Heterocyclic compounds for inhibiting and / or inducing KRAS protein degradation

Abstract

Provided is a compound useful as an active ingredient of a pharmaceutical composition for the treatment of cancer, in particular pancreatic cancer. The present inventors have studied a compound useful as an active ingredient of a pharmaceutical composition for the treatment of cancer, particularly pancreatic cancer, and found that a heterocyclic compound represented by formula (I) has an excellent degradation-inducing effect and / or KRAS inhibitory activity against KRAS protein, and is useful as a therapeutic agent for cancer, particularly pancreatic cancer, thereby completing the present invention. The heterocyclic compound or a salt thereof according to the present invention can be used as a therapeutic agent for cancer, particularly pancreatic cancer.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition, in particular to a heterocyclic compound, which has an excellent degradation-inducing effect on KRAS protein and / or is expected to be used as a KRAS inhibitor and can be used as an active ingredient of a pharmaceutical composition for treating cancer, in particular pancreatic cancer. Background Art

[0002] Pancreatic cancer, mainly including pancreatic ductal adenocarcinoma, is a cancer with a very poor prognosis, with a five-year survival rate of 10% or less (CA Cancer J. Clin., 2016, 66, pp. 7-30), and approximately 460,000 new cases are reported worldwide each year (CA Cancer J. Clin., 2018, 68, pp. 394-424). The most effective therapy for pancreatic cancer is surgery. However, cancer has usually metastasized because early detection is difficult, and in many cases the therapeutic effect of surgery cannot be expected. When cancer is not treated surgically, chemotherapy or radiotherapy is used, but the survival rate is poor. Today, FOLFIRINOX therapy (multi-drug therapy of three chemotherapy drugs, 5-FU, irinotecan and oxaliplatin, plus leucovorin) is used as a standard treatment for pancreatic cancer. However, due to its strong toxicity, subjects must be carefully selected, for example, the therapy is only applicable to patients with an ECOG performance status of 1 or lower (J. Clin. Oncol., 2018, 36, pp. 2545-2556). As a molecular targeted drug, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been approved for combined treatment with gemcitabine. However, compared with gemcitabine alone, the overall survival was only extended by about two weeks, and no satisfactory therapeutic effect was achieved. There is still a need for an efficient therapeutic agent (J. Clin. Oncol., 2007, 25, pp. 1960-1966).

[0003] RAS protein is a low molecular weight guanosine triphosphate (GTP) binding protein of about 21 kDa composed of 188-189 amino acids, including four main types of proteins produced by three genes of KRAS gene, NRAS gene and HRAS gene (KRAS (KRAS 4A and KRAS 4B), NRAS and HRAS). RAS protein is divided into active GTP-bound type and inactive GDP-bound type. RAS protein is activated by replacing guanosine diphosphate (GDP) with GTP, which is due to ligand stimulation of membrane receptors such as EGFR, for example. Active RAS binds to up to twenty effector proteins, such as RAF, PI3K and RALGDS, to activate downstream signaling cascades. On the other hand, due to the inherent GTP hydrolysis (GTPase) activity, active RAS is converted into an inactive type by replacing GTP with GDP. GTPase activity is enhanced by GTPase activating protein (GAP). From the above description, it can be seen that RAS has the important function of "molecular switch" in the intracellular signal transduction pathways of EGFR, etc., and plays a key role in cell growth, proliferation, angiogenesis, etc. (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] Due to the decreased function of RAS as a GTPase or the reduced responsiveness to GAP, the amino acid substitutions produced by spontaneous mutations of the RAS gene lead to a continuous activation state, after which signals are continuously sent downstream. Excessive signal transduction leads to cancer occurrence or accelerated cancer growth. Pancreatic ductal adenocarcinoma is said to undergo a weak heterotypic stage and a subsequent highly heterotypic stage in pancreatic intraepithelial neoplasia (PanIN), and mutations in the KRAS gene have been found in the initial stage of PanIN. Subsequently, INK4A, p53, and SMAD4, which are tumor suppressor genes, become abnormal, leading to malignant tumors (Nature Rev. Cancer, 2010, 10, pp. 683-695). In addition, in 90% or more cases of pancreatic ductal adenocarcinoma, mutations are observed in the KRAS gene, most of which are spontaneous point mutations located in codon 12 of KRAS exon 2 (Cancer Cell 2017, 32, pp. 185-203). From the above description, it can be seen that KRAS plays a key role in the occurrence and development of pancreatic cancer.

