4-aminoquinazoline compounds

Abstract

[Problem] To provide compounds that are useful as active ingredients of pharmaceutical compositions for the treatment of pancreatic cancer. [Solution] The present inventors studied compounds that are useful as active ingredients of pharmaceutical compositions for pancreatic cancer treatment, found that 4-aminoquinazoline compounds have exceptional G12D mutant KRAS inhibitory activity and can be used as therapeutic agents for pancreatic cancer, and completed the present invention. The 4-aminoquinazoline compound or salts thereof according to the present invention can be used as therapeutic agents for pancreatic cancer.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition, a 4-aminoquinazoline compound that is useful as an inhibitor of G12D mutant KRAS, and is expected to be useful, for example, as an active ingredient in a pharmaceutical composition for treating pancreatic cancer. [Background technology]

[0002] Pancreatic cancer, which is primarily pancreatic ductal adenocarcinoma, has an extremely poor prognosis, with a 5-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, pp. 7-30), and approximately 460,000 new cases are reported annually worldwide (CA Cancer J. Clin., 2018, 68, pp. 394-424). While surgery is the most effective treatment for pancreatic cancer, early detection is difficult, leading to frequent metastasis and often ineffective surgical treatment. If surgical treatment is not an option, chemotherapy and radiation therapy are used, but these have poor survival rates. Currently, FOLFRINOX therapy (a combination therapy of 5-FU, irinotecan, and oxaliplatin with the addition of levofolinate) is the standard treatment for pancreatic cancer. However, due to its high toxicity, careful patient selection is required, such as by limiting patients to those with an ECOG performance status of 1 or less (J. Clin. Oncol., 2018, 36, pp. 2545-2556). While the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved for use in combination with gemcitabine, its overall survival benefit is only about two weeks compared to gemcitabine alone, indicating that a satisfactory therapeutic effect has not been achieved. Therefore, there is still a need for more effective treatments (J. Clin. Oncol., 2007, 25, pp. 1960-1966).

[0003] RAS proteins are small guanosine triphosphate (GTP)-binding proteins of approximately 21 kDa, consisting of 188–189 amino acids. There are four major RAS proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) produced by three genes: KRAS, NRAS, and HRAS. RAS proteins exist in an active GTP-bound form and an inactive GDP-bound form. RAS proteins are activated by the exchange of guanosine diphosphate (GDP) for GTP upon ligand stimulation of cell membrane receptors such as EGFR. Active RAS binds to 20 effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signaling cascades. On the other hand, active RAS becomes inactive by converting GTP to GDP through its intrinsic GTP hydrolysis (GTPase) activity. This GTPase activity is enhanced by GTPase-activating proteins (GAPs). This indicates that RAS functions as an important "molecular switch" in intracellular signaling pathways such as EGFR, and plays an important role in processes such as cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, pp. 761-774; Nature Rev. Drug Discov., 2014, 13, pp. 828-851; Nature Rev. Drug Discov., 2016, 15, pp. 771-785).

[0004] When RAS mutations result in amino acid substitutions, RAS becomes constitutively active due to impaired GTPase function and reduced response to GAPs, resulting in continuous downstream signaling. This excessive signaling leads to carcinogenesis and accelerated tumor proliferation. Pancreatic ductal adenocarcinoma (PDA) is thought to develop through a process of mild to severe dysplasia (PanIN), and KRAS mutations are already present in early-stage PanIN. Subsequently, abnormalities in the tumor suppressor genes INK4A, p53, and SMAD4 occur, leading to malignant progression (Nature Rev. Cancer, 2010, 10, pp. 683-695). Furthermore, KRAS mutations are found in over 90% of PDAs, with the majority of these mutations being point mutations at codon 12 in KRAS exon 2 (Cancer Cell, 2017, 32, pp. 185-203). This indicates that KRAS plays an important role in the oncogenesis and development of pancreatic cancer.

[0005] Recently, the presence of an allosteric pocket near the switch II region of G12C mutant KRAS has been demonstrated (Nature, 2013, 503, pp. 548-551). Several compounds have been reported that irreversibly bind to G12C mutant KRAS by forming covalent bonds with the cysteine residues of G12C mutant KRAS (Cancer Discov., 2016, 6, pp. 316-329; Cell, 2018, 172, pp. 578-589; Nature, 2019, 575, pp. 217-223). Selective inhibitors of G12C mutant KRAS bind covalently to G12C mutant KRAS, inhibiting its conversion from inactive to active form and blocking downstream signaling, thereby inducing cancer cell death.

[0006] While G12C mutations in KRAS are common in non-small cell lung cancer, they occur in only a few percent of pancreatic cancers (Cancer Cell 2014, 25, pp. 272-281), and therapeutic agents for other KRAS mutations are needed. G12D mutations in KRAS are reported to be the most common KRAS mutation, occurring in approximately 34% of pancreatic cancers (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

[0007] Patent Documents 1, 2, and 3 disclose RAS inhibitors, and compounds represented by the following formula (A) and formula (B) are respectively disclosed in Patent Documents 2 and 3. Patent Documents 1, 2, and 3 describe that they are useful for cancers with KRAS codon 12 mutations, one of which is the G12D mutation, but do not disclose their effects on KRAS G12D mutant cancers. [ka] (A) TIFF0007725511000002.tif4161(B) (For the meaning of the symbols in the formula, see the publication.)

[0008] Furthermore, Patent Documents 4, 5 and 6 disclose KRAS G12D inhibitors. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2016 / 049565 [Patent Document 2] International Publication No. 2016 / 049568 [Patent Document 3] International Publication No. 2017 / 172979 [Patent Document 4] International Publication No. 2021 / 041671 [Patent Document 5] International Publication No. 2021 / 106231 [Patent Document 6] International Publication No. 2021 / 107160 Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention provides compounds that are useful as pharmaceutical compositions, for example, as inhibitors of G12D mutant KRAS, and are expected to be useful as active ingredients in pharmaceutical compositions for treating pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer. [Means for solving the problem]

[0011] The present inventors have conducted extensive research into compounds useful as active ingredients in pharmaceutical compositions for treating pancreatic cancer, and have discovered that the 4-aminoquinazoline compound of formula (I) has excellent inhibitory activity against G12D mutant KRAS, thereby completing the present invention. That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof and an excipient. [ka] (In the formula, R 1 is C optionally substituted with a group selected from the group consisting of F and OCH 1-3 Alkyl, halogen, cyclopropyl, or C 2-3 is alkenyl, R 2 is naphthyl optionally substituted with OH or a group selected from the group consisting of the following formulas (IIa) and (IIb), [ka] R 3 is the following formula (III): [ka] R 4 may be substituted C 1-6 Alkyl, optionally substituted C 3-6cycloalkyl, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted 6-membered heteroaryl, or tetrahydroisoquinolinyl; R 5 H,CONR 6 R 7 or a group selected from the group consisting of the following formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV): [ka] R 5a , R 5b are the same or different and represent H, optionally substituted C, 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 , R 7 are the same or different and represent H or optionally substituted C 1-6 alkyl, or R 6 , R 7 form a 4- to 7-membered saturated heterocyclic ring together with the nitrogen to which they are attached, and the 4- to 7-membered saturated heterocyclic ring is optionally substituted C 1-6 may be substituted with alkyl, W is CH or N; X is O or NR x and R x is H or C 1-3 is alkyl, Or XR 4 is a 4- to 7-membered saturated heterocyclic group or imidazolyl, Y, Y b is H, F, or Cl, Y a C optionally substituted with F 1-3 alkyl, cyano, or cyclopropyl; Or, Y a , Y btogether with the carbon to which they are attached to form a cyclopentenyl, Y c is H, F, or methyl, Z is N or CH.

[0012] Furthermore, one aspect of the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, R 1 is cyclopropyl, R 2 is the following formula (IIc): [ka] R 3 is the following formula (IIIa): [ka] R 4 is tetrahydropyranyl, optionally substituted pyridylmethyl, or tetrahydroisoquinolinyl; R 5 is a group selected from the group consisting of the following formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), [ka] R 5a , R 5b are the same or different and represent H, optionally substituted C, 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl; X is O, Y is F, Z is N or CH.

