Medicine for treating or preventing cancer

Abstract

Provided is a medicine for treating or preventing cancer that contains a first active ingredient and that is used in combination with a second active ingredient, wherein: the first active ingredient is a compound represented by formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof; and the second active ingredient is GDC-6036 or a pharmaceutically acceptable salt thereof.

Description

Medicines for treating or preventing cancer

[0001] The present invention relates to a pharmaceutical agent for treating or preventing cancer.

[0002] Cancer is a disease in which cells proliferate uncontrollably due to genetic abnormalities. Chemotherapy is a medical treatment for cancer, and various anticancer drugs are used. In recent years, numerous molecular targeted agents have been developed as anticancer drugs that specifically act on molecules specifically expressed in certain cancer cells or molecules whose expression is increased in cancer cells. Known molecular targeted agents include antibody drugs such as cetuximab, bevacizumab, and panitumumab (Patent Document 1), and small molecule drugs such as gefitinib, erlotinib, and afatinib (Patent Document 2). Furthermore, medium molecule drugs have also become known in recent years (Patent Document 3).

[0003] RAS proteins are molecules involved in cell proliferation and the like, and consist of three types: KRAS, NRAS, and HRAS. Mutations in the genes encoding these proteins cause cells to become cancerous. Molecularly targeted drugs known for treating cancers with the KRASG12C mutation include sotorasib, adagrasib, and GDC-6036 (Divarasib) (Patent Document 4, Non-Patent Document 1).

[0004] JP 2018-076369 A JP 2021-063014 A International Publication No. 2021 / 090855 International Publication No. 2020 / 097537

[0005] Jpn. J. Lung Cancer, 2022, 62, 188-199.

[0006] Under these circumstances, there is a current demand for pharmaceuticals with even greater efficacy in the treatment or prevention of cancer.

[0007] Therefore, an object of the present invention is to provide a pharmaceutical agent that is more effective than ever in treating or preventing cancer.

[0008] The present invention includes the following [1] to

[53] : [1] A pharmaceutical for treating or preventing cancer, which contains a first active ingredient and is used in combination with a second active ingredient, wherein the first active ingredient is a compound represented by the following formula (1) (hereinafter also referred to as "Compound 1") or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the second active ingredient is a compound represented by the following formula (2) (hereinafter also referred to as "Compound 2") or a pharmaceutically acceptable salt thereof. [2] A pharmaceutical for treating or preventing cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof, and the second active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. [3] The pharmaceutical according to [1] or [2], wherein the first active ingredient and the second active ingredient are provided as a kit. [4] A method for treating or preventing cancer, comprising administering a first active ingredient and a second active ingredient to a subject, wherein the first active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the second active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof. [5] A method for treating or preventing cancer, comprising administering a first active ingredient and a second active ingredient to a subject, wherein the first active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof, and the second active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. [6] A first active ingredient for use in the treatment or prevention of cancer, in combination with a second active ingredient, wherein the first active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the second active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof. [7] A first active ingredient for use in the treatment or prevention of cancer, in combination with a second active ingredient, wherein the first active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof, and the second active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. [8] Use of a first active ingredient for the manufacture of a medicament for the treatment or prevention of cancer, in combination with a second active ingredient, wherein the first active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the second active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof.[9] Use of a first active ingredient in the manufacture of a medicament for treating or preventing cancer, in combination with a second active ingredient, wherein the first active ingredient is Compound 2 or a pharmaceutically acceptable salt thereof, and the second active ingredient is Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[10] The medicament, method, first active ingredient for use, or use according to any of [1] to [9], wherein the combination of the first active ingredient and the second active ingredient is administered simultaneously or separately (i.e., the first active ingredient and the second active ingredient are administered simultaneously or separately).

[11] The medicament, method, first active ingredient for use, or use according to any of [1] to

[10] , wherein the first active ingredient and the second active ingredient are administered simultaneously or separately.

[12] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[11] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is compound 1 or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[13] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[11] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is compound 1 or a pharmaceutically acceptable solvate thereof.

[14] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[12] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is compound 1 or a hydrate thereof.

[15] The first active ingredient for the medicament, method, use, or use according to any one of [1] to

[11] and

[13] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is a pharmaceutically acceptable solvate of compound 1.

[16] The first active ingredient for the medicament, method, use, or use according to any one of [1] to

[15] , wherein the pharmaceutically acceptable solvate of compound 1 is a hydrate of compound 1.

[17] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[14] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is compound 1.

[18] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[12] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is a pharmaceutically acceptable salt of compound 1.

[19] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[18] , wherein the compound 2 or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of compound 2.

[20] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[19] , wherein the pharmaceutically acceptable salt of compound 2 is an adipic acid salt of compound 2.

[21] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[18] , wherein the compound 2 or a pharmaceutically acceptable salt thereof is compound 2.

[22] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[11] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is compound 1 or a hydrate thereof, and the compound 2 or a pharmaceutically acceptable salt thereof is compound 2 or an adipate salt thereof.

[23] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[11] or

[22] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is a hydrate of compound 1, and the compound 2 or a pharmaceutically acceptable salt thereof is an adipate salt of compound 2.

[24] The first active ingredient for the medicament, method, or use according to any one of [1] to

[11] and

[22] , or the use, wherein Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is a hydrate of Compound 1, and Compound 2 or a pharmaceutically acceptable salt thereof is Compound 2.

[25] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[11] and

[22] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is compound 1, and the compound 2 or a pharmaceutically acceptable salt thereof is an adipic acid salt of compound 2.

[26] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[11] and

[22] , wherein the compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is compound 1, and the compound 2 or a pharmaceutically acceptable salt thereof is compound 2.

[27] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[26] , wherein the cancer is a solid cancer or a blood cancer.

[28] The medicament, method, first active ingredient for use, or use according to any of [1] to

[27] , wherein the cancer is at least one selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, colorectal cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

[29] The medicament, method, first active ingredient for use, or use according to any of [1] to

[28] , wherein the cancer is lung cancer.

[30] The medicament, method, first active ingredient for use, or use according to any of [1] to

[29] , wherein the cancer is cancer associated with an abnormality in the RAS gene or the MAPK / ERK pathway (an abnormality in a protein in the MAPK / ERK pathway or a gene that produces the protein).

[31] The medicament, method, first active ingredient for use, or use according to

[30] , wherein the abnormality in the MAPK / ERK pathway is abnormal activation of the MAPK / ERK pathway.