[0005] As mutations of the KRAS gene, G12C mutant KRAS, G12D mutant KRAS, etc. are known. G12C mutant KRAS often occurs in non-small cell lung cancer pancreatic cancer, but the incidence in pancreatic cancer is very low (Cancer Cell 2014, 25, pp. 272-281), and a therapeutic agent for another KRAS mutation is needed. G12D mutant KRAS appears in about 34% of pancreatic cancer cases, and this rate is reported to be the highest among KRAS mutations (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

[0006] Patent Documents 1 and 2 disclose RAS inhibitors. Patent Documents 1 and 2 disclose compounds represented by the following formulae (A) and (B), respectively (the meanings of the symbols in the formulae can be found in the patent documents). [Chemical formula 1] [Chemical formula 2]

[0007] In addition, Patent Document 3 discloses a G12C mutant KRAS inhibitor, Patent Document 4 discloses a G12D mutant KRAS inhibitor, and Patent Document 5 discloses a pan-KRAS inhibitor.

[0008] In recent years, as a technology to induce target protein degradation, a bifunctional compound has been discovered, collectively referred to as PROTAC (PROteolysis-TArgeting Chimera) or SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser), and is expected to become a new technology for drug development (Drug. Discov. Today Technol., 2019, 31, pp. 15-27). This bifunctional compound promotes the formation of target protein and E3 ligase complex in cells and induces the degradation of target protein using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. A protein called E3 ligase recognizes the protein to be degraded and converts the protein into ubiquitin, thereby promoting the degradation of the proteasome. Typical examples of E3 ligases include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2).

[0009] The bifunctional compound composed of the E3 ligase ligand is a compound in which the target protein ligand and the ligand of the E3 ligase are bound by a linker, and some bifunctional compounds for degrading KRAS protein have been reported (Non-Patent Document 1, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 9 and Patent Document 10). In recent years, bifunctional compounds for inducing degradation of G12D mutant KRAS have also been reported (Patent Document 14, Patent Document 15, Patent Document 16, Patent Document 17, Patent Document 18, Patent Document 19 and Patent Document 20).

[0010] On the other hand, in recent years, several protein degradation induction techniques have also been reported, which are different from the method using a bifunctional compound consisting of an E3 ligase ligand. One of the new technologies is the protein degradation induction technique (patent documentation 11) using a ligand of a molecular chaperone heat shock protein 90 (HSP90). Known HSP90 and a chaperone complex comprising HSP90 interact with many different E3 ligases (Cell, 2012, 150, pages 987-1001), by using a bifunctional compound of a target protein and an HSP90 ligand to bring them close together, the target protein is converted into ubiquitin by the E3 ligase in the HSP90 complex. The result is that the target protein of polyubiquitination is degraded by the proteasome. In other words, this bifunctional compound promotes the formation of a target protein and an HSP90 protein complex, thereby inducing the degradation of the target protein.

[0011] The bifunctional compound composed of the ligand of the molecular chaperone is a compound in which the ligand of the target protein and the ligand of HSP90 are bound by a linker, and some bifunctional compounds for degrading KRAS protein have been reported previously (Patent Documents 12 and 13). However, to date, except for the G12C mutant KRAS, there are no reports of bifunctional compounds for inducing degradation of other mutant KRAS, such as the G12D mutant KRAS. Reference List Patent Literature

[0012] Patent Document 1: WO 2016 / 049568 Patent Document 2: WO 2017 / 172979 Patent Document 3: WO 2018 / 143315 Patent Document 4: WO 2022 / 002102 Patent document 5: WO 2022 / 132200 Patent Document 6: U.S. Patent Application Publication No. 2018 / 0015087 Patent Document 7: WO 2019 / 195609 Patent Document 8: WO 2020 / 018788 Patent Document 9: WO 2021 / 051034 Patent Document 10: WO 2021 / 207172 Patent Document 11: WO 2020 / 206608 Patent Document 12: WO 2022 / 078414 Patent Document 13: WO 2022 / 078470 Patent Document 14: WO 2022 / 148421 Patent Document 15: WO 2022 / 148422 Patent Document 16: WO 2022 / 173032 Patent Document 17: WO 2022 / 228576 Patent Document 18: Chinese Patent Application Publication No. 115785199 Patent Document 19: WO 2023 / 077441 Patent Document 20: WO 2023 / 280026 Non-patent literature

[0013] Non-patent literature 1: Cell.Chem.Biol., 2020, 27, pp. 19-31. Summary of the invention Technical issues

[0014] Provided is a pharmaceutical composition, for example, a heterocyclic compound, which has an excellent degradation-inducing effect on KRAS protein and / or is expected to be useful as a KRAS inhibitor, and can be used as an active ingredient of a pharmaceutical composition for treating cancer, particularly pancreatic cancer (e.g., mutant KRAS-positive pancreatic cancer). Technical solutions used to solve the problem

