4-aminoquinazoline compound

Abstract

FIELD: pharmaceuticals.SUBSTANCE: invention relates to a compound of formula (I), wherein R1 is cyclopropyl, R2 is a structure of formula (IIa) specified in the claims, R3 is formula (III) specified in the claims, R4 is pyridylmethyl, a 4-membered to 7-membered saturated heterocyclic group containing one O heteroatom, or tetrahydroisoquinolinyl, wherein pyridylmethyl is optionally substituted with C1-3 alkyl, R5 is H or a group selected from the group consisting of formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV) specified in the claims, wherein R5a and R5b, which are the same or different from each other, are H, C1-3 alkyl optionally substituted with two F atoms, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl, W is CH, X is O, Y is F, Ya is C1-3 alkyl, and Z is N or CH. The invention also relates to a pharmaceutical composition having the activity of inhibiting KRAS with the G12D mutation, containing an effective amount of a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, the use of a compound of formula (I) or a salt thereof for the production of a pharmaceutical composition for the treatment of pancreatic cancer, the use of a compound of formula (I) or a salt thereof for the treatment of pancreatic cancer and a method for treating pancreatic cancer, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject.EFFECT: compounds exhibiting inhibitory activity against KRAS with the G12D mutation for the treatment of pancreatic cancer.9 cl, 38 tbl, 99 ex

Description

AREA OF TECHNOLOGY

[0001] The present invention relates to pharmaceutical compositions and to a 4-aminoquinazoline compound, which is expected to be useful as a KRAS inhibitor with a G12D mutation and can be used as an active ingredient of, for example, a pharmaceutical composition for the treatment of pancreatic cancer.BACKGROUND ART

[0002] Pancreatic cancer, mainly including pancreatic ductal adenocarcinoma, is a cancer with a very poor prognosis, with a five-year survival rate of 10% or less (CA Cancer J. Clin., 2016, 66, p.7-30), and approximately 460,000 new cases are reported annually worldwide (CA Cancer J. Clin., 2018, 68, p.394-424). The most effective therapy for pancreatic cancer is surgery. However, cancer often metastasizes because early detection is difficult, and in many cases, a therapeutic effect cannot be expected from surgery. When cancer is not treated with surgery, chemotherapy or radiation therapy is used, but the survival rate is not so high. Currently, FOLFRINOX therapy (a combination treatment with three chemotherapeutic agents: 5-FU, irinotecan and oxaliplatin plus levofolinate) is used as a standard therapy for pancreatic cancer.However, due to severe toxicity, careful patient selection is necessary; for example, therapy should be limited to patients with an ECOG performance status of 1 or lower (J. Clin. Oncol., 2018, 36, pp. 2545-2556). As a molecular targeted drug, the epidermal growth factor receptor (EGFR) inhibitor Erlotinib is approved in combination therapy with Gemcitabine. However, the overall survival benefit is only approximately two weeks compared with Gemcitabine alone, and a satisfactory therapeutic effect has not been achieved. A highly effective therapeutic agent is still needed (J. Clin. Oncol., 2007, 25, pp. 1960-1966).

[0003] RAS proteins are low-molecular-weight guanosine triphosphate (GTP)-binding proteins of approximately 2.1 kDa, consisting of 188-189 amino acids, and comprising four main protein types (KRAS (KRAS 4A and KRAS 4B), NRAS, and HRAS) produced by three genes: the KRAS gene, the NRAS gene, and the HRAS gene. RAS proteins are divided into an active GTP-binding type and an inactive GDP-binding type. RAS is activated by the exchange of guanosine diphosphate (GDP) for GTP, for example, due to stimulation by a ligand of a membrane receptor such as EGFR. Active RAS binds to twenty effector proteins, such as RAF, PI3K, and RALGDS, to activate the downstream signaling cascade. On the other hand, active RAS is converted to inactive by replacing GTP with GDP through its own GTP hydrolysis activity (GTPase). GTPase activity is enhanced by GTPase-activating protein (GAP).As can be seen from the above statement, RAS has an important function as a “molecular switch” in the intracellular signaling pathway for EGFR or the like, and plays a critical role in the processes of cell growth, proliferation, angiogenesis, and the like (Nature Rev. Cancer, 2011, 11, p.761-774, Nature Rev. Drug Discov., 2014, 13, p.828-851, Nature Rev. Drug Discov., 2016, 15, p.771-785).

[0004] An amino acid substitution resulting from a spontaneous mutation in the RAS gene leads to a persistent activated state due to RAS hypofunction as a GTPase or hyporesponsiveness to GAP. Then, signals are continuously transmitted downstream. Excessive signaling causes carcinogenesis or accelerated cancer growth. Pancreatic ductal adenocarcinoma is said to arise through a weakly heteromorphic stage and then a highly heteromorphic stage of pancreatic intraepithelial neoplasm (PanIN), and the KRAS gene mutation has already been recognized in the initial stage of PanIN. Subsequently, an abnormality in INK4A, p5 3, and SMAD4, which are tumor suppressor genes, occurs, leading to malignancy (Nature Rev. Cancer, 2010, 10, p.683-695).Furthermore, in 90% or more of pancreatic ductal adenocarcinoma cases, a mutation is observed in the KRAS gene, and most of these are spontaneous point mutations in codon 12, located in exon 2 of KRAS (Cancer Cell 2017, 32, pp. 185-203). As can be seen from the above, KRAS plays a crucial role in carcinogenesis and pancreatic cancer development.

[0005] In recent years, the existence of an allosteric pocket near a region called switch II (Nature, 2013, 503, p.548-551) against the G12C mutant of KRAS has been shown. Several compounds that irreversibly bind to the G12C mutant KRAS by forming a covalent bond with the cysteine ​​of the G12C mutant KRAS have been reported (Cancer Discov., 2016, 6, p.316-329, Cell, 2018, 172, p.578-589, Nature, 2019, 575, p.217-223). A selective inhibitor of KRAS with the G12C mutation inhibits the conversion from inactive to active by covalently binding to KRAS with the G12C mutation and induces cancer cell death by blocking the downstream signal.

[0006] KRAS with G12C mutation is common in non-small cell lung cancer, but occurs in a few percent of cases in pancreatic cancer (Cancer Cell 2014, 25, p.272-281), and a therapeutic agent against a different KRAS mutation is required. KRAS with G12D mutation is observed in approximately 34% of pancreatic cancer cases, and this rate is reported to be the highest among KRAS mutations (Nat. Rev. Cancer, 2018, 18, p.767-777).

[0007] PTL 1, 2, and 3 describe RAS inhibitors, and PTL 2 and 3 describe compounds represented by the following formulas (A) and (B), respectively. PTL 1, 2, and 3 claim that the inhibitors are applicable to cancers with a mutation in codon 12 of KRAS. The G12D mutation is one of such mutations, but no effect on KRAS cancer with a G12D mutation has been reported. [Chemical formula 1] (A) (B)(For the meaning of symbols in formulas, see publications)

[0008] PTL 4, 5, and 6 describe KRAS G12D inhibitors. LIST OF CITATIONS PATENT LITERATURE

[0009] PTL 1: WO2016 / 049565PTL 2: WO2016 / 049568PTL 3: WO2017 / 172979PTL 4: WO2021 / 041671PTL 5: WO2021 / 106231PTL 6: WO2021 / 107160 SUMMARY OF THE INVENTION TECHNICAL PROBLEM

[0010] Proposed is a pharmaceutical composition, for example, a compound that is expected to be useful as a KRAS inhibitor with a G12D mutation and is useful as an active ingredient of a pharmaceutical composition for the treatment of pancreatic cancer, in particular, KRAS-positive pancreatic cancer with a G12D mutation. SOLUTION TO THE PROBLEM

[0011] The present inventors have intensively and extensively studied a compound that can be used as an active ingredient in a pharmaceutical composition for the treatment of pancreatic cancer. As a result, the present inventors have found that the 4-aminoquinazoline compound of formula (I) has excellent inhibitory activity against KRAS with the G12D mutation, thus completing the present invention. In particular, the present invention relates to a compound of formula (I) or a salt thereof and a pharmaceutical composition that contains the compound of formula (I) or a salt thereof and an excipient. [Chemical formula 2] (In the formula, R 1 represents C 1-3 alkyl optionally substituted with a group selected from the group consisting of F and OCH3, halogen, cyclopropyl or C 2-3 alkenyl,R 2is naphthyl optionally substituted with OH or a group selected from the group consisting of formula (IIa) and formula (IIb) below, [Chemical Formula 3] R 3 is the formula (III) below,[Chemical formula 4] R 4 is optionally substituted C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl, optionally substituted 4-membered to 7-membered saturated heterocyclic group, optionally substituted 6-membered heteroaryl or tetrahydroisoquinolinyl,R 5 represents H, CONR 6 R 7 or a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV) below, [Chemical Formula 5] where R 5a and R 5b, which are the same or different from each other, are H, optionally substituted with C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl, R 6 and R 7 , which are the same or different from each other, represent H or optionally substituted C 1-6 alkyl, or R 6 and R 7 , together with the nitrogen to which they are attached, can form a 4-membered to 7-membered saturated heterocyclic ring, wherein the 4-membered to 7-membered saturated heterocyclic ring is optionally substituted with an optionally substituted C 1-6 alkyl, W is CH or N, X is O or NR x ,where R x is H or C 1-3 alkyl, or XR 4 is a 4-membered to 7-membered saturated heterocyclic group or imidazolyl,Y and Y brepresent H, F or Cl,Y a represents C 1-3 alkyl optionally substituted with F, cyano or cyclopropyl, or Y a and Y b , together with the carbon atom to which they are attached, form cyclopentenyl,Y c represents H, F, or methyl, and Z represents N or CH.)

[0012] Further, an aspect of the present invention relates to a compound of formula (I) or a salt thereof and a pharmaceutical composition that comprises the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.[Chemical formula 6] (In the formula, R 1 is cyclopropyl,R 2 represents the formula (IIc) below,[Chemical formula 7] R 3 is the formula (IIIa) below,[Chemical formula 8] R 4is tetrahydropyranyl, optionally substituted pyridylmethyl or tetrahydroisoquinolinyl, R 5 is a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) below, [Chemical formula 9] where R 5a and R 5b , which are the same or different from each other, are H, optionally substituted with C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl, X is O, Y is F, and Z is N or CH.)

[0013] It should be noted that when a sign in a chemical formula in the present description is used in another chemical formula, the same sign represents the same meaning unless otherwise specified.

[0014] The present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and pharmaceutically acceptable excipients, in particular a pharmaceutical composition for the treatment of pancreatic cancer, in particular a pharmaceutical composition for the treatment of KRAS-positive pancreatic cancer with the G12D mutation. The pharmaceutical composition includes a therapeutic agent for the treatment of pancreatic cancer, in particular KRAS-positive pancreatic cancer with the G12D mutation, containing a compound of formula (I) or a salt thereof.The present invention relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of pancreatic cancer, in particular KRAS-positive pancreatic cancer with a G12D mutation, to the use of a compound of formula (I) or a salt thereof for the treatment of pancreatic cancer, in particular KRAS-positive pancreatic cancer with a G12D mutation, to a compound of formula (I) or a salt thereof for use in the treatment of pancreatic cancer, in particular KRAS-positive pancreatic cancer with a G12D mutation, and to a method for the treatment of pancreatic cancer, in particular KRAS-positive pancreatic cancer with a G12D mutation, including the administration to a subject of an effective amount of a compound of formula (I) or a salt thereof.The present invention also relates to a compound of formula (I) or a salt thereof, which is a KRAS inhibitor with a G12D mutation, to a compound of formula (I) or a salt thereof for use as a KRAS inhibitor with a G12D mutation, and to a KRAS inhibitor with a G12D mutation containing a compound of formula (I) or a salt thereof. It should be noted that the "subject" is a human or other animal in need of treatment, and an aspect of this is a human in need of prevention or treatment. ADVANTAGES OF THE INVENTION.

[0015] The compound of formula (I) or a salt thereof has inhibitory activity against KRAS with G12D mutation and can be used as a therapeutic agent for the treatment of pancreatic cancer. DESCRIPTION OF EMBODIMENTS

[0016] The present invention will be explained in detail below. In the present description, "optionally substituted" means unsubstituted or having one to five substituents. In one aspect, the term means unsubstituted or having one to three substituents. It should be noted that if there are multiple substituents, the substituents may be the same or different from each other.

