TW202019426A - Pharmaceutical composition comprising quinazoline compound as active ingredient - Google Patents

Abstract

To provide a pharmaceutical composition for treating colon cancer, in particular, KRAS G12C mutation-positive colon cancer. The present inventors have examined compounds having G12C mutation KRAS inhibitory effect. As a result, the present inventors have confirmed that specific quinazoline compounds have G12C mutation KRAS inhibitory effect and a pharmaceutical composition comprising such a compound as an active ingredient has a therapeutic effect on colon cancer, in particular, KRAS G12C mutation-positive colon cancer to thereby complete the present invention.

Description

Pharmaceutical composition with quinazoline compound as active ingredient

The present invention relates to a pharmaceutical composition for the treatment of colorectal cancer using a quinazoline compound or a pharmaceutically acceptable salt thereof as an active ingredient.

It has been reported that colorectal cancer is a cancer with a high attack rate and fatality rate in the world, and about 1 million people are newly infected in the world each year (World Cancer Report 2014). Although the most effective method in the treatment of colorectal cancer is surgery, recent advances in chemotherapy or radiation therapy have also been remarkable. The results of large-scale clinical trials centered on Europe and the United States have shown that it is effective for colorectal cancer to combine multiple types of anti-cancer chemical combination therapy, which can help tumor regression or prognosis prolongation (J. Clin. Oncol., 22, 229, 2004). In addition to chemotherapy, molecular target drugs such as anti-vascular endothelial growth factor (VEGF) antibodies or anti-epidermal growth factor receptor (EGFR) antibodies are also used as the first-selected drugs in combination with chemotherapy. Regarding anti-EGFR antibody drugs, RAS gene mutations are known to be a predictor of negative effects (Cancer Res. 66, 3992, 2006), and now anti-EGFR antibody drugs can only be adapted to patients with colorectal cancer who have wild type RAS genes.

The RAS protein is a low-molecular-weight guanosine triphosphate (GTP) binding protein of approximately 21 kDa made from 188-189 amino acids. There are four main types derived from the three genes of KRAS gene, NRAS gene and HRAS gene. Proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS). The RAS protein has an active GTP binding type and an inactive guanosine diphosphate (GDP) binding type. RAS protein is activated by the exchange of GDP and GTP due to ligand stimulation of cell membrane receptors such as EGFR. Active RAS combines with up to 20 types of effector proteins such as RAF, PI3K, and RALGDS to activate downstream communication cascade reactions. On the other hand, the active RAS becomes inactive by converting GTP to GDP by its inherent GTP hydrolysis activity (GTPase). This GTPase activity is enhanced by GAP (GTPase activating protein). Therefore, RAS acts as an important "molecular switch" in intracellular signal transmission pathways such as EGFR, and plays an important role in the process of cell growth, proliferation, and angiogenesis (Nature rev. cancer, 11, 761, 2011, Nature rev. drug discov., 13, 828, 2014, Nature rev. drug discov., 15, 771, 2016).

It is believed that if amino acid substitution occurs due to mutation of the RAS gene, the function of GTPase as RAS decreases or the affinity for GAP decreases, and the proportion of active types increases. The excessive signal transmission caused by this causes carcinogenesis or hyperproliferation of cancer. 30-40% of colorectal cancers have mutations found in the KRAS gene, especially KRAS exon 2 (codon 12, codon 13) point mutations (Ann. Oncol., 27, 1746, 2016). The current anticancer agents have not shown effectiveness for colorectal cancer with KRAS mutations, and the unmet medical needs for this part are high.

In recent years, the G12C mutant KRAS has shown the presence of allosteric pockets near the area called switch II (Nature, 503, 548, 2013), and it has been reported that The amino acid forms a covalent bond and is a compound that irreversibly binds to the G12C mutant KRAS (Cancer Discov., 6, 316, 2016, Cell, 172, 578, 2018). The G12C mutant KRAS selective inhibitor, by forming a covalent bond to the G12C mutant KRAS, inhibits the conversion from inactive to active form, and induces cancer cell death by blocking downstream signals. Since 3% of the KRAS mutations found in colorectal cancer are G12C mutations, it is believed that compounds with this mechanism of action are useful for the treatment of KRAS G12C mutation-positive colorectal cancer.

The compounds represented by the following formula (A) and formula (B) have been reported to have binding ability to the G12C mutant KRAS (Patent Documents 1, 2 and 3).

(式中記號的意思參照該公報)

(See the bulletin for the meaning of the symbols in the formula)

The earliest priority document published in the present case (Patent Document 4) discloses that the compound represented by the following formula (C) or a salt thereof has a G12C mutation KRAS inhibitory activity, and is a lung cancer, especially KRAS G12C mutation positive lung cancer The therapeutic agent is useful. In this document, although the compound of the active ingredient of the pharmaceutical composition of the present invention is specifically disclosed as an example compound, it does not disclose the effect on colorectal cancer, especially KRAS G12C mutation-positive colorectal cancer.

(式中記號的意思參照該公報)

(See the bulletin for the meaning of the symbols in the formula)

In addition, Non-Patent Document 1 reports that the compound of Example 353 disclosed in Patent Document 1 (also referred to as ARS-1620) has a cell proliferation inhibitory effect on human KRAS G12C mutation-positive colorectal cancer strain SW1463. [Prior Technical Literature] [Patent Literature]

[Patent Literature 1] International Publication No. 2015/054572 [Patent Document 2] International Publication No. 2016/164675 [Patent Literature 3] International Publication No. 2017/087528 [Patent Document 4] International Publication No. 2018/143315 [Non-patent literature]

[Non-Patent Document 1] Cell, 2018, Volume 172, No. 3, p.578-589

[Problems to be solved by the invention]

To provide a medical composition for the treatment of colorectal cancer, and as a certain aspect, to provide a KRAS G12C mutation-positive medical composition for the treatment of colorectal cancer. [Means to solve the problem]

The inventors of the present invention, for the purpose of creating a pharmaceutical composition for the treatment of colorectal cancer, in particular, a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer, as a result of in-depth study of compounds having an inhibitory effect of G12C mutation KRAS, discovered The oxazoline compound or its pharmaceutically acceptable salt has an excellent G12C mutation KRAS inhibitory effect, and the pharmaceutical composition using these compounds as an active ingredient is useful as a pharmaceutical composition for the treatment of colorectal cancer and completed the present invention. That is, the present invention relates to a pharmaceutical composition for the treatment of colorectal cancer, which contains (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-7-(5-methyl- 1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl }Prop-2-en-1-one (hereinafter sometimes referred to as "compound A"), (+)-1-{7-[6-cyclopropyl-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-(5-methyl- 1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl }Prop-2-en-1-one (hereinafter sometimes referred to as "compound B"), (+)-1-{7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-indazole-4 -Yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl} Prop-2-en-1-one (hereinafter sometimes referred to as "compound C"), and (+)-1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy Group]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (hereinafter, sometimes described as " Compound D'') The formed group of compounds, or their pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.