[0015] The present inventors have intensively and extensively studied a compound that can be used as an active ingredient of a pharmaceutical composition for treating cancer, particularly pancreatic cancer. As a result, the present inventors found that a heterocyclic compound of formula (I), for example, a bifunctional compound of formula (I), characterized in that a substituent at position 8 of a heterocyclic compound selected from quinazoline and quinoline is bound to a ligand of an E3 ligase via a linker, has excellent degradation inducing effect on KRAS protein and / or KRAS inhibitory activity, thereby completing the present invention. Specifically, 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. [Chemical formula 3] (In the formula, A is for CR A or N, R A Is H or C 1-3 alkyl; R 1 is naphthyl optionally substituted by OH, or R 1 is a group selected from the following formula (IIa) and formula (IIb), [Chemical formula 4] R 1a and R 1b are the same as or different from each other and are H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl, R 2 is H, halogen, optionally substituted C 1-3 Alkyl, cyclopropyl or vinyl, R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R 3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 5] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkylene-NR N1 R N2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3his an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NR N1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3k is attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, n is 1 or 2, p is 1 or 2, k is an integer from 0 to 2, R 4 is optionally substituted C 1-6alkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an optionally substituted 6-membered heteroaryl group containing one to three nitrogen atoms, X 1 is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X Is H or C 1-3 alkyl, Y is phenylene or pyridinediyl optionally substituted by a group selected from F and Cl, L is -(L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 )-, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 The same or different groups are selected from the group consisting of: bond, -O-, -S-, -NR L1 -, acetylene-1,2-diyl, optionally substituted azetidinediyl, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted diazepanediyl, optionally substituted C 1-3 alkylene, a saturated or unsaturated 7- or 8-membered bridged heterocyclic divalent group containing one or two nitrogen atoms, a saturated 7- to 11-membered spiro heterocyclic divalent group containing two nitrogen atoms, a saturated 8- to 10-membered bicyclic heterocyclic divalent group containing two nitrogen atoms, an optionally substituted phenylene, an optionally substituted pyridinediyl, C=O, S=O and S(=O)2, R L1 Is H or C 1-3 alkyl, Z is a group selected from the following formula (XVI), formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXIV) and formula (XXXV), [Chemical formula 6] Each Z 1 , are the same or different from each other, are CH or N, Z 2 is NH, NCH3, O or S, Each R 5a , which are the same or different from each other, are H, halogen, C 1-3 Alkyl or -(C=O)NH2, R 6a is C optionally substituted by F 1-6 alkyl, Each R 6b , the same or different from each other, is C 1-3 alkyl, R 6c is C optionally substituted by F 1-3 alkyl, R 6d Yes -(C=O)NR N3 R N4 , R N3 and R N4 Is H or C 1-3 Alkyl groups, identical or different from each other, R 7a is OH or -(C=O)NR N5 R N6 , R N5 and R N6 are the same as or different from each other and are H, cyclopropyl or C optionally substituted by F 1-3 Alkyl, and m is an integer from 0 to 2. )

[0016] The present invention also relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. [Chemical formula 7] (In the formula, A is for CR A or N, R A Is H or C 1-3 alkyl; R 1 is naphthyl optionally substituted by OH, or R 1 is a group selected from the following formula (IIa) and formula (IIb), [Chemical formula 8] R 1a and R 1b are the same as or different from each other and are H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl, R 2 is H, halogen, optionally substituted C 1-3 Alkyl, cyclopropyl or vinyl, R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R 3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 9] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkylene-NR N1 R N2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3h is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NRN1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3k is attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, n is 1 or 2, p is 1 or 2, k is an integer from 0 to 2, R 4 is optionally substituted C1-6 alkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an optionally substituted 6-membered heteroaryl group containing one to three nitrogen atoms, X 1 is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X Is H or C 1-3 alkyl, Y is phenylene or pyridinediyl optionally substituted by a group selected from F and Cl, L is -(L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 )-, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 The same or different groups are selected from the group consisting of: bond, -O-, -S-, -NR L1 -, acetylene-1,2-diyl, optionally substituted azetidinediyl, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted diazepanediyl, optionally substituted C 1-3 alkylene, a saturated or unsaturated 7- or 8-membered bridged heterocyclic divalent group containing one or two nitrogen atoms, a saturated 7- to 11-membered spiro heterocyclic divalent group containing two nitrogen atoms, a saturated 8- to 10-membered bicyclic heterocyclic divalent group containing two nitrogen atoms, an optionally substituted phenylene, an optionally substituted pyridinediyl, C=O, S=O and S(=O)2, R L1 Is H or C 1-3 alkyl, Z is a group selected from the following formula (XVI), formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXIV) and formula (XXXV), [Chemical formula 10] Each Z 1 , are the same or different from each other, are CH or N, Z 2 is NH, NCH3, O or S, Each R 5a , which are the same or different from each other, are halogen, C 1-3 Alkyl or -(C=O)NH2, R 6a is C optionally substituted by F 1-6 alkyl, Each R 6b , the same or different from each other, is C 1-3 alkyl, R 6c is C optionally substituted by F 1-3 alkyl, R 6d Yes -(C=O)NR N3 R N4 , R N3 and R N4 Is H or C 1-3 Alkyl groups, identical or different from each other, R 7a is OH or -(C=O)NR N5 R N6 , R N5 and R N6 are the same as or different from each other and are H, cyclopropyl or C optionally substituted by F 1-3 Alkyl, and m is an integer from 0 to 2. )