[32] The medicament, method, first active ingredient for use, or use according to

[30] or

[31] , wherein the abnormality in the MAPK / ERK pathway is abnormal activation due to amplification of a protein in the MAPK / ERK pathway.

[33] The medicament, method, first active ingredient for use, or use according to any of

[30] to

[32] , wherein the abnormality in the MAPK / ERK pathway is abnormal activation due to a genetic mutation in the MAPK / ERK pathway.

[34] The medicament, method, first active ingredient for use, or use according to any of [1] to

[33] , wherein the cancer is a cancer associated with an abnormality in the RAS gene.

[35] The medicament, method, first active ingredient for use, or use according to

[34] , wherein the abnormality in the RAS gene is a mutation in the coding region of the RAS gene and / or an amplification of the copy number of the RAS gene.

[36] The medicament, method, first active ingredient for use, or use according to any of

[30] to

[35] , wherein the RAS gene is at least one RAS gene selected from the group consisting of the KRAS gene, the NRAS gene, and the HRAS gene.

[37] The medicament, method, first active ingredient for use, or use according to any of

[30] to

[36] , wherein the RAS gene is the KRAS gene.

[38] The medicament, method, first active ingredient for use, or use according to any of

[30] to

[37] , wherein the RAS gene is a KRAS gene, and the KRAS gene has a KRAS-G12C mutation (KRAS-G12C mutation-positive).

[39] The medicament, method, first active ingredient for use, or use according to any of [1] to

[38] , wherein the cancer is associated with the production of a mutant RAS protein and / or increased production of a RAS protein.

[40] The medicament, method, first active ingredient for use, or use according to any of [1] to

[39] , wherein the cancer is associated with the production of a mutant RAS protein.

[41] The medicament, method, first active ingredient for use, or use according to

[39] or

[40] , wherein the mutant RAS protein is one or more mutant RAS proteins selected from the group consisting of a mutant KRAS protein, a mutant NRAS protein, and a mutant HRAS protein.

[42] The pharmaceutical, method, first active ingredient for use, or use according to any one of

[39] to

[41] , wherein the mutant RAS protein has a mutation at at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequence set forth in SEQ ID NO: 1, 2, or 3.

[43] The first active ingredient for the medicament, method, use, or use according to any of

[39] to

[42] , wherein the mutant RAS protein has a mutation (excluding the G12D mutation) at at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequence set forth in SEQ ID NO: 1, 2, or 3.

[44] The first active ingredient for the medicament, method, use, or use according to any of

[39] to

[43] , wherein the mutant RAS protein is a mutant KRAS protein.

[45] The first active ingredient for the medicament, method, use, or use according to any of

[39] to

[44] , wherein the mutant RAS protein is a mutant KRAS protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K in the amino acid sequence set forth in SEQ ID NO: 1.

[46] The pharmaceutical composition, method, first active ingredient for use, or use according to any one of

[39] to

[45] , wherein the mutant RAS protein is a mutant KRAS protein and has an amino acid mutation of G12C in the amino acid sequence set forth in SEQ ID NO: 1 (positive for KRAS-G12C mutation).

[47] The pharmaceutical composition, method, first active ingredient for use, or use according to any one of

[39] to

[43] , wherein the mutant RAS protein is a mutant NRAS protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L in the amino acid sequence set forth in SEQ ID NO: 2.

[48] The pharmaceutical composition, method, first active ingredient for use, or use according to any one of

[39] to

[43] , wherein the mutant RAS protein is a mutant HRAS protein and has an amino acid mutation of G13R in the amino acid sequence set forth in SEQ ID NO: 3.

[49] The pharmaceutical composition, method, first active ingredient for use, or use according to any one of [1] to

[46] , wherein the cancer is a KRAS-G12C mutation-positive cancer.

[50] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[49] , wherein the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is 0.001 to 100 mg / day.

[51] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[50] , wherein the daily dose of Compound 2 or a pharmaceutically acceptable salt thereof, is 5 to 600 mg / day.

[52] The first active ingredient for the medicament, method, use, or use according to any of [1] to

[51] , wherein the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is 50 to 100% of the recommended dose when administered alone.

[53] The medicament, method, first active ingredient for use, or use according to any of [1] to

[52] , wherein the daily dose of compound 2 or a pharmaceutically acceptable salt thereof is 50 to 100% of the recommended dose when administered alone.

[0009] According to the present invention, a pharmaceutical agent is provided that is more effective than ever in treating or preventing cancer.

[0010] FIG. 1 shows the results of evaluating the cell growth inhibitory activity of the combined use of Compound 1 and Compound 2 using NCI-H1373 in Example 1. FIG. 2 shows the results of evaluating the cell growth inhibitory activity of the combined use of Compound 1 and Compound 2 using NCI-H2122 in Example 1. FIG. 3 shows the results of evaluating the cell growth inhibitory activity of the combined use of Compound 1 and Compound 2 using HCC-1171 in Example 1. FIG. 4 shows the results of evaluating the in vivo antitumor activity of the combined use of Compound 1 and Compound 2 using LU65 (lung cancer: KRAS G12C mutant strain) in Example 2. The vertical axis represents tumor volume, and the horizontal axis represents the number of days elapsed since the start of administration, with the start of administration being day 0. FIG. 5 shows the results of evaluating the in vivo antitumor activity of the combined use of Compound 1 and Compound 2 using UM-UC-3 (bladder cancer: KRAS G12C mutant strain) in Example 2. The vertical axis represents tumor volume, and the horizontal axis represents the number of days elapsed since the start of administration, with the start of administration being day 0. Figure 6 shows the results of evaluating the RAS signal inhibitory activity of a combination of Compound 1 and Compound 2 using NCI-H1373 in Example 3. More specifically, Figure 6 is an electrophoretic image showing the results of Western blotting of proteins extracted from NCI-H1373 (KRAS, NRAS, HRAS, KRAS-GTP, NRAS-GTP, HRAS-GTP, ERK, AKT, MEK, pERK, pAKT, and pMEK).

