WEE1 inhibitors for cancer

Abstract

Disclosed herein is a WEE1 compound or a pharma- ceutically acceptable salt thereof, alone or in combination with a KRAS inhibitor or a pharma- ceutically acceptable salt thereof, for treating diseases or conditions such as colorectal cancer, pancreatic cancer, and / or non-small cell lung cancer.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) For example, any and all applications in which a claim of foreign or domestic priority is identified in an Application Data Sheet or claim filed with this application, including U.S. Provisional Application No. 63 / 265,438, filed December 15, 2021, which is incorporated by reference in its entirety, are incorporated by reference herein under 37 CFR 1.57 and Rules 4.18 and 20.6.

[0002] FIELD OF THEINVENTION This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, disclosed herein are combination therapies and methods of treating diseases and / or conditions using the combination therapies described herein. [Background technology]

[0003] Cancer is a group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Today's cancer treatments include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Survival rates vary by type of cancer and by the stage at which the cancer is diagnosed. In 2021, approximately 1.9 million people will be diagnosed with cancer in the United States, and an estimated 600,000 people will die from cancer. Thus, there remains a need for effective cancer treatments. Colorectal cancer is one of the most common cancers in both men and women worldwide. Summary of the Invention

[0004] Some embodiments described herein relate to the use of an effective amount of Compound (A) and / or Compound (B), or a pharma- ceutically acceptable salt of any of the above, for treating a cancer selected from colorectal cancer, pancreatic cancer, and non-small cell lung cancer (NSCLC) in a subject having a mutation selected from a TP53 mutation and a KRAS mutation. Other embodiments described herein relate to the use of an effective amount of Compound (A) and / or Compound (B), or a pharma- ceutically acceptable salt of any of the above, in the manufacture of a medicament for treating a cancer selected from colorectal cancer, pancreatic cancer, and NSCLC in a subject having a mutation selected from a TP53 mutation and a KRAS mutation. Yet other embodiments described herein relate to a method of treating cancer in a subject with a mutation selected from a TP53 mutation and a KRAS mutation, which may include administering a combination of compounds, the combination comprising an effective amount of Compound (A) and / or Compound (B), or a pharma- ceutically acceptable salt of any of the above, in a subject with a mutation selected from a TP53 and a KRAS mutation, and the cancer may be selected from colorectal cancer, pancreatic cancer, and NSCLC.

[0005] Some embodiments described herein relate to a combination of compounds that may include an effective amount of Compound (A) and / or Compound (B), or a pharma- ceutically acceptable salt of any of the above, and an effective amount of a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to the use of a combination of compounds for treating a cancer selected from colorectal cancer, pancreatic cancer, and NSCLC in a subject with a mutation selected from a TP53 mutation and a KRAS mutation, the combination comprising an effective amount of compound (A) and / or compound (B), or a pharma- ceutically acceptable salt of any of the above, and an effective amount of a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof. Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a cancer selected from colorectal cancer, pancreatic cancer, and NSCLC in a subject having a mutation selected from a TP53 mutation and a KRAS mutation, the combination comprising an effective amount of Compound (A) and / or Compound (B), or a pharmaceutically acceptable salt of any of the above, and an effective amount of a KRAS inhibitor, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to a method of treating a cancer in a subject having a mutation selected from a TP53 mutation and a KRAS mutation, which may comprise administering a combination of compounds, the combination comprising an effective amount of Compound (A) and / or Compound (B), or a pharmaceutically acceptable salt of any of the above, and an effective amount of a KRAS inhibitor, or a pharmaceutically acceptable salt thereof, and the cancer may be selected from colorectal cancer, pancreatic cancer, and NSCLC. [Brief description of the drawings]