[0013] Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0014] The present invention also relates to a pharmaceutical composition, particularly a pharmaceutical composition for treating pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer, containing the compound of formula (I) or a salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical composition also encompasses a therapeutic agent for pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer, containing the compound of formula (I) or a salt thereof. The present invention also relates to use of the compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer; use of the compound of formula (I) or a salt thereof for the treatment of pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer; the compound of formula (I) or a salt thereof for use in the treatment of pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer; and a method for treating pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer, which comprises administering an effective amount of the compound of formula (I) or a salt thereof to a subject. The present invention also relates to a compound of formula (I) or a salt thereof which is a G12D mutant KRAS inhibitor, a compound of formula (I) or a salt thereof for use as a G12D mutant KRAS inhibitor, and a G12D mutant KRAS inhibitor containing the compound of formula (I) or a salt thereof. The "subject" refers to a human or other animal in need of treatment, and in one embodiment, a human in need of prevention or treatment. [Effects of the Invention]

[0015] The compound of formula (I) or a salt thereof has inhibitory activity against G12D mutant KRAS and can be used as a therapeutic agent for pancreatic cancer. DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention will be described in detail below. In this specification, "optionally substituted" means unsubstituted or having 1 to 5 substituents. In one embodiment, it means unsubstituted or having 1 to 3 substituents. When multiple substituents are present, the substituents may be the same or different from each other.

[0017] "C 1-12 The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (Hereinafter, the number of carbon atoms will be expressed in the same manner). In one embodiment, it is ethyl or dodecyl, and in another embodiment, C 1-6 In one embodiment, it is alkyl, and in one embodiment, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, or n-hexyl, and in one embodiment, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or isopentyl. In one embodiment, C 1-3 In one embodiment, it is alkyl, and in one embodiment, it is methyl, ethyl, or isopropyl, in one embodiment, it is methyl or ethyl, in one embodiment, it is methyl or isopropyl, in one embodiment, it is ethyl, in one embodiment, it is isopropyl.

[0018] "C 2-3 The term "alkenyl" refers to alkenyl having 2 to 3 carbon atoms, such as vinyl and propenyl. In one embodiment, it is vinyl, 1-propenyl, or 2-propenyl. In one embodiment, it is vinyl.

[0019] "C 3-6The term "cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, it is cyclopropyl, cyclobutyl, or cyclohexyl, in another embodiment, it is cyclopropyl or cyclobutyl, in another embodiment, it is cyclopropyl, and in another embodiment, it is cyclobutyl.

[0020] The "4- to 7-membered saturated heterocyclic group" refers to, for example, a 4- to 7-membered saturated heterocyclic group containing, as ring-constituting atoms, 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, and may have a bridge or form a spiro ring, and further, the sulfur atom contained in the heterocyclic ring may be oxidized. In one embodiment, the alkyl group is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, or thiazaspiro[3.3]heptanyl. In another embodiment, the alkyl group is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, azaspiro[3.3]heptanyl, oxazaspiro[3.3]heptanyl, or thiazaspiro[3.3]heptanyl. pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, azaspiro[3.3]heptanyl, or oxazaspiro[3.3]heptanyl, and in one embodiment, azetidinyl, tetrahydropyranyl, morpholinyl, or oxazaspiro[3.3]heptanyl, and in one embodiment, azetidinyl or tetrahydropyranyl, and in one embodiment, morpholinyl or oxazaspiro[3.3]heptanyl, and in one embodiment, tetrahydropyranyl.

[0021] The "6-membered heteroaryl" is, for example, a 6-membered heteroaryl containing 1 to 3 nitrogen atoms as ring-constituting atoms. In one embodiment, the "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, in another embodiment, pyridyl or pyrimidinyl, and in another embodiment, pyrimidinyl.

[0022] "Halogen" means F, Cl, Br, and I. In one embodiment, it is F, Cl, or Br, in another embodiment, it is F or Cl, in another embodiment, it is F, in another embodiment, it is Cl, and in another embodiment, it is Br.

[0023] Some embodiments of the permissible substituents for "optionally substituted pyridyl", "optionally substituted oxazolyl" and "optionally substituted pyridylmethyl" include C 1-3 It is alkyl, and in one embodiment, it is methyl or isopropyl, and in one embodiment, it is methyl, and in one embodiment, it is isopropyl.

[0024] "Optionally substituted C 1-6 "Alkyl" and "Optionally substituted C 1-3 Some embodiments of the permissible substituents for "alkyl" include halogen, OH, OCH3, cyano, C 1-3 Alkyl, hydroxymethyl, methoxymethyl, cyanomethyl, difluoroethyl, optionally substituted C 3-6 cycloalkyl, optionally substituted pyridyl, or optionally substituted 4- to 7-membered saturated heterocyclic group, and in some embodiments, halogen, OCH3, cyano, optionally substituted C 3-6 cycloalkyl, optionally substituted pyridyl, or optionally substituted 4- to 7-membered saturated heterocyclic group, and in some embodiments, F, OCH3, cyano, optionally substituted C 3-6It is cycloalkyl, optionally substituted pyridyl, or an optionally substituted 4- to 7-membered saturated heterocyclic group, and in one embodiment, it is F, OCH3, or cyano, and in one embodiment, it is halogen or OCH3, and in one embodiment, it is F or OCH3, and in one embodiment, it is halogen.

[0025] "Optionally substituted C 3-6 Some embodiments of the permissible substituents for "cycloalkyl" include C-substituted with halogen, OCH3, or OCH3. 1-3 alkyl, and in one embodiment, C optionally substituted with F, OCH3, or OCH3. 1-3 alkyl, and in one embodiment, C 1-3 It is alkyl, and in one embodiment, F, OCH3, or methoxymethyl.

[0026] An embodiment of the substituents permitted in the "optionally substituted 4- to 7-membered saturated heterocyclic group" is a C group optionally substituted with OH, OCH3, or a group selected from the group consisting of F, OCH3, and cyano. 1-3 It is alkyl, and in one embodiment, it is OH, OCH3, trifluoromethyl, difluoroethyl, methoxyethyl, or cyanomethyl.

[0027] Some embodiments of the permissible substituents for the "optionally substituted 6-membered heteroaryl" include C 1-3 It is alkyl or N(CH3)2, and in one embodiment, it is ethyl or N(CH3)2.

[0028] The term "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is converted from glycine to aspartic acid. "G12D mutant KRAS" refers to KRAS having the above-mentioned "G12D mutation."

[0029] "Pancreatic cancer" refers to a malignant tumor that occurs in the pancreas, such as pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, and in one embodiment, pancreatic ductal carcinoma and in another embodiment, pancreatic ductal adenocarcinoma. "KRAS G12D mutation-positive pancreatic cancer" refers to pancreatic cancer that is positive for G12D-mutated KRAS, such as pancreatic cancer in which a KRAS G12D mutation has occurred, or pancreatic cancer with a high rate of positive for G12D-mutated KRAS. In one embodiment, it refers to KRAS G12D mutation-positive pancreatic ductal carcinoma and KRAS G12D mutation-positive pancreatic ductal adenocarcinoma, in another embodiment, it refers to KRAS G12D mutation-positive pancreatic ductal carcinoma, and in another embodiment, it refers to KRAS G12D mutation-positive pancreatic ductal adenocarcinoma.

[0030] Certain embodiments of the compound of formula (I) or a salt thereof of the present invention are shown below. (1-1)R 1 C optionally substituted with a group selected from the group consisting of F and OCH 1-3 Alkyl, halogen, cyclopropyl, or C 2-3 A compound or a salt thereof which is alkenyl. (1-2)R 1 is cyclopropyl or a salt thereof. (2-1)R 2 is naphthyl optionally substituted with OH or a group selected from the group consisting of the following formula (IIa) and formula (IIb), [ka] Y, Y b is H, F, or Cl; Y a C optionally substituted with F 1-3 alkyl, cyano, or cyclopropyl; Or, Y a , Y b together with the carbon to which they are attached to form a cyclopentenyl, Y c is H, F, or methyl, or a salt thereof. (2-2)R 2 is the following formula (IIc), [ka] A compound or a salt thereof wherein Y is F. (3-1)R 3 is the following formula (III), [ka] A compound or a salt thereof in which W is CH or N. (3-2)R 3 A compound or a salt thereof, wherein: [ka]

[0031] (4-1)R 4 optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted 6-membered heteroaryl, or tetrahydroisoquinolinyl; X is O or NR x and R x is H or C 1-3 is alkyl, Or XR 4 is a 4- to 7-membered saturated heterocyclic group or imidazolyl, or a salt thereof. (4-2)R 4 but, (1) C 1-6 is alkyl, where: The C in question 1-6 Alkyl is 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 C 1-3 pyridyl optionally substituted with alkyl; (2) C optionally substituted with OCH3 3-6cycloalkyl, (3) azetidinyl optionally substituted by F; (4) tetrahydropyranyl, (5) C 1-3 pyrimidinyl optionally substituted with a group selected from the group consisting of alkyl and N(CH3)2, or (6) tetrahydroisoquinolinyl, X is O or NR x and R x is H or C 1-3 is alkyl, Or XR 4 A compound or a salt thereof, wherein is morpholinyl, oxazaspiro[3.3]heptanyl or imidazolyl. (4-3)R 4 is tetrahydropyranyl, optionally substituted pyridylmethyl, or tetrahydroisoquinolinyl; A compound or a salt thereof in which X is O. (4-4)R 4 is tetrahydropyranyl, A compound or a salt thereof in which X is O.