[0011] Embodiments of the present invention will be described below. However, the present invention is not limited to the following embodiments. The therapeutic or preventive medicament and therapeutic or preventive method of the present invention may be administered or applied to humans. As used herein, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range equal to or greater than A and equal to or less than B. As used herein, the term "about," when used in combination with a numerical value, means a range of +10% and -10% of the numerical value. In the present invention, the meaning of the term "and / or" includes any combination of "and" and "or" as appropriate. Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

[0012] Herein, the position of an amino acid in an amino acid sequence may be represented by "the single-letter designation of the amino acid + the amino acid number counted from the N-terminal amino acid." For example, "G12" represents glycine, the 12th amino acid from the N-terminus of the reference sequence. Furthermore, an amino acid mutation may be represented by "the single-letter designation of the amino acid before the change + the amino acid number counted from the N-terminal amino acid + the letter designation of the amino acid position after the mutation." For example, "G12C" represents a mutation of glycine, the 12th amino acid from the N-terminus of the reference sequence, to cysteine.

[0013] As used herein, "a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof" includes the compound, a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable solvate of the compound, and a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound.

[0014] One embodiment of the present invention is a medicament for treating or preventing cancer, which comprises a first active ingredient and is used in combination with a second active ingredient, wherein the first active ingredient is a compound represented by the following formula (1) (hereinafter also referred to as "compound 1") or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and the second active ingredient is a compound represented by the following formula (2) (hereinafter also referred to as "compound 2") or a pharmaceutically acceptable salt thereof:

[0015] Another embodiment of the present invention is a medicament for treating or preventing cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is compound 2 or a pharmaceutically acceptable salt thereof, and the second active ingredient is compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0016] In the case where Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof is used in combination with Compound 2 or a pharmaceutically acceptable salt thereof, Compound 1 of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof can be used as either a first active ingredient or a second active ingredient, and Compound 2 of the present invention or a pharmaceutically acceptable salt thereof can be used as either a first active ingredient or a second active ingredient.

[0017] The first active ingredient and the second active ingredient may be provided as a kit. A further embodiment of the present invention can be referred to as a kit comprising the first active ingredient and the second active ingredient. The medicament of the present invention may be provided as a kit. Another embodiment of the present invention may be a kit comprising the medicament.

[0018] "Combined use" means the use of a combination of active ingredients. For example, the combined use of a first active ingredient and a second active ingredient includes "administration as a single preparation containing the first active ingredient and the second active ingredient" (i.e., an embodiment in which the first active ingredient and the second active ingredient are combined as a combination drug (combined drug)) and "an embodiment in which the first active ingredient and the second active ingredient are each administered simultaneously or separately as separate preparations." In the latter embodiment, the preparation containing the first active ingredient may be administered first, or the preparation containing the second active ingredient may be administered first. The latter embodiment may be any of the following: "a first active ingredient and a second active ingredient are formulated separately and administered simultaneously via the same administration route," "a first active ingredient and a second active ingredient are formulated separately and administered separately via the same administration route at different times," "a first active ingredient and a second active ingredient are formulated separately and administered simultaneously via different administration routes (administered from different sites in the same patient)," and "a first active ingredient and a second active ingredient are formulated separately and administered separately via different administration routes at different times." In the "a first active ingredient and a second active ingredient are formulated separately and administered simultaneously via the same administration route," both drugs (a drug containing the first active ingredient and a drug containing the second active ingredient) may be mixed immediately before administration. "Separately" means that one formulation is administered before or after the other.

[0019] In other words, "combined use" can also be said to be a method of use in which one active ingredient is present in the patient's body while the other active ingredient is present in the patient's body. That is, a preferred embodiment is one in which the first active ingredient and the second active ingredient are administered so that they are simultaneously present in the patient's body, for example, in the blood, and a preferred embodiment is one in which certain drugs containing the first active ingredient and the second active ingredient are administered to the patient simultaneously, or one drug containing the first active ingredient or the second active ingredient is administered to the patient within 48 hours after the other drug containing the first active ingredient or the second active ingredient is administered.

[0020] Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be Compound 1, a pharmaceutically acceptable solvate of Compound 1, or a hydrate of Compound 1.

[0021] "Pharmaceutically acceptable" means that a compound, a salt of a compound, a solvate of a compound, a solvate of a salt of a compound, or a substance (e.g., an excipient) contained in a particular formulation is suitable for administration to a patient, e.g., when administered appropriately to a patient.

[0022] "Stereoisomers" mean compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers, and the like.

[0023] The term "chiral" refers to the property of not being superimposable on its mirror image partner, while the term "achiral" refers to the property of being superimposable on its mirror image partner.

[0024] "Diastereomer" means a stereoisomer with two or more chiral centers and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectroscopic properties, or biological activity. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0025] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0026] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to designate the indication of the rotation of plane-polarized light by the compound; (-) or l means the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer is also referred to as an enantiomer, and a mixture of such isomers may be called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to a molar mixture, such as two enantiomeric species, lacking optical activity.

[0027] The term "tautomer" or "tautomeric form" means structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0028] "Atropisomers" are stereoisomers resulting from sterically hindered rotation about a single bond, where the energy difference due to steric strain or other factors creates a barrier to rotation high enough to allow isolation of individual conformers.

[0029] Compound 1 may be in the form of a salt, such as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of Compound 1 include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine. These salts are produced, for example, by contacting the compound with an acid or a base. Compound 1 may also be in the form of a pharmaceutically acceptable solvate or a pharmaceutically acceptable hydrate. As used herein, a pharmaceutically acceptable solvate is not particularly limited as long as it forms a single molecular group together with the solvent, but it is a solvate formed with a solvent that can be taken (ingested) in conjunction with the administration of a drug. Examples of solvates include not only hydrates, alcohol hydrates (ethanol hydrate, methanol hydrate, 1-propanol hydrate, 2-propanol hydrate, etc.), and solvates with a single solvent such as dimethyl sulfoxide, but also solvates of a single molecule of a compound with multiple solvent molecules and solvates of a single molecule of a compound with multiple solvents. When the solvent is water, it is called a hydrate. Solvates are produced, for example, by contacting a compound with a solvent, and solvates of salts are produced, for example, by contacting a compound salt with a solvent. Salts of Compound 1 or solvates of Compound 1 or salts of Compound 1 are all active forms, just like Compound 1 (free form). As used herein, "solvates (of these)" includes solvates of Compound 1 and solvates of salts of Compound 1.

[0030] Compound 1, its pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof may exist in the form of crystalline polymorphs, but may be a single crystalline form or a mixture of crystalline forms. Compound 1, its pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof also include amorphous forms.