[0007] [Figure 1-1] Figures 1-1 to 1-6 provide examples of KRAS inhibitors. [Figure 1-2] Figures 1-1 to 1-6 provide examples of KRAS inhibitors. [Figure 1-3] Figures 1-1 to 1-6 provide examples of KRAS inhibitors. [Figure 1-4] Figures 1-1 to 1-6 provide examples of KRAS inhibitors. [Figure 1-5] Figures 1-1 to 1-6 provide examples of KRAS inhibitors. [Figure 1-6] Figures 1-1 to 1-6 provide examples of KRAS inhibitors. [Diagram 2] FIG. 1 shows the effect of compound (A) or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor, used alone or in combination, on tumor volume in an H23 non-small cell lung model. [Diagram 3]FIG. 1 shows the effect of Compound (A) or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor, used alone or in combination, on tumor volume in a MiaPaca-2 pancreatic model. [Figure 4] FIG. 1 shows the effect of compound (A) or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor, used alone or in combination, on tumor volume in an H358 non-small cell lung cancer model. [Diagram 5] FIG. 1 shows the effect of compound (A) or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor, alone or in combination, on tumor volume in a SW837 CRC adenocarcinoma model. [Figure 6] FIG. 1 shows the effect of compound (A) or a pharma- ceutically acceptable salt thereof, and a KRAS inhibitor, alone or in combination, on tumor volume in a SW837 CRC adenocarcinoma model. [Figure 7] 1 shows the effect of using compound (A) or a pharma- ceutically acceptable salt thereof in a colorectal cancer LoVo xenograft model. [Figure 8] 1 shows the effect of using Compound (A) or a pharma- ceutically acceptable salt thereof in a colorectal cancer SW1116 xenograft model. [Figure 9] Representative assay data obtained for compound (A), or a pharmaceutically acceptable salt thereof, and KRAS inhibitor (sotrasib) in MiaPaca-2 (pancreatic cancer) cell line are shown. The results surprisingly show that the combination of compound (A), or a pharmaceutically acceptable salt thereof, and KRAS inhibitor results in synergistic activity. [Figure 10] Representative assay data obtained for compound (A), or a pharmaceutically acceptable salt thereof, and a KRAS inhibitor (MRTX849) in MiaPaca-2 (pancreatic cancer) cell line are shown. The results surprisingly show that the combination of compound (A), or a pharmaceutically acceptable salt thereof, and another KRAS inhibitor results in synergistic activity. [Figure 11]Representative assay data obtained for compound (A), or a pharmaceutically acceptable salt thereof, and a KRAS inhibitor (sotrasib) in SW1463 (colorectal adenocarcinoma) cell line are shown. The results surprisingly show that the combination of compound (A), or a pharmaceutically acceptable salt thereof, and a KRAS inhibitor resulted in synergistic activity in a second cell line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless otherwise stated. In the event that there are a plurality of definitions for a term herein, the definition in this section prevails unless otherwise stated.

[0009] The term "pharmaceutical acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not abolish the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate). Pharmaceutical salts can also be obtained by reacting a compound with an organic acid, such as an aliphatic or aromatic carboxylic acid or sulfonic acid, such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxopentanedioic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, sodium, potassium, or lithium salt, an alkaline earth metal salt, for example, calcium or magnesium salt, a salt of carbonate, a salt of bicarbonate, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. Those skilled in the art will appreciate that when a salt is formed by protonation of a nitrogen-based group (e.g., NH2), the nitrogen-based group may be associated with a positive charge (e.g., NH2 becomes NH3). + ), and the positive charge can be replaced by a negatively charged counterion (Cl - Understand that balance can be achieved by

[0010] In any compound described herein having one or more chiral centers, when the absolute stereochemistry is not explicitly indicated, it is understood that each center may be independently R or S configuration, or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure compounds, enantiomerically enriched compounds, racemic mixtures, diastereomerically pure compounds, diastereomerically enriched compounds, or stereoisomeric mixtures. In addition, in any compound described herein having one or more double bonds that generate geometric isomers that can be defined as E or Z, it is understood that each double bond may be independently E or Z, or a mixture thereof. Similarly, it is understood that in any compound described, all tautomeric forms are also intended to be included.

[0011] Where the compounds disclosed herein have unfilled valences, it is understood that the valences are filled with hydrogen or an isotope thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0012] It is understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element depicted in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be specifically disclosed or understood to be present in the compound. Hydrogen atoms at any position of the compound where they may be present may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference to compounds herein encompasses all possible isotopic forms, unless the context clearly indicates otherwise.

[0013] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in nonsolvated forms. Solvates contain either stoichiometric or nonstoichiometric amounts of solvent, and may be formed during the crystallization process with pharma-ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in nonsolvated as well as solvated forms. In general, solvated forms are considered equivalent to nonsolvated forms for the purposes of the compounds and methods provided herein.

[0014] When a range of values ​​is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of that range, are encompassed within an embodiment.

[0015] Terms and phrases used in this application, and variations thereof, particularly in the appended claims, should be construed as open-ended rather than limiting, unless expressly stated otherwise. As an example above, the term "including" should be construed to mean "including without limitation," "including but not limited to," and the like. As used herein, the term "comprising" is synonymous with "including," "containing," or "featuring," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. The term "having" should be construed as "having at least." The term "including" should be construed as "including but not limited to." The term "example" is used to provide illustrative examples rather than an exhaustive or exclusive list of the items under discussion. The use of terms such as "preferably," "preferred," "desired," or "desirable," as well as words of similar import, should not be understood as implying that a particular feature is critical, essential, or even important to the structure or function, but rather is intended merely to highlight alternative or additional features that may or may not be utilized in a particular embodiment. Additionally, the term "comprising" is intended to be construed as synonymous with the phrases "having at least" or "including at least." When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0016] With respect to the use of substantially any plural and / or singular term herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate depending on the context and / or application. Various singular / plural permutations may be expressly stated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain means are recited in mutually different dependent claims does not indicate that a combination of these means cannot be used to advantage. Any reference signs in the claims should not be interpreted as limiting the scope thereof.