[0032] (5-1) R in formula (III) 5 H, CONR 6 R 7 or a group selected from the group consisting of the following formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV): [ka] R 5a and R 5b are the same or different and represent H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 , R 7 are the same or different and represent H or optionally substituted C1-6 alkyl, or R 6 , R 7 are joined together with the nitrogen to which they are attached to form a 4- to 7-membered saturated heterocyclic ring, and the 4- to 7-membered saturated heterocyclic ring is optionally substituted C 1-6 may be substituted with alkyl, A compound or a salt thereof in which Z is N or CH. (5-2) R in formula (III) 5 H, CONR 6 R 7 or a group selected from the group consisting of formula (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV), R 5a and R 5b are the same or different and represent H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 , R 7 are the same or different and represent H or optionally substituted C 1-6 alkyl, or R 6 , R 7 together with the nitrogen to which they are attached to form a morpholinyl or piperazinyl, and the piperazinyl is optionally substituted C 1-6 may be substituted with alkyl, A compound or a salt thereof in which Z is N or CH. (5-3) R in formula (III) 5 H, CONR 6 R 7 or a group selected from the group consisting of formula (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV), R 5a and R 5b are the same or different and may be substituted with H or F; 1-3Alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, C 1-3 oxazolyl, thiazolyl or pyrazinyl optionally substituted by alkyl; R 6 , R 7 are the same or different and are H or C 1-6 alkyl, or R 6 , R 7 together with the nitrogen to which they are attached form a morpholinyl or piperazinyl, the piperazinyl being optionally substituted by methoxyethyl; A compound or a salt thereof in which Z is N or CH. (5-4) R in formula (IIIa) 5 is a group selected from the group consisting of the following formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), [ka] R 5a and R 5b are the same or different and represent H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl; A compound or a salt thereof in which Z is N or CH. (5-5) R in formula (IIIa) 5 is a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), R 5a and R 5b are the same or different and may be substituted with H or F; 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl; A compound or a salt thereof in which Z is N or CH. (6)R 4In one embodiment, R is tetrahydropyranyl, optionally substituted pyridylmethyl, or tetrahydroisoquinolinyl, or a salt thereof. 4 In one embodiment, R is tetrahydropyranyl or a salt thereof. 4 In one embodiment, R is an optionally substituted pyridylmethyl, or a salt thereof. 4 is tetrahydroisoquinolinyl or a salt thereof. (7) R in formula (III) 5 is a group selected from the group consisting of formulas (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), and (XIV), or a salt thereof. 5 In one embodiment, a compound or a salt thereof, wherein R 5 In one embodiment, the compound or salt thereof is represented by formula (V). 5 In one embodiment, the compound or salt thereof is represented by formula (VI). 5 In one embodiment, the compound or salt thereof is represented by formula (VII). 5 In one embodiment, a compound or a salt thereof, wherein R 5 In one embodiment, a compound or a salt thereof, wherein R 5 In one embodiment, a compound or a salt thereof, wherein R 5 In one embodiment, a compound or a salt thereof, wherein R 5 In one embodiment, the compound or salt thereof is represented by formula (XII): 5 In one embodiment, a compound or a salt thereof, wherein R 5 or a salt thereof, wherein: (8)R 5a and R 5b may be the same or different and may be substituted C 1-3 In one embodiment, R is a compound or a salt thereof, wherein R is alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl, or pyrazinyl. 5a and R 5b may be the same or different and may be substituted C 1-3In one embodiment, R 5a and R 5b are the same or different and are cyclopropyl, or a salt thereof. 5a and R 5b are the same or different and are cyclopropylmethyl, or a salt thereof. 5a and R 5b are the same or different and are oxetanyl, or a salt thereof. 5a and R 5b are the same or different and are tetrahydropyranyl, or a salt thereof. 5a and R 5b are the same or different and are thiazolyl, or a salt thereof. 5a and R 5b are the same or different and are pyrazinyl, or a salt thereof. (9) A compound or a salt thereof that is a combination of any two or more of the embodiments described in (1-1) to (8) that are not contradictory.

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

[0034] As examples of specific compounds encompassed by the present invention, in one embodiment, the following compounds can be mentioned. 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, and salts thereof.

[0035] The compound of formula (I) may exist in the form of tautomers or geometric isomers depending on the type of substituents. In this specification, the compound of formula (I) may be described in only one isomeric form, but the present invention also includes other isomers, and also includes isolated isomers and mixtures thereof. Furthermore, the compound of formula (I) may have an asymmetric carbon atom or axial asymmetry, and therefore may have diastereomers. The present invention also encompasses separated diastereomers of the compound of formula (I) or mixtures thereof.

[0036] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I). A 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 that form prodrugs include those described in Prog. Med., 1985, 5, pp. 2157-2161 and "Drug Development," Vol. 7, Molecular Design, Hirokawa Shoten, 1990, pp. 163-198.

[0037] The salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), which may form an acid addition salt or a salt with a base depending on the type of substituents. Examples include salts described in Handbook of Pharmaceutical Salts Properties, Selection, and Use by P. Heinrich Stahl, Wiley-VCH, 2008. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids 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; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine; and ammonium salts.

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

[0039] (manufacturing method) The compound of formula (I) and its salts can be produced by various known synthetic methods, taking advantage of characteristics based on its basic structure or the type of substituents. In this case, depending on the type of functional group, it may be effective from a manufacturing technology perspective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 5th Edition, by P.G.M. Wuts and T.W. Greene, John Wiley & Sons Inc., 2014, and the like. These protecting groups can be appropriately selected and used depending on the reaction conditions. In such methods, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary. Furthermore, prodrugs of the compound of formula (I) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, as in the case of the above-mentioned protecting group, or by further reacting the obtained compound of formula (I). The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc. Representative methods for producing the compound of formula (I) are described below. Each method can be performed by referring to the references attached to the description. However, the production methods of the present invention are not limited to the examples shown below.

[0040] In this specification, the following abbreviations may be used. 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: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd / C: palladium on carbon, LAH: lithium aluminum hydride, Me: methyl group.

[0041] [ka] (PG in the formula 1 is a protecting group, PG 2 represents a protecting group or a hydrogen atom.

[0042] The compound of formula (I)-1, which is a representative compound of formula (I), can be obtained by deprotecting compound (1a). Examples of protecting groups that can be deprotected under acidic conditions include tert-butoxycarbonyl, triphenylmethyl, and tetrahydro-2H-pyran-2-yl. This reaction is carried out under cooling or reflux with stirring, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, water, and mixtures thereof. Examples of deprotection reagents include, but are not limited to, hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, and other acids. By selecting a protecting group, deprotection can also be carried out by catalytic hydrogenation. Examples of protecting groups include benzyl, p-methoxybenzyl, and benzyloxycarbonyl groups. Deprotection can also be carried out using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl and (trimethylsilyl)ethoxymethyl groups. Examples of protecting groups that can be deprotected under basic conditions include acetyl, trifluoroacetyl, and benzoyl groups. PG 1 , P.G. 2 Alternatively, protecting groups that can be deprotected under different deprotection conditions may be selected and deprotection may be carried out stepwise. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014 When the starting compound (1a) has axial chirality, the compound (1a) may be separated and the obtained optically active compound may be used to carry out this reaction. In addition, R in formula (I) 2 The compound of formula (IIb) wherein R is a naphthyl group optionally substituted with OH can be obtained by the same production method as above.

[0043] The compound of formula (I) can be subjected to the following procedure as a salt formation reaction to obtain the hydrochloride of the compound of formula (I). The compound of formula (I), which is believed to form a salt with hydrochloric acid based on its chemical structure, is dissolved in a halogenated hydrocarbon such as dichloromethane and an alcohol such as MeOH, and hydrogen chloride (4M DOX solution) is added under ice-cooling. The mixture is stirred under ice-cooling, usually for 0.1 hour to 1 day. 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 obtain the hydrochloride salt of the compound of formula (I).