[0031] In one embodiment of the combination therapy, Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is administered daily at a dose of about 0.001 to 100 mg, 0.001 to 50 mg, 0.001 to 40 mg, 0.001 to 30 mg, 0.001 to 20 mg, 0.001 to 15 mg, 0.001 to 12 mg, 0.001 to 10 mg, 0.001 to 9 mg, 0.001 to 6 mg, 0.01 to 100 mg, 0.01 to 50 mg, 0.01 to 40 mg, 0.01 to 30 mg, 0.01 to 20 mg, 0.01 to 15 mg, 0. ... It is administered at 2 mg, 0.01-10 mg, 0.01-9 mg, 0.01-6 mg, 0.1-100 mg, 0.1-50 mg, 0.1-40 mg, 0.1-30 mg, 0.1-20 mg, 0.1-15 mg, 0.1-12 mg, 0.1-9 mg, 0.1-6 mg, 1-100 mg, 1-50 mg, 1-40 mg, 1-30 mg, 1-20 mg, 1-15 mg, 1-12 mg, 1-9 mg, 1-6 mg, 4.5-50 mg, 4.5-30 mg, 4.5-12 mg, or 4.5-9 mg, 4.5-6 mg, 6-12 mg, 6-9 mg. The dosage of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is preferably 0.001 to 100 mg per day (0.001 to 100 mg / day), more preferably 0.01 to 50 mg / day, even more preferably 0.1 to 20 mg / day, and most preferably 1 to 12 mg / day. When the dosage of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is within these ranges, the therapeutic or preventive effect on cancer is further enhanced. The frequency of administration of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof can be, for example, once a day, twice a day, or three times a day, with once a day being more preferred. The same dosage and / or administration method can be applied to Compound 2 or a pharmaceutically acceptable salt thereof.

[0032] Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof can be synthesized by, for example, the method described in WO 2021 / 090855, the method described in WO 2022 / 234864, peptide synthesis using the Fmoc method, or solid phase peptide synthesis. (Published by Bachem [Retrieved June 21, 2023], Internet URL: https: / / www.bachem.com / wp-admin / admin-ajax.php?juwpfisadmin=false&action=wpfd&task=file.download&wpfd_category_id=180&wpfd_file_id=213455&token=&preview=1, or Peptide Guide, No: 2004505, published by Global Marketing Bachem AG, 2019.) etc.

[0033] Compound 2 or a pharmaceutically acceptable salt thereof can be prepared according to known methods.

[0034] Compound 2 (CAS number: 2417987-45-0, 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one) is a compound represented by the following formula (2). Compound 2 is used as GDC-6036 or Divarasib.

[0035] Compound 2 may be in the form of a salt, such as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts of compound 2 include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and adipic acid; salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and salts with amino acids such as arginine. These salts are prepared, for example, by contacting the compound with an acid or a base. In one embodiment, the pharmaceutically acceptable salt of compound 2 is the adipic acid salt of compound 2. All salts of compound 2 are active, just like compound 2 (free form).

[0036] In one embodiment of the combination therapy, Compound 2 or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-100 mg, 5-50 mg, 5-25 mg, 25-600 mg, 25-500 mg, 25-400 mg, 25-300 mg, 25-250 mg, 25-200 mg, 25-150 mg, 25-100 mg, 25- It is administered at 50 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-100 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg, 200-600 mg, 200-500 mg, 200-400 mg, 200-300 mg, or 200-250 mg. The dosage of compound 2 or a pharmaceutically acceptable salt thereof is preferably 5 to 600 mg per day (5 to 600 mg / day), more preferably 25 to 500 mg / day, even more preferably 50 to 500 mg / day, and most preferably 50 to 400 mg / day, 100 mg / day, 200 mg / day, or 400 mg / day. When the dosage of compound 2 or a pharmaceutically acceptable salt thereof is within these ranges, the therapeutic or preventive effect on cancer is further enhanced. The frequency of administration of compound 2 or a pharmaceutically acceptable salt thereof can be, for example, once a day, twice a day, or three times a day, with once a day being more preferred. The same dosage and / or administration method can also be applied to compound 1, its pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof.

[0037] The dosage of Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and Compound 2 or a pharmaceutically acceptable salt thereof is preferably 0.001 to 100 mg / day for Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and 5 to 600 mg / day for Compound 2 or a pharmaceutically acceptable salt thereof, and more preferably 0.01 to 50 mg / day for Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and 5 to 600 mg / day for Compound 2 or a pharmaceutically acceptable salt thereof. The salt is more preferably 25 to 500 mg / day, and compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof is 0.1 to 20 mg / day and compound 2 or a pharmaceutically acceptable salt thereof is 50 to 500 mg / day, and compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof is 1 to 12 mg / day and compound 2 or a pharmaceutically acceptable salt thereof is 50 to 400 mg / day, 100 mg / day, 200 mg / day, or 400 mg / day are most preferred. When the dosages of compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and compound 2 or a pharmaceutically acceptable salt thereof are within these ranges, the therapeutic or preventive effect on cancer is further enhanced. The dosage and administration method can be adjusted appropriately while observing blood drug concentrations such as AUC and Cmax and the patient's condition. Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof may be administered, for example, once a day, twice a day, or three times a day, with once a day being more preferred. Compound 2 or a pharmaceutically acceptable salt thereof may be administered, for example, once a day, twice a day, or three times a day, with once a day being more preferred.

[0038] Embodiments of the present invention include all manner of rotamers and conformationally restricted states. Embodiments of the present invention also include atropisomers of the compounds of the present invention. By way of example, in embodiments of the present invention, compound 2 may exist as a mixture of atropisomers, or may be purified or enriched for the presence of a single atropisomer.

[0039] In some embodiments, compound 2 is a mixture of atropisomers. In other embodiments, compound 2 is a substantially purified atropisomer. In some embodiments, compound 2 is a substantially purified R-atropisomer. In some other embodiments, compound 2 is a substantially purified R-atropisomer.

[0040] In the present invention, administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous, transdermal), intracisternal, intravaginal, intraperitoneal, intravesical, or topical (injection, infusion, powder, ointment, gel, or cream) administration, and inhalation (oral or nasal spray). Dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for individual dosages. Dosage forms can also be adapted for various administration methods, including controlled-release formulations such as subcutaneous implants. The administration methods are equally applicable to the first active ingredient and the second active ingredient. The first active ingredient and the second active ingredient can be used as pharmaceuticals and can be administered as formulations or combinations.