[0017] In addition, in one embodiment, the compound of formula (I) or a salt thereof is a bifunctional compound, wherein the ligand of the KRAS protein and the ligand of the HSP90 are bound via a linker, and Z in the compound of formula (I) or a salt thereof is a group capable of binding to the HSP90 protein. For example, reference may be made to, but not limited to, the following references. [References] J.Med.Chem.2020,63,pp.1798-1822

[0018] Note that when a symbol in a chemical formula herein is used in another chemical formula, the same symbol represents the same meaning unless otherwise specified.

[0019] The present invention also relates to a pharmaceutical composition, comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition is used to treat cancer, especially pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat mutant KRAS-positive cancer, especially mutant KRAS-positive pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat metastatic cancer, especially metastatic pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat locally advanced cancer, especially locally advanced pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat relapsed or refractory cancer, especially relapsed or refractory pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat unresectable Cancer of patients being treated and / or having a history of treatment, in particular pancreatic cancer in patients who have not been treated and / or have a history of treatment. In one embodiment, the pharmaceutical composition is used to treat metastatic mutant KRAS-positive cancer, in particular mutant KRAS-positive pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat locally advanced mutant KRAS-positive cancer, in particular mutant KRAS-positive pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat relapsed or refractory mutant KRAS-positive cancer, in particular mutant KRAS-positive pancreatic cancer. In one embodiment, the pharmaceutical composition is used to treat mutant KRAS-positive cancer, in particular mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment. Note: The pharmaceutical composition is used to treat cancer, especially pancreatic cancer. In one embodiment, mutant KRAS-positive cancer, especially mutant KRAS-positive pancreatic cancer. The pharmaceutical composition, which comprises a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, is a therapeutic agent for cancer, especially pancreatic cancer, comprising a compound of formula (I) or a salt thereof. In one embodiment, it is a therapeutic agent for mutant KRAS-positive cancer, especially mutant KRAS-positive pancreatic cancer.

[0020] The present invention also relates to the use of a compound of formula (I) or a salt thereof for preparing a pharmaceutical composition for treating cancer, wherein the cancer is particularly pancreatic cancer, in one embodiment, mutant KRAS-positive cancer, particularly mutant KRAS-positive pancreatic cancer, in one embodiment, metastatic cancer, particularly metastatic pancreatic cancer, in one embodiment, locally advanced cancer, particularly locally advanced pancreatic cancer, in one embodiment, recurrent or refractory cancer, particularly recurrent or refractory pancreatic cancer, in one embodiment, cancer in patients who have not been treated and / or have a history of treatment, particularly pancreatic cancer in patients who have not been treated and / or have a history of treatment, in one embodiment, metastatic mutant KRAS-positive cancer, particularly metastatic mutant KRAS-positive pancreatic cancer, in one embodiment, locally advanced mutant KRAS-positive cancer, particularly locally advanced mutant KRAS-positive pancreatic cancer, in one embodiment, recurrent or refractory mutant The invention relates to a method for treating cancer, especially pancreatic cancer, in one embodiment, mutant KRAS-positive cancer, especially relapsed or refractory mutant KRAS-positive pancreatic cancer. In one embodiment, mutant KRAS-positive cancer in patients who have not been treated and / or have a history of treatment, especially mutant KRAS-positive pancreatic cancer in patients who have not been treated and / or have a history of treatment. The invention relates to the use of a compound of formula (I) or a salt thereof for treating cancer, especially pancreatic cancer, in one embodiment, mutant KRAS-positive cancer, especially mutant KRAS-positive pancreatic cancer. The invention relates to a method for treating cancer, especially pancreatic cancer, in one embodiment, mutant KRAS-positive cancer, especially mutant KRAS-positive pancreatic cancer, comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0021] The present invention also relates to a compound of formula (I) or a salt thereof as a mutant KRAS protein degradation inducer and / or a mutant KRAS inhibitor, to a compound of formula (I) or a salt thereof used as a mutant KRAS protein degradation inducer and / or a mutant KRAS inhibitor, and to a mutant KRAS protein degradation inducer and / or a mutant KRAS inhibitor comprising a compound of formula (I) or a salt thereof.