In addition, the present invention relates to a therapeutic agent for colorectal cancer containing a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof. A therapeutic agent for KRAS G12C mutation-positive colorectal cancer, which contains a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention relates to the use of a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof, for manufacturing a pharmaceutical composition for the treatment of colorectal cancer , As an aspect, it relates to a compound selected from the group consisting of compound A, compound B, compound C, and compound D for the manufacture of a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer, or its pharmaceutically acceptable Use of a salt; a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof for the treatment of colorectal cancer, as a form of A compound selected from the group consisting of Compound A, Compound B, Compound C and Compound D, or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer; A compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof, as a form of use for treating KRAS G12C mutation-positive colorectal cancer A compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof; and one containing a compound selected from the group consisting of compound A, compound B, compound C and compound D The compound of the group, or a pharmaceutically acceptable salt thereof, is administered to the subject in an effective amount of colorectal cancer treatment method. As an aspect, it relates to a group consisting of compound A, compound B, compound C and A therapeutic method for KRAS G12C mutation-positive colorectal cancer in which an effective amount of a compound formed by Compound D, or a pharmaceutically acceptable salt thereof is administered to a subject. In addition, the so-called "subject" is a human or other animal in need of the treatment, as a certain form, a human in need of the treatment. [Effect of invention]

The active ingredient of the pharmaceutical composition of the present invention is a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof, has a G12C mutation KRAS inhibitory effect, and can be used as As an aspect, the pharmaceutical composition for the treatment of colorectal cancer can be used as the active ingredient of the pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer.

Hereinafter, the present invention will be described in detail.

The so-called "G12C mutation" refers to a mutation in which a residue corresponding to the twelfth residue in the wild-type protein is changed from glycine to cysteine.

The so-called "G12C mutant KRAS" refers to the KRAS with the above-mentioned "G12C mutation" in the gene encoding KRAS.

An aspect of the present invention is shown below. (1-1) A pharmaceutical composition for the treatment of colorectal cancer containing Compound A or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. As another aspect, it is a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer containing Compound A or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (1-2) A therapeutic agent for colorectal cancer containing Compound A or a pharmaceutically acceptable salt thereof. As another aspect, it is a therapeutic agent for KRAS G12C mutation-positive colorectal cancer containing Compound A or a pharmaceutically acceptable salt thereof. (1-3) Use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of colorectal cancer. As another aspect, it is the use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer. (1-4) Use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of colorectal cancer. As another aspect, it is the use of Compound A or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (1-5) Compound A or a pharmaceutically acceptable salt thereof for the treatment of colorectal cancer. As another aspect, Compound A or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (1-6) A method for treating colorectal cancer containing an effective amount of Compound A or a pharmaceutically acceptable salt thereof administered to a subject. As another aspect, it is a therapeutic method containing KRAS G12C mutation-positive colorectal cancer in which an effective amount of Compound A or a pharmaceutically acceptable salt thereof is administered to a subject.

(2-1) A pharmaceutical composition for the treatment of colorectal cancer containing Compound B or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. As another aspect, it is a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer containing Compound B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (2-2) A therapeutic agent for colorectal cancer containing Compound B or a pharmaceutically acceptable salt thereof. As another aspect, it is a therapeutic agent for KRAS G12C mutation-positive colorectal cancer containing Compound B or a pharmaceutically acceptable salt thereof. (2-3) Use of Compound B or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of colorectal cancer. As another aspect, it is the use of Compound B or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer. (2-4) Use of Compound B or its pharmaceutically acceptable salts for the treatment of colorectal cancer. As another aspect, it is a compound B or a pharmaceutically acceptable salt thereof for treating KRAS G12C mutation-positive colorectal cancer. (2-5) Compound B or a pharmaceutically acceptable salt thereof for the treatment of colorectal cancer. As another aspect, Compound B or a pharmaceutically acceptable salt thereof is used for the treatment of KRAS G12C mutation-positive colorectal cancer. (2-6) A treatment method for colorectal cancer containing an effective amount of Compound B or a pharmaceutically acceptable salt thereof administered to a subject. As another aspect, it is a therapeutic method containing KRAS G12C mutation-positive colorectal cancer in which an effective amount of Compound B or a pharmaceutically acceptable salt thereof is administered to a subject.

(3-1) A pharmaceutical composition for the treatment of colorectal cancer containing Compound C or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients. As another aspect, it is a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer containing Compound C or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (3-2) A therapeutic agent for colorectal cancer containing Compound C or a pharmaceutically acceptable salt thereof. As another aspect, it is a therapeutic agent for KRAS G12C mutation-positive colorectal cancer containing Compound C or a pharmaceutically acceptable salt thereof. (3-3) Use of Compound C or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treatment of colorectal cancer. As another aspect, it is the use of compound C or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer. (3-4) Use of Compound C or its pharmaceutically acceptable salts for the treatment of colorectal cancer. As another aspect, it is a compound C or a pharmaceutically acceptable salt thereof for treating KRAS G12C mutation-positive colorectal cancer. (3-5) Compound C or its pharmaceutically acceptable salt for the treatment of colorectal cancer. As another aspect, Compound C or a pharmaceutically acceptable salt thereof is used for the treatment of KRAS G12C mutation-positive colorectal cancer. (3-6) A method for treating colorectal cancer containing an effective amount of Compound C or a pharmaceutically acceptable salt thereof administered to a subject. As another aspect, it contains a therapeutic method of KRAS G12C mutation-positive colorectal cancer in which an effective amount of Compound C or a pharmaceutically acceptable salt thereof is administered to a subject.

(4-1) A pharmaceutical composition for the treatment of colorectal cancer containing Compound D or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. As another aspect, a pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer containing Compound D or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (4-2) A therapeutic agent for colorectal cancer containing Compound D or a pharmaceutically acceptable salt thereof. As another aspect, a therapeutic agent for KRAS G12C mutation-positive colorectal cancer containing Compound D or a pharmaceutically acceptable salt thereof. (4-3) Use of Compound D or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of colorectal cancer. As another aspect, it is used for the manufacture of Compound D or a pharmaceutically acceptable salt thereof for the pharmaceutical composition for the treatment of KRAS G12C mutation-positive colorectal cancer. (4-4) The use of Compound D or its pharmaceutically acceptable salts for the treatment of colorectal cancer. As another aspect, the use of Compound D or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (4-5) Compound D or its pharmaceutically acceptable salt for the treatment of colorectal cancer. As another aspect, Compound D or a pharmaceutically acceptable salt thereof for the treatment of KRAS G12C mutation-positive colorectal cancer. (4-6) A treatment method for colorectal cancer containing an effective amount of Compound D or a pharmaceutically acceptable salt thereof administered to a subject. As another aspect, it contains a therapeutic method of KRAS G12C mutation-positive colorectal cancer in which an effective amount of Compound D or a pharmaceutically acceptable salt thereof is administered to a subject.