[0041] The first active ingredient can be administered, for example, by any of the administration methods described above, and the second active ingredient can be administered, for example, by the same or different administration method as the first active ingredient. The interval between administrations of the first active ingredient and the second active ingredient can be, for example, 0 to 14 days, 0 to 10 days, or 0 to 7 days. The administration interval can be determined, for example, using the AUC, Cmax, Tmax, elimination half-life, or the subject's health status as indicators. For example, Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, can be administered orally (tablets, capsules, etc.), and Compound 2 or a pharmaceutically acceptable salt thereof can be administered by infusion. For example, Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and Compound 2 or a pharmaceutically acceptable salt thereof can both be administered orally (tablets, capsules, etc.). For example, Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof can be administered by infusion, and Compound 2 or a pharmaceutically acceptable salt thereof can be administered orally (tablets, capsules, etc.). For example, Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and Compound 2 or a pharmaceutically acceptable salt thereof can both be administered by infusion. In such cases, Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and Compound 2 or a pharmaceutically acceptable salt thereof can be administered at any interval, such as twice a day, once a day, once a week, or once every two weeks. More specifically, Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and Compound 2 or a pharmaceutically acceptable salt thereof can both be administered once a day, and in this case, they can be administered before, between, or after meals. "Before a meal, between meals, or after a meal" may refer to before, between, or after any of breakfast, lunch, dinner, a midnight snack, or a snack. When the administration interval between Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and Compound 2 or a pharmaceutically acceptable salt thereof is within 24 hours, both can be considered to be administered once a day.If necessary, Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and Compound 2 or a pharmaceutically acceptable salt thereof may be administered twice a day and once a day, once a day and once a day, once a day and twice a day, once a day and once every two days, once a day and once every three days, once a day and once every seven days, or twice a day and once every seven days, respectively. If necessary, the administration interval of only Compound 2 or a pharmaceutically acceptable salt thereof, or the administration interval of only Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be increased or decreased based on the AUC, Cmax, Tmax, or elimination half-life of Compound 1 and / or Compound 2, or the health condition of the patient. Administration of compound 2 or a pharmaceutically acceptable salt thereof may be initiated on the same day as the administration of compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Alternatively, the administration of compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof may be initiated on a different day. One course of administration is 7 days, and the total number of courses may be one or more, or may be two or more. Furthermore, each course may be administered consecutively, or a drug-free period may be provided. A drug-free period may be provided midway through a course. If necessary, during a course, only compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be continuously administered, and compound 2 or a pharmaceutically acceptable salt thereof may be suspended, or only compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be suspended, and compound 2 or a pharmaceutically acceptable salt thereof may be continuously administered. Compound 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and Compound 2 or a pharmaceutically acceptable salt thereof can also be contained in the same tablet, capsule, etc.

[0042] The pharmaceutical formulations of the present invention can be formulated by known methods by incorporating a pharmaceutically acceptable carrier in addition to an active ingredient such as Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or Compound 2 or a pharmaceutically acceptable salt thereof. For formulation, commonly used excipients, binders, lubricants, colorants, flavorings, and, if necessary, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. can be used. The formulations can be formulated by conventional methods by blending ingredients commonly used as raw materials for pharmaceutical formulations. In the formulations, the active ingredients used in pharmaceuticals can be processed into optimal shapes and properties, i.e., dosage forms, according to the method and purpose of use, using known methods. Commonly used dosage forms include liquid pharmaceutical formulations (liquids) such as injections, suspensions, emulsions, and eye drops, and solid pharmaceutical formulations (solid formulations) such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories. For example, a preparation containing an active ingredient exemplified by Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or Compound 2 or a pharmaceutically acceptable salt thereof can be used as the medicament of the present invention.

[0043] In the therapeutic or preventive medicament of the present invention, either or both of the first active ingredient and the second active ingredient may be mixed with a pharmaceutically acceptable additive. The pharmaceutically acceptable additive may be appropriately selected from additives well known to those skilled in the art, and multiple additives may be appropriately used as needed. The additive may be appropriately selected depending on whether the preparation is for oral administration or injection, and may be mixed with, for example, water, ethanol, physiological saline, liquid paraffin, a surfactant, sucrose, etc., and the resulting mixture may be encapsulated.

[0044] Cancers include solid cancers and blood cancers, both of which are composed of abnormal cells that grow uncontrollably. Solid cancers form one or many tumors, while blood cancers circulate throughout the body via the bloodstream. The cancer may be, for example, at least one selected from the group consisting of lung cancer, esophageal cancer, stomach cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma. The cancer may be cancer associated with an abnormality in the RAS gene. Preferably, the cancer is lung cancer, pancreatic cancer, bladder cancer, or colon cancer, more preferably lung cancer or bladder cancer.

[0045] As used herein, "abnormality" refers to a state in which various chromosomes, genes, proteins, and signal transduction cascades within a cell deviate from their normal functions and controls, and is usually triggered by their constitutive activation.

[0046] As used herein, the term "abnormal activation" refers to a state in which various chromosomes, genes, proteins, and signal cascades in cells are more activated than in normal cells. For example, genetic mutations may be one of the causes (Cancer Metastasis Rev., 2013, 32, 147-162). To directly and quantitatively measure the involvement of mutations in cells, cell activation can be measured, for example, by an LC / MS-MS-based assay (Cancer Discov., 2016, 6, 316-329).

[0047] "Protein amplification" refers to the synthesis and amplification of proteins in living cells, such as the amplification of proteins involved in the MAPK / ERK pathway (e.g., KRAS, NRAS, HRAS, KRAS-GTP, NRAS-GTP, HRAS-GTP, ERK, AKT, MEK, pERK, pAKT, pMEK). Protein amplification can be confirmed by measuring using Western blotting or comparative genomic hybridization (CGH), etc., and comparing the results with those of normal cells (Nat. Rev. Drug Discov., 2020, 19, 533-552, Molecular Cytogenetics, 2015, 8:103).

[0048] In one aspect, cancer includes cancer associated with abnormalities in the RAS gene (RAS mutation-positive cancer). Cancer associated with abnormalities in the RAS gene refers to, for example, cancer in which cancer cells have a mutation in the coding region of the RAS gene and / or an amplification of the copy number of the RAS gene, and an increase in RAS activity (including an increase in the production of RAS protein) is observed. Mutations in the coding region of the RAS gene refer, for example, to one or more base deletions, additions, or substitutions in the coding region of the RAS gene. An amplification of the copy number of the RAS gene refers to the presence of a greater number of copies of the RAS gene than the number of copies of the RAS gene normally present on the chromosome. A large copy number means a greater number than that in normal cells, and a copy number of 4 or more can be said to be an amplified copy number.