[0022] Note that the "subject" refers to a human or other animal in need of treatment. In one embodiment, the "subject" is a human in need of prevention or treatment. Advantageous Effects of the Invention

[0023] The compound of formula (I) or a salt thereof has a degradation-inducing effect on KRAS protein and / or KRAS inhibitory activity, and can be used as a therapeutic agent for cancer, particularly pancreatic cancer, such as mutant KRAS-positive pancreatic cancer. Detailed description of implementation method

[0024] The present invention will be described in detail below.

[0025] As used herein, "optionally substituted" means unsubstituted or has one to five substituents. In one embodiment, "optionally substituted" means unsubstituted or has one to three substituents. Note that when multiple substituents are present, the substituents may be the same or different from each other.

[0026] "C 1-12 "Alkyl" is a straight or branched chain alkyl group having 1 to 12 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (the number of carbon atoms is similar to that described herein below). In one embodiment, "C 1-12 "Alkyl" is ethyl or dodecyl. Similarly, "C 1-6 "Alkyl" is a straight or branched chain alkyl group having 1 to 6 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. In one embodiment, "C 1-6 "Alkyl" is methyl, ethyl, n-propyl, isopropyl or sec-butyl, in one embodiment, is methyl, ethyl, n-propyl, isopropyl or tert-butyl, in one embodiment, is methyl, ethyl, n-propyl, isopropyl or n-butyl, in one embodiment, is methyl, ethyl or n-propyl, in one embodiment, is methyl, in one embodiment, is ethyl, or in one embodiment, is n-propyl. Similarly, "C 1-3 "Alkyl" is a straight or branched chain alkyl group having 1 to 3 carbon atoms, examples of which include methyl, ethyl, n-propyl, isopropyl. In one embodiment, "C 1-3 "Alkyl" is methyl or ethyl, in one embodiment, is n-propyl or isopropyl, in one embodiment, is methyl or isopropyl, in one embodiment, is ethyl or isopropyl, in one embodiment, is methyl, in one embodiment, is ethyl, in one embodiment, isopropyl, or in one embodiment, is n-propyl. Similarly, "C 2-3 "Alkyl" is a straight or branched chain alkyl group having 2 or 3 carbon atoms, examples of which include ethyl, n-propyl and isopropyl. In one embodiment, "C 2-3"Alkyl" is ethyl, in one embodiment is isopropyl, or in one embodiment is n-propyl.

[0027] "C 3-6 "Cycloalkyl" is a cycloalkyl group having 3 to 6 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In one embodiment, "C 3-6 "Cycloalkyl" is cyclobutyl, cyclopentyl or cyclohexyl, in one embodiment, cyclobutyl or cyclopentyl, in one embodiment, cyclopentyl or cyclohexyl, in one embodiment, cyclopropyl or cyclobutyl, in one embodiment, cyclopropyl, in one embodiment, cyclobutyl, in one embodiment, cyclopentyl, or in one embodiment, cyclohexyl.

[0028] "C 1-3 "Alkylene" is obtained by 1-3 A divalent group formed by removing a hydrogen atom from an alkyl group. 1-3 "Alkylene" is a straight or branched C 1-3 Alkylene, examples of which include methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. In one embodiment, "C 1-3 "Alkylene" is a straight or branched C 1-3 Alkylene, in one embodiment, is methylene, ethylene, or trimethylene, in one embodiment, is methylene or ethylene, in one embodiment, is methylene, or in one embodiment, is ethylene. Similarly, "C 2-3 "Alkylene" is obtained by 2-3 A divalent group formed by removing a hydrogen atom from an alkyl group. 2-3 "Alkylene" is a straight or branched C 2-3 Alkylene, ethylene or trimethylene, in one embodiment trimethylene or in one embodiment ethylene.

[0029] The "saturated heterocyclic group" is a saturated hydrocarbon ring group containing a heteroatom selected from nitrogen, oxygen and sulfur as a ring-forming atom. In addition, the sulfur atom as a ring-forming atom of the saturated heterocyclic group is optionally oxidized. Therefore, a "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing a heteroatom selected from nitrogen, oxygen and sulfur as a ring-forming atom. In one embodiment, the "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from nitrogen, oxygen and sulfur as a ring-forming atom. In one embodiment, the 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms is a 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from oxygen, sulfur and nitrogen as ring atoms, in one embodiment, a 5- or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, in one embodiment, a 4-membered saturated heterocyclic group containing one heteroatom selected from oxygen, sulfur and nitrogen as ring atoms, in one embodiment, a 5-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, in one embodiment, a 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, in one embodiment, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, Morpholinyl, thiomorpholinyl or dioxothiomorpholinyl, in one embodiment, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxothiomorpholinyl, in one embodiment, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or morpholinyl, in one embodiment, is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl, in one embodiment, is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, in one embodiment, is pyrrolidinyl or piperidinyl, in one embodiment, is oxetanyl, in one embodiment, is tetrahydrofuranyl, in one embodiment, is tetrahydropyranyl, in one embodiment, is pyrrolidinyl, in one embodiment, is piperidinyl, in one embodiment, is morpholinyl, or in one embodiment, is oxazolidinyl.