In this specification, "a pharmaceutically acceptable salt of a compound selected from the group consisting of compound A, compound B, compound C, and compound D" refers to the acid of compound A, compound B, compound C, or compound D The meaning of the addition salt can be specifically exemplified by inorganic acids such as hydrochloric acid, hydrobromic acid, hydrogen iodide acid, sulfuric acid, nitric acid, and phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, and succinic acid , Fumaric acid, maleic acid, lactic acid, malic acid, amygdalic acid, tartaric acid, dibenzoyl tartaric acid, xylene methyl tartaric acid, citric acid, mesylic acid, ethanesulfonic acid, benzene Acid addition salts of organic acids such as sulfonic acid, p-toluenesulfonic acid (p-toluenesulfonic acid), aspartic acid, and glutamic acid. In addition, "a compound selected from the group consisting of compound A, compound B, compound C, and compound D" includes various solvates of compound A, compound B, compound C, or compound D, specifically, including hydration Or ethanolate. Furthermore, "additionally acceptable salts of pharmacy" also include acid addition salts of these solvates. In addition, as a form of "a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof", a free base that does not form a salt can be exemplified, that is, Compound A, Compound B, Compound C, or Compound D, as other aspects, are Compound A, further as other aspects, as Compound B, further as other aspects, as Compound C, and further as other aspects, as Compounds D.

A pharmaceutical composition containing a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof as an active ingredient can use excipients commonly used in the field, namely The excipient for pharmaceuticals, the carrier for pharmaceuticals, etc. are prepared by a commonly used method. The administration may be oral administration of tablets, pills, capsules, granules, powders, liquids, etc., or intra-articular, intravenous, intramuscular injections, suppositories, eye drops, eye ointment, transdermal, etc. Any form of non-oral administration with liquid, ointment, transdermal patch, transmucosal liquid, transmucosal patch, inhalation, etc.

As a solid composition for oral administration, lozenges, powders, granules and the like are used. In such a solid composition, one or more active ingredients are mixed with at least one inert excipient. The composition may also contain inert additives such as lubricants or disintegrants, stabilizers, and dissolution aids in accordance with conventional methods. Lozenges or pills can be coated with sugar coating or a film of stomach-soluble or enteric-substance, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and generally used inert diluents, such as purified water or ethanol. The liquid composition may contain auxiliary agents such as co-solvents, wetting agents, suspending agents, sweeteners, flavoring agents, fragrances, preservatives in addition to the inert diluent.

Injections for non-oral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline solution. Examples of non-aqueous solvents include alcohols such as ethanol. Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or co-solvents. These are sterilized by, for example, filtering through a bacteria-retaining filter, blending or irradiation of a bactericide. In addition, these can produce sterile solid compositions, which are dissolved or suspended in sterile water or sterile injectable solvents before use.

In the case of general oral administration, the daily dose is about 0.001~100mg/kg body weight, preferably 0.1~30mg/kg, more preferably 0.1~10mg/kg is appropriate, this one or divided into 2 From 4 to 4 times. In the case of intravenous administration, the amount of administration per day is about 0.0001 to 10 mg/kg body weight, and it is once per day to be divided into multiple administrations.

Although it differs depending on the administration route, dosage form, administration site, excipient or additive, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, as an active ingredient of 0.01 to 50% by weight Compound selected from the group consisting of compound A, compound B, compound C and compound D, or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention can be used in combination with various therapeutic agents believed to show effectiveness in colorectal cancer, especially KRAS G12C mutation-positive colorectal cancer. The combination can be administered at the same time, or it can be administered individually continuously, or at a desired time interval. In the case of simultaneous administration, it may be a compounding agent or may be formulated separately.

Hereinafter, the production methods of compound A, compound B, compound C, and compound D will be described in detail as reference examples. In addition, the manufacturing method of these raw material compounds is shown in a manufacturing example. In addition, the production methods of compound A, compound B, compound C and compound D are not limited to the production methods of the specific reference examples shown below, and other combinations of these production methods may be used, or the industry is self-explanatory Method.

In this specification, naming software such as ACD/Name (registered trademark, Advanced Chemistry Development, Inc.) is sometimes used for naming compounds.

Also, for convenience, the concentration mol/L is represented by M. For example, 1M sodium hydroxide aqueous solution means 1mol/L sodium hydroxide aqueous solution.

Manufacturing Example 1 2-Amino-4-bromo-3-fluorobenzoic acid (4.0g), N-iodosuccinate amide imide (4.0g), N,N-dimethylformamide (hereinafter abbreviated as DMF) (40 mL) of the mixture was stirred at 50°C for 2 hours under a stream of argon. To the reaction mixture, N-iodosuccinic acid imide (1.5 g) was added at 50°C, and stirred at the same temperature for 1.5 hours. To the reaction mixture, N-iodosuccinate amide imine (1.5 g) was added at 50°C, and stirred at the same temperature overnight. After the reaction mixture was allowed to cool to room temperature, water was added and stirred at room temperature for 5 hours. The precipitated solid was taken out by filtration and dried at room temperature with ventilation. The obtained solid was suspended in water and stirred at room temperature for 1 hour. The solid was taken out by filtration, washed with water, and dried under reduced pressure at 50° C. to obtain solid 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5.6 g).

Manufacturing Example 2 A mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5.6 g) and urea (4.7 g) was stirred at 200°C for 3 hours. After the reaction mixture was left to cool to room temperature, water was added and stirred at room temperature for 15 minutes. The solid was taken out by filtration, washed with water, and then dried under reduced pressure at 50°C. After grinding the obtained solid into a powder, it was mixed with phosphazene chloride (80 mL) and ice-cooled. Under a nitrogen stream, N,N-diisopropylethylamine (hereinafter, abbreviated as DIPEA) (8.0 mL) was added dropwise. The reaction mixture was stirred at 150°C for 2.5 hours. After the reaction mixture was left to cool to room temperature, it was concentrated under reduced pressure, and ethyl acetate was added to the resulting residue. After the reaction mixture was poured into ice water, insoluble materials were filtered off, and the filtrate was extracted with ethyl acetate. After the organic layer was washed with a saturated sodium chloride aqueous solution, it was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a solid 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (3.6 g).

烷(35mL)之混合物進行冰冷後，在氮氣流下，加入DIPEA(8.0mL)、2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(2.0g)，於室溫攪拌1.5小時。於反應混合物中加入水，以氯仿進行萃取。將有機層以無水硫酸鎂進行乾燥後，減壓下，濃縮溶液。以二氧化矽凝膠管柱色層分析(氯仿/乙酸乙酯)純化所得之殘渣，得到固體之7-(7-溴-2-氯-8-氟-6-碘喹唑啉-4-基)-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(4.6g)。Production Example 3 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (3.6 g), 1,4-bis

After the mixture of alkane (35mL) was ice-cooled, DIPEA (8.0mL) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (2.0g) were added under a nitrogen stream. Warm for 1.5 hours. Water was added to the reaction mixture, and extraction was performed with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform/ethyl acetate) to obtain solid 7-(7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4- Radical)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (4.6 g).