[0049] Whether a cancer is associated with an abnormality in the RAS gene (RAS mutation-positive cancer) can be determined by confirming whether a subject with cancer has an abnormality in the RAS gene. For example, by identifying a mutation in the base sequence of the coding region of the RAS gene in a biological sample obtained from a subject with cancer and further confirming that a mutated RAS protein is expressed, it can be determined that the cancer is associated with an abnormality in the RAS gene (RAS mutation-positive cancer).

[0050] Whether a cancer is associated with an abnormality in the RAS gene (RAS mutation-positive cancer) can be determined by checking whether a subject with cancer has an amplification of the copy number of the RAS gene. For example, by checking whether the copy number of the RAS gene is amplified and / or the production of RAS protein is increased in a biological sample obtained from a subject with cancer, it can be determined that the cancer is associated with an abnormality in the RAS gene. The increase in the production of RAS protein can also be referred to as overexpression of RAS protein. Whether the production of RAS protein is increased can be determined, for example, by comparing the expression level of a general RAS protein with the expression level of a RAS protein in a subject not affected by the cancer, or the expression level of a RAS protein in a subject before the cancer.

[0051] When a subject suffering from cancer has a mutation in the base sequence of the coding region of the RAS gene and the copy number of the RAS gene is amplified, the cancer can also be said to be related to an abnormality in the RAS gene (RAS mutation-positive cancer).

[0052] Any method can be used as long as it can detect mutations in the coding region of the RAS gene or amplification of the copy number of the RAS gene in a biological sample from a subject suffering from cancer, and can be performed by a conventional method by those skilled in the art. For example, the RAS gene can be isolated from a biological sample obtained from a subject suffering from cancer, amplified by PCR or the like, and its base sequence can be directly determined using a sequencer or the like. Alternatively, for example, a commercially available in vitro diagnostic agent capable of detecting mutations in the RAS gene can be used.

[0053] Three types of RAS protein isoforms are known: KRAS protein, NRAS protein, and HRAS protein. In one aspect, the RAS gene is one or more RAS genes selected from the group consisting of KRAS gene, NRAS gene, and HRAS gene. Preferably, the RAS gene is a KRAS gene. The KRAS gene may have a mutation in the nucleotide sequence of the coding region corresponding to at least one amino acid mutation site selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K in the amino acid sequence set forth in SEQ ID NO: 1. Preferably, the KRAS gene is a KRAS-G12C gene having a mutation in the nucleotide sequence of the coding region corresponding to the amino acid sequence of G12 of KRAS (KRAS-G12C mutation-positive). Here, "mutation-positive" means having a mutation in the amino acid sequence of the protein and / or having a mutation in the nucleotide sequence of the coding region corresponding to that amino acid sequence. The method for detecting whether a cancer is mutation-positive is not particularly limited, and detection may be performed through a pathological test of the cancer, a hematological test, or a test kit.

[0054] In one aspect, the cancer includes cancers associated with the production of mutant RAS proteins and / or increased production of RAS proteins (RAS mutation-positive cancers), which are typically caused by abnormalities in the RAS genes described above.

[0055] In one aspect, the mutant RAS protein is at least one mutant RAS protein selected from the group consisting of a mutant KRAS protein, a mutant NRAS protein, and a mutant HRAS protein. Preferably, the mutant RAS protein is a mutant KRAS protein.

[0056] In one aspect, the mutant RAS protein has a mutation at at least one amino acid position selected from the group consisting of G12, G13, and Q61 in the amino acid sequence set forth in SEQ ID NO: 1, 2, or 3. In the amino acid sequence set forth in SEQ ID NO: 1, 2, or 3, the 12th and 13th amino acids are glycine, and the 61st amino acid is glutamine.

[0057] In one aspect, the mutant RAS protein is a mutant KRAS protein and has at least one amino acid mutation selected from the group consisting of G12A, G12C, G12D, G12S, G12V, G13D, Q61H, and Q61K in the amino acid sequence set forth in SEQ ID NO: 1.

[0058] In one aspect, the mutant RAS protein is a mutant KRAS protein and has an amino acid mutation of G12C in the amino acid sequence set forth in SEQ ID NO: 1 (KRAS-G12C mutation positive).

[0059] In one aspect, the mutant RAS protein is a mutant NRAS protein and has at least one amino acid mutation selected from the group consisting of G12C, G12D, G13D, G13V, Q61K, and Q61L in the amino acid sequence set forth in SEQ ID NO:2.

[0060] In one aspect, the mutant RAS protein is a mutant HRAS protein and has an amino acid mutation of G13R in the amino acid sequence set forth in SEQ ID NO:3.

[0061] In one aspect, the cancer is a KRAS-G12C mutation-positive cancer.

[0062] From the viewpoint of enhancing the antitumor effect, the daily dose of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is preferably 50 to 100% of the recommended dose when Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is administered alone. Specifically, the recommended dose when Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is administered alone to humans is preferably 0.001 to 100 mg / day, more preferably 0.01 to 50 mg / day, even more preferably 0.1 to 20 mg / day, and most preferably 1 to 12 mg / day.

[0063] From the viewpoint of enhancing the antitumor effect, the daily dose of compound 2 or a pharmaceutically acceptable salt thereof is preferably 50 to 100% of the recommended dose when compound 2 or a pharmaceutically acceptable salt thereof is administered alone. Specifically, the recommended dose when compound 2 or a pharmaceutically acceptable salt thereof is administered alone to humans is preferably 5 to 600 mg / day, more preferably 25 to 500 mg / day, even more preferably 50 to 500 mg / day, and most preferably 50 to 400 mg / day.

[0064] In the present invention, the term "recommended dose" refers to a dose that brings about the greatest therapeutic effect within a range that can be safely used without causing serious side effects, as determined by clinical trials or the like. Specifically, this refers to a dose approved, recommended, or advised by public institutions or organizations such as the Pharmaceuticals and Medical Devices Agency (PMDA; Pharmaceuticals and Medical Devices Agency), the U.S. Food and Drug Administration (FDA; Food and Drug Administration), the European Medicines Agency (EMA; European Medicines Agency), etc., and is described in package inserts, interview forms, treatment guidelines, etc., and is preferably a dose approved by any of the public institutions, such as the PMDA, FDA, or EMA.