[0030] A "bridged heterocyclic group" is a saturated or unsaturated bridged hydrocarbon ring group containing one or two nitrogen atoms as ring-forming atoms. Therefore, a "saturated or unsaturated 7-membered or 8-membered bridged heterocyclic group" is a saturated 7-membered or 8-membered bridged heterocyclic group containing one or two nitrogen atoms as ring atoms, or a 7-membered or 8-membered bridged heterocyclic group having an unsaturated bond containing one or two nitrogen atoms. In one embodiment, a "saturated or unsaturated 7-membered or 8-membered bridged heterocyclic group" is a saturated 7-membered or 8-membered bridged heterocyclic group containing two nitrogen atoms, in one embodiment, a saturated 7-membered or 8-membered bridged heterocyclic group containing two nitrogen atoms, wherein one of the two nitrogen atoms is bonded to a hydrogen atom, or in one embodiment, a saturated 7-membered or 8-membered bridged heterocyclic group containing one nitrogen atom. Examples include diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octenyl, diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptenyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azabicyclo[3.1.1]heptyl and azabicyclo[2.2.1]heptyl. In one embodiment, the "saturated or unsaturated 7-membered or 8-membered bridged heterocyclic group" is diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]oct-6-enyl, diazabicyclo[3.2.1]oct-2-enyl, diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, ]hept-5-enyl, azabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, azabicyclo[3.1.1]heptyl or azabicyclo[2.2.1]heptyl, in one embodiment, diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.1.1]heptyl, diazabicyclo[2.2.1]heptyl or azabicyclo[2.2.1]heptyl. [3.2.1]octyl, in one embodiment, is diazabicyclo[2.2.2]octyl, diazabicyclo[3.2.1]octyl, diazabicyclo[3.1.1]heptyl or diazabicyclo[2.2.1]heptyl, in one embodiment, is 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl or 2,5-diazabicyclo[2.2.1]heptyl, in one embodiment, is diazabicyclo[2.2.1]heptyl, in one embodiment, is 2,5-diazabicyclo[2.2.1]heptyl, in one embodiment, is 2,5-diazabicyclo[2.2.1]hept-2-yl, or in one embodiment, is azabicyclo[3.2.1]octyl. Note that the "bridged heterocyclic divalent group" is a divalent group formed by removing any one hydrogen atom from the "bridged heterocyclic group". Therefore, the “saturated or unsaturated 7-membered or 8-membered bridged heterocyclic divalent group” is a saturated 7-membered or 8-membered bridged heterocyclic divalent group containing one or two nitrogen atoms as ring-forming atoms, or a 7-membered or 8-membered bridged heterocyclic divalent group having an unsaturated bond containing one or two nitrogen atoms.

[0031] The "spiro heterocyclic divalent group" is a divalent group formed by removing a hydrogen atom from a saturated spiro hydrocarbon ring group containing one or two nitrogen atoms as ring-constituting atoms. Therefore, a "saturated 7- to 11-membered spiro heterocyclic divalent group" is a saturated 7- to 11-membered spiro heterocyclic divalent group comprising one or two nitrogen atoms as ring atoms. In one embodiment, a "saturated 7- to 11-membered spiro heterocyclic divalent group" is a saturated 7- to 11-membered spiro heterocyclic divalent group comprising two nitrogen atoms. Examples thereof include diazaspiro[3.3]heptanediyl, diazaspiro[3.4]octanediyl, diazaspiro[3.5]nonanediyl, diazaspiro[4.5]decanediyl, and diazaspiro[5.5]undecanediyl.

[0032] The "bicyclic heterocyclic divalent group" is a divalent group formed by removing a hydrogen atom from a saturated bicyclic hydrocarbon ring group containing one or two nitrogen atoms as ring-forming atoms. Therefore, a "saturated 8- to 10-membered bicyclic heterocyclic divalent group" is a saturated 8- to 10-membered bicyclic heterocyclic divalent group containing one or two nitrogen atoms as ring atoms. In one embodiment, a "saturated 8- to 10-membered bicyclic heterocyclic divalent group" is a saturated 8- to 10-membered bicyclic heterocyclic divalent group containing two nitrogen atoms. Examples thereof include azabicyclo[3.3.0]octanediyl and diazabicyclo[3.3.0]octanediyl.