Manufacturing Example 4 7-(7-Bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (9.5g), 1-(3-methoxypropyl) piperidin-4-ol (6.8g), cesium carbonate (15g), 1,4-diazepine [2.2.2]octane (hereinafter, Abbreviated as a mixture of DABCO) (260 mg), DMF (76 mL), and tetrahydrofuran (hereinafter abbreviated as THF) (76 mL), and stirred at room temperature overnight under an argon atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After the organic layer was washed with a saturated sodium chloride aqueous solution, it was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, diisopropyl ether was added to the resulting solid and stirred at room temperature. The solid was taken out by filtration, and dried at 50°C under reduced pressure to obtain 7-(7-bromo-8-fluoro-6-iodo-2-{[1-(3-methoxypropyl)piperidine- 4-yl]oxy}quinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (9.1 g).

Manufacturing Example 5 7-(7-Bromo-8-fluoro-6-iodo-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}quinazolin-4-yl)- 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (5.0g), 2,2,2-trifluoroethanol (1.4mL), cesium carbonate (6.5g), DMF ( 50 mL) of the mixture was stirred at room temperature for 5 hours. The reaction mixture was stirred at 50°C for 1.5 hours. After the reaction mixture was left to cool to room temperature, water was added, and extraction was performed with ethyl acetate. After washing the organic layer with water and a saturated sodium chloride aqueous solution, it was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-[7-bromo-6- Iodo-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl ]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (5.5g).

烷(20mL)、乙腈(20mL)、水(8.6mL)之混合物，在氬氛圍下，於100℃攪拌4小時。將反應混合物放置冷卻至室溫後，加入飽和氯化鈉水溶液，以乙酸乙酯進行萃取。將有機層以無水硫酸鎂進行乾燥後，減壓下，濃縮溶液。以二氧化矽凝膠管柱色層分析(鹼性二氧化矽凝膠、己烷/乙酸乙酯)純化所得之殘渣，得到7-[7-溴-6-環丙基-2-{[1-(3-甲氧基丙基)哌啶-4-基]氧基}-8-(2,2,2-三氟乙氧基)喹唑啉-4-基]-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(1.9g)。Production Example 6 7-[7-Bromo-6-iodo-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-8-(2,2,2- Trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (2.7g), cyclopropylboronic acid (560mg), Tripotassium phosphate (2.5g), [1,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloride dichloromethane adduct (hereinafter, abbreviated as PdCl ₂ (dppf) ・CH ₂ Cl ₂ ) (270mg), 1,4-di

A mixture of alkane (20 mL), acetonitrile (20 mL) and water (8.6 mL) was stirred at 100° C. for 4 hours under argon atmosphere. After the reaction mixture was left to cool to room temperature, a saturated aqueous sodium chloride solution was added, and extraction was performed with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-[7-bromo-6-cyclopropyl-2-{[ 1-(3-methoxypropyl)piperidin-4-yl)oxy)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (1.9 g).

烷(15mL)、水(2.8mL)，在微波照射下，於120℃攪拌70分鐘。將反應混合物在減壓下，進行濃縮，以二氧化矽凝膠管柱色層分析(鹼性二氧化矽凝膠、己烷/乙酸乙酯)純化所得之殘渣。於所得之純化物中加入乙腈，於室溫攪拌30分鐘。過濾取出析出之固體，得到固體之7-[6-環丙基-2-{[1-(3-甲氧基丙基)哌啶-4-基]氧基}-7-(5-甲基-1H-吲唑-4-基)-8-(2,2,2-三氟乙氧基)喹唑啉-4-基]-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(630mg)。Production Example 7 Under argon atmosphere, 7-[7-bromo-6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-8- (2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (1.9g), ( 5-methyl-1H-indazol-4-yl)boronic acid (710mg), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one/palladium (3:2 ) (Hereinafter abbreviated as Pd ₂ (dba) ₃ ) (230mg), dicyclohexyl (2', 6'-dimethoxybiphenyl-2-yl) phosphine (hereinafter abbreviated as SPhos) (210mg), Tripotassium phosphate (2.2g), 1,4-di

Alkane (15 mL) and water (2.8 mL) were stirred at 120°C for 70 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate). Acetonitrile was added to the resulting purified product, and stirred at room temperature for 30 minutes. The precipitated solid was removed by filtration to obtain 7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-7-(5-methyl Yl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane- Tertiary butyl 2-carboxylate (630 mg).

Manufacturing Example 8 7-[6-Cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-indazole-4 -Yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester A mixture of (630 mg) and 1M hydrochloric acid (5.5 mL) was stirred at 50°C for 1 hour under an argon atmosphere. After the reaction mixture was ice-cooled, dichloromethane (3.2 mL), 3-chloropropionyl chloride (0.17 mL), and sodium bicarbonate (670 mg) were added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, isopropanol (hereinafter abbreviated as IPA) (9.3 mL) and 4M aqueous sodium hydroxide solution (3.0 mL) were added at the same temperature, and stirred at room temperature for 3 hours. After the reaction mixture was ice-cooled, 1M hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate solution, and ethyl acetate were added, and stirred at room temperature for 5 minutes. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride solution. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol). Acetonitrile was added to the resulting purified product, and stirred at room temperature for 1 hour. The precipitated solid was removed by filtration to obtain 1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-7-( 5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5] Non-2-yl}prop-2-en-1-one (230 mg).

Manufacturing Example 9 7-(7-Bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (8.1g), a mixture of 1-(2-methoxyethyl) piperidin-4-ol (5.3g), cesium carbonate (13g), DABCO (220mg), DMF (65mL), THF (65mL), Stir at room temperature for 3 days under argon atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After the organic layer was washed with a saturated sodium chloride aqueous solution, it was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-(7-bromo-8- Fluoro-6-iodo-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}quinazolin-4-yl)-2,7-diazaspiro[3.5 ] Nonane-2-carboxylic acid tertiary butyl ester (7.9g).

Manufacturing Example 10 7-(7-Bromo-8-fluoro-6-iodo-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}quinazolin-4-yl)- 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (3.8g), 2,2,2-trifluoroethanol (0.75mL), cesium carbonate (3.4g), DMF ( 40 mL) of the mixture was stirred at room temperature for 20 hours under an argon atmosphere. 2,2,2-Trifluoroethanol (0.40 mL) and cesium carbonate (1.7 g) were added to the reaction mixture, and stirred at room temperature for 24 hours. Water was added to the reaction mixture and stirred at room temperature for 10 minutes. After removing the precipitated solid by filtration, chloroform/methanol (9:1) was added, and the resulting solution was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-[7-bromo- 6-iodo-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-8-(2,2,2-trifluoroethoxy)quinazoline-4 -Yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (3.1 g).