[0017] compound Some embodiments described herein involve the use of TP53 mutations and KRAS mutations. The present invention relates to the use of an effective amount of compound (A) and / or compound (B), or a pharma- ceutically acceptable salt of either of the above, for treating colorectal cancer in a subject having a mutation selected from:

[0018] The human TP53 gene is located on chromosome 17p and consists of 11 exons and 10 introns. The wild-type p53 protein consists of 393 amino acid residues. Several p53 mutations have been identified in colorectal cancer. Examples of p53 mutations include those described in Li et al., World J Gastroenterol (2015) 21(l): 84-93 and Bouaoun et al., Hum Mutat. (2016) 37(9): 865-876. KRAS mutations are considered to be one of the most frequent and predominant mutations in cancers, including colorectal cancer, pancreatic cancer and NSCLC. (See Maitra R,(2021).Therapeutic Approach to KRAS Mutated Colorectal Cancer.Cancer Therapy,MedDocs Publishers.Vol.4,Chapter 1,pp.1-5 and J.Luo,Semin Oncol.(2021)48(1):10-18). KRAS mutations occur most commonly in codons 12, 13, 59, or 61 (including KRAS G12A, G12C, G12D, G12F, G12L, G12R, G12S, G12V, G12Y, G13A, G13C, G13D, G13R, G13S, G13V, A59T, Q61E, Q61H, Q61K, Q61L, Q61P, and Q61R) and less commonly in other KRAS codons, including codons 117 or 146 (including KRAS K117N, A146P, A146T, or A146V). (See Moore et al., Nat. Rev. Drug Discov. (2020) 19(8):533-552).

[0019] Some embodiments disclosed herein relate to the use of a combination of compounds for treating a cancer selected from colorectal cancer, pancreatic cancer and NSCLC in a subject having a mutation selected from a TP53 mutation and a KRAS mutation, the combination may comprise an effective amount of compound (A) and / or compound (B), or a pharmaceutically acceptable salt of any of the above, and an effective amount of a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0020] Some embodiments described herein relate to the use of an effective amount of AZD-1775 (hereinafter "Compound (B)") and a KRAS inhibitor (such as those described herein), or a pharma- ceutically acceptable salt of any of the above, for treating a cancer selected from colorectal cancer, pancreatic cancer and NSCLC in a subject having a mutation selected from a TP53 mutation and a KRAS mutation.

[0021] Compound (A), including its pharma- ceutically acceptable salts,

[0022] [ka] It could be. Examples of KRAS inhibitors include sotorasib, adagrasib, JDQ443, MRTX-1257, MRTX1133, ARS-1620, ARS-853, ARS-107, BAY-293, BI-3406, BI-2852, BMS-214662, MRTX849, MRTX849-VHL(LC2), PROTAC K-Ras Degrader-1 (compound 518, CAS number 2378258-52-5), lonafarnib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963, and AU-8653 (AU-BEI-8653).

[0023] Embodiments of combinations of Compound (A) and KRAS inhibitors (including any pharma- ceutically acceptable salts thereof) and Compound (B) and KRAS inhibitors (including any pharma- ceutically acceptable salts thereof) are shown in Table 1. In Table 1, "A" represents Compound (A) (including any pharma- ceutically acceptable salts thereof), "B" represents Compound (B) (including any pharma- ceutically acceptable salts thereof), and numbers 1-23 represent the compounds provided in FIG. 1, including any pharma- ceutically acceptable salts thereof. For example, in Table 1, the combination represented by 1:A is a combination of sotorasib and

[0024] [ka] (including pharma- ceutically acceptable salts of any of the above).

[0025] [Table 1]

[0026] When the treatment is a combination of compounds, the order of administration of the compounds in the combination described herein may vary. In some embodiments, compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts described above) may be administered before any KRAS inhibitor, or any pharma- ceutically acceptable salts described above. In other embodiments, compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts described above) may be administered before at least one KRAS inhibitor, or a pharma- ceutically acceptable salt thereof. In still other embodiments, compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts described above) may be administered simultaneously with a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof. In still yet other embodiments, compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts described above) may be administered following administration of at least one KRAS inhibitor, or a pharma- ceutically acceptable salt thereof. In some embodiments, compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts thereof) may be administered subsequent to administration of any KRAS inhibitor, or any pharma- ceutically acceptable salt thereof.