[0044] The hydrochloride of the compound of formula (I) can be desalted by the following procedure to obtain the compound of formula (I). The hydrochloride salt of the compound of formula (I) is purified by octadecylsilyl (ODS) column chromatography (MeCN / 0.1% formic acid solution), and the fractions containing the target product are pooled and basified with saturated aqueous sodium bicarbonate solution, followed by extraction with CHCl3 / MeOH (5 / 1). The combined organic layers are dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure to obtain a solid, which is washed with diethyl ether and dried under reduced pressure to obtain the compound of formula (I).

[0045] (Raw material synthesis 1) [ka] (PG in the formula 3 is the protecting group for OH, R LG is C 1-12 BLG is a boronic acid group, a boronic acid group protected by a protecting group of boronic acid such as a boronic acid pinacol ester group, or a trifluoroborate group (hereinafter sometimes referred to as a boronic acid group, etc.), LG is a 1 represents a leaving group. Examples of the leaving group include Cl, Br, I, a methanesulfonyl group, and a p-toluenesulfonyl group.

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

[0047] (first step) This step is a method for producing compound (4) by ipso substitution reaction between compound (2) and compound (3). This reaction involves using equal amounts of compound (2) and compound (3), or an excess of either compound. The mixture is stirred in a reaction-inert solvent, or without solvent, under cooling to reflux, preferably at 0°C to 80°C, typically for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. It may be advantageous to carry 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), or tBuOK, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction progress.

[0048] (Second process) This process involves the reaction of compound (4) with R LG This method produces compound (5) by ipso substitution reaction with —SH. LG An example of -SH is C 1-12 Alkyl thiols are exemplified. The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0049] (Third step) This process involves the reaction of compound (5) with PG 3 This method produces compound (6) by ipso substitution reaction with -OH. 3 Examples of -OH include benzyl alcohol and p-methoxybenzyl alcohol. The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0050] (Fourth step) This step involves the reaction of compound (6) with R 1 This method involves the Suzuki-Miyaura coupling reaction with a boronic acid derivative containing a -boronic acid group or the like to produce compound (7). Examples of the boronic acid group or the like used here include, but are not limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triolborate base, and a trifluoroborate base. This reaction is carried out by reacting compound (6) with R 1A mixture of these compounds is stirred in the presence of a base and a palladium catalyst in a reaction-inert solvent at room temperature to reflux, preferably at 20°C to 140°C, typically for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, and butanol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, and sodium hydroxide. Palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (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. In order to ensure smooth reaction, it may be advantageous to carry out the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine or dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine. It may also be advantageous to heat the mixture by microwave irradiation. [Literature] J. Am. Chem. Soc., 2005, 127, p.4685-4696

[0051] (Fifth step) This step is a method for producing compound (9) by Suzuki-Miyaura coupling reaction between compound (7) and compound (8). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 1.

[0052] (Sixth step) This step is a method for producing compound (10) by oxidation of compound (9). In this reaction, compound (9) is treated with an equivalent or excess amount of an oxidizing agent in a reaction-inert solvent under cooling to heating, preferably at -20°C to 80°C, for typically 0.1 hours to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used. Examples of solvents include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of other oxidizing agents include cumene hydroperoxide, oxone, activated manganese dioxide, chromic acid, potassium permanganate, and sodium periodate. [Literature] Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 17, Maruzen, 2004

[0053] (Seventh step) This step is a method for producing compound (12) by ipso substitution reaction between compound (10) and compound (11). The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0054] (Eighth process) This step is a method for producing compound (13) by catalytic hydrogenation of compound (12). This reaction can be carried out by stirring compound (12) under a hydrogen atmosphere in a reaction-inert solvent such as MeOH, EtOH, or ethyl acetate under cooling to heating, preferably at room temperature, for 1 hour to 5 days, under atmospheric to elevated pressure in the presence of a metal catalyst. Examples of the metal catalyst include palladium catalysts such as Pd / C or palladium black, platinum catalysts such as platinum plate or platinum oxide, and nickel catalysts such as reduced nickel or Raney nickel.

[0055] (Ninth step) This step is a method for producing compound (1) by reacting compound (13) with compound (14). This reaction is carried out by reacting a mixture of compound (13) and compound (14) in the presence of a base in a reaction-inert solvent under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of bases include, but are not limited to, organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. It may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride. As references for this reaction, for example, the following can be referred to. Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 14, Maruzen, 2005

[0056] (Raw material synthesis 2) [ka]

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

[0058] (first step) This step is a method for producing compound (16) by ipso substitution reaction between compound (5) and compound (15). The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0059] (Second process) This step involves the reaction of compound (16) with R 1 This method involves the Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like to produce compound (17). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 1.

[0060] (Third step) This step is a method for producing compound (18) by Suzuki-Miyaura coupling reaction between compound (17) and compound (8). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 1.

[0061] (Fourth step) This step is a method for producing compound (19) by oxidation of compound (18). The reaction conditions were the same as those in the sixth step of Raw Material Synthesis 1.

[0062] (Fifth step) This step is a method for producing compound (1) by ipso substitution reaction between compound (19) and compound (11). The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0063] (Raw material synthesis 3) [ka] (wherein A in compound (25) represents a cyclic amide moiety of formula (IV), (V), (VI), or (VII).)

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

[0065] (first step) This step is a method for producing compound (20) by ipso substitution reaction between compound (4) and compound (11). The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0066] (Second process) This step is a method for producing compound (22) by ipso substitution reaction between compound (20) and compound (21). The reaction conditions were the same as those in the first step of Raw Material Synthesis 1.

[0067] (Third step) This step involves the reaction of compound (22) with R 1 This method involves the Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like to produce compound (23). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 1.

[0068] (Fourth step) This step is a method for producing compound (24) by Suzuki-Miyaura coupling reaction of compound (23) and compound (8). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 1.

[0069] (Fifth step) This step is a method for producing compound (1)-1 by converting the hydroxyl group of compound (24) into a leaving group and then reacting it with compound (25). In this reaction, a compound obtained by reacting compound (24) with a sulfonyl halide compound such as thionyl chloride, methanesulfonic anhydride, or methanesulfonyl chloride or paratoluenesulfonyl chloride in a reaction-inert solvent in the presence of a base under ice-cooling to heating under reflux, preferably at −20° C. to 60° C., usually for 0.1 hours to 5 days, and compound (25) are used in equal amounts or in an excess amount, and a mixture of these is stirred in a reaction-inert solvent in the presence of a base under ice-cooling to heating under reflux, preferably at 0° C. to 120° C., usually for 0.1 hours to 5 days. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as DOX, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of the base include organic bases such as TEA, DIPEA, NMM, or tBuOK, and inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, or potassium hydroxide.

[0070] (Raw material synthesis 4) [ka] (PG in the formula 4 is a protecting group or a hydrogen atom, LG 2 indicates a leaving group.)

[0071] In this method, R in the starting compound (14) 3 is formula (III), and R in formula (III) 5 The compound (14)-1 is represented by the formula (IV) or (V).

[0072] (first step) This step is a method for producing compound (27) by converting the hydroxyl group of compound (26) into a leaving group and then reacting it with compound (25). The reaction conditions were the same as those in the fifth step of Raw Material Synthesis 3.

[0073] (Second process) This step is a method for producing compound (28) by subjecting compound (27) to a deprotection reaction. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014

[0074] (Third step) This step is a method for producing compound (14)-1 by converting the hydroxyl group of compound (28) into a leaving group. The reaction conditions are the same as those for the conversion reaction to a leaving group described in the fifth step of Starting Material Synthesis 3.

[0075] (Raw material synthesis 5) [ka] (wherein R is C1-3 Alkyl group, PG 5 is a protecting group or a hydrogen atom, LG 3 represents a leaving group or a hydroxyl group.)

[0076] In this method, R in the starting compound (14) 3 is formula (III), and R in formula (III) 5 The compound (14)-2 represented by the formula (VIII) is prepared by the method of the present invention.

[0077] (first step) This step is a method for producing compound (31) by reacting compound (29) with compound (30). This reaction uses equal amounts of compound (29) and compound (30), or an excess of either, and the mixture is stirred in a reaction-inert solvent under cooling to heating, preferably at -20°C to 60°C, for typically 0.1 hours to 5 days. Examples of solvents include, but are not limited to, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, pyridine, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, in order to ensure smooth reaction progress.