Manufacturing Example 13 7-[6-Cyclopropyl-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-indazole-4 -Yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester After ice-cooling a mixture of (800 mg) and dichloromethane (4.0 mL), trifluoroacetic acid (hereinafter abbreviated as TFA) (1.2 mL) was added, and the mixture was stirred at room temperature for 6 hours. Chloroform/IPA (4:1) and 2M aqueous potassium carbonate solution (11 mL) were added to the reaction mixture. The aqueous layer was extracted with chloroform/IPA (4:1), the organic layer was dried over anhydrous magnesium sulfate, and the solution (residue A) was concentrated under reduced pressure. After cooling a mixture of DIPEA (0.45 mL) and THF (16 mL) with an ice-methanol bath, propylene acetyl chloride (0.20 mL) was added. To this mixture, a solution of residue A in THF (12 mL) was added dropwise and stirred at the same temperature for 20 minutes. To the reaction mixture, 1M aqueous sodium hydroxide solution (5.0 mL) was added dropwise at the same temperature, and stirred at room temperature for 4 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extraction was performed with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol/28% ammonia). Acetonitrile was added to the obtained purified product and subjected to ultrasonic oscillation treatment. The precipitated solid was taken out by filtration to obtain 1-{7-[6-cyclopropyl-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-( 5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5] Non-2-yl}prop-2-en-1-one (410 mg).

烷(30mL)、水(3.0mL)之混合物中加入碳酸鉀(1.5g)、PdCl₂ (dppf)・CH₂ Cl₂ (30mg)，在氮氛圍下，於50℃攪拌2小時。於反應混合物中加入PdCl₂ (dppf)・CH₂ Cl₂ (150mg)，在氮氛圍下，於60℃攪拌4小時。將反應混合物放置冷卻至室溫後，加入乙酸乙酯、水。將不溶物濾掉後，以乙酸乙酯萃取濾液。將有機層以無水硫酸鎂進行乾燥後，減壓下，濃縮溶液。以二氧化矽凝膠管柱色層分析(鹼性二氧化矽凝膠、己烷/乙酸乙酯)純化所得之殘渣，得到7-[7-溴-2-{[1-(2-甲氧基乙基)哌啶-4-基]氧基}-8-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基]-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(2.2g)。Production Example 14 In 7-[7-bromo-6-iodo-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-8-(2,2,2- Trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (3.0g), potassium trifluoroborate (640mg) ), 1,4-two

To a mixture of alkane (30 mL) and water (3.0 mL) was added potassium carbonate (1.5 g), PdCl ₂ (dppf)·CH ₂ Cl ₂ (30 mg), and stirred at 50° C. for 2 hours under a nitrogen atmosphere. PdCl ₂ (dppf)·CH ₂ Cl ₂ (150 mg) was added to the reaction mixture, and stirred at 60° C. for 4 hours under a nitrogen atmosphere. After the reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added. After filtering off the insoluble matter, the filtrate was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-[7-bromo-2-{[1-(2-methyl Oxyethyl)piperidin-4-yl]oxy)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl]-2,7-di Azaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (2.2g).

烷(10mL)、水(2.0mL)之混合物中加入(5-甲基-1H-吲唑-4-基)硼酸(490mg)、Pd₂ (dba)₃₍ 130mg)、SPhos(120mg)，在氬氛圍下，於130℃攪拌4小時。將反應混合物放置冷卻至室溫後，加入乙酸乙酯、水。將不溶物濾掉後，以乙酸乙酯萃取濾液。將有機層以無水硫酸鎂進行乾燥後，減壓下，濃縮溶液。以二氧化矽凝膠管柱色層分析(氯仿/甲醇/28%氨水)純化所得之殘渣。以二氧化矽凝膠管柱色層分析(鹼性二氧化矽凝膠、己烷/乙酸乙酯)純化所得之純化物。於所得之固體中加入乙腈，於室溫攪拌。過濾取出析出之固體，得到固體之7-[2-{[1-(2-甲氧基乙基)哌啶-4-基]氧基}-7-(5-甲基-1H-吲唑-4-基)-8-(2,2,2-三氟乙氧基)-6-乙烯基喹唑啉-4-基]-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(630mg)。Production Example 15 In 7-[7-bromo-2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-8-(2,2,2-trifluoroethoxy Yl)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (1.0g), tripotassium phosphate (900mg), 1,4-two

(5-methyl-1H-indazol-4-yl)boronic acid (490mg), Pd ₂ (dba) _{3 (} 130mg), SPhos (120mg) was added to the mixture of alkane (10mL) and water (2.0mL). Under an argon atmosphere, the mixture was stirred at 130°C for 4 hours. After the reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added. After filtering off the insoluble matter, the filtrate was extracted with ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol/28% ammonia). The purified product was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate). Acetonitrile was added to the obtained solid and stirred at room temperature. The precipitated solid was removed by filtration to obtain 7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-indazole -4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2 -Tertiary butyl carboxylate (630 mg).

Manufacturing Example 16 7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-indazol-4-yl)-8- (2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester ( 470 mg), 1M hydrochloric acid (4.1 mL), and stirred at 50°C for 1 hour. After the reaction mixture was ice-cooled, dichloromethane (2.3 mL), 3-chloropropionyl chloride (0.13 mL), and sodium bicarbonate (520 mg) were added, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, IPA (4.7 mL) and 4M aqueous sodium hydroxide solution (2.3 mL) were added at the same temperature, and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After the organic layer was washed with a saturated sodium chloride aqueous solution, it was dried over anhydrous magnesium sulfate. Under reduced pressure, the solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol/28% ammonia). Acetonitrile was added to the obtained purified product, and stirred at room temperature for 5 minutes. After filtering out the precipitated solid, it was dried under reduced pressure at 30°C to obtain 1-{7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy of the solid }-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2 ,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one (320mg).

Manufacturing Example 17 7-(7-Bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (6.0g), DMF (60mL), THF (60mL) mixture, under argon atmosphere, add 1-methylpiperidin-4-ol (3.5mL), cesium carbonate (9.6g), DABCO (220mg) , Stir at room temperature for 14 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with a saturated sodium chloride aqueous solution, it was dried over anhydrous sodium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform/methanol/28% ammonia) to obtain 7-{7-bromo-8-fluoro-6-iodine-2 -[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (6.3 g).

Manufacturing Example 18 7-{7-Bromo-8-fluoro-6-iodo-2-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}-2,7-diaza Sodium ethoxide (390 mg) was added to a mixture of spiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (3.3 g) and THF (65 mL), and stirred overnight at 40°C. Sodium ethoxide (390 mg) was added to the reaction mixture, and stirred at 40°C overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was performed with ethyl acetate. After the organic layer was washed with a saturated sodium chloride aqueous solution, it was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-{7-bromo- 8-ethoxy-6-iodo-2-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}-2,7-diazaspiro[3.5]nonane -2-carboxylic acid tertiary butyl ester (1.3 g).