[0027] There may be some advantages to using the combination of compounds described herein.For example, combining compounds that attack multiple pathways simultaneously may be more effective in treating cancers such as those described herein compared to when the combination compounds are used as monotherapy.

[0028] In some embodiments, the combination and / or monotherapy of Compound (A) and / or Compound (B) (including any pharma- ceutically acceptable salts of the above) described herein with a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, may reduce the number and / or severity of side effects that may be attributable to the compounds described herein, such as the KRAS inhibitor, or a pharma- ceutically acceptable salt thereof.

[0029] The use of the combinations of compounds described herein can result in additive, synergistic, or strongly synergistic effects. The combinations of compounds described herein can result in effects that are not antagonistic.

[0030] In some embodiments, the combination of compound (A) (including any pharma- ceutically acceptable salt thereof) described herein with a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, may produce an additive effect. In some embodiments, the combination of compound (A) and / or compound (B) (including any pharma- ceutically acceptable salt thereof) described herein with a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, may produce a synergistic effect. In some embodiments, the combination of compound (A) and / or compound (B) (including any pharma- ceutically acceptable salt thereof) described herein with a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, may produce a strong synergistic effect. In some embodiments, the combination of compound (A) and / or compound (B) (including any pharma- ceutically acceptable salt thereof) described herein with a KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, is not antagonistic.

[0031] As used herein, the term "antagonistic" means that the activity of the combination of compounds is lower than the sum of the activities of each compound in the combination when the activity of each compound is measured individually (i.e., as a single compound). As used herein, the term "synergistic" means that the activity of the combination of compounds is higher than the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually. As used herein, the term "additive" means that the activity of the combination of compounds is approximately equal to the sum of the individual activities of each compound in the combination when the activity of each compound is measured individually.

[0032] A potential advantage of utilizing the combinations described herein may be that a reduced amount of the compounds required to be effective in treating a disease condition disclosed herein may be required compared to when each compound is administered as a monotherapy. For example, the amount of KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, used in the combinations described herein may be less than the amount of KRAS inhibitor, or a pharma- ceutically acceptable salt thereof, required to achieve the same reduction in a disease marker (e.g., tumor size) when administered as a monotherapy. Another potential advantage of utilizing the combinations described herein is that the use of two or more compounds with different mechanisms of action may be a higher barrier to the development of resistance compared to when the compounds are administered as a monotherapy. Further advantages of utilizing the combinations described herein include little or no cross-resistance between each compound of the combinations described herein, different routes of elimination for each compound of the combinations described herein, and different combinations of the compounds described herein. and / or there is little overlapping toxicity between each compound in the combinations described herein.

[0033] Pharmaceutical Compositions Compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts thereof) may be provided in a pharmaceutical composition. Similarly, the KRAS inhibitor (including any pharma- ceutically acceptable salts thereof) may be provided in a pharmaceutical composition.

[0034] The term "pharmaceutical composition" refers to a mixture of one or more compounds and / or salts disclosed herein with other chemical components, such as diluents, carriers, and / or excipients. Pharmaceutical compositions facilitate administration of a compound to an organism. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions are generally tailored to the specific intended route of administration.

[0035] As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0036] As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that has no apparent pharmacological activity, but may be pharma- ceutically necessary or desirable. For example, a diluent may be used to bulk a potent drug whose mass is too small for manufacture and / or administration. It may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A common form of diluent in the art is a buffered aqueous solution, such as, without limitation, phosphate buffered saline, which mimics the pH and isotonicity of human blood.

[0037] As used herein, "excipient" refers to an essentially inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelators are excipients. In one embodiment, the pharmaceutical composition includes an antioxidant and / or a metal chelator. A "diluent" is a type of excipient.

[0038] In some embodiments, the KRAS inhibitor may be provided in a pharmaceutical composition comprising Compound (A) and / or Compound (B) (including any pharma- ceutically acceptable salts described above) together with a pharma- ceutically acceptable salt thereof. In other embodiments, the KRAS inhibitor may be administered in a pharmaceutical composition separate from the pharmaceutical composition comprising Compound (A) and / or Compound (B) (including any pharma- ceutically acceptable salts described above) together with a pharma- ceutically acceptable salt thereof.