[0017] "S 1-12 "Alkyl" is a linear or branched alkyl containing from 1 to 12 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, and the like (the numbers of carbon atoms are described similarly below). One aspect thereof is ethyl or dodecyl; the other aspect is C 1-6alkyl; another aspect is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl or n-hexyl; and another aspect is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or isopentyl. One of its aspects is C 1-3 alkyl; another aspect is methyl, ethyl or isopropyl; another aspect is methyl or ethyl; another aspect is methyl or isopropyl; another aspect is ethyl or isopropyl; another aspect is methyl; another aspect is ethyl; and another aspect is isopropyl.

[0018] "C 2-3 "Alkenyl" is an alkenyl group containing two to three carbon atoms, and examples include vinyl and propenyl. One aspect of it is vinyl, 1-propenyl, or 2-propenyl. Another aspect is vinyl.

[0019] "C 3-6"Cycloalkyl" is a cycloalkyl containing from three to six carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. One aspect thereof is cyclopropyl, cyclobutyl, or cyclohexyl; another aspect is cyclopropyl or cyclobutyl; another aspect is cyclopropyl; and another aspect is cyclobutyl.

[0020] The "4-membered to 7-membered saturated heterocyclic group" is, for example, a 4-membered to 7-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring atoms, and can form a bridge ring or can form a spiro ring. In addition, the sulfur atom contained in the heterocyclic group may be oxidized.One of its aspects is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, zaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl or thiazaspiro[3.3]heptanyl; another aspect is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azaspiro[3,3]heptanyl or oxazaspiro[3,3]heptanyl; another aspect is azetidinyl, tetrahydropyranyl, morpholinyl or oxazaspiro[3,3]heptanyl; another aspect is azetidinyl or tetrahydropyranyl, another aspect is morpholinyl or oxazaspiro[3,3]heptanyl; and another aspect is tetrahydropyranyl.

[0021] "6-membered heteroaryl" is, for example, a 6-membered ring heteroaryl containing one to three nitrogen atoms as the ring constituent atoms. One aspect of the "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; another aspect is pyridyl or pyrimidinyl; and another aspect is pyrimidinyl.

[0022] "Halogen" means F, Cl, Br, and I. One aspect thereof is F, Cl, or Br; another aspect is F or Cl; another aspect is F; another aspect is Cl; and yet another aspect is Br.

[0023] The aspect of the substituent acceptable in "optionally substituted pyridyl", "optionally substituted oxazolyl" and "optionally substituted pyridylmethyl" is C 1-3 alkyl; the other aspect is methyl or isopropyl; the other aspect is methyl; and the other aspect is isopropyl.

[0024] Aspect of a substituent acceptable in "optionally substituted C 1-6 alkyl" and "optionally substituted C 1-3 "alkyl" represents halogen, OH, OCH3, cyano, C 1-3 alkyl, hydroxymethyl, methoxymethyl, cyanomethyl, difluoroethyl, optionally substituted with C 3-6 cycloalkyl, optionally substituted pyridyl or optionally substituted 4-7-membered saturated heterocycle; another aspect is halogen, OCH3, cyano, optionally substituted C 3-6 cycloalkyl, optionally substituted pyridyl or an optionally substituted 4-membered to 7-membered saturated heterocyclic group; another aspect is F, OCH3, cyano, optionally substituted C 3-6cycloalkyl, optionally substituted pyridyl or an optionally substituted 4-membered to 7-membered saturated heterocyclic group; another aspect is F, OCH3 or cyano; another aspect is halogen or OCH3; another aspect is F or OCH3; and yet another aspect is halogen.

[0025] Aspect of a substituent acceptable in "optionally substituted C 3-6 cycloalkyl" is a halogen, OCH3, or C 1-3 alkyl optionally substituted with OCH3; another aspect is F, OCH3 or C 1-3 alkyl optionally substituted with OCH3; another aspect is C 1-3 alkyl optionally substituted with OCH3; and another aspect is F, OCH3, or methoxymethyl.

[0026] The aspect of the substituent acceptable in the "4-membered to 7-membered saturated heterocyclic group" is OH, OCH3, or C 1-3alkyl optionally substituted with a group selected from the group consisting of F, OCH3 and cyano; and the other aspect is OH, OCH3, trifluoromethyl, difluoromethyl, methoxyethyl or cyanomethyl.

[0027] Aspect of a substitute acceptable in "optionally substituted 6-membered heteroaryl" is C 1-3 alkyl or N(CH3)2, and in another aspect is ethyl or N(CH3)2.

[0028] "G12D mutation" is a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is converted from glycine to aspartic acid.

[0029] "KRAS with G12D mutation" represents KRAS that has "G12D mutation".

[0030] "Pancreatic cancer" is a malignant tumor that originates in the pancreas. Examples include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. One type is pancreatic ductal carcinoma, and the other is pancreatic ductal adenocarcinoma.

[0031] "KRAS G12D mutation-positive pancreatic cancer" is a pancreatic cancer that is positive for KRAS G12D mutation, and its examples include pancreatic cancer harboring KRAS G12D mutation and pancreatic cancer that is characterized by a high rate of KRAS G12D mutation positivity. One aspect of it is KRAS G12D mutation-positive pancreatic ductal carcinoma and KRAS G12D mutation-positive pancreatic ductal adenocarcinoma; another aspect is KRAS G12D mutation-positive pancreatic ductal carcinoma; and another aspect is KRAS G12D mutation-positive pancreatic ductal adenocarcinoma.

[0032] Aspects of the compound of formula (I) or a salt thereof of the present invention are shown below.(1-1)The compound or a salt thereof in which R 1 represents C 1-3alkyl optionally substituted with a group selected from the group consisting of F and OCH3, halogen, cyclopropyl or C 2-3 alkenyl(1-2) A compound or its salt in which R 1 is a cyclopropyl(2-1) compound or its salt in which R 2 is naphthyl optionally substituted with OH or a group selected from the group consisting of formula (IIa) and formula (IIb) below, [Chemical Formula 10] where Y and Y b represent H, F or Cl,Y a represents C 1-3 alkyl optionally substituted with F, cyano or cyclopropyl, or Y a and Y b , together with the carbon atom to which they are attached, form cyclopentenyl, and c represents H, F, or methyl.(2-2)A compound or its salt in which R 2 represents the formula (IIc) below,[Chemical formula 11] where Y is F.(3-1)A compound or its salt in which R 3 is the formula (III) below,[Chemical formula 12] where W is CH or N.(3-2)A compound or its salt in which R 3 is the formula (IIIa) below.[Chemical formula 13] (4-1) A compound or its salt in which R 4 is optionally substituted C 1-6 alkyl optionally substituted with C 3-6 cycloalkyl, an optionally substituted 4-membered to 7-membered saturated heterocyclic group, an optionally substituted 6-membered heteroaryl or tetrahydroisoquinolinyl, X is O or NR x ,where R x is H or C 1-3 alkyl, or XR 4 is a 4-membered to 7-membered saturated heterocyclic group or imidazolyl.(4-2) Compound or its salt in which R 4 represents C 1-6alkyl, where C 1-6 alkyl optionally substituted with a group selected from the group consisting of F; OCH3; cyclopropyl optionally substituted with OCH3; cyclobutyl optionally substituted with a group selected from the group consisting of F and methoxymethyl; oxetanyl optionally substituted with OCH3; tetrahydrofuranyl; tetrahydropyranyl optionally substituted with a group selected from the group consisting of OH, CF3 and cyanomethyl; and pyridyl optionally substituted with C 1-3 alkyl, C 3-6 cycloalkyl optionally substituted with OCH3, azetidinyl optionally substituted with F, tetrahydropyranyl, pyrimidinyl optionally substituted with a group selected from the group consisting of C 1-3 alkyl and N(CH3)2, or tetrahydroisoquinolinyl, X is O or NR x ,where R x is H or C 1-3 alkyl, or XR 4 is a morpholinyl, oxazaspiro[3,3]heptanyl, or imidazolyl(4-3) compound or its salt in which R 4is tetrahydropyranyl, optionally substituted pyridylmethyl or tetrahydroisoquinolinyl, and X is O.(4-4)A compound or a salt thereof in which R 4 is tetrahydropyranyl, and X is O.(5-1)A compound or its salt in which R 5 in formula (III) represents H, CONR 6 R 7 or a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV) below, [Chemical Formula 14] where R 5a and R 5b , which are the same or different from each other, are H, optionally substituted with C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl, R 6 and R 7 , which are the same or different from each other, represent H or optionally substituted C 1-6alkyl, or R 6 and R 7 , together with the nitrogen to which they are attached, can form a 4-membered to 7-membered saturated heterocyclic ring, wherein the 4-membered to 7-membered saturated heterocyclic ring is optionally substituted with an optionally substituted C 1-6 alkyl, and Z is N or CH.(5-2)A compound or its salt in which R 5 in formula (III) represents H, CONR 6 R 7 or a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV), where R 5a and R 5b , which are the same or different from each other, are H, optionally substituted with C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl, R 6 and R 7, which are the same or different from each other, represent H or optionally substituted C 1-6 alkyl, or R 6 and R 7 , together with the nitrogen to which they are attached, can form morpholinyl or piperazinyl, where piperazinyl is optionally substituted with an optionally substituted C 1-6 alkyl, and Z is N or CH.(5-3)A compound or salt thereof in which R 5 in formula (III) represents H, CONR 6 R 7 or a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV), where R 5a and R 5b , which are the same or different from each other, are H, C 1-3 alkyl optionally substituted with F, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, oxazolyl optionally substituted with C 1-3 alkyl, thiazolyl or pyrazinyl,R 6 and R 7, which are the same or different from each other, represent H or C 1-6 alkyl, or R 6 and R 7 , together with the nitrogen to which they are attached, can form morpholinyl or piperazinyl, wherein piperazinyl is optionally substituted with methoxyethyl, and Z is N or CH.(5-4)A compound or salt thereof in which R 5 in formula (IIIa) represents a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) below, [Chemical formula 15] where R 5a and R 5b , which are the same or different from each other, are H, optionally substituted with C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl, and Z is N or CH.(5-5)A compound or salt thereof in which R 5in formula (IIIa) represents a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), where R 5a and R 5b , which are the same or different from each other, are H, C 1-3 alkyl optionally substituted with F, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl, and Z is N or CH.(6) A compound or salt thereof in which R 4 represents tetrahydropyranyl, optionally substituted pyridylmethyl, or tetrahydroisoquinolinyl. Its aspect is a compound or a salt thereof, in which R 4 is tetrahydropyranyl. Another aspect is a compound or its salt in which R 4 is optionally substituted pyridylmethyl. Another aspect is a compound or salt thereof in which R 4is tetrahydroisoquinolinyl.(7) A compound or its salt in which R 5 in formula (III) is a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV). Its aspect is a compound or a salt thereof, in which R 5 is the formula (IV). Another aspect is a compound or a salt thereof, in which R 5 is a formula (V). Another aspect is a compound or a salt thereof, in which R 5 is a formula (VI). Another aspect is a compound or a salt thereof, in which R 5 is a formula (VII). Another aspect is a compound or a salt thereof, in which R 5 is a formula (VIII). Another aspect is a compound or a salt thereof in which R 5is the formula (IX). Another aspect is a compound or a salt thereof, in which R 5 represents the formula (X). Another aspect is a compound or a salt thereof in which R 5 is a formula (XI). Another aspect is a compound or a salt thereof in which R 5 is a formula (XII). Another aspect is a compound or a salt thereof in which R 5 is a formula (XIII). Another aspect is a compound or a salt thereof in which R 5 represents the formula (XIV).(8)A compound or its salt in which R 5a and R 5b , which are the same or different from each other, represent optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl. Its aspect is a compound or a salt thereof in which R 5a and R 5b, which are the same or different from each other, represent optionally substituted C 1-3 alkyl. Another aspect is a compound or a salt thereof, in which R 5a and R 5b , which are the same or different from each other, are cyclopropyl. Another aspect is a compound or a salt thereof, in which R 5a and R 5b , which are the same or different from each other, is cyclopropylmethyl. Another aspect is a compound or a salt thereof, in which R 5a and R 5b , which are the same or different from each other, represent oxetanyl. Another aspect is a compound or a salt thereof, in which R 5a and R 5b , which are the same or different from each other, are tetrahydropyranyl. Another aspect is a compound or a salt thereof, in which R 5a and R 5b, which are the same or different from each other, are thiazolyl. Another aspect is a compound or a salt thereof, in which R 5a and R 5b , which are the same as or different from each other, are pyrazinyl.(9)A compound or a salt thereof, which is a compatible combination of any two or more aspects described in (1-1) to (8) above.