[0078] (Second process) In this step, compound (31) is subjected to a deprotection reaction, and then the resulting compound is acylated with compound (32), followed by a cyclization reaction to produce compound (33). As references for the deprotection reaction of this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014 In this reaction, compound (31) is deprotected, and then the resulting compound and compound (32) are used in equal amounts, or in excess of either one. The resulting mixture is stirred in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at temperatures between -20°C and 60°C, typically for 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, and diphenylphosphoric acid azide. The use of an additive (e.g., 1-hydroxybenzotriazole) may be preferable for the reaction. In some cases, it may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, in order to ensure smooth progress of the reaction. Alternatively, a method can be used in which compound (32) is converted into a reactive derivative and then acylated. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reaction with a halogenating agent such as phosphorus oxychloride, thionyl chloride, or oxalyl dichloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, or the like, and activated esters obtained by condensation with 1-hydroxybenzotriazole, or the like. The reaction of these reactive derivatives with the compound obtained by deprotecting compound (31) can be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling or heating, preferably at -20°C to 60°C. [Literature] S.R. Sandler and W. Karo, Organic Functional Group Preparations, 2nd ed., Vol. 1, Academic Press Inc., 1991 Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 16, Maruzen, 2005 Furthermore, in this reaction, the compound obtained by the acylation reaction is stirred in a solvent inert to the reaction at room temperature or under heating, preferably at 20° C. to 150° C., usually for 0.1 hours to 5 days. Examples of the solvent are not particularly limited, but include aromatic hydrocarbons such as xylene, alcohols such as isoamyl alcohol, DMF, DMA, DMSO, and mixtures thereof.

[0079] (Third step) This step is a method for producing compound (34) by reduction of compound (33). This reaction is carried out by reacting compound (33) with an equivalent or excess amount of a reducing agent in a reaction-inert solvent under cooling to reflux, preferably at temperatures between -20°C and 60°C, for typically 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane. Examples of the reducing agent include, but are not limited to, LAH, borane-tetrahydrofuran complex, and diborane. As references for this reaction, for example, the following can be referred to. Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 14, Maruzen, 2005

[0080] (Fourth step) This step is a method for producing compound (14)-2 by converting the hydroxyl group of compound (34) into a leaving group. The reaction conditions are the same as those for the conversion reaction to a leaving group described in the fifth step of Starting Material Synthesis 3.

[0081] (Raw material synthesis 6) [ka]

[0082] This production method is a method for producing the starting compound (1)-2 contained in compound (1).

[0083] (first step) This step is a method for producing compound (36) by reacting compound (13) with compound (35). The reaction conditions were the same as those in the ninth step of Raw Material Synthesis 1.

[0084] (Second process) This step is a method for producing compound (37) by hydrolyzing compound (36). This reaction is carried out by stirring compound (36) under cooling or reflux, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols, acetone, N,N-dimethylformamide, and tetrahydrofuran. Mixing the above solvents with water may also be suitable for the reaction. Examples of hydrolysis reagents include, but are not limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, and trimethyltin hydroxide. As references for this reaction, for example, the following can be referred to. "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0085] (Third step) This step is a method for producing compound (1)-2 by amidation reaction of compound (37). In this reaction, a mixture of compound (37) and an amine compound in equal amounts or one in excess is stirred in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at −20° C. to 60° C., usually for 0.1 hours to 5 days. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, N,N-dimethylformamide, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), and diphenylphosphoryl azide (DPPA). The use of an additive (e.g., 1-hydroxybenzotriazole) may be preferable for the reaction. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide may be advantageous for smooth reaction progression. Alternatively, a method can be used in which compound (37) is converted into a reactive derivative and then acylated. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, and activated esters obtained by condensation with 1-hydroxybenzotriazole. The reaction of these reactive derivatives with an amine compound can be carried out in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling or heating, preferably at -20°C to 120°C. [Literature] S.R. Sandler and W. Karo, "Organic Functional Group Preparations," 2nd ed., Vol. 1, Academic Press Inc., 1991 "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen)

[0086] (Raw material synthesis 7) [ka]

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

[0088] (first step) This step is a method for producing compound (1)-4 by ozonolysis of compound (1)-3 followed by reduction reaction. This reaction involves first using equal amounts of compound (1)-3 and ozone, or an excess of either, and stirring the mixture in a reaction-inert solvent at room temperature, preferably at −78°C to 0°C, for typically 0.1 hours to 1 day. After removing the ozone with oxygen or other solvents, an equal or excess amount of a reducing agent is added to the reaction solution, followed by stirring at room temperature, preferably at −78°C to 0°C, for typically 0.1 hours to 1 day. Examples of reducing agents used here include phosphites such as trimethyl phosphite, dimethyl sulfide, and the like. Examples of solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols such as methanol and ethanol; hydrocarbons such as pentane; ethyl acetate; water; and mixtures thereof. The subsequent reduction reaction is carried out by adding an equal or excess amount of a reducing agent to the reaction solution and reacting it under cooling to reflux, preferably at a temperature of −20° C. to 60° C., usually for 0.1 hours to 5 days. Examples of the reducing agent used here include, but are not limited to, LAH and sodium borohydride. As references for this reaction, for example, the following can be referred to. J. Med. Chem., 2012, 55, p.3364-3386 "New Experimental Chemistry Lectures" edited by the Chemical Society of Japan, Vol. 14 (1977) (Maruzen)

[0089] (Second process) This step is a method for producing compound (1)-5 by methylation of compound (1)-4. This reaction involves using equal amounts of compound (1)-4 and a methylating agent, or an excess of either. The mixture is stirred in a reaction-inert solvent or without a solvent, under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of methylating agents include methyl iodide, dimethyl sulfate, and methyl trifluoromethanesulfonate. Examples of solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, 1,4-diazabicyclo[2.2.2]octane (DABCO), or tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction progress.

[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 ozonolysis production method in the first step of Raw Material Synthesis 7. As references for this reaction, for example, the following can be referred to. "New Experimental Chemistry Lectures" edited by the Chemical Society of Japan, Vol. 15 (1976) (Maruzen)

[0091] (Fourth step) This step is a method for producing compound (1)-6 by reacting compound (38) with a difluoroolefinating agent, followed by a trifluoromethylation reaction using a fluorinating agent. In this reaction, a mixture of compound (38) and a difluoroolefinating agent is used in equal amounts or in excess of one of them, and is stirred in a solvent inert to the reaction under cooling to reflux, preferably at 0°C to 80°C, usually for 0.1 hours to 5 days. Subsequently, an equivalent or excess amount of a fluorinating agent in a solvent inert to the reaction is added to the reaction solution, and the mixture is stirred under cooling to reflux, preferably at 0 to 80°C, for usually 0.1 hours to 5 days. Examples of difluoroolefinating agents include Ph3P + CF2CO2 - , (Me2N)3P + CF2CO2 - Examples of the fluorinating agent include tetra-n-butylammonium fluoride, etc. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF, DOX, 1,2-dimethoxyethane, DMF, DMA, ethyl acetate, MeCN, and mixtures thereof. As references for this reaction, for example, the following can be referred to. J. Org. Chem., 2014, 79, p.7122-7131

[0092] The compound of formula (I) is isolated and purified as a free compound, a salt thereof, a hydrate, a solvate, or a crystalline polymorph or an amorphous solid substance. A salt of the compound of formula (I) can also be prepared by subjecting it to a conventional salt-forming reaction. Isolation and purification are carried out by applying conventional chemical procedures such as extraction, fractional crystallization, and various fractional chromatography. Various isomers can be produced by selecting appropriate starting compounds, or can be separated by taking advantage of the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by a general optical resolution method for a racemate (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, or chromatography using chiral columns, etc.), or can also be produced from appropriate optically active starting compounds. In addition, the compound of formula (I) or an intermediate thereof may have axial asymmetry and be obtained as a mixture of diastereomers. However, each diastereomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

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

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

[0095] [Table 1]