[0039] The pharmaceutical compositions described herein can be administered to human patients by themselves or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with carriers, diluents, excipients, or combinations thereof.The appropriate formulation depends on the route of administration selected.Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0040] The pharmaceutical compositions disclosed herein can be prepared in a manner known per se, for example, by conventional mixing, dissolving, granulating, dragee-making, elutriating, emulsifying, encapsulating, entrapping or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharma-ceutically compatible counterions.

[0041] There are multiple techniques in the art for administering compounds, salts, and / or compositions, including, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injection. In some embodiments, compound (A) and / or compound (B) (including any pharma- ceutically acceptable salts described above) can be administered orally. In some embodiments, compound (A) and / or compound (B) (including any pharma-ceutically acceptable salts described above) can be provided to a subject by the same route of administration as the KRAS inhibitor with its pharma-ceutically acceptable salt. In other embodiments, compound (A) and / or compound (B) (including any pharma-ceutically acceptable salts described above) can be provided to a subject by a different route of administration than the KRAS inhibitor with its pharma-ceutically acceptable salt.

[0042] The compounds, salts, and / or compositions may also be administered in a local rather than systemic manner, for example, by injecting or implanting the compounds directly into the affected area, often as a depot or sustained release formulation. Additionally, the compounds can be administered in targeted drug delivery systems, for example, in liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or intrapulmonary delivery may be desired to target respiratory diseases or conditions.

[0043] The composition may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice associated with the container, in a format prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the form of the drug for human or animal administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs, or an approved product insert. The composition may comprise the compound and / or salt described herein, formulated in a compatible pharmaceutical carrier, and may also be prepared for the treatment of the indicated condition, placed in an appropriate container, and labeled.

[0044] Methods of Use and Treatment As provided herein, in some embodiments, a combination of compounds comprising an effective amount of Compound (A) and / or Compound (B) (including any pharma- ceutically acceptable salt thereof) and an effective amount of a KRAS inhibitor, or any pharma- ceutically acceptable salt thereof, can be used to treat a disease or condition described herein, such as a cancer selected from colorectal cancer, pancreatic cancer, and non-small cell lung cancer.

[0045] In some cases, following cancer treatment, a subject may experience a relapse or recurrence of cancer. As used herein, the terms "relapse" and "recurrence" are used in their ordinary sense as understood by those of skill in the art. Thus, the cancer may be a recurrent cancer.

[0046] As used herein, "subject" refers to an animal that is the object of treatment, observation, or experiment. "Animals" include cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, crustaceans, reptiles, and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and especially humans. In some embodiments, the subject may be a human. In some embodiments, the subject may be a child and / or infant. In other embodiments, the subject may be an adult.

[0047] As used herein, the terms "treat," "treating," "treatment," "therapeutic," and "therapy" do not necessarily mean a complete cure or elimination of a disease or condition. Any alleviation of any undesirable signs or symptoms of a disease or condition, to any degree, may be considered treatment and / or therapy. Additionally, treatment may include actions that may worsen a subject's overall feeling of health or appearance.

[0048] The term "effective amount" is used to indicate the amount of an active compound or drug that induces the indicated biological or pharmaceutical response. For example, an effective amount of a compound, salt or composition may be the amount necessary to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or to prolong the survival of the subject being treated. This response may occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the particular animal under consideration. Dosages may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent medications, and other factors that one of ordinary skill in the medical arts would recognize.

[0049] For example, an effective amount of a compound or radiation is an amount that results in (a) reduction, alleviation, or elimination of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) elimination of the tumor, and / or (d) long-term disease stabilization (growth cessation) of the tumor.

[0050] The amount of compound, salt, and / or composition required for use in treatment varies depending on the specific compound or salt selected, the route of administration, the nature and / or symptoms of the disease or condition being treated, and the age and condition of the patient, and is ultimately at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage amount can be calculated as a free base. As will be understood by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts that exceed or even far exceed the dosage ranges described herein in order to effectively and aggressively treat, particularly progressive, diseases or conditions.

[0051] As will be readily apparent to those skilled in the art, the useful in vivo dosages and the specific administration methods administered will vary depending on the age, weight, severity of the affliction, and mammalian species being treated, the specific compounds used, and the specific applications for which these compounds are used. Determination of effective dosage levels, i.e., the dosage levels required to achieve the desired results, can be accomplished by those skilled in the art using routine methods, such as human clinical trials, in vivo studies, and in vitro studies. For example, useful dosages of Compound (A), Compound (B), and / or KRAS inhibitors, or pharma- ceutically acceptable salts of the above, can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparisons can be used to , by comparison with established drugs such as cisplatin and / or gemcitabine.

