodiment 74 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 2 to 10.

76. In embodiment 76, the MAT2A inhibitor of any one of embodiments 73 to 75 is selected from the group consisting of the compounds in Table 1 , or a pharmaceutically acceptable salt thereof.

77. In embodiment 77, the PARP inhibitor of any of embodiments 73 to 76 is selected from the group consisting of the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

78. In embodiment 78, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

79. In embodiment 79, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound C or a pharmaceutically acceptable salt thereof.

80. In embodiment 80, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound D or a pharmaceutically acceptable salt thereof.

81. In embodiment 81 , provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound E or a pharmaceutically acceptable salt thereof.

82. In embodiment 82, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound F or a pharmaceutically acceptable salt thereof.

83. In embodiment 83, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

84. In embodiment 84, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound B or a pharmaceutically acceptable salt thereof.

85. In embodiment 85, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound C or a pharmaceutically acceptable salt thereof.

86. In embodiment 86, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound D or a pharmaceutically acceptable salt thereof.

87 In embodiment 87, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound E or a pharmaceutically acceptable salt thereof.

88. In embodiment 88, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is Compound F or a pharmaceutically acceptable salt thereof.

89. In embodiment 89, provided is a use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor; wherein the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof; and the PARP inhibitor is AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

90. In embodiment 90, the use of any one of embodiments 56 to 89, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-smali cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophagogastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

91. In embodiment 91 , the use of any one of embodiments 56 to 90, wherein the cancer is a solid tumor.

92. In embodiment 92, the use of any one of embodiments 56 to 91 , wherein the cancer is a solid malignant tumor.

93. In embodiment 93, the use of any one of embodiments 56 to 92, wherein the tumor has an MTAP gene deletion.

94. In embodiment 94, the use of any one of embodiments 56 to 93, wherein the MAT2A inhibitor and the PARP inhibitor are in separate dosage forms. 95. In embodiment 95, the use of any one of embodiments 56 to 93, wherein the MAT2A inhibitor and the PARP inhibitor are in the same dosage form.

96. In embodiment 96, provided is the method of any one of claims 1-24, wherein the MAT2A inhibitor and the PARP inhibitor are in same dosage forms.

In an aspect, provided herein is a pharmaceutical composition comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, a PARP inhibitor, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In an embodiment, a pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a PARP inhibitor is provided.

In another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of a PARP inhibitor.

In an embodiment, the MAT2A inhibitor is a compound of Formula (I):

In another embodiment, the PARP inhibitor is selected from the group consisting of the compounds in Table 2, AZD5305, AZD9574, or a pharmaceutically acceptable salt or hydrate thereof.

In another embodiment, the MAT2A inhibitor is Compound A:

Compound A or a pharmaceutically acceptable salt thereof.

In another embodiment, the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is Compound B :

Compound B or a pharmaceutically acceptable salt thereof. In another embodiment, the PARP inhibitor is Compound C:

or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is Compound D:

Compound D or a pharmaceutically acceptable salt thereof. In another embodiment, the PARP inhibitor is Compound E:

Compound E or a pharmaceutically acceptable salt thereof. In another embodiment, the PARP inhibitor is Compound F:

Compound F or a pharmaceutically acceptable salt thereof.

In another embodiment, the PARP inhibitor is AZD5305 or AZD9574 or a pharmaceutically acceptable salt thereof

In yet another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound B or a pharmaceutically acceptable salt thereof.

In still another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.

In an aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound D or a pharmaceutically acceptable salt thereof.

In yet another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound E or a pharmaceutically acceptable salt thereof.

In yet another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound F or a pharmaceutically acceptable salt thereof.

In yet another aspect, provided herein is a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; Compound B or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In yet another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; Compound C, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In still another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; Compound D or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; Compound E or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; Compound F or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof; AZD5305, AZD9574, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In an embodiment, the pharmaceutical composition is for use in the treatment of cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of a solid tumor in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of a solid malignant tumor in a patient.

Administration / Dosac/e / Formulations

In another aspect, provided herein is a pharmaceutical composition or pharmaceutical combination comprising the compounds disclosed herein, together with a pharmaceutically acceptable carrier. In an embodiment of the combination product, MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and PARP inhibitor, or a pharmaceutically acceptable salt thereof, are in the same formulation. In another embodiment of the combination product, MAT2A inhibitor and a PARP inhibitor are in separate formulations. In a further embodiment of this embodiment, the formulations are for simultaneous or sequential administration.

Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route. The dosage of the individual agents of the combination may require more frequent administration of one of the agent(s) as compared to the other agent(s) in the combination. Therefore, to permit appropriate dosing, packaged pharmaceutical products may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents, but not the other agent(s) of the combination.

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

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

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient.

In one embodiment, the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

The optimum ratios, individual and combined dosages, and concentrations of the drug compounds that yield efficacy without toxicity are based on the kinetics of the active ingredients’ availability to target sites.

Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. In one embodiment, the preferred route of administration is oral.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions are not limited to the particular formulations and compositions that are described herein.

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gel caps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.

In an embodiment, the total daily dose of niraparib is 100 mg, 200 mg or 300 mg taken once daily. In a particular embodiment, the total daily dose of niraparib is 200 mg or 300 mg taken once daily. The dose may be provided as 100 mg capsules (in particular, hard capsules) or 100 mg tablets. In an embodiment, each capsule or tablet contains niraparib tosylate monohydrate equivalent to 100 mg niraparib.

In one embodiment, in particular when the PARP inhibitor is niraparib, it may be administered orally by capsule or tablet. In one embodiment, niraparib is administered by capsule. In another embodiment, niraparib is administered by tablet.

In an embodiment, the dose of olaparib is 300 mg taken twice daily, equivalent to a total daily dose of 600 mg. The dose may be provided as capsules, in particular hard capsules containing 50 mg of olaparib. Therefore, to achieve a dose of 300 mg it is necessary for a patient to take six capsules. The dose may also be provided as 100 mg or 150 mg tablets, where the tablets may be film-coated.

In an embodiment, the dose of rucaparib is 600 mg taken twice daily, equivalent to a total daily dose of rucaparib of 1200 mg. The dose may be provided as tablets available as 200 mg, 250 mg and 300 mg tablets, which may be film-coated.

In an embodiment, the dose of talazoparib is 1 mg taken once daily. The dose may be provided as capsules containing talazoparib tosylate equivalent to 0.25 mg or 1 mg talazoparib.

In an embodiment, the PARP inhibitor is administered daily.

Kits

In an aspect, the present disclosure provides a kit for treating cancer comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor or a pharmaceutically acceptable salt thereof.

In certain embodiments, the kit comprises a pharmaceutical product comprising a pharmaceutical composition comprising MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent; and a pharmaceutical composition comprising Poly (ADP-ribose)Polymerase (PARP) inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.

In some embodiments, the kit comprises a pharmaceutical composition comprising MAT2A inhibitor, or a pharmaceutically acceptable salt thereof; Poly (ADP-ribose) Polymerase (PARP) inhibitor, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

In additional embodiments, pharmaceutical kits are provided. The kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions. In some embodiments, the sealed container minimizes the contact of air with the ingredients, e.g. an airless bottle. In other embodiments, the sealed container is a sealed tube. An instruction for the use of the composition and the information about the composition are to be included in the kit.

In a particular embodiment, the compounds of the combination can be dosed on the same schedule, whether by administering a single formulation or unit dosage form containing all of the compounds of the combination, or by administering separate formulations or unit dosage forms of the compounds of the combination. However, some of the compounds used in the combination may be administered more frequently than once per day, or with different frequencies that other compounds in the combination. Therefore, in one embodiment, the kit contains a formulation or unit dosage form containing all of the compounds in the combination of compounds, and an additional formulation or unit dosage form that includes one of the compounds in the combination of agents, with no additional active compound, in a container, with instructions for administering the dosage forms on a fixed schedule.

The kits provided herein include prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation. Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.

In all of the foregoing the combination of compounds of the invention can be administered alone, as mixtures, or with additional active agents.

A kit provided herein can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing). A kit can contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism(s) of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Labels or inserts can include manufacturer information such as lot numbers and expiration dates. The label or packaging insert can be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, syringe or vial).

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this disclosure and covered by the claims appended hereto.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present disclosure. However, they are in no way a limitation of the teachings of the present disclosure as set forth.