[0096] Test Example 2: Evaluation of ERK phosphorylation inhibitory effect on human KRAS G12D mutation-positive pancreatic cancer line AsPC-1 The inhibitory effect of test compounds on ERK phosphorylation was evaluated by measuring phosphorylation of threonine 202 (Thr202) and tyrosine 204 (Tyr204) of ERK, which is downstream of KRAS signaling, by cell ELISA. AsPC-1 cells (ATCC, CRL-1682) were added at 2.0x10 per well. 4 The cells were seeded in a 384-well plate (Greiner Bio-One) at 36 μL / well. Cell culture was performed at 37°C in the presence of 5% CO2 using RPMI1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum (GE Life Sciences). The next day, test compounds (six final concentrations ranging from 10 μM to 3.0 nM), trametinib (MEK inhibitor) as a positive control at a final concentration of 1 μM, and DMSO (the solvent for the test compounds) as a negative control were diluted 100-fold with fresh medium and added in 4 μL portions to each well and incubated for 2 hours. Immediately after incubation, 30 μL of 30% glyoxal solution (40% glyoxal [Wako] diluted with Phosphate Buffered Saline [PBS; Wako]) was added to each well and incubated at room temperature for 1 hour to fix the cells. The plate was then centrifuged (110 × g, 7 seconds; centrifugation conditions were the same unless otherwise noted) to remove the supernatant, and 20 μL of PBS containing 0.1% Triton X-100 (Amersham Biosciences) was added to each well. After incubation at room temperature for 10 minutes, the supernatant was removed by centrifugation and the same procedure was repeated. Next, 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; Invitrogen) was added to each well. After incubation at room temperature for 30 minutes, the wells were centrifuged to remove the supernatant. Next, 20 μL of blocking solution (Intercept Blocking Buffer; LI-COR Biosciences) was added to each well and incubated at room temperature for 1 hour. The supernatant was then removed by centrifugation, and 10 μL of a primary antibody (phosphorylated ERK (Thr202 / Tyr204) antibody [Phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (D13.14.4E) XP Rabbit mAb; Cell Signaling Technology) diluted 2,500-fold in blocking solution was added to each well and incubated overnight at 4°C. The next day, the plate was centrifuged to remove the supernatant. 20 μL of PBS containing 0.05% Tween-20 (Thermo Scientific; 20x PBS Tween-20 diluted 20-fold with ion-exchanged water) was added to each well, and the wells were washed by centrifugation to remove the supernatant. Washing was performed three times. After washing, 10 μL of IRDye 800CW Goat anti-Rabbit IgG (LI-COR Biosciences) diluted 1:1,000 in blocking solution was added to each well as the secondary antibody and incubated at room temperature for 1 hour. The plate was centrifuged to remove the supernatant, and each well was washed three times with PBS containing 0.05% Tween-20 in the same manner as after the primary antibody reaction. After the third wash, centrifugation was performed at 171 x g for 17 seconds. After removing the supernatant, the plate was air-dried at room temperature for 3 hours or more, and the fluorescent signal at 800 nm was measured using Aerius (LI-COR Biosciences). The signal value when DMSO was added was defined as 0% inhibition, and the signal value when 1 μM trametinib was added was defined as 100% inhibition. The 50% inhibition value (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) are shown in Table 2.

[0097] [Table 2]

[0098] Test Example 3 Evaluation of the inhibitory effect on anchorage-independent cell growth against human KRAS G12D mutation-positive pancreatic cancer line AsPC-1 The inhibitory effect of test compounds on anchorage-independent cell growth was evaluated using three-dimensional spheroid culture. 5x10 AsPC-1 cells per well 2 The cells were seeded in a low cell-adsorption U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite Co., Ltd.) at 36 μL / well. Cell culture was carried out under the same conditions as in Test Example 2. The next day, test compounds (six concentrations ranging from 10 μM to 3.0 nM) and DMSO, the solvent for the test compounds, were diluted 100-fold with fresh medium and added at 4 μL per well. After incubation at 37°C in the presence of 5% CO for 6 days, 20 μL of CellTiter Glo 2.0 (Promega) was added to each well. After stirring at room temperature for 1 hour using a plate mixer (FINEPCR), luminescence signals were measured using an ARVO X3 (PerkinElmer). The signal value in DMSO treatment was defined as 0% inhibition, the signal value in the absence of cells and medium alone was defined as 100% inhibition, and the 50% inhibition value (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) are shown in Table 3.

[0099] [Table 3]

[0100] Test Example 4: Evaluation of antitumor activity in mice bearing the human KRAS G12D mutation-positive pancreatic cancer line PK-1 PK-1 cells (RIKEN BRC, RCB1972) were cultured in RPMI1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum (GE Life Sciences) at 37°C in the presence of 5% CO2. PK-1 cells were harvested and suspended in PBS. An equal volume of Matrigel (Becton Dickinson) was added to the suspension, resulting in a 3.0x10 7 The cell suspension, adjusted to cells / mL, was then injected into 4-5 week old male nude mice (CAnN.Cg-Foxn1 nuA 100μL volume of 100μL ... [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] x [Tumor short diameter (mm)] 2 x 0.5 The tumor growth inhibition rate (%) by the test compound was calculated by defining the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition and the tumor volume of the vehicle group on the final day of administration as 0% inhibition. When the tumor volume of the test compound administration group was lower than the tumor volume on the day before the start of administration, the tumor volume on the day before the start of administration was defined as 0% regression, and a tumor volume of 0 was defined as 100% regression, and the tumor regression rate (%) of the test compound was calculated.

[0101] As a result of the above tests, it was confirmed that some compounds of formula (I) have inhibitory activity against G12D mutant KRAS and antitumor activity. Therefore, the compounds of formula (I) can be used for the treatment of pancreatic cancer, particularly KRAS G12D mutation-positive pancreatic cancer.

[0102] Pharmaceutical compositions containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using intra-articular, intravenous, intramuscular, etc. injections, suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc.

[0103] Solid compositions for oral administration include tablets, powders, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar or a film of a gastric or enteric substance, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inert diluents, such as purified water or EtOH (ethanol). In addition to the inert diluents, the liquid compositions may contain adjuvants such as solubilizing agents, wetting agents, and suspending agents, as well as sweeteners, flavors, aromatics, and preservatives.

[0104] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as EtOH. Such compositions may further contain an isotonic agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizer, or irradiation. Alternatively, sterile solid compositions can be prepared and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0105] Transmucosal agents such as inhalants and nasal agents may be in solid, liquid, or semisolid form and may be prepared according to conventional methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., may be added as appropriate. Administration can be performed using a suitable inhalation or insufflation device. For example, known devices such as metered-dose inhalers or nebulizers can be used to administer the compound alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers and the like may be for single or multiple doses, and can utilize dry powders or powder-containing capsules. Alternatively, the compound may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0106] In general, for oral administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, administered once or in two to four divided doses. For intravenous administration, the daily dosage is approximately 0.0001 to 10 mg / kg of body weight, administered once or in multiple divided doses. For transmucosal administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, administered once or in multiple divided doses. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, etc.

[0107] Although it varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment 0.01 to 50% by weight, of one or more compounds of formula (I) or salts thereof as active ingredients.

[0108] The compound of formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the compound of formula (I) is considered to be effective. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately. [Example]

[0109] The production method of the compound of formula (I) will be explained in more detail below based on examples. Note that the present invention is not limited to the compounds described in the following examples. In addition, the production methods of the starting compounds are shown in the respective production examples. In addition, the production method of the compound of formula (I) is not limited to the production methods of the specific examples shown below, and the compound of formula (I) can also be produced by a combination of these production methods or by methods that are obvious to those skilled in the art.

[0110] In this specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

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

[0112] Manufacturing Example 1 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) was cooled on ice, followed by the addition of DIPEA (240 mL) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (48 g) and stirring at room temperature overnight. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a total volume of approximately 400 mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000 mL) was added to the resulting solution, which was then stirred at room temperature for 2 hours. The precipitated solid was collected by filtration 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] Manufacturing Example 2 To a 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), and DABCO (3.85 g), cesium carbonate (12.3 g) and dodecane-1-thiol (9.05 mL) were added under ice cooling and stirred at 50 °C overnight. Ethyl acetate and water were added to the reaction mixture, and the organic and aqueous layers were separated by liquid separation. The resulting aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed twice with aqueous sodium chloride, and then dried over anhydrous magnesium 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 oil.

[0114] Manufacturing Example 4 Under an argon atmosphere, tBuOK (6.54 g) was added 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) under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours. Benzyl alcohol (0.5 mL) and tBuOK (540 mg) were added to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for an additional 1 hour. Water and saturated aqueous ammonium chloride were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium 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 gum.