[0052] Dosage amount and interval are adjusted individually to provide plasma concentrations of the active moiety sufficient to maintain the modulating effect or minimal effective concentration (MEC). The MEC may be determined by the method of the present invention. The MEC varies for each compound but can be estimated from in vivo and / or in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% of the time, and most preferably 50-90% of the time. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0053] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response is not adequate (precluding toxicity). The magnitude of the dose administered in the management of the disease of interest will vary with the severity of the disease or condition to be treated and with the route of administration. The severity of the disease or condition can, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps the frequency of administration will also vary with the age, weight, and response of the individual patient. Programs comparable to those discussed above can be used in veterinary medicine.

[0054] The compounds, salts, and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound or a subset of compounds sharing a certain chemical moiety can be established by evaluating in vitro toxicity on cell lines, such as mammalian cell lines, preferably human cell lines. The results of such studies often predict toxicity in animals, such as mammals, or especially humans. Alternatively, the toxicity of a particular compound in an animal model, such as mice, rats, rabbits, dogs, or monkeys, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, a person skilled in the art can be guided by the state of the art in selecting the appropriate model, dose, route of administration, and / or regimen. EXAMPLES

[0055] Further embodiments, which are not intended to limit the scope of the claims in any way, are disclosed in more detail in the following examples.

[0056] 20,000 H23 cells were incubated in triplicate with 40 nM sotorasib or 120 nM compound (A) as single agents or in combination with both for 72 hours in a 96-well plate (Figure 2). 20,000 MiaPaca-2 cells were incubated in triplicate with 350 nM sotorasib or 1,000 nM compound (A) as single agents or in combination with both for 72 hours in a 96-well plate (Figure 3). 20,000 H358 cells were incubated in triplicate with 10 nM sotorasib or 300 nM compound (A) as single agents or in combination with both for 72 hours in a 96-well plate (Figure 4). 20,000 SW837 cells were incubated in triplicate with 12 nM sotorasib or 1,000 nM compound (A) as single agents or a combination of both for 72 hours in 96-well plates (Figure 5). For each cell line, cell viability was assessed using the CellTiter-Glo® (CTG) assay. Table 2 and Figures 2-5 provide the data and show that compound (A) or its pharma- ceutical acceptable salt, compound ( A) with a KRAS inhibitor (sotorasib) demonstrated synergistic or additive effects (CI<0.3) in all cell lines tested.

[0057] [Table 2]

[0058] For tumor development, 95% viable tumor cells (1 × 10) were cultured in 100 µL of serum-free L-15 Matrigel mixture (1:1 ratio). 7 ) SW837 cells were inoculated subcutaneously into the right flank of mice. The average tumor size was approximately 200 mm 3 (Individual tumors ranged from 180 to 220 mm 3Treatment was initiated when tumor volume reached 100%. Animals were randomly assigned to treatment groups of 8 animals each and dosed with vehicle (top line shown as circles) and the indicated compound at the indicated doses and frequencies as depicted in FIG. 6 and Table 3. In FIG. 6, single agent activity is depicted for Compound (A) and sotorasib at the indicated doses. Additionally, the bottom line is Compound (A) (60 mg / kg, orally, qd x 18 times) + sotorasib (30 mg / kg, orally, pd x 18 times). The combination of Compound (A) and sotorasib resulted in synergistic TGI activity and tumor regression. Tumor volumes were assessed twice weekly to calculate tumor volume over time and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition, The tumor growth index (TGI) was calculated using the following formula: TGI=(1-(Td-T0) / (Cd-C0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as (1-(Td / T0))×100% tumor volume (TV) reduction (Td end TV divided by T0 initial TV). Figure 6 and Table 3 show the monotherapy and dual therapy of Compound (A) at 60 mg / kg and Sotorasib at 30 mg / kg. The combination of Compound (A) (60 mg / kg) + Sotorasib (30 mg / kg) showed 109% tumor growth inhibition and 23% tumor regression at day 18.

[0059] [Table 3]

[0060] The antitumor activity of compound (A) was evaluated using a colorectal cancer LoVo xenograft model (KRAS mutant) in BALB / c nude mice. For tumor development, 5×10 6 Each mouse was inoculated with 100 μL of LoVo tumor cells subcutaneously into the right flank. The average tumor size was 207 mm 3 When the sigma-positive mice reached 10 mg / kg, the animals were randomized into 4 groups (10 animals / group) and treatment was initiated according to Table 4. Figure 7 shows the results of this study.

[0061] [Table 4]

[0062] Study endpoints included daily body weights, clinical observations and tumor volumes. Table 5 and Figure 7 show that compound (A) as a single agent produced robust inhibition of tumor growth that increased with dose level (40 mg / kg / day, 60 mg / kg / day and 80 mg / kg / day) with tumor growth inhibition (TGI) of 21.4%, 32.1% and 70.3%, respectively. There were no adverse clinical observations in any dose group and no significant effect of treatment on mean body weight.