[0033] Specific examples of the combination described in (9) above include the aspects below.(10-1) A compound or a salt thereof which is a combination of the aspects (1-1), (2-1), (3-1), (4-1) and (5-1) above.(10-2) A compound or a salt thereof which is a combination of the aspects (1-1), (2-1), (3-1), (4-2) and (5-2) above.(10-3) A compound or a salt thereof which is a combination of the aspects (1-2), (2-2), (3-2), (4-3) and (5-4) above.(10-4) A compound or a salt thereof which is a combination of the aspects (1-2), (2-2), (3-2), (4-4) and (5-5) above.

[0034] Examples of specific compounds included in the present invention as an aspect include the following compounds: 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b ]pyrazin-2-one,1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-methylpiperazin-2-one,6-cycloprop yl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]-8-[(4-{[1-(oxetan-3-yl)-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]quinazoline,1-({4-[({6-cyclopropyl-4-[(1 (S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-ethylpiperazin-2-one,1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-(oxan-4-yl)piperazin-2-one,1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl) (4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-(propan-2-yl)piperazin-2-one,1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-( cyclopropylmethyl)piperazin-2-one,1-[(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(5R)-5,6,7,8-tetrahydroisoquinolin-5-yl]oxy}quinazolin-8-yl)oxy]methyl}phenyl)methyl]-3-methyl-1,3-dihydro-2H-im idazo[4,5-b]pyridin-2-one,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-8-({4-[(5,7-dimethylimidazo[1,2-a]pyrimidin-2-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline,1-[(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[2-(propan-2-yl)pyridin-3-yl]methoxy}quinazolin-8-yl)oxy]methyl}phenyl)methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl l-1H-indazol-4-yl)-8-[(4-{[5-methyl-3-(pyrazin-2-yl)-1H-1,2,4-triazol-1-yl]methyl}phenyl)methoxy]-2-[(oxan-4-yl)oxy]quinazoline,2-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl} methyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]- 8-({4-[([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]phenyl}methoxy)quinazoline,6-cyclopropyl-8-({ 4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methoxy)-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-8-({4-[(5-ethyl-1-methyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl- 1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6- fluoro-5-methyl-1H-indazol-4-yl)-8-({4-[(2-methyl-2H-tetrazol-5-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl)oxy]quinazoline ,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-8-[(4-{[5-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline,6-cyclopropyl-4-[(1S,4S) -2,5-diazabicyclo[2,2,1]heptan-2-yl]-8-({4-[(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]-8-[(4-{[1-(oxan-4-yl)-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]quinazoline,6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-({4-[(imidazo[1,2-a]pyrazin-2-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl) ... cyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(4-{[1-methyl-5-(1,3-thiazol-2-yl)-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]-2-[(oxan-4-yl)oxy]quinazoline,6-cyclopropyl-8-({4-[(5-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methoxy)-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline and1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2,2,1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl} methyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one, and their salt.,

[0035] The compound of formula (I) may have tautomers or geometric isomers depending on the type of the substituent. In this description, the compound of formula (I) is sometimes described as only one of the isomers, but the present invention includes isomers other than those specified above and includes individual isomers or mixtures thereof. In addition, the compound of formula (I) may have an asymmetric carbon atom or axial chirality and may have diastereomers based on them. The present invention includes separated diastereomers of the compound of formula (I) or mixtures thereof.

[0036] Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compound represented by formula (I). The pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups for forming a prodrug include those described in Prog. Med., 1985, 5, p.2157-2161 or in "Iyakuhin no Kaihatsu (development of pharmaceuticals)", Vol.7, Bunshi-sekkei (molecular design), Hirokawa Shoten, 1990, p.163-198.

[0037] Furthermore, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I) and may be an acid addition salt or a salt formed with a base, depending on the type of the substituent. Examples thereof include the salts listed in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific examples include an acid addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, or with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid, salts with inorganic metals such as sodium, potassium, magnesium, calcium and aluminum, salt with an organic base such as methylamine, ethylamine and ethanolamine, salt with various amino acids and amino acid derivatives such as acetylleucine, lysine and ornithine, ammonium salt and the like.,

[0038] Furthermore, the present invention also includes various hydrates, solvates, and substances with crystalline polymorphism of the compound of formula (I) and its salts. The present invention also includes compounds that are labeled with various radioactive or non-radioactive isotopes.

[0039] (Production Method)The compound of formula (I) and its salt can be produced by various known synthetic methods using the characteristics based on the basic structure or the type of its substituent. Herein, depending on the type of the functional group, it is sometimes effective as a production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into a functional group) in the process of going from the starting material to the intermediate. Examples of the protecting group include the protecting groups described in P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis," 5 thedinion, John Wiley & Sons Inc., 2014, and the like, and a group appropriately selected from the protecting groups are used depending on the reaction conditions. In such a method, the reaction is carried out with the introduced protecting group, and then the protecting group is removed if necessary, whereby the desired compound can be obtained. In addition, a prodrug of the compound of formula (I) can be obtained by introducing a special group in the process from the starting material to the intermediate product, as for the above-mentioned protecting group, or by further carrying out the reaction using the obtained compound of formula (I). This reaction can be carried out using a method known to a person skilled in the art, such as conventional esterification, amidation and dehydration. Typical methods for producing a compound of formula (I) will be explained below. The production methods can also be carried out with reference to the reference attached to the explanation.It should be noted that the production method according to the present invention is not limited to the examples described below.

[0040] The following abbreviations are sometimes used in this description. DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)⋅CH2Cl2: addition product of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane, Pd / C: palladium carbon, AHL: lithium aluminum hydride, Me: methyl group.

[0041] [Chemical formula 16] (In the formula, PG 1 is a protective group, and PG 2 represents a protecting group or a hydrogen atom.)

[0042] The compound of formula (I)-1, which is a compound of formula (I), can be obtained by the deprotection reaction of compound (1a). Examples of the protecting group that can be removed under acidic conditions herein include a tert-butoxycarbonyl group, a triphenylmethyl group, a tetrahydro-2H-pyran-2-yl group, and the like. This reaction is carried out by stirring the compound under conditions from cooling to refluxing with heating, usually for 0.1 hour to five days. Examples of the solvent used include, but are not limited to, an alcohol such as MeOH and EtOH, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, and chloroform, an ether such as diethyl ether, THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN, or water, and a mixture thereof. Examples of the deprotecting reagent include, but are not limited to, an acid such as hydrogen chloride (DOX solution), trifluoroacetic acid, and methanesulfonic acid.Once a protecting group is selected, deprotection can be accomplished by a catalytic hydrogenation reaction. Examples of the protecting group include a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, and the like. Deprotection can also be accomplished using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of the protecting group include a tert-butyl(dimethyl)silyl group, a (trimethylsilyl)ethoxymethyl group, and the like. Furthermore, examples of the protecting group that can be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, a benzoyl group, and the like. PG can also be used as a deprotector. 1 and PG 2 Protecting groups can be selected that can be removed under different deprotection conditions, and deprotection can be carried out stepwise. For example, the following can be cited as a reference for this reaction. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5 thedition, John Wiley & Sons Inc., 2014. It should be noted that when compound (1a) as a starting material has axial chirality, an optically active substance, which is obtained by single resolution of compound (1a), can be used for this reaction. A compound in which R 2 in formula (I) is naphthyl optionally substituted with OH, or a compound of formula (IIb), can be obtained by the same preparation method as described above.

[0043] By subjecting the compound of formula (I) to the following operation as a salt formation reaction, the hydrochloride of the compound of formula (I) can be obtained. The compound of formula (I), which is believed to form a salt with hydrochloric acid based on the characteristics of the chemical structure, is dissolved in a halogenated hydrocarbon such as dichloromethane and an alcohol such as MeOH and stirred under ice-cooling, usually for 0.1 hour to a day after adding hydrogen chloride (4M DOX solution) under ice-cooling. The reaction mixture is concentrated under reduced pressure, and an ether such as diethyl ether is added to the resulting residue. The resulting solid is filtered and dried under reduced pressure to thereby obtain the hydrochloride of the compound of formula (I).

[0044] By subjecting the hydrochloride of the compound of formula (I) to the following operation as a desalting reaction, the compound of formula (I) can be obtained. The hydrochloride of the compound of formula (I) is purified by octadecylsilyl (ODS) column chromatography (MeCN / 0.1% aqueous formic acid solution), and the fraction containing the target substance is collected and alkalized with a saturated aqueous sodium hydrogen carbonate solution. Then, the solution is extracted with CHCl3 / MeOH (5 / 1). The combined organic layer is dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure. The resulting solid is washed with diethyl ether and dried under reduced pressure, thus obtaining the compound of formula (I).

[0045] (Synthesis of raw material 1)[Chemical formula 17] Ninth step Eighth step (In PG formulas 3 represents a protective group OH, RLG represents C 1-12 an alkyl group, BLG is a boronic acid group, a boronic acid group protected by a boronic acid protecting group such as a pinacol ester of boronic acid group or a trifluoroboronic acid salt group (sometimes referred to as a boronic acid group or the like below), and LG 1 is a leaving group. Examples of the leaving group shown herein include Cl, Br, I, methanesulfonyl group, p-toluenesulfonyl group and the like.)

[0046] This production method is the first method for obtaining the starting compound (1).

[0047] (First step)This step is a method for producing compound (4) by the ipso-substitution reaction of compound (2) and compound (3). In this reaction, compound (2) and compound (3) are used in an equal amount or with one compound thereof in excess amount, and the mixture of compounds is stirred in a solvent inactive for the reaction or without a solvent, under conditions from cooling to refluxing with heating, preferably at a temperature of from 0°C to 80°C, usually for from 0.1 hour to five days. Examples of the solvent used herein include, but are not limited to, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon such as benzene, toluene and xylene, an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof.Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4-diazabicyclo[2,2,2]octane (DABCO) and tBuOK, or an inorganic base such as potassium carbonate, sodium carbonate and cesium carbonate is sometimes favorable for the smooth progress of the reaction.

[0048] (Second step)This step is a method for producing compound (5) by the ipso-substitution reaction of compound (4) and R LG -SH. Examples of R used in this document LG -SH include C 1-12 alkylthiols. The reaction conditions are the same as in the first stage of the synthesis of starting material 1.

[0049] (Third Step)This step is a method for producing compound (6) by ipso-substitution reaction of compound (5) and PG 3 -OH. Examples of PG used in this document 3 -OH include benzyl alcohol and p-methoxybenzyl alcohol. The reaction conditions are the same as in the first step of the synthesis of starting material 1.

[0050] (Fourth Step)This step is a method for producing compound (7) by the Suzuki-Miyaura coupling reaction of compound (6) and a boronic acid derivative consisting of an R group 1 -boronic acid or the like. Examples of the boronic acid or the like group used herein include, but are not limited to, a boronic acid group, a boronic acid ester group, a pinacol boronic acid ester group, a triolborate group, and a trifluoroboronic acid salt group. In this reaction, compound (6) and a boronic acid derivative consisting of the R group 1-boronic acid or the like is used in an equal amount or with one of the compounds in excess, and the mixture of compounds is stirred in a solvent inactive for the reaction in the presence of a base and a palladium catalyst at a temperature from room temperature to reflux temperature, with heating, preferably from 20°C to 140°C, usually for 0.1 hour to five days. Examples of the solvent used herein include, but are not limited to, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, and chloroform, an aromatic hydrocarbon such as benzene, toluene, and xylene, an ether such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, an alcohol such as MeOH, EtOH, isopropyl alcohol, and butanol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water, and a mixture thereof. The base is an inorganic base such as tripotassium phosphate, sodium carbonate, potassium carbonate, and sodium hydroxide.The palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, the addition product of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride and dichloromethane, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate or the like. Carrying out the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine is sometimes favorable for the smooth progress of the reaction. In addition, heating the mixture with microwave irradiation is sometimes favorable for the smooth progress of the reaction.[Ref] J. Am. Chem. Soc., 2005, 127, p.4685-4696.