[0033] "Heteroaryl" is an aromatic heterocyclic group containing as a ring-forming atom a heteroatom selected from oxygen, sulfur and nitrogen. Thus, a "5-membered heteroaryl" is a 5-membered aromatic heterocyclic group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen as ring-forming atoms. In one embodiment, the "5-membered heteroaryl" is a 5-membered aromatic heterocyclic group containing one to three heteroatoms selected from oxygen, sulfur and nitrogen as ring atoms, in one embodiment, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, in one embodiment, pyrazolyl, imidazolyl, triazolyl, oxazolyl or thiazolyl, in one embodiment, pyrazolyl, imidazolyl, oxazolyl or thiazolyl, in one embodiment, pyrazolyl, imidazolyl, triazolyl or oxazolyl, in one embodiment, pyrazolyl, oxazolyl or thiazolyl, in one embodiment, pyrazolyl, triazolyl or oxazolyl, in one embodiment, pyrazolyl or thiazolyl, in one embodiment, pyrazolyl or triazolyl, in one embodiment, pyrazolyl, in one embodiment, imidazolyl, in one embodiment, oxazolyl, in one embodiment, thiazolyl, or in one embodiment, triazolyl.

[0034] "6-membered heteroaryl" is a 6-membered aromatic heterocyclic group containing one to three nitrogen atoms as ring atoms. In one embodiment, "6-membered heteroaryl" is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or triazinyl, in one embodiment, pyridyl or pyridazinyl, in one embodiment, pyridyl or pyrimidinyl, in one embodiment, pyridyl or pyrimidinyl, in one embodiment, pyridyl or pyrimidinyl.

[0035] "Halogen" means F, Cl, Br or I. In one embodiment, "halogen" is F, Cl or Br, in one embodiment, is F or Cl, in one embodiment, is F or Br, in one embodiment, is F, in one embodiment, is Cl, or in one embodiment, is Br.

[0036] In one embodiment, "optionally substituted C 1-6 "alkyl" and "optionally substituted C 1-3 The acceptable substituents in the "alkyl" are F, OH, OCH3, N(CH3)2, optionally substituted C 3-6cycloalkyl, azabicyclo [3.3.0] octyl, or an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, in one embodiment, is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, morpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl or azabicyclo [3.3.0] octyl, in one embodiment, is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl or optionally substituted pyrrolidinyl, in one embodiment, is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl or methylpyrrolidinyl, in one embodiment, is F, OH, OCH3, (methoxymethyl)cyclopropyl, tetrahydrofuranyl or methylpyrrolidinyl, in one embodiment, is F, OH or cyclopropyl, in one embodiment, is F, OH or OCH3, in one embodiment, is OH or OCH3, in one embodiment, is F or OCH3, in one embodiment, is OH, in one embodiment, is F, or in one embodiment, is OCH3.

[0037] In one embodiment, "optionally substituted 5-membered heteroaryl", "optionally substituted 6-membered heteroaryl", "optionally substituted C 3-6 The acceptable substituents in "optionally substituted cycloalkyl", "optionally substituted pyrazolyl", "optionally substituted pyridinyl", "optionally substituted pyrimidinyl", "optionally substituted phenyl" and "optionally substituted cyclopropyl" are C optionally substituted by a group selected from the following group: 1-3 Alkyl: OH and OCH3, -SO2CH3, halogen, OH, OCH3 or C 3-6 Cycloalkyl, in one embodiment, is C 1-3 Alkyl, in one embodiment, is C 1-3 Alkyl, in one embodiment, is C optionally substituted with OCH3 1-3 Alkyl, in one embodiment, is C 1-3 Alkyl or halogen, in one embodiment, is methyl, ethyl, methoxymethyl or F, or in one embodiment, is methyl, ethyl or F.

[0038] In one embodiment, the acceptable substituents in "optionally substituted 4- to 6-membered saturated heterocyclic group", "optionally substituted pyrrolidinyl", "optionally substituted piperidinyl", "optionally substituted oxetanyl", "optionally substituted tetrahydrofuranyl" and "optionally substituted tetrahydropyranyl" are C optionally substituted by a group selected from the group consisting of 1-3 Alkyl: F, OH and OCH3, F, OH, OCH3, oxo or oxetanyl, in one embodiment, F, OH or OCH3, in one embodiment, OH or methyl, in one embodiment, C optionally substituted by a group selected from the group consisting of 1-3 Alkyl: F, OH and OCH3, F, oxo or oxetanyl, in one embodiment, is C optionally substituted by a group selected from the group consisting of 1-3 Alkyl: F, OH and OCH3 or oxo, in one embodiment, is C optionally substituted by a group selected from the group consisting of 1-3 Alkyl: F, OH and OCH3, in one embodiment, is C optionally substituted by F 1-3 Alkyl, in one embodiment, is C 1-3 Alkyl, in one embodiment, is C optionally substituted with OCH3 1-3 Alkyl, or in one embodiment, is C 1-3 alkyl.