[0063] [Table 5]

[0064] The antitumor activity of compound (A) was evaluated using a colorectal cancer SW1116 xenograft model (TP53 mutant; KRAS mutant) in NOD / SCID nude mice. For tumor development, 1×10 7 (+ high-concentration Matrigel) / 200 μL of SW1116 tumor cells were inoculated subcutaneously into the right flank of each mouse. The average tumor size was 229 mm 3 When the NIH score reached 0.01, the animals were randomized into 4 groups (10 animals / group) and treatment was initiated according to Table 6.

[0065] [Table 6]

[0066] Study endpoints included daily body weights, clinical observations, and tumor volumes. Table 7 and Figure 8 show that compound (A) as a single agent produced robust inhibition of tumor growth, with tumor growth inhibition (TGI) of 49.0 percent, 75.1 percent, and 98.5 percent, respectively, increasing with dose level (40 mg / kg / day, 60 mg / kg / day, and 80 mg / kg / day). Treatment was generally well tolerated by the majority of study animals.

[0067] [Table 7]

[0068] For tumor development, 95% viable tumor cells (1 × 10) were cultured in 100 µL of serum-free L-15 Matrigel mixture (1:1 ratio). 7 ) MiaPaca-2 cells were inoculated subcutaneously into the right flank of mice. The average tumor size was approximately 200 mm. 3 (Individual tumors ranged from 180 to 220 mm 3 ) was reached. Animals were randomly assigned to treatment groups of 8 animals each and dosed with vehicle and the indicated compound at the indicated doses and frequencies as shown in Figures 9 and 10 and Tables 8 and 9. In Figures 9 and 10, single agent activity with the indicated doses of Compound (A) and sotorasib or MRTX849 is shown. In Figure 9, the bottom line is Compound (A) 80 mg / kg, oral, qd x 21 + sotorasib 10 mg / kg, oral, pd x 21, the second line from the bottom is sotorasib, the second line from the top is Compound (A), and the top line is vehicle. In Figure 10, the bottom line is Compound (A) 80 mg / kg, oral, qd x 21 + MRTX849 10 mg / kg, oral, pd x 21, the second line from the bottom is MRTX849, the second line from the top is Compound (A), and the top line is vehicle. As shown in Figures 9 and 10 and Tables 8 and 9, combination of compound (A) with sotorasib or MRTX849 resulted in synergistic TGI activity and tumor regression.

[0069] Tumor volumes were assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following formula: Calculation was performed using: TGI=(1-(Td-T0) / (Cd-C0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as (1-(Td / T0))×100% tumor volume (TV) reduction (Td end TV divided by T0 initial TV). Tables 8 and 9, along with Figures 9 and 10, show the monotherapy and dual therapy of 80 mg / kg compound (A) and 10 mg / kg sotorasib or MRTX849. The combination of compound (A) (80 mg / kg) + sotorasib (10 mg / kg) showed 121% tumor growth inhibition and 88% tumor regression at day 21. The combination of Compound (A) (80 mg / kg) + MRTX849 (10 mg / kg) showed 109% tumor growth inhibition and 31% tumor regression at day 21.

[0070] [Table 8]

[0071] [Table 9]

[0072] For tumor development, 95% viable tumor cells (1 × 10) were cultured in 100 µL of serum-free L-15 Matrigel mixture (1:1 ratio). 7 ) SW1463 cells were inoculated subcutaneously into the right flank of mice. The average tumor size was approximately 200 mm. 3 (Individual tumors ranged from 180 to 220 mm 3) was reached. Animals were randomly assigned to treatment groups of 8 animals each and dosed with vehicle (top line marked with border) and the indicated compound at the indicated doses and frequencies as shown in Figure 11 and Table 10. In Figure 11, single agent activity is shown for Compound (A) and sotorasib at the indicated doses, the bottom line is Compound (A) 80 mg / kg, orally, qd x 21 + sotorasib 30 mg / kg, orally, pd x 21. The combination of Compound (A) and sotorasib resulted in synergistic TGI activity and tumor regression.

[0073] Tumor volumes were assessed twice weekly to calculate tumor volume over time, and mice were weighed twice weekly as a surrogate for signs of toxicity. Tumor growth inhibition (TGI) was calculated using the following formula: Calculation was performed using: TGI=(1-(Td-T0) / (Cd-C0))×100%. Td and Cd are the mean tumor volumes of treated and control animals, and T0 and C0 are the mean tumor volumes of treated and control animals at the start of the study. Tumor regression was defined as (1-(Td / T0))×100% tumor volume (TV) reduction (Td end TV divided by T0 initial TV). Figure 11 and Table 10 show the monotherapy and dual therapy of 80 mg / kg Compound (A) and 30 mg / kg Sotorasib. The combination of Compound (A) (80 mg / kg) + Sotorasib (30 mg / kg) showed 94 percent tumor growth inhibition at day 21.