[0051] (Fifth Step)This step is a method for producing compound (9) by the Suzuki-Miyaura coupling reaction of compound (7) and compound (8). The reaction conditions are the same as those in the fourth step of the synthesis of starting material 1.

[0052] (Sixth Step)This step is a method for producing compound (10) by the oxidation reaction of compound (9). In this reaction, compound (9) is treated with an oxidizing agent in an equal amount or excess amount in a solvent inactive for the reaction, under conditions of cooling to heating, preferably at a temperature of from -20°C to 80°C, usually for 0.1 hour to three days. In this reaction, oxidation with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is suitably used. Examples of the solvent include an aromatic hydrocarbon, an ether, a halogenated hydrocarbon such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Other examples of oxidizing agents include cumene hydroperoxide, oxone, active manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like.[Reference]The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5 thedition, Vol. 17, Maruzen, 2004.

[0053] (Seventh Step)This step is a method for producing compound (12) by the ipso-substitution reaction of compound (10) and compound (11). The reaction conditions are the same as those in the first step of synthesizing the starting material 1.

[0054] (Eighth Step)This step is a method for producing compound (13) by the catalytic hydrogenation reaction of compound (12).This reaction can be carried out by stirring compound (12) in a hydrogen atmosphere, under normal pressure to elevated pressure, in a reaction-inactive solvent such as MeOH, EtOH and ethyl acetate, in the presence of a metal catalyst, under cooling to heating, preferably at room temperature, for one hour to five days.As the metal catalyst, a palladium catalyst such as Pd / C and palladium black, a platinum catalyst such as platinum plate and platinum oxide, a nickel catalyst such as reduced nickel and Raney nickel, or the like are used.

[0055] (Ninth Step)This step is a method for producing a compound (1) by reacting a compound (13) and a compound (14). This reaction is carried out using a compound (13) and a compound (14) in an equal amount or with one compound thereof in an excess amount, by reacting the mixture of compounds in the presence of a base in a solvent inactive for the reaction, under conditions of cooling to refluxing with heating, preferably at a temperature of from 0°C to 80°C, usually for from 0.1 hour to five days. The solvent used herein is not particularly limited, and examples thereof include an aromatic hydrocarbon such as benzene, toluene and xylene, an alcohol such as MeOH and EtOH, an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane and chloroform, DMF, DMSO, ethyl acetate, MeCN and mixtures thereof.Examples of the base include, but are not limited to, an organic base such as TEA, DIPEA, 1,8-diazabicyclo[5,4,0]-7-undecene, n-butyllithium, and tBuOK, and an inorganic base such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. Carrying out the reaction in the presence of a phase-transfer catalyst such as tetra-n-butylammonium chloride is sometimes favorable. For example, the following can be referred to as a reference for this reaction.The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5. th edition, Vol. 14, Maruzen, 2005.

[0056] (Synthesis of raw material 2)[Chemical formula 18]

[0057] This production method is the second method for obtaining the starting compound (1).

[0058] (First Step)This step is a method for producing compound (16) by the ipso-substitution reaction of compound (5) and compound (15). The reaction conditions are the same as those in the first step of synthesizing the starting material 1.

[0059] (Second step)This step is a method for producing compound (17) by the Suzuki-Miyaura coupling reaction of compound (16) and a boronic acid derivative consisting of an R group 1 -boronic acid or similar. The reaction conditions are the same as in the fourth stage of the synthesis of the starting material 1.

[0060] (Third Step)This step is a method for producing compound (18) by the Suzuki-Miyaura coupling reaction of compound (17) and compound (8). The reaction conditions are the same as those in the fourth step of the synthesis of starting material 1.

[0061] (Fourth step)This step is a method for producing compound (19) by the oxidation reaction of compound (18). The reaction conditions are the same as those in the sixth step of the synthesis of starting material 1.

[0062] (Fifth Step)This step is a method for producing compound (1) by the ipso-substitution reaction of compound (19) and compound (11). The reaction conditions are the same as those in the first step of synthesizing the starting material 1.

[0063] (Synthesis of raw material 3)[Chemical formula 19] (In formulas A in compound (25) represents a cyclic amide group of formula (IV), (V), (VI) or (VII).)

[0064] This production method is a method for producing the starting compound (1)-1 included in the compound (1).

[0065] (First Step)This step is a method for producing compound (20) by the ipso-substitution reaction of compound (4) and compound (11). The reaction conditions are the same as those in the first step of synthesizing the starting material 1.

[0066] (Second step)This step is a method for producing compound (22) by the ipso-substitution reaction of compound (20) and compound (21). The reaction conditions are the same as those in the first step of synthesizing the starting material 1.

[0067] (Third step)This step is a method for producing compound (23) by the Suzuki-Miyaura coupling reaction of compound (22) and a boronic acid derivative consisting of an R group 1 -boronic acid or similar. The reaction conditions are the same as in the fourth stage of the synthesis of the starting material 1.

[0068] (Fourth Step)This step is a method for producing compound (24) by the Suzuki-Miyaura coupling reaction of compound (23) and compound (8). The reaction conditions are the same as those in the fourth step of the synthesis of starting material 1.

[0069] (Fifth Step)This step is a method for producing compound (1)-1 by converting the hydroxy group of compound (24) into a leaving group, which is then reacted with compound (25).In this reaction, a compound obtained by reacting a compound (24) with thionyl chloride, methanesulfonic anhydride or a halogenated sulfonyl compound such as methanesulfonyl chloride and p-toluenesulfonyl chloride in a solvent inactive for the reaction in the presence of a base, under conditions of ice-cooling to refluxing with heating, preferably at a temperature of -20°C to 60°C, usually for 0.1 hour to five days, and a compound (25) are used in an equal amount or with one compound thereof in excess, and the mixture of compounds is stirred in a solvent inactive for the reaction in the presence of a base, under conditions of ice-cooling to refluxing with heating, preferably at a temperature of 0°C to 120°C, usually for 0.1 hour to five days.Examples of the solvent include, but are not limited to, an aromatic hydrocarbon such as toluene, an ether such as DOX, a halogenated hydrocarbon such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Examples of the base include an organic base such as TEA, DIPEA, NMM, and tBuOK, and an inorganic base such as sodium hydroxide, potassium carbonate, sodium carbonate, and potassium hydroxide, and the like.

[0070] (Synthesis of raw material 4)[Chemical formula 20] (In the PG formula 4 represents a protecting group or a hydrogen atom, and LG 2 represents the outgoing group.)

[0071] The production method is a method for producing compound (14)-1, in which R 3 in the starting compound (14) is formula (III), and R 5 in formula (III) represents formula (IV) or formula (V).

[0072] (First Step)This step is a method for producing compound (27) by converting the hydroxy group of compound (26) into a leaving group, followed by reacting the obtained compound with compound (25). The reaction conditions are the same as those in the fifth step of the synthesis of starting material 3.

[0073] (Second Step)This step is a method for producing compound (28) by carrying out a deprotection reaction of compound (27).For example, the following can be referred to as a reference to this reaction.PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5 th edition, John Wiley & Sons Inc., 2014.

[0074] (Third Step)This step is a method for producing compound (14)-1 by converting the hydroxy group of compound (28) into a leaving group. The reaction conditions are the same as those in the leaving group conversion reaction described in the fifth step of the synthesis of starting material 3.

[0075] (Synthesis of raw material 5)[Chemical formula 21] (In the formulas, R represents C 1-3 alkyl group, PG 5 represents a protecting group or a hydrogen atom, and LG 3 represents a leaving group or a hydroxyl group.)

[0076] The production method is a method for producing compound (14)-2, in which R 3 in the starting compound (14) is formula (III), and R 5 in formula (III) represents formula (VIII).

[0077] (First Step)This step is a method of producing compound (31) by reacting compound (29) and compound (30). In this reaction, compound (29) and compound (30) are used in an equal amount or with one of the compounds in excess amount, and the mixture of compounds is stirred in a reaction-inactive solvent under conditions of cooling to heating, preferably at a temperature of from -20°C to 60°C, usually for 0.1 hour to 5 days. Examples of the solvent include, but are not limited to, an ether such as THF and DOX, a halogenated hydrocarbon such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN, pyridine, and a mixture thereof. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA and NMM or an inorganic base such as potassium carbonate, sodium carbonate and potassium hydroxide is sometimes beneficial for the reaction to proceed smoothly.

[0078] (Second Step)This step is a method for producing compound (33) by deprotection reaction of compound (31) and then acylation reaction of the obtained compound and compound (32), followed by cyclization reaction. For example, the following can be referred to as a reference to the deprotection reaction of this reaction.PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5 thedition, John Wiley & Sons Inc., 2014. In this reaction, compound (31) is subjected to a deprotection reaction, and then the resulting compound and compound (32) are used in an equal amount or with one of the compounds in excess amount, and the mixture of compounds is stirred in the presence of a condensing agent in a solvent inactive for the reaction under conditions of cooling to heating, preferably at a temperature of from -20°C to 60°C, usually for 0.1 hour to 5 days. Examples of the solvent include, but are not limited to, an aromatic hydrocarbon such as toluene, an ether such as THF and DOX, a halogenated hydrocarbon such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, diphenylphosphoryl azide and the like.Sometimes, it is preferable to use an additive (e.g., 1-hydroxybenzotriazole) for the reaction. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, and NMM, or an inorganic base such as potassium carbonate, sodium carbonate, and potassium hydroxide is sometimes favorable for the smooth progress of the reaction. Alternatively, a method can be used in which the compound (32) is converted into a reactive derivative, which is then subjected to an acylation reaction. Examples of the reactive carboxylic acid derivative include an acid halogenation product obtained by reaction with a halogenating agent such as phosphorus oxychloride, thionyl chloride, and oxalyl dichloride, a mixed acid anhydride obtained by reaction with isobutyl chloroformate or the like, an inactive ester obtained by condensation with 1-hydroxybenzotriazole or the like, and the like.The reaction of such a reactive derivative and a compound obtained by deprotecting compound (31) can be carried out in a solvent inactive for the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon, or an ether, under conditions of cooling to heating, preferably at a temperature of from -20°C to 60°C. [Reference] S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2. nd edition, Vol. 1, Academic Press Inc., 1991;The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5 thedition, Vol. 16, Maruzen, 2005. Furthermore, in this reaction, the compound obtained by the acylation reaction is stirred in a solvent inactive for the reaction under conditions of from room temperature to heating, preferably from 20°C to 150°C, usually for from 0.1 hour to 5 days. Examples of the solvent include, but are not limited to, an aromatic hydrocarbon such as xylene, an alcohol such as isoamyl alcohol, DMF, DMA, DMSO, and a mixture thereof.

[0079] (Third Step)This step is a method for producing compound (34) by reducing compound (33).This reaction is carried out by reacting compound (33) with a reducing agent in an equal or excess amount in a solvent inactive for the reaction, under conditions of cooling to refluxing with heating, preferably at a temperature of from -20°C to 60°C, usually for 0.1 hour to five days.Examples of the solvent used include, but are not limited to, an aromatic hydrocarbon such as benzene, toluene and xylene, and an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane. Examples of the reducing agent include, but are not limited to, AHL, borane-tetrahydrofuran complex, diborane, and the like. For example, the following can be referred to as a reference to this reaction.The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5 th edition, Vol. 14, Maruzen, 2005.

[0080] (Fourth Step)This step is a method for producing compound (14)-2 by converting the hydroxy group of compound (34) into a leaving group. The reaction conditions are the same as those in the leaving group conversion reaction described in the fifth step of the synthesis of starting material 3.

[0081] (Synthesis of raw material 6)[Chemical formula 22]

[0072] This production method is a method for producing the starting compound (1)-2 included in the compound (1).