[0065] The present invention is further illustrated, but not limited, in the following examples. All compounds and reagents were obtained from commercial suppliers or synthesized using known methods.

[0066] Compound 1 ((5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-8-((S)-sec-butyl)-18-cyclopentyl-29-(3,5-difluoro-4-(trifluoromethyl)phenethyl)-36-ethyl-11-isobutyl-N,N,5,6,12,16,19,33-octamethyl-35-(4-methylbenzyl)-4,7,10,13,17,20,23,28,31 Hydrate of 2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontin-21,1′-cyclopentane]-15-carboxamide) was prepared according to the Fmoc peptide synthesis method described in WO 2021 / 090855. That is, 1) (3S)-4-(dimethylamino)-3-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-butanoic acid carboxyl group was supported on 2-chlorotrityl resin, and from the N-terminus of the amino acid, peptide elongation reaction by the Fmoc method according to the sequence of compound 1 2) cleavage reaction of the peptide from 2-chlorotrityl resin 3) amide cyclization reaction by condensation of the carboxyl group and the amino group of the peptide chain N-terminus (N-methylleucine) released from the 2-chlorotrityl resin by the cleavage reaction 4) purification of the compound by preparative HPLC It was produced in a four-step process. Alternatively, the hydrate of compound 1 was produced according to the synthesis method described in WO 2022 / 234864.

[0067] The adipic acid salt of compound 2 (1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one) was prepared according to the method described in J. Am. Chem. Soc. 2022, 144, 20955-20963. That is, 1) tert-butyl (S)-4-(7-bromo-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate, which can be synthesized from 2-amino-4-bromo-3-fluorobenzoic acid, was subjected to a Negishi coupling reaction with 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, which can be synthesized from 2,6-dichloro-4-methylnicotinic acid, to obtain tert-butyl (S)-4-((R)-7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-2,8-difluoroquinazolin-4-yl)-3-methylpiperazine-1-carboxylate. 2) The compound obtained above was subjected to an SNAr reaction using N-methyl-L-prolinol, followed by deprotection of the tert-butoxycarbonyl (Boc) group, and then reaction with acrylic anhydride to give 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one (production of the free form of GDC-6036). 3) The compound obtained above was treated with adipic acid to give 1-((S)-4-((R)-7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one adipate (production of adipate of GDC-6036).4) The compound obtained above was purified by HPLC.

[0068] <Pharmacological Test Examples> (Example 1 Evaluation of Cell Proliferation Inhibitory Activity of the Combined Use of Compound 1 Hydrate and Compound 2 Adipic Acid Salt) Human cancer cell lines (NCI-H1373 (KRAS-G12C), NCI-H2122 (KRAS-G12C), and HCC-1171 (KRAS-G12C)) were seeded onto low-adhesion surface U-bottom 384 plates (Sumitomo Bakelite) at a concentration of 500 cells per well (n=2), and cultured in a 37°C, 5% carbon dioxide incubator. Media containing Compound 1 and / or Compound 2 were prepared so that Compound 1 was serially diluted in five steps at a common ratio of 5 and Compound 2 was serially diluted in nine steps at a common ratio of 3. The combined effects of the two drugs were evaluated by mixing all combinations of the set concentrations (six concentrations and ten concentration combinations, including a DMSO group). In Table 1, for example, "0.16-100" for the Compound 1 concentration indicates that the highest concentration was 100 nM, and indicates that dilutions of 100, 20, 4, 0.8, or 0.16 nM were used. After 168 hours of culture following the addition of DMSO alone or Compound 1 and / or Compound 2, ATP levels were measured using CellTitorGlo 2.0 for cells treated with DMSO alone (DMSO-treated group), cells treated with Compound 1 and / or Compound 2 (compound-treated group), or cells treated with medium alone (no cells seeded). The cancer cell line names, medium, compound names, and final test compound concentrations are shown in Table 1. The cell growth inhibition rate (CGI%) was calculated from the signal values ​​obtained by CellTitorGlo 2.0 using the following formula: Cell proliferation inhibition rate (CGI%) = (1 - (TV - V0) / (CV - V0)) x 100 TV: ATP signal value at 168 hours in the compound-treated group CV: ATP signal value at 168 hours in the DMSO-treated group V0: ATP signal value at 168 hours in the medium alone (no cells seeded)

[0069] Using the obtained CGI values, analysis based on the isobologram method was performed according to the following procedure. The results of evaluating the cell growth inhibitory activity of Compound 1 and Compound 2 are shown in Figures 1 to 3. The X-axis (horizontal axis) and Y-axis (vertical axis) represent the concentrations of Compound 1 and Compound 2, respectively. First, the concentrations of Compound 1 and Compound 2 alone required to exert a CGI of 80% (NCI-H1373, NCI-H2122) or a CGI of 50% (HCC-1171) were plotted on the X-axis and Y-axis, respectively. The straight line connecting the plots on the X-axis and the Y-axis indicates the case where the cell growth inhibitory effect of the combined use of Compound 1 and Compound 2 is a simple sum of the cell growth inhibitory effects of each compound used alone (the effect is additive). Next, the concentrations of Compound 1 and Compound 2 required to exert that CGI value when the drugs are used in combination were plotted. When the plot for the combined use is located below the line connecting the plots on the X-axis and the Y-axis, it means that the combination of Compound 1 and Compound 2 exhibited a synergistic cell growth inhibitory effect, and the further the plot deviates from the line, the stronger the synergistic effect. As shown in Figures 1 to 3, the fact that the plots deviate from the line indicates that the combined use of Compound 1 and Compound 2 exhibited a synergistic cell growth inhibitory effect.