烷(100mL)、水(10mL)之混合物中加入碳酸鉀(5.5g)、PdCl₂ (dppf)・CH₂ Cl₂ (1.1g)，在氬氛圍下，於80℃攪拌1小時。將反應混合物放置冷卻至室溫後，加入乙酸乙酯、飽和氯化鈉水溶液、矽藻土，於室溫攪拌10分鐘。將不溶物濾掉後，以乙酸乙酯萃取濾液，將有機層以無水硫酸鎂進行乾燥。減壓下，濃縮溶液後，以二氧化矽凝膠管柱色層分析(鹼性二氧化矽凝膠、己烷/乙酸乙酯)純化所得之殘渣，得到固體之7-{7-溴-8-乙氧基-2-[(1-甲基哌啶-4-基)氧基]-6-乙烯基喹唑啉-4-基}-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(6.8g)。Production Example 19 In 7-{7-bromo-8-ethoxy-6-iodo-2-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}-2, 7-Diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (9.5g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-diox Cyclopentane (4.5mL), 1,4-di

To a mixture of alkane (100 mL) and water (10 mL), potassium carbonate (5.5 g), PdCl ₂ (dppf)·CH ₂ Cl ₂ (1.1 g) were added, and the mixture was stirred at 80° C. for 1 hour under an argon atmosphere. After the reaction mixture was left to cool to room temperature, ethyl acetate, saturated aqueous sodium chloride solution, and diatomaceous earth were added, and stirred at room temperature for 10 minutes. After filtering off the insoluble matter, the filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (alkaline silica gel, hexane/ethyl acetate) to obtain 7-{7-bromo- 8-ethoxy-2-[(1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non Alkane-2-carboxylic acid tertiary butyl ester (6.8 g).

烷(60mL)、磷酸三鉀(10g)、水(12mL)之混合物，在氬氛圍下，於120℃攪拌4小時。將反應混合物放置冷卻至室溫後，加入乙酸乙酯、飽和氯化鈉水溶液，將不溶物濾掉。以乙酸乙酯萃取濾液。將有機層以無水硫酸鎂進行乾燥。減壓下，濃縮溶液後，以二氧化矽凝膠管柱色層分析(氯仿/甲醇/28%氨水)純化所得之殘渣。於所得之純化物中加入乙腈，於室溫攪拌6小時。過濾取出析出之固體，得到固體之7-{8-乙氧基-7-(5-甲基-1H-吲唑-4-基)-2-[(1-甲基哌啶-4-基)氧基]-6-乙烯基喹唑啉-4-基}-2,7-二氮雜螺[3.5]壬烷-2-羧酸三級丁酯(2.2g)。Production Example 20 7-{7-Bromo-8-ethoxy-2-[(1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2 ,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (5.7g), (5-methyl-1H-indazol-4-yl)boronic acid (2.4g), Pd ₂ ( dba) _{3 (} 850mg), SPhos (760mg), 1,4-di

A mixture of alkane (60 mL), tripotassium phosphate (10 g), and water (12 mL) was stirred at 120° C. for 4 hours under an argon atmosphere. After the reaction mixture was left to cool to room temperature, ethyl acetate and saturated aqueous sodium chloride solution were added, and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentrating the solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform/methanol/28% ammonia). Acetonitrile was added to the obtained purified product, and stirred at room temperature for 6 hours. The precipitated solid was taken out by filtration to obtain 7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl )Oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (2.2 g).

Production Example 21 7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy]-6-ethylene Quinazolin-4-yl}-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tertiary butyl ester (1.3g), 1M hydrochloric acid (13mL) mixture, stirred at room temperature 18 hour. After the reaction mixture was ice-cooled, dichloromethane (6.5 mL), 3-chloropropionyl chloride (0.41 mL), and sodium bicarbonate (1.6 g) were added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, IPA (13 mL) and 4M aqueous sodium hydroxide solution (4.9 mL) were added at the same temperature, and stirred at room temperature for 4 hours. After the reaction mixture was ice-cooled, 1M hydrochloric acid (6.4 mL), 5% sodium bicarbonate aqueous solution (26 mL), and chloroform (39 mL) were added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through celite, and the filtrate was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol/28% ammonia). Acetonitrile was added to the obtained purified product, and the precipitated solid was filtered out. The obtained solid was dried under reduced pressure at 50°C to obtain 1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2- [(1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)propan-2 -En-1-one (980 mg).

The compounds shown in Tables 4 to 10 described below were produced by the production method shown in the above production example and the same method. In addition, the manufacturing method, structure, and physicochemical data of the compounds of each manufacturing example are shown in Table 4 to Table 10.

Reference example 1 1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-ind Azole-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}propane- 2-En-1-one (2.2 g) was divided by supercritical fluid chromatography (CHIRALPAK AS-H (manufactured by DAICEL), carbon dioxide/ethanol/triethylamine). The obtained fraction was purified by silica gel column chromatography (chloroform/methanol) to obtain (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methyl Oxypropyl)piperidin-4-yl]oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quin Oxazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one (compound A) (1.1 g).

Reference Example 3 Put 1-{7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7-(5-methyl-1H-indazol-4-yl) -8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}propan-2 -En-1-one (2.0 g) was divided by supercritical fluid chromatography (CHIRALPAK AS-H (manufactured by DAICEL), carbon dioxide/methanol/triethylamine, carbon dioxide/ethanol/triethylamine). The obtained fraction was purified by silica gel column chromatography (chloroform/methanol/28% ammonia) to obtain (+)-1-{7-[2-{[1-(2-methoxy Ethyl)piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6- Vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one (Compound C) (810 mg).

Reference Example 4 1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy]- 6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one (1.5g) by supercritical fluid chromatography (CHIRALPAK AS-H (manufactured by DAICEL), carbon dioxide/ethanol/triethylamine). Hexane and ethyl acetate were added to the obtained division to conduct trituration. The precipitated solid was taken out by filtration to obtain (+)-1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methyl Piperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene-1- Ketone (670mg). The solid (3.0 g) obtained by performing the above method a plurality of times was purified by silica gel column chromatography (ODS silica gel, water/methanol). Acetonitrile was added to the obtained purified product and stirred at room temperature. The precipitated solid was taken out by filtration, and the obtained solid was dried under reduced pressure at 40°C to obtain crystalline (+)-1-(7-{8-ethoxy-7-(5-methyl-1H- Indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5 ] Non-2-yl)prop-2-en-1-one (Compound D) (2.0 g).