[0083] (First Step)This step is a method for producing compound (36) by reacting compound (13) and compound (35). The reaction conditions are the same as those in the ninth step of the synthesis of starting material 1.

[0084] (Second step)This step is a method for producing compound (37) by hydrolyzing compound (36). This reaction is carried out by stirring compound (36) under conditions from cooling to refluxing with heating, usually for 0.1 hour to five days. Examples of the solvent used include, but are not limited to, alcohol, acetone, N,N-dimethylformamide, tetrahydrofuran and the like. In addition, a mixed solvent of the above solvent and water is sometimes suitable for the reaction. Examples of the hydrolysis reagent include, but are not limited to, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, trimethyltin hydroxide and the like. For example, the following can be said to be a reference to this reaction.The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry) (5 th edition)", Vol. 16 (2005) (Maruzen). Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0085] (Third Step)This step is a method of producing compound (1)-2 by the amidation reaction of compound (37). In this reaction, compound (37) and an amine compound are used in an equal amount or with one of the compounds in excess amount, and the mixture of compounds is stirred in the presence of a condensing agent in a solvent inactive for the reaction under conditions of cooling to heating, preferably at a temperature of from -20°C to 60°C, usually for 0.1 hour to five days. Examples of the solvent include, but are not limited to, an aromatic hydrocarbon such as toluene, an ether such as THF and DOX, a halogenated hydrocarbon such as dichloromethane, an alcohol, N,N-dimethylformamide, DMSO, ethyl alcohol, acetate, MeCN, and a mixture thereof.Examples of the condensing agent include (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-N, N,N',N'-tetramethyluronium hexafluorophosphate (GATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N, N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), and the like. Sometimes, it is preferable to use an additive (e.g., 1-hydroxybenzotriazole) for the reaction. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA and NMM, or an inorganic base such as potassium carbonate, sodium carbonate and potassium hydroxide is sometimes favorable for the smooth progress of the reaction. Alternatively, a method can be used in which compound (37) is converted into a reactive derivative, which is then subjected to an acylation reaction.Examples of the reactive derivative of a carboxylic acid include a halogenation product of an acid obtained by reaction with a halogenating agent such as phosphorus oxychloride and thionyl chloride, a mixed acid anhydride obtained by reaction with isobutyl chloroformate or the like, an active ester obtained by condensation with 1-hydroxybenzotriazole or the like, and the like. The reaction of such a reactive derivative and an amine compound can be carried out in a solvent inactive for the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon, and an ether, under conditions of cooling to heating, preferably at a temperature of from -20°C to 120°C. [Reference] S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2. nd edition, Vol. 1, Academic Press Inc., 1991;The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry (5 th edition)", Vol. 16 (2005) (Maruzen).

[0086] (Synthesis of raw material 7)[Chemical formula 23]

[0087] This production method is a method for producing the starting compounds (1)-4, (1)-5 and (1)-6 included in the compound (1).

[0088] (First Step) This step is a method for producing compound (1)-4 by ozonolysis of compound (1)-3 and then reducing reaction. In this reaction, compound (1)-3 and ozone are first used in equal amounts or with one compound in excess amount, and the mixture of compounds is stirred in a solvent inactive for the reaction under conditions of cooling to room temperature, preferably from -78°C to 0°C, usually for 0.1 hour to 1 day. Then, ozone is removed with oxygen or the like. Then, a reducing agent is added to the reaction solution in equal amounts or in excess amount, and the mixture is stirred while cooling to room temperature, preferably from -78°C to room temperature, usually for 0.1 hour to 1 day. Examples of the reducing agent used include a phosphite ester such as trimethyl phosphite, dimethyl sulfide and the like.Examples of the solvent include, but are not limited to, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, and chloroform, an alcohol such as methanol and ethanol, a hydrocarbon such as pentane, ethyl acetate, water, and mixtures thereof. The subsequent reduction reaction is carried out by adding a reducing agent in an equal or excess amount to the reaction solution and reacting the mixture under conditions of cooling to refluxing with heating, preferably at a temperature of from -20°C to 60°C, usually for 0.1 hour to 5 days. Examples of the reducing agent include, but are not limited to, AHL, sodium borohydride, and the like. For example, the following can be referred to as a reference to this reaction. J. Med. Chem., 2012, 55, p.3364-3386; The Chemical Society of Japan, "Shin Jikken Kagaku Koza (lectures on new experimental chemistry)", Vol. 14 (1977) (Maruzen).

[0089] (Second Step)This step is a method for producing compound (1)-5 by methylating compound (1)-4. In this reaction, compound (1)-4 and a methylating agent are used in an equal amount or with one compound in excess, and the compound mixture is stirred in a solvent inactive for the reaction or without a solvent, under conditions from cooling to refluxing with heating, preferably at a temperature of from 0°C to 80°C, usually for from 0.1 hour to five days. Examples of the methylating agent include methyl iodide, dimethyl sulfate, methyl trifluoromethanesulfonate, and the like. Examples of the solvent include, but are not limited to, a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane and chloroform, an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof.Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, 1,4-diazabicyclo[2,2,2]octane (DABCO) and tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate is sometimes favorable for the reaction to proceed smoothly.

[0090] (Third Step)This step is a method for producing compound (38) by ozonolysis of compound (1)-3. The reaction conditions are the same as those in the method for producing ozonolysis in the first step of the synthesis of starting material 7. For example, the following can be referred to as a reference for this reaction.The Chemical Society of Japan, "Shin Jikken Kagaku Koza (lectures on new experimental chemistry)", Vol. 15 (1976) (Maruzen).

[0091] (Fourth step)This step is a method of producing compound (1)-6 by reacting compound (38) with a difluoroolefining agent, followed by trifluoromethylation reaction using a fluorinating agent. In this reaction, compound (38) and the difluoroolefining agent are used in an equal amount or with one compound in excess, and the mixture of compounds is stirred in a solvent inactive for the reaction under conditions of cooling to refluxing, preferably at a temperature of from 0°C to 80°C, usually for from 0.1 hour to five days. Then, a fluorinating agent in a solvent inactive for the reaction is added to the reaction solution in an equal amount or excess, and the mixture is stirred under conditions of cooling to refluxing with heating, preferably at a temperature of from 0°C to 80°C, usually for from 0.1 hour to five days. Examples of difluoroolefining agent include Ph3P + CF2CO2 -, (Me2N)3P + CF2CO2 - and the like. Examples of the fluorinating agent include tetra-n-butylammonium fluoride and the like. Examples of the solvent include, but are not limited to, an aromatic hydrocarbon such as toluene, an ether such as THF, DOX and 1,2-dimethoxyethane, DMF, DMA, ethyl acetate, MeCN, and a mixture thereof. For example, the following can be referred to as a reference to this reaction. J. Org. Chem., 2014, 79, p.7122-7131.

[0092] The compound of formula (I) is isolated and purified in the form of a free compound, its salt, hydrate, solvate, or crystalline polymorphic substance or substance in amorphous solid form. A salt of the compound of formula (I) can also be obtained by subjecting the compound to a salt formation reaction, which is a conventional method. Isolation and purification are carried out by applying conventional chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography. Different types of isomers can be obtained by selecting an appropriate starting compound or can be separated by utilizing differences in the physicochemical properties of the isomers.For example, an optical isomer can be obtained by a method of general optical resolution of a racemate (for example, fractional crystallization to obtain a diastereomeric salt with an optically active base or acid, chromatography using a chiral column, and the like, and the like), and can also be obtained from a corresponding optically active starting compound. In addition, the compound of formula (I) or an intermediate thereof sometimes has axial chirality and is obtained as a mixture of diastereomers, and each diastereomer can be isolated by separation using a conventional separation operation, for example, ODS column chromatography or silica gel column chromatography.

[0093] The pharmacological activity of the compounds of formula (I) was confirmed by the following tests.

[0094] Experimental Example 1: Evaluation of Inhibitory Activity on KRAS G12D / SOS / c-Raf Complex Formation Using recombinant human KRAS G12D, SOS, and c-Raf proteins, the inhibitory activity of the compounds on protein complex formation was examined by time-resolved fluorescence inductive resonance energy transfer (TR-FRET). Biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5 μL; 400 nM) and the compounds dissolved in assay buffer (50 mM HEPES, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween 20, pH 7.0) were added to a 384-well plate (manufactured by Corning) in a liquid volume of 2.5 μL at a concentration of from 40,000 nM to 40 nM. Son of Sevenless (SOS) (amino acid range 564-1049, 2.5 μL; 1.3 μM) and c-Raf (amino acid range 51-131) GST (2.5 μL; 130 nM) containing GTP (from Sigma-Aldrich; 2 μM) were added to the plate, and the plate was left to stand for 1 hour at room temperature.Then, a liquid mixture (10 μl) of LANCE Ulight-anti-GST (PerkinElmer; 120 nM) and LANCE Eu-W1024 labeled with Streptavidin (PerkinElmer; 100 ng / ml) was added, and the fluorescence intensity at 620 nm and 665 nm was measured using an EnVision 2104 (PerkinElmer) under the conditions of an excitation wavelength of 337 nm. After standardizing the values ​​with the fluorescence intensity at a reference wavelength of 620 nm, 50% inhibitory concentrations (IC. 50 ) are calculated using a nonlinear regression analysis of the Sigmoid-Emax model with the signal value under solvent treatment taken as 0% inhibition and the signal value without addition of GTP taken as 100% inhibition. The results for some of the compounds of formula (I) under consideration are shown in Table 1 below.

[0095] [Table 1] Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) 1 44 9 44 18 92 2 96 10 33 19 65 3 75 11 110 20 70 4 100 12 74 22 161 5 107 13 77 23 68 6 91 14 143 7 105 15 88 8 40 16 226

[0096] Experimental Example 2: Evaluation of ERK phosphorylation inhibitory activity against KRAS-positive G12D mutation human pancreatic cancer cell line AsPC-1The inhibitory activity of the compounds on ERK phosphorylation was evaluated by measuring the phosphorylation of ERK 202 threonine (Thr202) and 204 tyrosine (Tyr204) downstream of the KRAS signal by cell-based ELISA.AsPC-1 cells (ATCC, CRL-1682) were seeded at 36 μl / well in a 384-well plate (from Greiner bio-one) to obtain 2.0×10 4cells per well. For cell culture conditions, RPMI-1640 medium (from Sigma-Aldrich) containing 10% fetal bovine serum (from GE Life Sciences) was used in the presence of 5% CO2 at 37°. The next day, the test compounds (6 points with final concentrations ranging from 10 μM to 0.3 nM), trametinib (MEK inhibitor) with a final concentration of 1 μM as a positive control, and DMSO, which serves as a solvent for the compounds under study as a negative control, were diluted 100-fold with fresh medium and each was added at 4 μl per well, followed by culturing for 2 hours. After culturing, 30% glyoxal solution (40% glyoxal [from Wako] diluted in phosphate-buffered saline [PBS; from Wako)) was quickly added at 30 µl per well, and the plate was left to stand for an hour at room temperature to immobilize the cells.The plate is then centrifuged (110×g, seven seconds; centrifugation conditions are the same thereafter unless otherwise stated) to remove the supernatant, and PBS containing 0.1% Triton X-100 (Amersham Biosciences) is added at a volume of 20 μl per well. After the plate is left at room temperature for 10 minutes, the supernatant is removed by centrifugation, and the same procedure is repeated. PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen) is then added at a volume of 20 μl per well. The plate is left at room temperature for 30 minutes and then centrifuged to remove the supernatant. Blocking solution (Intercept Blocking Buffer; LI-COR Biosciences) is then added at a volume of 20 μl per well, and the plate is left at room temperature for one hour.The supernatant is removed by centrifugation, and rabbit Phospho-p44 / 42 MAPK (Erk 1 / 2) (Thr202 / Tyr204) (D13,14,4E) XP mAb; Cell Signaling Technology) diluted 2500-fold with blocking solution is added at 10 μl per well as the primary antibody. The plate is incubated at 4°C overnight. The next day, the plate is centrifuged to remove the supernatant, and 0.05% PBS containing Tween-20 (Thermo Scientific; 20x PBS Tween-20, diluted 20-fold with ion-exchange water and used) is added to 20 μl of well. The supernatant is removed by centrifugation to wash each well. Washing is performed three times in total. After washing, IRDye 800CW goat anti-rabbit IgG (LI-COR Biosciences) diluted 1000-fold with blocking solution was added at 10 µl per well as a secondary antibody, and the plate was incubated for one hour at room temperature.The plate is centrifuged to remove the supernatant, and each well is washed three times with 0.05% PBS containing Tween-20, in the same manner as after the reaction with primary antibodies. After the third wash, centrifugation is carried out at 171 g for 17 seconds. After removing the supernatant, the plate is air-dried at room temperature for three or more hours, and fluorescent signals are measured at 800 nm using an Aerius (LI-COR Biosciences). With the signal value during the addition of DMSO taken as 0% inhibition and the signal value during the addition of 1 μl trametinib taken as 100% inhibition, the 50% inhibition values ​​(IC ). 50 ) are calculated using a nonlinear regression analysis of the Sigmoid-Emax model. The results for some of the compounds of formula (I) under consideration are shown in Table 2 below.