[0070]

[0071] Example 2: Evaluation of in vivo antitumor activity of a combination of Compound 1 hydrate and Compound 2 adipate. The in vivo antitumor activity of a combination of Compound 1 and Compound 2 was evaluated using xenograft models transplanted with the lung cancer line LU65 (KRAS-G12C) or the bladder cancer line UM-UC-3 (KRAS-G12C). Nude mice were subcutaneously administered 5 × 10 per mouse. ６ The cells were transplanted and the tumor volume was 200-300 mm ３When the tumor size reached 100 μg / mL, nude mice were randomized and administration of Compound 1 and / or Compound 2 was initiated (n=6). Compound 1 and Compound 2 were orally administered separately once daily for 21 days. The drug doses were 5 mg / kg for Compound 1 and 10 mg / kg or 25 mg / kg for Compound 2. Compound 1 was dissolved in 10% DMSO / 5% Cremphor EL / 85% distilled water, and Compound 2 was administered in 0.5% Methocel. The results of the in vivo antitumor activity evaluation are shown in Figures 4 and 5. In a lung cancer model (LU65) and a bladder cancer model (UM-UC-3), tumor volume increase was suppressed in the group administered with Compound 2 alone and the group administered with both Compounds 1 and 2, compared to the vehicle group. Furthermore, a comparison between the single-drug administration group and the two-drug administration group (combination group) showed that the tumor volume was reduced in the two-drug administration group, demonstrating the enhanced in vivo antitumor activity of compound 1 and compound 2 in combination.

[0072] Example 3: Evaluation of in vitro RAS signal inhibitory activity by combined use of Compound 1 hydrate and Compound 2 adipate. The effects of combined use of Compound 1 and Compound 2 on the phosphorylation of ERK, AKT, and MEK, and on the binding of KRAS, NRAS, and HRAS to GTP in human cancer cells were examined by Western blotting as follows. Human lung cancer cell line NCI-H1373 (KRAS-G12C) was cultured in a 3D culture plate PrimeSurface (Sumitomo Bakelite) at 4 × 10 ６ or 6 x 10 ６The cells were seeded on a 1000-well plate and cultured at 37°C for 24 hours. Then, 10 nM of compound 1 and 1 nM of compound 2 were added to the cells. The cells were cultured at 37°C in a 5% carbon dioxide incubator, and harvested after the treatment times shown in Table 2. The human cancer cell line name, medium, cell seeding number, compound 1 concentration, compound 2 concentration, and treatment time are shown in Table 2. The harvested cells were lysed in lysis buffer (ThermoFisher Scientific) containing a protease phosphatase inhibitor (ThermoFisher Scientific). Protein concentration was measured using a Direct Detect spectrometer (Merck KGaA), and protein solution 1 was prepared to a concentration of 20 μg per sample.

[0073] From 700 μg of the resulting protein solution 1, the activated form, RAS-GTP, was recovered using an Active Ras Pull-Down and Detection Kit (ThermoFisher Scientific) to prepare protein solution 2. SDS-PAGE was performed using the protein solutions 1 and 2 and a gradient gel with an acrylamide concentration of 5-20%, and the electrophoresed proteins were transferred to a PVDF membrane using a Transfer-Blot Turbo Transfer System (Bio-Rad Laboratories). After blocking, the PVDF membrane was reacted with primary and secondary antibodies in that order. Chemiluminescence was generated using Chemi-Lumi One Super (Nacalai Tesque), and bands were detected using a ChemiDoc Touch Imaging System (Bio-Rad Laboratories). The primary and secondary antibodies used, their dilutions, reaction temperatures, and reaction times are shown in Tables 3 and 4. Figure 6 shows electrophoretic images of Western blotting results for the evaluation of RAS signal inhibitory activity. In Figure 6, "pERK," "pAKT," and "pMEK" represent phosphorylated ERK, AKT, and MEK, respectively. "KRAS-GTP," "NRAS-GTP," and "HRAS-GTP" represent GTP-bound KRAS, NRAS, and HRAS, respectively. The results shown in Figure 6 indicate that the combined use of Compound 1 and Compound 2 enhanced the inhibitory effect on RAS signaling compared with the use of Compound 1 or Compound 2 alone.

[0074]

[0075]

[0076]

Claims

1. A pharmaceutical for treating or preventing cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is a compound represented by the following formula (1) or a pharma- ceutical acceptable salt thereof, or a pharma-ceutical acceptable solvate thereof, and the second active ingredient is a compound represented by the following formula (2) or a pharma-ceutical acceptable salt thereof: .

2. A pharmaceutical for treating or preventing cancer, comprising a first active ingredient and used in combination with a second active ingredient, wherein the first active ingredient is a compound represented by the following formula (2) or a pharma- ceutical acceptable salt thereof, and the second active ingredient is a compound represented by the following formula (1) or a pharma- ceutical acceptable salt thereof, or a pharma- ceutical acceptable solvate thereof: .

3. The pharmaceutical according to claim 1 or 2, wherein the first active ingredient and the second active ingredient are provided as a kit.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the first active ingredient and the second active ingredient are administered simultaneously or separately.

5. The pharmaceutical according to any one of claims 1 to 4, wherein the first active ingredient and the second active ingredient are used together as a combination drug.

6. The medicine according to any one of claims 1 to 5, wherein the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof is the compound represented by formula (1) or a pharma- ceutically acceptable solvate thereof.

7. The medicine according to any one of claims 1 to 6, wherein the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof is a pharma- ceutically acceptable solvate of the compound represented by formula (1).

8. The pharmaceutical agent according to any one of claims 1 to 7, wherein the pharma- ceutically acceptable solvate of the compound represented by formula (1) is a hydrate of the compound represented by formula (1).

9. The pharmaceutical agent according to any one of claims 1 to 6, wherein the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof is the compound represented by formula (1).

10. The pharmaceutical agent according to any one of claims 1 to 9, wherein the compound represented by formula (2) or a pharma- ceutically acceptable salt thereof is a pharma- ceutically acceptable salt of the compound represented by formula (2).

11. The pharmaceutical agent according to any one of claims 1 to 10, wherein the pharma- ceutically acceptable salt of the compound represented by formula (2) is an adipic acid salt of the compound represented by formula (2).

12. The pharmaceutical agent according to any one of claims 1 to 9, wherein the compound represented by formula (2) or a pharma- ceutically acceptable salt thereof is a compound represented by formula (2).

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the cancer is a solid cancer or a blood cancer.

14. The pharmaceutical according to any one of claims 1 to 13, wherein the cancer is at least one selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, colon cancer, uterine cancer, ovarian cancer, pancreatic cancer, bladder cancer, thyroid cancer, skin cancer, leukemia, malignant lymphoma, and multiple myeloma.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the cancer is a cancer associated with an abnormality in the RAS gene or the MAPK / ERK pathway.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the cancer is a cancer associated with an abnormality in the RAS gene.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the cancer is a KRAS-G12C mutation-positive cancer.

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