Reference Example 2 (Compound B) was produced in the same manner as the production method of Reference Example 4 shown above. In addition, the structures of the compounds of each reference example are shown in Tables 11 to 12 described later, and the manufacturing method and physicochemical data of each reference example compound are shown in Table 13.

In the following table, the following abbreviations may be used. PEx: manufacturing example number, REx: reference example number, PSyn: manufacturing example number made by the same method, Syn: reference example number made by the same method (for example, R1 means reference example 1), Str: chemical structure formula (Indicates Me: methyl, Et: ethyl, Boc: tert-butoxycarbonyl. In addition, compounds with "#" added to the chemical structural formula represent single optical isomers based on axis asymmetry.), Dat: physicochemical data, ESI+: m/z value in mass analysis (ionization method ESI, [M+H] ⁺ unless otherwise specified), ESI-: m/z value in mass analysis (ionization Method ESI, [MH] ^- ) without special instructions, CI+: m/z value in mass analysis (ionization method CI, [M+H] ⁺ without special instructions), NMR: DMSO-d6 Δ value (ppm) of signal in ¹ H-NMR, s: single line (spectrum), d: double line (spectrum), t: triple line (spectrum), m: multiple line (spectrum), [α] _D ²⁰ : Specific optical rotation at 20°C, c: concentration when measuring the specific optical rotation (g/100 mL). [Example]

The pharmacological effect of the pharmaceutical composition of the present invention is confirmed by the following examples.

Example 1 Evaluation of KRAS G12C/SOS/c-Raf complex formation inhibition using human recombinant KRAS G12C, SOS and c-Raf proteins to investigate the time-lapse fluorescence-fluorescence resonance energy transfer (TR-FRET) method Compounds inhibit the formation of complexes of these proteins. Biotinylated AviTag-KRAS G12C (amino acid region 1-185, GDP) (2.5μL; 400nM) dissolved in assay buffer (50mM HEPES, 150mM NaCl, 5mM MgCl ₂ , 0.05% Tween 20, pH7.4) The test compound was added to a 384-well dish (Corning) in a volume of 2.5 μL of 4,000 nM to 4 nM. Add Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 μL; 1.3 μM), c-Raf (amino acid region 51-131) containing GTP (Sigma-Aldrich) GST (2.5 μL ; Respectively 4μM and 130nM) at room temperature for 1 hour. Then add a mixture (10μL) of LANCE Ulight-anti-GST (120nM, PerkinElmer) and LANCE Eu-W1024 labeled Streptoavidin (100ng/mL, PerkinElmer), and use EnVision 2103 Multilabel Reader (PerkinElmer) at an excitation wavelength of 337nm Under the conditions, the fluorescence intensity at 620 nm and 665 nm was measured. After normalizing the value with the fluorescence intensity at the reference wavelength of 620nm, the signal value of the solvent treatment is set to 0% suppression, and the signal value without GTP is set to 100% suppression, and the 50% is calculated by the nonlinear regression analysis of the Sigmoid-Emax model Inhibition concentration (IC ₅₀ ). The test results of using compound A, compound B, compound C, and compound D as test compounds are shown in Table 1.

Example 2 Evaluation of pERK inhibition in tumors Using the pERK assay kit (Advanced ERK phospho-T202/Y204 kit, Cisbio), TR-FRET method was used to investigate the phosphorylation of ERK in tumor samples after administration of test compounds. SW1463 cells (ATCC, CCL-234) were cultured in Leibovitz's L-15 medium (Life technologies) containing 10% bovine fetal serum (GE Life Sciences) at 37°C, and the same amount of Matrigel (Becton, Dickinson and Company) prepared 2.0x10 ⁶ solutions. The cell suspension was injected into a 4-week-old male SCID mouse (CB17/Icr-Prkdcscid/CrlCrlj, Charles River Corporation, Japan) at a dose of 100 μL and implanted subcutaneously and used in the test 25 days later. The test was carried out in three groups each of the solvent group and the test compound administration group, and the test compound was prepared using the solvent so as to be the administration amount described in Table 2. The test compound was administered orally, and 6% aqueous solution of 2-hydroxypropyl-β-cyclodextrin (Sigma-Aldrich) was used as a solvent. Six hours after administration, tumors were removed from mice undergoing cervical dislocation under isoflurane anesthesia, and a part was placed in a 2 mL microcentrifuge tube (eppendorf) and frozen with liquid nitrogen. Tumor samples were stored in a cryogenic freezer at -80°C until the pERK measurement test. Add 500 μL of lysis buffer1 (Phospho lysis buffer [Cisbio], Complete EDTA free [Roche], Phosphatase inhibitor cocktail2 [Sigma-Aldrich]] and 1 bead (YTZ ball 5mm [NIKKATO]) to the tumor sample, Tissue Lyser II (QIAGEN) was used for crushing (frequency 25/s, 3 minutes). The entire amount was transferred to a new tube, and centrifuged using a micro high-speed cooling centrifuge (20,400xg, 10 minutes, 4°C) to obtain the supernatant, that is, tumor lysate. The protein quantification kit (Pierce 660 nm Protein Assay Kit [Thermo Fisher]) was used to quantify the protein of the tumor lysate, and lysis buffer 2 (Phospho lysis buffer [Cisbio]) was used in such a way that the concentration became 1.0 μg/μL , Blocking Agent [attached to pERK assay kit] Dilute each sample. Dilute pERK1/2 Cryptate antibody and pERK1/2 d2 antibody (attached to pERK assay kit) with detection buffer (attached to pERK assay kit) 40 times, A mixed solution of these two kinds of antibodies was prepared. The mixed solution of antibodies was added to a 384-well dish at a liquid volume of 4 μL/well. Furthermore, a tumor lysate diluted to 1.0 μg/μL was added at a liquid volume of 16 μL/well. After standing at room temperature for about 17 hours in a wet box, use EnVision 2103 Multilabel Reader (PerkinElmer) to measure the fluorescence intensity at 620nm and 665nm under the excitation wavelength of 337nm. The value is based on the fluorescence intensity at the reference wavelength of 620nm After standardization, the count of the vehicle-administered group was set to 0% inhibition, and the count of no added lysate was set to 100% inhibition, and the inhibition value of the test compound administered to the sample was calculated as the% inhibition rate. Used as the test compound The test results of Compound A, Compound B, Compound C and Compound D are shown in Table 2.