[0097] [Table 2] Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) 2 49 8 30 13 78 3 55 9 44 14 42 4 37 10 41 16 93 5 32 11 81 6 36 12 72

[0098] Experimental Example 3: Evaluation of Non-Substrate-Dependent Cell Growth Inhibitory Activity of KRAS-Positive G12D Mutation Human Pancreatic Cancer Line AsPC-1The non-substrate-dependent cell growth inhibitory activity of the test compounds was evaluated using 3D spheroid cell culture. AsPC-1 cells were seeded at 36 μl / well in a 384-well round-bottom low-adhesion plate (Prime Surface: from Sumitomo Bakelite) to obtain 5×10 2cells per well. Cell cultivation is carried out under the same conditions as in Experimental Example 2. The following day, the compounds in question (6 points with final concentrations ranging from 10 μM to 3.0 nM) and DMSO, which is a solvent for the compounds in question, as a negative control, are diluted 100-fold with fresh medium, and 4 μl of each are added per well. After culturing in the presence of 5% CO2 at 37°C for six days, CellTiter Glo 2.0 (from Promega) is added at 20 μl per well. After mixing with a plate mixer (from FINEPCR) at normal temperature for an hour, the luminescent signals were measured with an ARVO X3 (from PerkinElmer). With the signal value during DMSO treatment taken as 0% inhibition and the signal value in the cell-free medium alone taken as 100% inhibition, the 50% inhibition values ​​(IC 50) are calculated using a nonlinear regression analysis of the Sigmoid-Emax model. The results for some of the compounds of formula (I) under consideration are shown in Table 3 below.

[0099] [Table 3] Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) 1 68 8 73 15 152 2 166 9 84 16 216 3 128 10 77 18 192 4 99 11 133 19 189 5 83 12 153 20 138 6 92 13 130 22 209 7 80 14 154

[0100] Experimental Example 4: Evaluation of Antitumor Activity in Mice Bearing Xenograft of KRAS-Positive Human Pancreatic Cancer Cell Line PK-1 with G12D MutationPK-1 cells (RIKEN BRC, RCB1972) were cultured using RPMI-1640 medium (from Sigma-Aldrich) containing 10% fetal bovine serum (from GE Life Sciences) in the presence of 5% CO2 at 37°C. PK-1 cells were collected and suspended in PBS, and Matrigel equivalent (from Becton, Dickinson and Company) was added. The cell suspension prepared at a concentration of 3.0×10 7 cells / ml, subcutaneously inoculated in a volume of 100 μl into 4-5-week-old male nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj (nu / nu), from Charles River Laboratories Japan). About two weeks after inoculation, the mice were divided into groups so that all groups had approximately the same tumor volume and body weight, and the next day, the administration of the subject compound was started. The test was performed on five mice for each of the vehicle group and the subject compound administration group. An aqueous solution (solvent A) of 10% propylene glycol (from Maruishi Pharmaceutical Co., Ltd.), 5% polyoxyethylene sorbitan monooleate (Tween 80; from Nacalai Tesque, Inc.), 2.5% citric acid monohydrate (from Nacalai Tesque), and 2.5% KLEPTOSE HPB (from Roquette) was orally administered to the vehicle group, while a mixture of solvent A and the subject compounds was orally administered to the subject compound administration group. Administration is performed twice daily for 14 weeks, and tumor size and body weight are measured twice a week. Tumor volume is calculated using the following formula. [Tumor volume (mm3 )]=[Tumor major axis (mm)] x [Tumor minor axis (mm)] 2 ×0.5Tumor growth inhibition (%) by the test compound is calculated by taking the tumor volume of the test compound administration group on the day preceding the start of administration as 100% inhibition, and taking the tumor volume of the vehicle-treated group on the day of the final measurement as 0% inhibition. In addition, when the tumor volume in the test compound administration group is smaller than the tumor volume on the day preceding the start of administration, the tumor regression (%) under the action of the test compound is calculated by taking the tumor volume on the day preceding the start of administration as 0% regression and with tumor volume 0 as 100% regression.

[0101] As a result of the above tests, some compounds of formula (I) were found to exhibit inhibitory activity against KRAS with the G12D mutation and antitumor activity. Accordingly, the compound of formula (I) can be used for the treatment of pancreatic cancer and similar diseases, particularly KRAS-positive pancreatic cancer with the G12D mutation.

[0102] A pharmaceutical composition that contains one or two or more compounds of the formula (I) or their salts as active ingredients can be prepared by a commonly used method using an excipient commonly used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier or the like. Administration can be oral administration in the form of a tablet, pill, capsule, granule, powder, liquid or other agent, or parenteral administration by intra-articular, intravenous, intramuscular or other injection, suppository, eye drop, eye ointment, transdermal solution, ointment, transdermal patch, transmucosal solution, transmucosal patch, inhalant or the like.

[0103] A tablet, powder, granule, or other agent is used as a solid composition for oral administration. In such a solid composition, one, two, or more active ingredients are mixed with at least one inactive excipient. The composition may contain an inactive additive, such as a lubricant, disintegrant, stabilizer, or dissolving additive, according to a conventional method. If necessary, the tablet or pill can be coated with a sugar coating or a film soluble in the stomach or intestine. Liquid compositions for oral administration include a pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir, and the like, and contain a commonly used inactive diluent, such as purified water or EtOH (ethanol). The liquid composition may contain, in addition to the inactive diluent, an adjuvant such as a solubilizer, a wetting agent and a suspending agent, a sweetener, a flavoring agent, a perfume or a preservative.

[0104] Injectable agents for parenteral administration include a sterile aqueous or non-aqueous solution, suspension, or emulsifying agent. Examples of an aqueous solvent include distilled water for injection or physiological saline solution. An example of a non-aqueous solvent is an alcohol such as EtOH. Such a composition may further contain an isotonizing agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, or a solubilizing additive. They are sterilized, for example, by filtration through a bacteria-retaining filter, the addition of a microbicide, or irradiation. In addition, such a composition can be prepared as a sterile solid composition that is dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0105] A transmucosal agent such as an inhalation or transnasal agent is used in a solid, liquid, or semi-solid form, and can be produced according to a generally known method. For example, a known excipient and, in addition, a pH modifier, preservative, surfactant, lubricant, stabilizer, thickener, or the like can be appropriately added. Administration can be carried out using an appropriate inhalation or insufflation device. For example, the agent can be administered using a known device such as a metered-dose inhalation device or a nebulizer, in the form of a compound alone or in the form of a powder or a formulated mixture, or in the form of a solution or suspension in combination with a pharmaceutically acceptable carrier. A dry powder inhaler or the like can be designed for single administration or multiple administrations, and a dry powder or a capsule containing the powder can be used.Alternatively, the agent may be used in the form of a pressurized aerosol spray or the like using a suitable propellant, for example a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0106] For conventional oral administration, the daily dose is suitably about 0.001 to 100 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, and even more preferably 0.1 to 10 mg / kg body weight, administered all at once or divided into two to four doses. For intravenous administration, the daily dose is suitably about 0.0001 to 10 mg / kg body weight, administered all at once or divided into several doses per day. In addition, the daily dose of the transmucosal agent is about 0.001 to 100 mg / kg body weight, administered all at once or divided into several doses per day. The dose is appropriately selected depending on the individual case, taking into account the symptom, age, gender, etc.

[0107] Depending on the route of administration, dosage form, site of administration and types of filler and additive, the pharmaceutical composition of the present invention contains from 0.01 to 100% by weight, in aspect from 0.01 to 50% by weight, of one or more compounds of formula (I) or their salts, which are active ingredients.

[0108] The compound of formula (I) can be used in combination with various therapeutic agents or prophylactic agents for the treatment of a disease for which the compound of formula (I) is believed to be effective. The combined use may be simultaneous administration or separate administration, either sequentially or at a desired interval. The preparation for simultaneous administration may be a compounded agent or may be separately compounded. EXAMPLES

[0109] The method for producing the compound of formula (I) will be explained in more detail below based on Examples. It should be noted that the present invention is not limited to the compounds described in the following Examples. The methods for producing the starting compounds are also shown in the Production Examples. The method for producing the compound of formula (I) is not limited only to the production methods of the specific Examples described below, and the compound of formula (I) can also be produced by a combination of production methods or a method that is obvious to one skilled in the art.

[0110] It should be noted that in the present description, the compound is sometimes named using naming software, such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.).

[0111] For convenience, the mol / L concentration is shown as M. For example, 1M sodium hydroxide aqueous solution means an aqueous sodium hydroxide solution with a concentration of 1 mol / L.

[0112] Production Example 1A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 ml), THF (500 ml) was cooled in ice, and then DIPEA (240 ml), tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (48 g) were added. The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure until the total amount of the solution became about 400 ml. A mixed solvent (hexane / ethyl acetate=4 / 1, 1000 ml) was added to the resulting solution, and the mixture was stirred at room temperature for two hours. The precipitated solid was filtered to obtain tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (123 g) as a solid.

[0113] Production Example: A 2K mixture of tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (20.1 g), DMF (150 ml), DABCO (3.85 g), cesium carbonate (12.3 g), and dodecane-1-thiol (9.05 ml) were added under ice-cooling. The mixture was stirred at 50°C overnight. Ethyl acetate and water were added to the reaction mixture, and the organic layer and the aqueous layer were separated by partition operation. The resulting aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with an aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give tert-butyl (1S,4S)-5-[7-bromo-2-(dodecylsulfanyl)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (26.0 g) as an oily substance.

[0114] Production Example 4Under a flow of argon, to a mixture of tert-butyl (1S,4S)-5-[7-bromo-2-(dodecylsulfanyl)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (38.5 g), benzyl alcohol (6.12 g) and THF (390 ml), tBuOK (6.54 g) were added under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. To the reaction mixture, benzyl alcohol (0.5 ml) and tBuOK (540 mg) were added under ice-cooling, and the mixture was further stirred at the same temperature for an hour. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (1S,4S)-5-[8-(benzyloxy)-7-bromo-2-(dodecylsulfanyl)-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (41.5 g) as a resin.

[0115] Production Example 7 Under an argon atmosphere, a mixture of tert-butyl (1S,4S)-5-[8-(benzyloxy)-7-bromo-2-(dodecylsulfanyl)-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (41.5 g), MeCN (500 ml), DOX (330 ml), water (165 ml), cyclopropyl borate (8.0 g), tripotassium phosphate (38 g), PdCl2(dppf)∙CH2Cl2(4.0 g) was stirred at 100°C for 3 hours. After cooling the reaction mixture to room temperature, the solution was concentrated under reduced pressure. A saturated aqueous sodium chloride solution was added to the resulting residue, and the mixture was extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (1S,4S)-5-[8-(benzyloxy)-7-bromo-6-cyclopropyl-2-(dodecylsulfanyl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (27.1 g) as a gum.