EXAMPLES

The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

Example 1. Proliferation screen identifies combination benefit with MAT2A and PARP inhibition

A 10-day proliferation screen was performed in 15 pancreatic, non-small cell lung, and bladder cancer cell lines: 9 MTAP null, 1 MTAP CRISPR knock-out, and 5 MTAP wildtype. Optimal cell seeding for all cell lines was determined by assessing the growth over a range of seeding densities in a 384-well format to identify conditions that permitted proliferation for 10 days. Cells were then plated at the optimal seeding density in the presence of 20-150 nM of Compound A or DMSO vehicle control. Cells were incubated at 37°C with 5% CO2 for 4 days to allow for target engagement of the pre-treatment compound. Maintaining the pre-treatment condition, cells were also treated with an 11-point, three-fold titration series of compounds from a chemically diverse library. The combination compound concentrations ranged from 0.2 nM to 14,679 nM. A plate of cells was harvested at the time of combination compound addition to quantify the number of cells at the start of the combination (To). For cell quantification, the harvested cells were lysed with CellTiter-Glo (CTG) (Promega) reagent according to the manufacturer’s protocol and the chemiluminescent signal was detected on a Synergy Neo plate reader (ThermoFisher, serial # 140715A). CTG estimates cell number through detection of cellular ATP levels. Cells were incubated with the drug combinations at 37°C with 5% CO2 for an additional 6 days for a total of a 10-day assay including the pre-treatment. Cells were then lysed with CTG and the chemiluminescent signal was measured. CTG values obtained after the 10-day treatment were background subtracted, expressed as a percent of the To value, and plotted against compound concentration. Data were fit with a four-parameter equation to generate concentration response curves. Growth IC50 values and maximal growth inhibition were compared between the DMSO and the Compound A pre-treated cells for each combination titration. Combination hit calling was based on the observation of >2-fold shift in growth IC50 and/or greater than 20% decrease in growth inhibition.

Of the compounds tested, the PARP inhibitor Talazoparib was identified as a combination hit in the NCI-H838, HuP-T4, RT112/84, and UMUC5 cell lines where 5.2-, 7.5-, 2.5-, and 2.9-fold shifts in growth IC50 were observed, respectively (Table 3). Combination benefit was not observed in any of the MTAP wild type cell lines tested. In addition to Talazoparib, the PARP inhibitor Olaparib was identified as a combination hit in the UMUC5 cell line where a 3-fold shift in growth IC50 was observed.

Table 3: Growth IC50 values in cancer cell lines

Example 2: MAT2A inhibitor and PARP inhibitor Combinations

A 10-day proliferation assay was performed in a panel of 8 pancreatic, non-small cell lung, and bladder cancer cell lines: 4 MTAP null, 1 MTAP CRISPR knock-out, and 3 MTAP wild type. Combinations included double titrations of MAT2A inhibitor Compound A with three different PARP inhibitor compounds including Talazoparib, Niraparib, and Olaparib.

Optimal cell seeding for all cell lines was determined by assessing the growth over a range of seeding densities in a 384-well format to identify conditions that permitted proliferation for 10 days. Cells were then plated at the optimal seeding density and treated with a double titration of a 16-point two-fold dilution series of Compound A and a 16-point two-fold dilution series of the PARP inhibitor compounds. This double titration was compared to 16-point two-fold dilution series of each single agent alone or to 0.15% DMSO. An untreated plate of cells was harvested at the time of compound addition (To) to quantify the starting number of cells using CTG as described in example 1. Concentrations tested for Compound A and the PARP inhibitors alone or in combination ranged from 0.6 nM to 19,250 nM. The double matrix design allowed for an assessment across the full titration of each compound in the combination. Plates were incubated for 10 days at 37 °C in 5% CO2. Cells were then lysed and measured with CTG.

Combination synergy was assessed using the Excess over Bliss model for the combinations of compound doses across the full dose range tested. The observed growth inhibition was compared to the predicted inhibition based on the additive activity of each single agent. Predicted inhibition was calculated using (Ea+Eb) - (Ea*Eb) where E equals the effect (inhibition) of each single agent (a and b). A difference between the observed inhibition percentage and the predicted inhibition percentage greater than 10% was considered synergistic. An Excess over Bliss score was only calculated for combinations eliciting >20% growth inhibition.