Example 3 Evaluation of anti-tumor effect in human KRAS G12C mutation-positive colorectal cancer strain SW1463 cancer-bearing mice SW1463 cells 2.0x10 ⁶ were prepared by adding an equal amount of Matrigel (Becton, Dickinson and Company) in PBS A 100-L injection was implanted subcutaneously into 4-week-old male SCID mice (CB17/Icr-Prkdcscid/CrlCrlj, Charles River, Japan). About 3 weeks after implantation, the tumor volume and body weight of each group were almost the same, and the test compound was administered from the next day. The test was conducted with 5 animals each in the solvent group and the test compound administration group, and 6% 2-hydroxypropyl-β-cyclodextrin (Sigma-Aldrich) aqueous solution was orally administered in the solvent group to the test compound In the administration group, the test compound (10 or 40 mg/kg) was mixed with 6% 2-hydroxypropyl-β-cyclodextrin aqueous solution orally. The administration was performed once a day for 14 days, and the tumor diameter and body weight were measured twice a week. The calculation of tumor volume uses the following formula. [Tumor volume (mm ³ )]=[Long diameter of tumor (mm)]×[Small diameter of tumor (mm)] ² ×0.5 The tumor growth inhibition rate (%) caused by the test compound will be the day before the start of administration The tumor volume of the test compound administration group was determined to be 100% inhibition, and the tumor volume of the solvent group at the end of administration was determined to be 0% inhibition. In addition, when the tumor volume of the test compound administration group decreased compared with the tumor volume on the day before the start of administration, the tumor volume on the day before the start of administration was regarded as 0% retreat and the tumor volume 0 as 100% retreat to calculate the test compound The tumor shrinkage rate (%). The test results of using compound A, compound B, compound C, and compound D as test compounds are shown in Table 3.

From the above results, it was confirmed that Compound A, Compound B, Compound C, and Compound D, which are active ingredients of the pharmaceutical composition of the present invention, inhibit G12C mutation KRAS. Furthermore, it was confirmed that these compounds have an antitumor effect on mice transplanted with KRAS G12C mutation-positive colorectal cancer cells.

Therefore, a compound selected from the group consisting of compound A, compound B, compound C, and compound D or a pharmaceutically acceptable salt thereof can be used for the treatment of colorectal cancer, especially KRAS G12C mutation-positive colorectal cancer.

[產業上之可利用性]

[Industry availability]

The active ingredient of the pharmaceutical composition of the present invention is a compound selected from the group consisting of compound A, compound B, compound C, and compound D, or a pharmaceutically acceptable salt thereof, which has the G12C mutation KRAS inhibitory effect and is The therapeutic pharmaceutical composition can be used as an active ingredient of the therapeutic pharmaceutical composition for KRAS G12C mutation-positive colorectal cancer.

Claims (18)

A medical composition for the treatment of colorectal cancer, which is selected from (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidine-4- Yl]oxy}-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2, 7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, (+)-1-{7-[6-cyclopropyl-2-{[1-(2- (Methoxyethyl) piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy) Quinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, (+)-1-{7-[2-{[ 1-(2-methoxyethyl)piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-tri Fluoroethoxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, and (+) -1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy]- 6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one, or a compound thereof Pharmaceutically acceptable salts and pharmaceutically acceptable excipients. The pharmaceutical composition according to claim 1, wherein the compound is (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl] Oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]non-2-yl}prop-2-en-1-one. The pharmaceutical composition according to claim 1, wherein the compound is (+)-1-{7-[6-cyclopropyl-2-{[1-(2-methoxyethyl)piperidin-4-yl] Oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]non-2-yl}prop-2-en-1-one. The pharmaceutical composition according to claim 1, wherein the compound is (+)-1-{7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}-7- (5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7-di Azaspiro[3.5]non-2-yl}prop-2-en-1-one. The pharmaceutical composition according to claim 1, wherein the compound is (+)-1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[( 1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-ene -1-one. The pharmaceutical composition according to any one of claim 1 to claim 5, wherein the colorectal cancer is KRAS G12C mutation-positive colorectal cancer. A use for treating colorectal cancer is selected from (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl]oxygen Yl)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7-di Azaspiro[3.5]non-2-yl}prop-2-en-1-one, (+)-1-{7-[6-cyclopropyl-2-{[1-(2-methoxy Ethyl)piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazoline -4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, (+)-1-{7-[2-{[1-( 2-methoxyethyl)piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy Group)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, and (+)-1- (7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy]-6-ethylene Quinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one, or its pharmacologically acceptable Salt. If the compound of claim 7 or a pharmaceutically acceptable salt thereof, the compound is (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piper Pyridin-4-yl]oxy}-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl ]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one. If the compound of claim 7 or a pharmaceutically acceptable salt thereof, the compound is (+)-1-{7-[6-cyclopropyl-2-{[1-(2-methoxyethyl)piper Pyridin-4-yl]oxy}-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl ]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one. If the compound of claim 7 or a pharmaceutically acceptable salt thereof, the compound is (+)-1-{7-[2-{[1-(2-methoxyethyl)piperidin-4-yl] Oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl] -2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein the compound is (+)-1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl )-2-[(1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl ) Prop-2-en-1-one. If the compound of any one of claim 7 to claim 11 or a pharmaceutically acceptable salt thereof, the colorectal cancer is KRAS G12C mutation-positive colorectal cancer. A treatment method for colorectal cancer, which will be selected from (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidin-4-yl] Oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl)-2,7- Diazaspiro[3.5]non-2-yl}prop-2-en-1-one, (+)-1-{7-[6-cyclopropyl-2-{[1-(2-methoxy Ethyl)piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazol Lin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, (+)-1-{7-[2-{[1- (2-Methoxyethyl)piperidin-4-yl)oxy)-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethane Oxy)-6-vinylquinazolin-4-yl]-2,7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one, and (+)-1 -(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2-[(1-methylpiperidin-4-yl)oxy]-6- Vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)prop-2-en-1-one group of compounds or pharmaceutically acceptable The effective amount of the salt is administered to the target. The treatment method for colorectal cancer according to claim 13, wherein the compound is (+)-1-{7-[6-cyclopropyl-2-{[1-(3-methoxypropyl)piperidine-4- Yl]oxy}-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2, 7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one. The treatment method for colorectal cancer according to claim 13, wherein the compound is (+)-1-{7-[6-cyclopropyl-2-{[1-(2-methoxyethyl)piperidine-4- Yl]oxy}-7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)quinazolin-4-yl]-2, 7-diazaspiro[3.5]non-2-yl}prop-2-en-1-one. The treatment method for colorectal cancer as claimed in claim 13, wherein the compound is (+)-1-{7-[2-{[1-(2-methoxyethyl)piperidin-4-yl]oxy}- 7-(5-methyl-1H-indazol-4-yl)-8-(2,2,2-trifluoroethoxy)-6-vinylquinazolin-4-yl)-2,7 -Diazaspiro[3.5]non-2-yl}prop-2-en-1-one. The treatment method for colorectal cancer according to claim 13, wherein the compound is (+)-1-(7-{8-ethoxy-7-(5-methyl-1H-indazol-4-yl)-2- [(1-methylpiperidin-4-yl)oxy]-6-vinylquinazolin-4-yl}-2,7-diazaspiro[3.5]non-2-yl)propan-2 -En-1-one. The treatment method for colorectal cancer according to any one of claim 13 to claim 17, wherein the colorectal cancer is KRAS G12C mutation-positive colorectal cancer.