[0116] Production Example 10A mixture of tert-butyl (1S,4S)-5-[8-(benzyloxy)-7-bromo-6-cyclopropyl-2-(dodecylsulfanyl)quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (33.6 g), 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (19.3 g), tripotassium phosphate (38 g), dicyclohexyl (2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (3.1 g), methanesulfonate (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (5.6 g), DOX (500 ml) and water (80 ml) were bubbled with argon and then stirred under argon atmosphere at 100°C for 3.5 hours. Then, the reaction mixture was concentrated under reduced pressure to approximately 1 / 2 solution volume, aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. Then, anhydrous sodium sulfate and celite were added to the organic layer, followed by stirring, and the insoluble matter was filtered through celite.The filtrate was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (33.0 g) as a foamy solid.

[0117] Production Example 13To a solution of tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (34.5 g) in CH2Cl2(350 ml), m-chloroperbenzoic acid (water content about 30%, 10 g) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Under ice-cooling, an aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction mixture. The aqueous and organic layers are separated by partitioning, and the resulting aqueous layer is extracted twice with CH2Cl2. The resulting organic layer is combined and dried over anhydrous sodium sulfate. The resulting solution is then concentrated under reduced pressure, and toluene is added to the residue.The mixture was again concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.1 g) as a foamy solid.

[0118] Production Example 15To a mixture of tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-2-(dodecane-1-sulfinyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.1 g) and THF (420 ml) were added tetrahydro-2H-pyran-4-ol (5.9 g) and tBuOK (6.4 g) at room temperature, and the mixture was stirred for an hour. Water and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was mixed, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (23.9 g) as a foam-like solid.

[0119] Production Example 18A mixture of tert-butyl (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (23.9 g), 10% Pd / C (water content 50%, 4.8 g), and EtOH (290 mL) was stirred under a hydrogen atmosphere at room temperature for eight hours. The resulting reaction mixture was filtered through celite and washed with EtOH (100 mL). 10% Pd / C (50% water content, 2.4 g) was added to the filtrate again, and the mixture was stirred under hydrogen atmosphere at room temperature overnight. After the resulting reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure to give tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (20.9 g) as a foamy solid.

[0120] Production Example To a 19K CH2Cl2(66 mL) solution of 1-{[4-(hydroxymethyl)phenyl]methyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (3.3 g), thionyl chloride (3.5 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for two hours. The reaction mixture was concentrated under reduced pressure to obtain a residue as a solid (3.6 g). To a DMF (60 ml) solution of tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (6.0 g) and the above-obtained solid (2.91 g) were added cesium carbonate (8.3 g) at room temperature, and the mixture was stirred at the same temperature for an hour and then at 50°C overnight. Water was added to the reaction mixture, and the mixture was stirred for 10 minutes.The resulting insoluble material was collected by filtration to obtain tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-({4-[(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (7.88 g) as a solid.

[0121] Production Example: To a 38K CH2Cl2 (140 mL) solution of [4-({[tert-butyldi(methyl)silyl]oxy}methyl)phenyl]methanol (7.0 g), methanesulfonic anhydride (9.66 g) and DIPEA (11.4 mL) were added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture under ice-cooling. The organic layer and the aqueous layer were separated by partitioning, and the aqueous layer was extracted twice with CH2Cl2. The resulting organic layer was mixed and then dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. To a DMF (140 ml) solution of the obtained residue and 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (5.0 g) was added tBuOK (4.70 g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, then at room temperature for 1 hour. Under ice-cooling, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. Tetra-n-butylammonium fluoride (1M THF solution, 42 mL) was added to a THF (70 mL) solution of the resulting residue, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 1-{[4-(hydroxymethyl)phenyl]methyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (4.84 g) as a solid.

[0122] Production Example 45 To a mixture of 2-(chloromethyl)imidazo[1,2-a]pyrazine (1 g), [4-(hydroxymethyl)phenyl]borate (1.8 g), DOX (24 ml), water (4.8 ml), and tripotassium phosphate (3.2 g) were added PdCl2(dppf)⋅CH2Cl2 (490 mg), and the mixture was stirred under microwave irradiation at 130°C for two hours. The resulting reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give {4-[(imidazo[1,2-a]pyrazin-2-yl)methyl]phenyl}methanol (1.15 g) as a solid.

[0123] Production Example 48Trifluoroacetic acid (18 mL) was added to a mixture of 6-fluoro-5-methyl-1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (16 g), triisopropylsilane (24 mL) and CH2Cl2 (320 mL) at room temperature, and the mixture was stirred for four days. The resulting reaction mixture was concentrated under reduced pressure to approximately the same amount of solvent in which the CH2Cl2 used was distilled off. THF and water were added to the resulting residue, and a saturated aqueous sodium hydrogen carbonate solution was added portionwise with stirring under ice-cooling until the reaction solution became slightly alkaline. The resulting mixture was extracted with CHCl3, and the organic layer was dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (11.2 g) as a solid.

[0124] Production Example 49 To a pyridine (20 ml) solution of tert-butyl 2-methylcarbamate (1.58 ml), methyl 4-(2-imino-2-methoxyethyl)benzoate monohydrochloride (2.0 g) was added at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent (hexane / ethyl acetate=1 / 4) to obtain tert-butyl 2-{2-[4-(methoxycarbonyl)phenyl]ethanimidoyl}-1-methylhydrazine-1-carboxylate monohydrochloride (2.06 g) as a solid.

[0125] Production Example: To a 50K pyridine (6.0 mL) solution of cyclopropylhydrazine dihydrochloride (392 mg), methyl 4-(2-imino-2-methoxyethyl)benzoate monohydrochloride (600 mg) was added at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure, and formic acid (6.0 mL) was added to the resulting residue. The mixture was stirred at 105 °C for three hours and then at 110 °C for two hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate.The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give methyl 4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl] benzoate (210 mg) as an oily substance.

[0126] Production Example: To a 52K pyridine (20 mL) solution of 1-aminopyrrolidin-2-one monohydrochloride (1.3 g), methyl 4-(2-imino-2-methoxyethyl)benzoate monohydrochloride (2.55 g) was added at room temperature. The mixture was stirred at the same temperature for an hour and then at 100 °C for three days. Toluene was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was adsorbed onto basic silica gel and then purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain methyl 4-[(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl]benzoate (1.13 g) as a solid.

[0127] Production Example 53 Under a stream of nitrogen, AHL (30 mg) was added to a THF (4.0 mL) solution of methyl 4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl]benzoate (205 mg) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Sodium sulfate decahydrate (513 mg) was added in small portions to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 30 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain {4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methanol (182 mg) as an oily substance.

[0128] Production Example 63: Under an argon atmosphere, iodomethane (5.2 ml) was added to a mixture of methyl 4-[(2H-tetrazol-5-yl)methyl]benzoate (3.63 g), potassium carbonate (3.5 g), and DMF (80 ml) under ice cooling. The mixture was stirred at room temperature for 3 hours, and then a saturated aqueous ammonium chloride solution was added under ice cooling. Ethyl acetate and water were added to the reaction mixture, and the organic layer and aqueous layer were separated by partitioning. The resulting aqueous layer was extracted three times with ethyl acetate. The organic layer was mixed and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (extended with hexane / ethyl acetate and then CHCl3 / MeOH) to give a mixture (3.7 g) of methyl 4-[(2-methyl-2H-tetrazol-5-yl)methyl] benzoate and its positional isomer as a solid.

[0129] Production Example 64A mixture of benzyl 4-[(1H-1,2,4-triazol-3-yl)methyl]benzoate (1.85 g), cesium carbonate (3.2 g), N-methylpyrrolidone (15 ml), and 3-iodoxetane (1.79 g) was stirred under microwave irradiation at 150°C for 30 minutes. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (extended with hexane / ethyl acetate, then CHCl3 / MeOH) to give benzyl 4-{[1-(oxetan-3-yl)-1H-1,2,4-triazol-3-yl]methyl}benzoate (1.70 g) as an oil.

[0130] Production Example 65K tert-butyl 2-{2-{2-[4-(methoxycarbonyl)phenyl]ethanimidoyl}-1-methylhydrazine-1-carboxylate monohydrochloride (400 mg), DOX (4.0 ml), MeOH (4.0 ml), and hydrogen chloride (4M DOX solution, 2.8 ml) were added in that order at room temperature, and the mixture was stirred at room temperature for three hours. Hydrogen chloride (4M DOX solution, 2.8 ml) was added, and the mixture was stirred for another two hours at room temperature. The reaction mixture was concentrated under reduced pressure, and CH2Cl2 (8.0 ml) was added to the resulting residue. Under ice cooling, DIPEA (0.957 ml) and cyclopropanecarboxylic acid chloride (0.154 ml) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. M (4.0 ml) was added to the resulting residue, and the mixture was stirred at 120°C for 4 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.The combined organic layers were washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give methyl 4-[(5-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-yl)methyl]benzoate (168 mg) as an oily substance.

[0131] Preparation Example 69K A mixture of 2-(5-methyl-1H-1,2,4-triazol-3-yl)pyrazine (3.9 g), methyl 4-(bromomethyl)benzoate (4.4 g), and DMF (60 ml) was added with potassium carbonate (6.7 g) and potassium iodide (4.0 g) under ice cooling, and the mixture was stirred at 60 °C overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and then water and ethyl acetate were added thereto. The organic layer and the aqueous layer were separated by partitioning, and the resulting aqueous layer was extracted twice with ethyl acetate. The organic layer was mixed and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give methyl 4-{[5-methyl-3-(pyrazin-2-yl)-1H-1,2,4-triazol-1-yl]methyl}benzoate (1.33 g) as a solid.

[0132] Production Example 70A mixture of 4-[(4H-1,2,4-triazol-5-yl)methyl]benzoic acid (1.0 g), 2-methyl-6-nitrobenzoic anhydride (3.7 g), TEA (1.5 ml), N,N-dimethyl-4-aminopyridine (122 mg) and CH2Cl2 (20 ml) was stirred at room temperature for 30 minutes. Then, benzyl alcohol (2.4 ml) was added, and the mixture was stirred at room temperature for one hour. Potassium carbonate (1.5 g) was added to the reaction mixture, and the mixture was stirred at room temperature for two hours. Acetic acid (0.62 ml) and water were added to the resulting reaction mixture, and the mixture was extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. Potassium carbonate (1.5 g), benzyl alcohol (5.0 ml), and THF (5.0 ml) were added to the resulting residue, and the mixture was stirred at 80°C for two hours. After cooling the reaction mixture to room temperature, acetic acid (0.62 ml) and water were added, and the mixture was extracted with CHCl3.The organic layer was dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) and then solidified by adding hexane to afford benzyl 4-[(1H-1,2,4-triazol-3-yl)methyl]benzoate (1.24 g) as a solid.

[0133] Production Example 71To a solution of tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(hydroxymethyl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (400 mg) in CH2Cl2(5.0 mL), DIPEA (0.30 mL) and methanesulfonic anhydride (210 mg) were added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture under ice-cooling. The organic and aqueous layers are separated by partitioning, and the aqueous layer is extracted three times with CH2Cl2. The resulting organic layers are combined and then dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure.Separately, sodium hydride (approximately 60% dispersion in mineral oil, 48 mg) was added to a solution of 4-methyl-3,4-dihydropyridin[2,3-b]pyrazin-2(1H)-one (196 mg) in DMF (5.0 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes under an argon atmosphere. A solution of the concentrated residue in DMF (5.0 ml) was added to the resulting reaction mixture under ice-cooling, and then the mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture under ice-cooling. The organic layer and the aqueous layer were separated by partition operation, and the aqueous layer was extracted twice with ethyl acetate. The resulting organic layers were mixed and then dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure.The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-({4-[(4-methyl-2-oxo-3,4-dihydropyrido[2,3-b]pyrazin-1(2H)-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (250 mg) as a foamy solid.

[0134] According to the preparation methods of the Preparation Examples described above, the compounds shown in Tables 4-29 below were obtained. In addition, the preparation methods, structures, and physicochemical data of the compounds in the Preparation Examples are shown in Tables 4-29.