Synergistic growth inhibition was observed with Compound A in combination with all three PARP inhibitors across numerous combination concentrations as assessed by Excess over Bliss in /WTAP-deficient cell lines. This was most readily observed in the NCI-H838 cell line where a focused area of synergy was observed across several concentrations for all three PARP inhibitors (Table 4A-4C and Figures 1A-1C). Combination synergy was observed in three additional /WTAP-deficient cell lines and one /WTAP-knock-out cell line for all three PARP inhibitors albeit with fewer doses of the inhibitors than in the NCI-H838 cell line (Tables 5A-5C, 6A-6C, 7A-7C, and 8A-8C; Figures 2A-2C, 3A-3C, 4A-4C, and 5A-5C). Synergy is measured at all tested concentrations of Compound A across all concentrations of Talazoparib (A), Niraparib (B), or Olaparib (C) using excess over Bliss analyses. Scores between 1 and 10 (highlighted light gray) were considered additive, scores >10 (highlighted black) were considered synergistic. Excess over Bliss scores were only calculated for combinations exhibiting greater than 20% growth inhibition. Beyond the combination doses where synergy was observed, additive growth inhibition was observed at additional concentrations in all /WTAP-deficient cell lines tested. The MTAP wild type cell lines also exhibited enhanced growth inhibition at some of the combination dose combinations (Tables 9A-9C, 10A-10C, and 11A-11C; Figures 6A-6C, 7A-7C, and 8A-8C), but to a lesser extent than in the /WTAP-deficient cell lines. Increased growth inhibition was also observed for the PARP inhibitor combinations with Compound A in the /WTAP-deficient cell lines over that observed in the wild type cell lines.

Tables 4A-4C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in NCI-H838 cell line.

Table 4A

Table 4B

Table 4C

Tables 5A-5C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in NCI-H2228 cell line.

Table 5A

Table 5B

Table 5C

Tables 6A-6C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in RT112/84 cell line.

Table 6A

Table 6B

Table 6C

Tables 7A-7C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in UMUC5 cell line.

Table 7A

Table 7B

Table 7C

Tables 8A-8C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in Pane 03.27 MTAP CRISPR knock-out cell line

(Clone 31).

Table 8A

Table 8B

Table 8C

Tables 9A-9C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in Pane 03.27 MTAP wild type cell line.

Table 9A

Table 9B

Table 9C

Tables 10A-10C: Excess over Bliss Synergy of Compound A and PART inhibitor combinations in NCI-H520 MTAP wild type cell line.

Table 10A

Table 10B

Table IOC

Tables 11A-11C: Excess over Bliss Synergy of Compound A and PARP inhibitor combinations in TCCSUP MTAP wild type cell line.

Table 11A

Table 11B

Table 11C

Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Upon reading the foregoing, description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is expected that those skilled artisans may employ such variations as appropriate. Accordingly, it is intended that the invention be practiced otherwise than as specifically described herein, and that the invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

All patent applications, patents, and printed publications cited herein are incorporated herein by reference in the entireties, except for any definitions, subject matter disclaimers or disavowals, and except to the extent that the incorporated material is inconsistent with the express disclosure herein, in which case the language in this disclosure controls. Other embodiments are within the following claims.

Claims

1 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a MAT2A inhibitor and administering to the subject a therapeutically effective amount of a PARP inhibitor, wherein the MAT2A inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is N or CH;

R³ is C1-6 haloalkyl, halo, or C3-6 cycloalkyl;

R² is -NR⁴R⁵;

R⁴ is hydrogen or C1-6 alkyl;

R⁵ is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and

R¹ is phenyl, wherein phenyl is substituted with 0-2 halo.

2. The method of claim 1 , wherein X is N.

3. The method of claim 1 , wherein X is CH.

4. The method of any one of claims 1 to 3, wherein R⁴ is hydrogen and R⁵ is hydrogen or C1-3 alkyl.

5. The method of any one of claims 1 to 4, wherein R⁵ is hydrogen or methyl.

6. The method of any one of claims 1 to 5, wherein R¹ is phenyl substituted with chloro.

7. The method of any one of claims 1 to 6, wherein R³ is C1-3 haloalkyl or halo.

8. The method of any one of claims 1 to 7, wherein R³ is trifl uromethyl or chloro.

9. The method of any one of claims 1 to 6, wherein R³ is cyclopropyl.

10. The method of any one of claims 1 to 9, wherein the MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1 to 10, wherein the MAT2A inhibitor is Compound A:

Compound A or a pharmaceutically acceptable salt thereof.