[0074] [Table 10]

[0075] Moreover, although the above has been described in some detail with reference to the figures and examples for purposes of clarity and understanding, it will be understood by those skilled in the art that numerous and various modifications may be made without departing from the spirit of the present disclosure. It should therefore be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather encompass all modifications and alternative forms consistent with the true scope and spirit of the present invention.

Claims

1. A pharmaceutical for treating cancer, comprising an effective amount of compound (A) or a pharmaceutically acceptable salt thereof, Compound (A) is 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; the cancer is selected from colorectal cancer, pancreatic cancer, and non-small cell lung cancer; The cancer has a mutation selected from the group consisting of a TP53 mutation and a KRAS mutation.

2. A pharmaceutical for treating cancer, comprising an effective amount of compound (B) or a pharmaceutically acceptable salt thereof, Compound (B) is AZD-1775 or a pharmaceutically acceptable salt thereof; the cancer is selected from colorectal cancer, pancreatic cancer, and non-small cell lung cancer; The cancer has a mutation selected from the group consisting of a TP53 mutation and a KRAS mutation.

3. The medicines include sotorasib, adagrasib, JDQ443, MRTX-1257, MRTX1133, ARS-1620, ARS-853, ARS-107, BAY-293, B and an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof selected from the group consisting of I-3406, BI-2852, BMS-214662, MRTX849, MRTX849-VHL(LC2), PROTAC K-Ras Degrader-1 (compound 518, CAS number 2378258-52-5), lonafamib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963, and AU-8653 (AU-BEI-8653), The pharmaceutical composition according to claim 1, wherein compound (A) or a pharmaceutically acceptable salt thereof and the KRAS inhibitor or a pharmaceutically acceptable salt thereof are provided in a single pharmaceutical composition or in separate pharmaceutical compositions.

4. The pharmaceutical composition of claim 3, wherein the KRAS inhibitor is sotorasib, adagrasib, MRTX849, or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 3, wherein compound (A) or a pharmaceutically acceptable salt thereof is provided before the KRAS inhibitor or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 3, wherein compound (A) or a pharmaceutically acceptable salt thereof is provided simultaneously with the KRAS inhibitor or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 3, wherein compound (A) or a pharmaceutically acceptable salt thereof is provided after the KRAS inhibitor or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical according to claim 1 , wherein the mutation is a KRAS mutation.

9. The pharmaceutical according to claim 1, wherein the mutation is a TP53 mutation.

10. The pharmaceutical composition of claim 1, wherein the mutations are TP53 mutations and KRAS mutations.

11. The method of claim 1, wherein the cancer is colorectal cancer.

12. The pharmaceutical composition of claim 1 , wherein the cancer is pancreatic cancer.

13. The pharmaceutical composition of claim 1, wherein the cancer is non-small cell lung cancer.

14. The medicine is sotorasib, adagrasib, JDQ443, MRTX-1257, MRTX1133, ARS-1620, ARS-853, ARS-107, BAY-293, BI-3406, BI-2852, BMS-214662, MRTX849, MRTX849-VHL(LC2), PROTAC K-Ras It is used in combination with an effective amount of a KRAS inhibitor selected from the group consisting of Degrader-1 (compound 518, CAS number 2378258-52-5), lonafamib (SCH66336), RMC-0331, GDC-6036, LY3537982, D-1553, ARS-3248 (JNJ74699157), BI-1701963, and AU-8653 (AU-BEI-8653), or a pharmaceutically acceptable salt thereof; The pharmaceutical composition according to claim 2, wherein compound (B) or a pharmaceutically acceptable salt thereof and the KRAS inhibitor or a pharmaceutically acceptable salt thereof are provided in a single pharmaceutical composition or in separate pharmaceutical compositions.

15. The KRAS inhibitor is sotorasib, adagrasib, MRTX849, or any of them. The pharmaceutical composition according to claim 14, which is a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 14, wherein compound (B) or a pharmaceutically acceptable salt thereof is provided before the KRAS inhibitor or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 14, wherein compound (B) or a pharmaceutically acceptable salt thereof is provided simultaneously with the KRAS inhibitor or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 14, wherein compound (B) or a pharmaceutically acceptable salt thereof is provided after the KRAS inhibitor or a pharmaceutically acceptable salt thereof.

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