[0135] Example 1 Trifluoroacetic acid (13 ml) was added to a mixture of tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-({4-[(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (7.88 g), triisopropylsilane (3.0 ml) and CH2Cl2(30 ml) at room temperature, and then the mixture was stirred overnight. The resulting reaction mixture was concentrated under reduced pressure to obtain a mixture containing two diastereomers of 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one. The resulting mixture was purified by ODS column chromatography (MeCN / 0.1% aqueous formic acid) to give a fraction containing (1) a highly polar diastereomer (peak-1) and (2) a low polar diastereomer (peak-2).Saturated aqueous sodium hydrogen carbonate solution was added to the fraction containing low polar diastereomer (peak-2), and the mixture was extracted with a mixed solvent (CHCl3 / MeOH=4 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain low polar diastereomer (2.39 g) of 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one as a solid.

[0136] According to the preparation methods of the Examples described above, the compounds shown in Tables 30-37 below were obtained. In addition, the structures of the compounds of the Examples are shown in Tables 30-37 below, and the physicochemical data of the compounds of the Examples are shown in Table 38.

[0137] In the tables below, the following abbreviations are sometimes used. PE: Preparation Example No., Ex: Example No., PSyn: Preparation Example No. obtained in the same manner, Syn: Example No. obtained in the same manner (e.g., 1 represents Example 1), PG: chemical structural formula (the compound with “*” in the chemical structural formula means that the compound is a single diastereomer based on axial chirality and a low-polar diastereomer (peak-2) under the separation conditions of ODS column chromatography (MeCN / 0.1% aqueous formic acid solution). The compound with “#” in the chemical structural formula means a mixture of positional isomers.), DATA: physicochemical data, ESI+: m / z value in mass spectrometry (ESI ionization method, [M+H] + unless otherwise stated), NMR: δ value (ppm) of the peak in 1 H-NMR (500 MHz) in DMSO-d6, s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), m: multiplet (spectrum), w: broad (spectrum) (example: shs).

[0138] [Table 4] PP PSin Pg. DATA 1 1 IER+: 583.1, 585.1 2 2 IER+: 751.3 3 2 IER+: 651.0

[0139] [Table 5] PP PSin Pg. DATA 4 4 IER+: 837.5 5 4 IER+: 769.3

[0140] [Table 6] PP PSin Pg. DATA 6 4 IER+: 998.4, 1000.3 7 7 IER+: 753.5

[0141] [Table 7] PP PSin Pg. DATA 8 7 IER+: 683.3 9 7 IER+: 912.7, 914.6

[0142] [Table 8] PP PSin Pg. DATA 10 10 IER+: 905.8 11 10 IER+: 835.7

[0143] [Table 9] PP PSin Pg. DATA 12 10 IER+: 982.8 13 13 IER+: 921.8

[0144] [Table 10] PP PSin Pg. DATA 14 13 IER+: 998.6 15 15 IER+: 805.7

[0145] [Table 11] PP PSin Pg. DATA 16 15 IER+: 931.8 17 15 IER+: 929.6

[0146] [Table 12] PP PSin Pg. DATA 18 18 IER+: 715.5 19 19 IER+: 967.8

[0147] [Table 13] PP PSin Pg. DATA 20 19 IER+: 942.7 21 19 IER+: 901.7

[0148] [Table 14] PP PSin Pg. DATA 22 19 IER+: 937.7 23 19 IER+: 970.7

[0149] [Table 15] PP PSin Pg. DATA 24 19 IER+: 940.8 25 19 IER+: 945.6

[0150] [Table 16] PP PSin Pg. DATA 26 19 IER+: 1001.8 27 19 IER+: 986.7 [M+Na]+

[0151] [Table 17] PP PSin Pg. DATA 28 19 IER+: 926.7 29 19 IER+: 959.7

[0152] [Table 18] PP PSin Pg. DATA 30 19 IER+: 971.6 31 19 IER+: 1000.7 [M+Na]+

[0153] [Table 19] PP PSin Pg. DATA 32 19 IER+: 928.6 33 19 IER+: 931.7

[0154] ​​[Table 20] PP PSin Pg. DATA 34 19 IER+: 936.7 35 19 IER+: 950.7

[0155] [Table 21] PP PSin Pg. DATA 36 19 IER+: 983.7 37 19 IER+: 926.7

[0156] [Table 22] PP PSin Pg. DATA 38 38 IER+: 271.3 39 38 IER+: 270.2 40 38 IER+: 235.3

[0157] [Table 23] PP PSin Pg. DATA 41 38 IER+: 249.3 42 38 IER+: 305.3 43 38 IER+: 263.4 44 38 IER+: 275.4 45 45 IER+: 240.3 46 45 IER+: 268.4

[0158] [Table 24] PP PSin Pg. DATA 47 45 IER+: 241.4 48 48 IER+: 277.3 49 49 IER+: 322.6 50 50 IER+: 258.4 51 50 IER+: 302.3

[0159] [Table 25] PP PSin Pg. DATA 52 52 IER+: 258.3 53 53 IER+: 230.4 54 53 IER+: 246.4 55 53 IER+: 282.3 56 53 IER+: 232.2 57 53 IER+: 205.3

[0160] [Table 26] PP PSin Pg. DATA 58 53 IER+: 274.4 59 53 IER+: 244.4 60 53 IER+: 230.4 61 53 IER+: 254.3 62 53 IER+: 287.3

[0161] [Table 27] PP PSin Pg. DATA 63 63 IER+: 233.2 64 64 IER+: 350.3 65 65 IER+: 272.3 66 65 IER+: 260.2 67 65 IER+: 315.3

[0162] [Table 28] PP PSin Pg. DATA 68 65 IER+: 282.3 69 69 IER+: 310.3 70 70 IER+: 294.2

[0163] [Table 29] PP PSin Pg. DATA 71 71 IER+: 980.9 72 71 IER+: 958.8

[0164] [Table 30] Pr. Pg. 1 2 3

[0165] [Table 31] Pr. Pg. 4 5 6

[0166] [Table 32] Pr. Pg. 7 8 9

[0167] [Table 33] Pr. Pg. 10 11 12

[0168] [Table 34] Pr. Pg. 13 14 15

[0169] [Table 35] Pr. Pg. 16 17 18

[0170] [Table 36] Pr. Pg. 19 20 21

[0171] [Table 37] Pr. Pg. 22 23

[0172] [Table 38] Pr. Pretty DATA 1 1 IER+: 783.6 NMR: 0.49-0.68 (4H, m), 1.27-1.35 (1H, m), 1.53-1.64 (2H, m), 1.68-1.75 (1H, m), 1.84-1.90 (1H, m), 2.94-3.02 (1H, m), 3.05-3.21 (3H, m), 3.35 (3H, s), 3.67-3.77 (4H, m), 4.19-4.24 (1H, m), 4.65 (1H, d, J=11.4 Hz), 4.9-3.02 (1H, 5.5 s), (2H, m), 5.19 (1H, d, J=11.4 Hz), 6.73 (2H, d, J=8.1 Hz), 7.16 (2H, d, J=8.1 Hz), 7.34 (1H, d, J=9.9 Hz), 7.41-7.46 (2H, d, J=9.9 Hz), 7.41-7.46 (2H, d, J=1.3 Hz), 7.95 (1H, d, J=3.3 Hz), 13.07 (1H, shs) 2 1 IER+: 747.5 3 1 IER+: 758.6 4 1 IER+: 761.6 5 1 IER+: 817.7 6 1 IER+: 775.6 7 1 IER+: 787.6 8 1 IER+: 829.5 9 1 IER+: 780.5 10 1 IER+: 831.5 11 1 IER+: 794.6 12 1 IER+: 774.5 13 1 IER+: 753.6 14 1 IER+: 742.6 15 1 IER+: 744.6 16 1 IER+: 717.6 17 1 IER+: 766.5 18 1 IER+: 742.5 19 1 IER+: 786.5 20 1 IER+: 752.5 21 1 IER+: 799.5 22 1 IER+: 756.7 23 1 IER+: 796.6

[0173] Compounds having any of the following structures are given as examples of specific compounds of formula (I) included in the present invention. These compounds were obtained by the conventional production methods described above, the production methods of Production Examples and Examples, a combination of production methods, or a method obvious to a person skilled in the art. Furthermore, the compounds were found to have inhibitory activity against KRAS with the G12D mutation by the test methods described in the Experimental Examples described above. Accordingly, the compounds can be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the treatment of pancreatic cancer. [Chemical formula 24] INDUSTRIAL APPLICABILITY

[0174] The compound of the present invention or a salt thereof is useful as a KRAS inhibitor with a G12D mutation, and can be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the treatment of pancreatic cancer.

Claims

1. A compound of formula (I) or a salt thereof: [Chemical formula 1] Where R 1 is cyclopropyl, R 2 represents the structure of formula (IIa) below, [Chemical formula 2] R 3 represents formula (III) below, [Chemical formula 3] R 4 represents pyridylmethyl, a 4-membered to 7-membered saturated heterocyclic group containing one O heteroatom, or tetrahydroisoquinolinyl, wherein pyridylmethyl is optionally substituted with C 1-3 alkyl, R 5 represents H or a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV) below, [Chemical formula 4] where R 5a and R 5b , which are the same or different from each other, are H, C 1-3 alkyl optionally substituted with two F atoms, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl, W is CH, X represents O, Y represents F, Y a represents C 1-3 alkyl, and Z represents N or CH.

2. The compound according to item 1 or its salt, characterized in that R 2 represents the formula (IIc) below, [Chemical formula 5] R 3 represents formula (IIIa) below, [Chemical formula 6] R 4 is tetrahydropyranyl, pyridylmethyl, optionally substituted with C1-3 alkyl, or tetrahydroisoquinolinyl, R 5 is a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV) below, [Chemical formula 7] .

3. The compound according to item 2 or its salt, characterized in that the compound of formula (I) is selected from the group consisting of 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one, 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-methylpiperazin-2-one, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]-8-[(4-{[1-(oxetan-3-yl)-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]quinazoline, 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-ethylpiperazin-2-one, 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-(oxan-4-yl)piperazin-2-one, 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-(propan-2-yl)piperazin-2-one, 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-(cyclopropylmethyl)piperazin-2-one, 1-[(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[(5R)-5,6,7,8-tetrahydroisoquinolin-5-yl]oxy}quinazolin-8-yl)oxy]methyl}phenyl)methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-8-({4-[(5,7-dimethylimidazo[1,2-a]pyrimidin-2-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline, 1-[(4-{[(6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-{[2-(propan-2-yl)pyridin-3-yl]methoxy}quinazolin-8-yl)oxy]methyl}phenyl)methyl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(4-{[5-methyl-3-(pyrazin-2-yl)-1H-1,2,4-triazol-1-yl]methyl}phenyl)methoxy]-2-[(oxan-4-yl)oxy]quinazoline, 2-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-2,5,6,8-tetrahydro-3H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-one, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]-8-({4-[([1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]phenyl}methoxy)quinazoline, 6-cyclopropyl-8-({4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methoxy)-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-8-({4-[(5-ethyl-1-methyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-({4-[(2-methyl-2H-tetrazol-5-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-8-[(4-{[5-(difluoromethyl)-1-methyl-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-8-({4-[(6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]-8-[(4-{[1-(oxan-4-yl)-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-({4-[(imidazo[1,2-a]pyrazin-2-yl)methyl]phenyl}methoxy)-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(4-{[1-methyl-5-(1,3-thiazol-2-yl)-1H-1,2,4-triazol-3-yl]methyl}phenyl)methoxy]-2-[(oxan-4-yl)oxy]quinazoline, 6-cyclopropyl-8-({4-[(5-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methoxy)-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazoline and 1-({4-[({6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}methyl)-4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one.

4. A pharmaceutical composition having an activity of inhibiting KRAS with the G12D mutation, containing an effective amount of a compound according to any one of claims 1-3 or a salt thereof and one or more pharmaceutically acceptable excipients.

5. The pharmaceutical composition according to claim 4, which is a pharmaceutical composition for the treatment of pancreatic cancer.

6. Use of a compound according to any one of claims 1-3 or a salt thereof for the production of a pharmaceutical composition for the treatment of pancreatic cancer.

7. A compound according to any one of claims 1 to 3 or a salt thereof for use in the treatment of pancreatic cancer.

8. Use of a compound according to any one of claims 1-3 or a salt thereof for the treatment of pancreatic cancer.

9. A method for treating pancreatic cancer, comprising administering an effective amount of a compound according to any one of claims 1-3 or a salt thereof to a subject.

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