12. The method of any one of claims 1 to 10, wherein the MAT2A inhibitor is Compound

A1 :

Compound A1 or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 1 to 12, wherein the PARP inhibitor is selected from the group consisting of

14. The method of any one of claims 1 to 13, wherein the PARP inhibitor is Compound B:

Compound B or a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 1 to 13, wherein the PARP inhibitor is Compound

or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1 to 13, wherein the PARP inhibitor is Compound D:

Compound D or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 1 to 13, wherein the PARP inhibitor is Compound E:

Compound E or a pharmaceutically acceptable salt thereof.

The method of any one of claims 1 to 13, wherein the PARP inhibitor is Compound F:

Compound F or a pharmaceutically acceptable salt thereof.

19. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A

Compound A or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the PARP inhibitor is Compound B:

Compound B or a pharmaceutically acceptable salt thereof.

21. The method of claim 19, wherein the PARP inhibitor is Compound C:

Compound C or a pharmaceutically acceptable salt thereof. The method of claim 19, wherein the PARP inhibitor is Compound D:

Compound D or a pharmaceutically acceptable salt thereof. The method of claim 19, wherein the PARP inhibitor is Compound E:

Compound E or a pharmaceutically acceptable salt thereof. The method of claim 19, wherein the PARP inhibitor is Compound F:

Compound F or a pharmaceutically acceptable salt thereof. The method of claim 19, wherine the PARP inhibitor is:

or pharmaceutically acceptable salts thereof.

26. The method of any one of claims 1 to 25, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin lymphoma, esophagogastric cancer, malignant peripheral nerve sheath tumor, and mesothelioma.

27. The method of any of claims 1 to 26, wherein the cancer is a solid tumor.

28. The method of any of claims 1 to 27, wherein the cancer is a solid malignant tumor.

29. The method of claim 27 or 28, wherein the tumor has an MTAP gene deletion.

30. The method of any one of claims 1 to 29, wherein the MAT2A inhibitor and the PARP inhibitor are in separate dosage forms.

31. The method of any one of claims 1 to 29, wherein the MAT2A inhibitor and the PARP inhibitor are in the same dosage form.

32. A combination comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a PARP inhibitor, or a pharmaceutically acceptable salt thereof.

33. The combination of claim 32, wherein the MAT2A inhibitor is a compound of Formula I and the PARP inhibitor is selected from the group consisting of a Compound B, Compound C, Compound D, Compound E, Compound F, AZD5305, and AZD9574, or a pharmaceutically acceptable salt thereof.

34. The combination of claim 32 or 33, wherein the MAT2A inhibitor is Compound A or

Compound A1 , and the PARP inhibitor is is selected from the group consisting of a Compound B, Compound C, Compound D, Compound E, and Compound F or a pharmaceutically acceptable salt thereof.

35. A MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with a PARP inhibitor, and wherein the MAT2A inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is N or CH;

R³ is C1-6 haloalkyl, halo, or C3-6 cycloalkyl;

R² is -NR⁴R⁵;

R⁴ is hydrogen or C1-6 alkyl;

R⁵ is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and

R¹ is phenyl, wherein phenyl is substituted with 0-2 halo.

36. The use of claim 35, wherein the PARP inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F, AZD5305, and AZD9574, or a pharmaceutically acceptable salt thereof.

37. The use of claim 36, wherein the MAT2A inhibitor is Compound A or Compound A1.

38. Use of a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be adminisered simultaneously or sequentially with a PARP inhibitor, and wherein the MAT2A inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein X is N or CH;

R³ is C1-6 haloalkyl, halo, or C3-6 cycloalkyl;

R² is -NR⁴R⁵;

R⁴ is hydrogen or C1-6 alkyl; R⁵ is hydrogen, C1-6 alkyl or C3-6 cycloalkyl; and

R¹ is phenyl, wherein phenyl is substituted with 0-2 halo.

39. The use of claim 38, wherein the PARP inhibitor is selected from the group consisting of Compound B, Compound C, Compound D, Compound E, Compound F, AZD5303, and AZD9574 or a pharmaceutically acceptable salt thereof. 40. The use of claim 39, wherein the MAT2A inhibitor is Compound A.