[0115] Manufacturing Example 7 Under an argon atmosphere, 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 Boronic acids A mixture of (8.0 g), tripotassium phosphate (38 g), and PdCl2(dppf)·CHCl2 (4.0 g) was stirred at 100 °C for 3 hours. After allowing the reaction mixture to cool to room temperature, the solution was concentrated under reduced pressure. Saturated aqueous sodium chloride was added to the resulting residue, which was then extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to 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] Manufacturing Example 10 (1S,4S)-tert-butyl 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 Argon was bubbled into a mixture of (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (5.6 g), DOX (500 mL), and water (80 mL), followed by stirring at 100°C under an argon atmosphere for 3.5 hours. The reaction mixture was concentrated under reduced pressure to approximately half its original volume, followed by addition of aqueous sodium chloride solution and extraction with ethyl acetate. Anhydrous magnesium sulfate and Celite were added to the organic layer, followed by stirring, and the insoluble matter was filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (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 tert-butyl ester (33.0 g) as a foamy solid.

[0117] Manufacturing Example 13 To 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 CHCl (350 mL) was added m-chloroperbenzoic acid (approximately 30% water content, 10 g) under ice cooling and stirred at the same temperature for 30 minutes. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction mixture under ice cooling. The aqueous and organic layers were separated by liquid separation, and the resulting aqueous layer was extracted twice with CHCl. The resulting organic layers were combined and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure, and then toluene was added to the residue. The mixture was concentrated again 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] Manufacturing Example 15 To a mixture of (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), tetrahydro-2H-pyran-4-ol (5.9 g) and tBuOK (6.4 g) were added at room temperature and stirred for 1 hour. Water and saturated aqueous ammonium chloride were added to the reaction mixture, which was then extracted twice with ethyl acetate. The resulting organic layers were combined, washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium 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 (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 tert-butyl ester (23.9 g) as a foamy solid.

[0119] Manufacturing Example 18 A 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 (50% aqueous, 4.8 g), and EtOH (290 ml) was stirred under a hydrogen atmosphere at room temperature for 8 hours. The resulting reaction mixture was filtered through Celite and washed with EtOH (100 ml). Another 10% Pd / C (50% aqueous, 2.4 g) was added to the filtrate, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered through Celite, and 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] Manufacturing Example 19 To a solution of 1-{[4-(hydroxymethyl)phenyl]methyl}-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (3.3 g) in CHCl (66 mL) was added thionyl chloride (3.5 mL) under ice-cooling and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue (3.6 g) as a solid. To a 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 solid obtained above (2.91 g) in DMF (60 mL), cesium carbonate (8.3 g) was added at room temperature, and the mixture was stirred at the same temperature for 1 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 matter was collected by filtration, and (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 tert-butyl ester (7.88 g) was obtained as a solid.

[0121] Manufacturing Example 38 To a solution of [4-({[tert-butyldi(methyl)silyl]oxy}methyl)phenyl]methanol (7.0 g) in CHCl (140 mL), 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, and the organic and aqueous layers were separated by liquid separation. The aqueous layer was extracted twice with CHCl. The resulting organic layers were combined, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. tBuOK (4.70 g) was added to a solution of the resulting residue and 1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (5.0 g) in DMF (140 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour, then at room temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution of the resulting residue in THF (70 mL) was added with tetra-n-butylammonium fluoride (1M in THF, 42 mL) and 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] Manufacturing Example 45 To a mixture of 2-(chloromethyl)imidazo[1,2-a]pyrazine (1 g), [4-(hydroxymethyl)phenyl]boronic acid (1.8 g), DOX (24 mL), water (4.8 mL), and potassium phosphate tribasic (3.2 g), PdCl(dppf)·CHCl (490 mg) was added and stirred at 130 °C for 2 h under microwave irradiation. The resulting reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl / MeOH) to give {4-[(imidazo[1,2-a]pyrazin-2-yl)methyl]phenyl}methanol (1.15 g) as a solid.

[0123] Manufacturing Example 48 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 CHCl (320 mL) was added with trifluoroacetic acid (18 mL) at room temperature and stirred for 4 days. The resulting reaction mixture was concentrated under reduced pressure until an amount of solvent equivalent to the amount of CHCl used was removed. THF and water were added to the resulting residue, and saturated aqueous sodium bicarbonate was added portionwise with stirring under ice cooling until the reaction mixture became weakly basic. The resulting mixture was extracted with CHCl, and the organic layer was dried over anhydrous magnesium 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] Manufacturing Example 49 To a solution of tert-butyl 2-methylcarbazate (1.58 mL) in pyridine (20 mL) was added methyl 4-(2-imino-2-methoxyethyl)benzoate monohydrochloride (2.0 g) at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent (hexane / ethyl acetate = 1 / 4) to give tert-butyl 2-{2-[4-(methoxycarbonyl)phenyl]ethanimidoyl}-1-methylhydrazine-1-carboxylate monohydrochloride (2.06 g) as a solid.

[0125] Manufacturing Example 50 To a solution of cyclopropylhydrazine dihydrochloride (392 mg) in pyridine (6.0 mL) was added methyl 4-(2-imino-2-methoxyethyl)benzoate monohydrochloride (600 mg) at room temperature and stirred overnight at the same temperature. 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 3 hours and then at 110°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium 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 oil.

[0126] Manufacturing Example 52 To a solution of 1-aminopyrrolidin-2-one monohydrochloride (1.3 g) in pyridine (20 mL), methyl 4-(2-imino-2-methoxyethyl)benzoate monohydrochloride (2.55 g) was added at room temperature and stirred at the same temperature for 1 hour, followed by stirring at 100°C for 3 days. Toluene was added to the reaction mixture, which was then concentrated under reduced pressure. The resulting residue was adsorbed onto basic silica gel and purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give 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] Manufacturing Example 53 Under a nitrogen atmosphere, LAH (30 mg) was added to a solution of methyl 4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl]benzoate (205 mg) in THF (4.0 mL) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Sodium sulfate decahydrate (513 mg) was added portionwise to the reaction mixture under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, then at room temperature for 30 minutes. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give {4-[(1-cyclopropyl-1H-1,2,4-triazol-3-yl)methyl]phenyl}methanol (182 mg) as an oil.

[0128] Manufacturing 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 saturated aqueous ammonium chloride was added under ice-cooling. Ethyl acetate and water were added to the reaction mixture, and the organic and aqueous layers were separated by liquid separation. The resulting aqueous layer was extracted three times with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with hexane / ethyl acetate, followed by CHCl3 / MeOH) to give a mixture of methyl 4-[(2-methyl-2H-tetrazol-5-yl)methyl]benzoate and its regioisomer (3.7 g) as a solid.

[0129] Manufacturing Example 64 A 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-iodooxetane (1.79 g) was stirred at 150 °C for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature, and water was added. The mixture was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developed with hexane / ethyl acetate, followed by 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] Manufacturing Example 65 DOX (4.0 mL), MeOH (4.0 mL), and hydrogen chloride (4M DOX solution, 2.8 mL) were added sequentially to tert-butyl 2-{2-[4-(methoxycarbonyl)phenyl]ethanimidoyl}-1-methylhydrazine-1-carboxylate monohydrochloride (400 mg) at room temperature, and the mixture was stirred at room temperature for 3 hours. Hydrogen chloride (4M DOX solution, 2.8 mL) was added, and the mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was concentrated under reduced pressure, and CHCl (8.0 mL) was added to the resulting residue. DIPEA (0.957 mL) and cyclopropanecarboxylic acid chloride (0.154 mL) were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and M (4.0 mL) was added to the resulting residue, and the mixture was stirred at 120 °C for 4 hours. Aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium 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 oil.

[0131] Manufacturing Example 69 To 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 potassium carbonate (6.7 g) and potassium iodide (4.0 g) under ice-cooling, followed by stirring at 60 °C overnight. Saturated aqueous ammonium chloride was added to the reaction mixture under ice-cooling, followed by water and ethyl acetate. The organic and aqueous layers were separated by liquid separation, and the resulting aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, 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] Manufacturing Example 70 A 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 CHCl (20 mL) was stirred at room temperature for 30 minutes, followed by the addition of benzyl alcohol (2.4 mL) and stirring at room temperature for 1 hour. Potassium carbonate (1.5 g) was added to the reaction mixture, which was then stirred at room temperature for 2 hours. Acetic acid (0.62 mL) and water were added to the resulting reaction mixture, which was then extracted with CHCl. The organic layer was dried over anhydrous magnesium 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, which was then stirred at 80 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, followed by the addition of acetic acid (0.62 mL) and water, and the mixture was extracted with CHCl. The organic layer was dried over anhydrous magnesium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) and solidified with hexane to give benzyl 4-[(1H-1,2,4-triazol-3-yl)methyl]benzoate (1.24 g) as a solid.

[0133] Manufacturing Example 71 To 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 CHCl (5.0 mL) was added DIPEA (0.30 mL) and methanesulfonic anhydride (210 mg) under ice cooling and stirred at the same temperature for 1 hour. Water was added to the reaction mixture under ice cooling, and the organic and aqueous layers were separated by liquid separation. The aqueous layer was extracted three times with CHCl. The resulting organic layers were combined, dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. Separately, to a solution of 4-methyl-3,4-dihydropyridine[2,3-b]pyrazin-2(1H)-one (196 mg) in DMF (5.0 mL) was added sodium hydride (approximately 60% dispersion in mineral oil, 48 mg) under ice cooling, and the mixture was stirred at the same temperature for 10 minutes under an argon atmosphere. A solution of the above concentrated residue in DMF (5.0 mL) was added to the resulting reaction mixture under ice cooling, and the mixture was then stirred overnight at room temperature. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction mixture under ice cooling, and the organic and aqueous layers were separated by liquid separation. The aqueous layer was extracted twice with ethyl acetate. The resulting organic layers were combined, 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] The compounds shown in Tables 4 to 29 below were produced in the same manner as in the production examples shown above. The production method, structure and physicochemical data of each compound in the production examples are shown in Tables 4 to 29.

[0135] Example 1 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 CHCl (30 mL) was added trifluoroacetic acid (13 mL) at room temperature and stirred overnight. The resulting reaction mixture was concentrated under reduced pressure to give 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% formic acid aqueous solution) to give fractions containing (1) the more polar diastereomer (peak-1) and (2) the less polar diastereomer (peak-2). The fraction containing the less polar diastereomer (peak 2) was mixed with saturated aqueous sodium bicarbonate and extracted with a mixed solvent (CHCl3 / MeOH = 4 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the less polar diastereomer 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 (2.39 g) as a solid.

[0136] The compounds shown in Tables 30 to 37 below were produced in the same manner as in the production methods of the above-mentioned Examples. The structures of the compounds of the Examples are shown in Tables 30 to 37 below, and the physicochemical data of the compounds of the Examples are shown in Table 38.

[0137] In addition, the following abbreviations may be used in the tables below. PEx: Production Example number, Ex: Example number, PSyn: Production Example number produced by a similar method, Syn: Example number produced by a similar method (for example, 1 indicates Example 1), Str: Chemical structural formula (compounds with an "*" in the chemical structural formula indicate that the compound is a single diastereomer based on axial chirality, and is the less polar diastereomer (peak-2) under the separation conditions of ODS column chromatography (MeCN / 0.1% formic acid aqueous solution). Compounds with a "#" indicate that the compound is a mixture with a positional isomer), DAT: physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] unless otherwise specified). + ), NMR: in DMSO-d 1 δ value (ppm) of peak in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), m: multiplet (spectrum), br: broad line (spectrum) (e.g., brs).

[0138] [Table 4]

[0139]

Table 5

[0140]

Table 6

[0141]

Table 7

[0142]

Table 8

[0143]

Table 9

[0144]

Table 10

[0145]

Table 11

[0146]

Table 12

[0147]

Table 13

[0148]

Table 14

[0149]

Table 15

[0150] Table 16

[0151] Table 17

[0152] Table 18

[0153] Table 19

[0154] Table 20

[0155] Table 21

[0156] Table 22

[0157] Table 23

[0158] Table 24

[0159] Table 25

[0160] Table 26

[0161] Table 27

[0162] Table 28

[0163] Table 29

[0164]

Table 30

[0165] Table 31

[0166] Table 32

[0167]

Table 33

[0168] Table 34

[0169] Table 35

[0170] Table 36

[0171] Table 37

[0172] Table 38

[0173] Furthermore, specific examples of compounds of formula (I) encompassed by the present invention include compounds having any of the following structures: These compounds were produced by the representative production methods, the production methods in the Production Examples and Examples shown above, or a combination of these production methods, or methods obvious to those skilled in the art. Furthermore, the inhibitory effect of these compounds on G12D mutant KRAS was confirmed by the test methods in the test examples shown above. Therefore, these compounds can be used as active ingredients in pharmaceutical compositions, for example, pharmaceutical compositions for treating pancreatic cancer. [ka] TIFF0007725511000064.tif77148 TIFF0007725511000065.tif61144 TIFF0007725511000066.tif56137 TIFF0007725511000067.tif62138 TIFF0007725511000068.tif62139 TIFF0007725511000069.tif56136 TIFF0007725511000070.tif62139 TIFF0007725511000071.tif71153 TIFF0007725511000072.tif62138 TIFF0007725511000073.tif57136 TIFF0007725511000074.tif56142 TIFF0007725511000075.tif56140 TIFF0007725511000076.tif62143 TIFF0007725511000077.tif62138 TIFF0007725511000078.tif78150 TIFF0007725511000079.tif82144 TIFF0007725511000080.tif77144 TIFF0007725511000081.tif93147 TIFF0007725511000082.tif83141 TIFF0007725511000083.tif62145 [Industrial Applicability]

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

Claims

1. A compound of formula (I) or a salt thereof: 【Chemical 1】 (In the formula, R 1 F and OCH 3 C optionally substituted with a group selected from the group consisting of 1-3 Alkyl, halogen, cyclopropyl, or C 2-3 is alkenyl, R 2 is naphthyl optionally substituted with OH or a group selected from the group consisting of the following formula (IIa) and formula (IIb), 【Chemistry 2】 R 3 is the following formula (III), 【Chemistry 3】 R 4 may be substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted 6-membered heteroaryl, or tetrahydroisoquinolinyl; R 5 H,CONR 6 R 7 or a group selected from the group consisting of the following formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV) and (XV): 【Chemistry 4】 R 5a , R 5b are the same or different and represent H, optionally substituted C, 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 , R 7 are the same or different and represent H or optionally substituted C 1-6 alkyl, or R 6 , R 7 form a 4- to 7-membered saturated heterocyclic ring together with the nitrogen to which they are attached, and the 4- to 7-membered saturated heterocyclic ring is optionally substituted. 1-6 may be substituted with alkyl, W is CH or N; X is O or NR x and R x is H or C 1-3 is alkyl, Or XR 4 is a 4- to 7-membered saturated heterocyclic group or imidazolyl, Y, Y b is H, F, or Cl, Y a C optionally substituted with F 1-3 alkyl, cyano, or cyclopropyl; Or Y a , Y b together with the carbon to which they are attached to form a cyclopentenyl, Y c is H, F, or methyl, Z is N or CH).

2. R 1 is cyclopropyl, R 2 is the following formula (IIc), 【Chemistry 5】 R 3 is the following formula (IIIa), 【Chemistry 6】 R 4 is tetrahydropyranyl, optionally substituted pyridylmethyl, or tetrahydroisoquinolinyl; R 5 is a group selected from the group consisting of the following formulae (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV), 【Chemistry 7】 R 5a , R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, thiazolyl or pyrazinyl; X is O, Y is F, 2. The compound or salt thereof according to claim 1, wherein Z is N or CH.

3. R 4 However, (1) C 1-6 alkyl, wherein the C 1-6 Alkyl is F; OCH 3 ;OCH 3 cyclopropyl optionally substituted with F; cyclobutyl optionally substituted with a group selected from the group consisting of F and methoxymethyl; OCH 3 oxetanyl optionally substituted with; tetrahydrofuranyl; OH, CF 3 and tetrahydropyranyl optionally substituted with a group selected from the group consisting of cyanomethyl and C 1-3 (2) OCH 3 C optionally substituted with 3-6 (3) azetidinyl optionally substituted with F; (4) tetrahydropyranyl; (5) C 1-3 Alkyl and N(CH 3 ) 2 or (6) tetrahydroisoquinolinyl, X is O or NR x and R x is H or C 1-3 is alkyl, Or XR 4 The compound or salt thereof according to claim 1, wherein is morpholinyl, oxazaspiro[3.3]heptanyl, or imidazolyl.

4. 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, 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, or Those salts.

5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a salt thereof and a pharmaceutically acceptable excipient.

6. The pharmaceutical composition according to claim 5, which is a pharmaceutical composition for treating pancreatic cancer.

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