[0039] In one embodiment, "optionally substituted azetidinediyl", "optionally substituted pyrrolidinediyl", "optionally substituted piperidinediyl", "optionally substituted piperazinediyl", "optionally substituted diazepanediyl" and "optionally substituted C 1-3 The acceptable substituents in the "alkylene" are F, OH, OCH3 or optionally substituted C 1-3 Alkyl, in one embodiment, is F, OH, OCH3, methyl, ethyl, hydroxymethyl or methoxymethyl, or in one embodiment, is F, OH, OCH3 or methyl.

[0040] In one embodiment, the acceptable substituents in "optionally substituted phenylene" and "optionally substituted pyridinediyl" are F, Cl or optionally substituted C 1-3 Alkyl, in one embodiment, is F or Cl, or in one embodiment is F.

[0041] In one embodiment, C optionally substituted with F 1-3"C alkyl" is methyl optionally substituted by F or ethyl optionally substituted by F. Examples include methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl and trifluoroethyl. In one embodiment, "C alkyl optionally substituted by F" is methyl, ethyl, monofluoromethyl, difluoroethyl and trifluoroethyl. 1-3 "Alkyl" is methyl, ethyl, monofluoromethyl, difluoromethyl or difluoroethyl, in one embodiment, is monofluoromethyl or difluoromethyl, in one embodiment, is monofluoromethyl or difluoroethyl, in one embodiment, is difluoromethyl or difluoroethyl, in one embodiment, is monofluoromethyl, in one embodiment, is difluoromethyl, in one embodiment, is difluoroethyl, or in one embodiment, is 2,2-difluoroethyl.

[0042] In one embodiment, C optionally substituted with OH 1-3 "C alkyl" is methyl optionally substituted with one OH or ethyl optionally substituted with one or two OH. Examples include methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1,2-dihydroxyethyl. In one embodiment, "C alkyl optionally substituted with OH" is methyl optionally substituted with one OH or ethyl optionally substituted with one or two OH. Examples include methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1,2-dihydroxyethyl. 1-3 "Alkyl" is methyl, ethyl or hydroxymethyl, in one embodiment, is methyl or hydroxymethyl, in one embodiment, is hydroxymethyl or hydroxyethyl, in one embodiment, is hydroxymethyl, or in one embodiment, is hydroxyethyl.

[0043] In one embodiment, "C optionally substituted with OCH3 1-3 "C alkyl" is methyl optionally substituted by one OCH3, ethyl optionally substituted by one or two OCH3, or propyl optionally substituted by one to three OCH3. Examples include methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl, and 2-methoxypropyl. In one embodiment, "C alkyl optionally substituted by OCH3" is methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl, and 2-methoxypropyl. 1-3 "Alkyl" is methoxymethyl or methoxyethyl, in one embodiment, is methoxymethyl, in one embodiment, is methoxyethyl, or in one embodiment, is 2-methoxypropyl.

[0044] In one embodiment, "phenylene optionally substituted by F" is phenylene optionally substituted by one or two F. In one embodiment, "phenylene optionally substituted by F" is phenylene optionally substituted by one F, in one embodiment, phenylene or fluorophenylene, in one embodiment, phenylene, in one embodiment, 2-fluoro-1,4-phenylene, or in one embodiment, 3-fluoro-1,4-phenylene.

[0045] In one embodiment "naphthyl optionally substituted by OH" is naphthyl optionally substituted by one OH. In one embodiment "naphthyl optionally substituted by OH" is 3-hydroxy-1-naphthyl.

[0046] In one embodiment, the "saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms optionally substituted by OH" is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms optionally substituted by one OH or a saturated 7- or 8-membered bridged heterocyclic group containing one nitrogen atom optionally substituted by one OH. Examples thereof include diazabicyclo [2.2.2] octyl, diazabicyclo [3.2.1] octyl, diazabicyclo [3.1.1] heptyl, diazabicyclo [2.2.1] heptyl, azabicyclo [3.2.1] octyl and hydroxy azabicyclo [3.2.1] octyl. In one embodiment, the "saturated or unsaturated 7-membered or 8-membered bridged heterocyclic group optionally substituted with OH and containing one or two nitrogen atoms" is 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 3,6-diazabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3-hydroxy-6-azabicyclo[3.2.1]octyl or 6-hydroxy In one embodiment, 3-azabicyclo[3.2.1]octyl is 1-(2-azabicyclo[3.2.1]octyl) and 6-(2-azabicyclo[3.2.1]octyl is 1-(2-azabicyclo[3.2.1]octyl) and 3-(2-azabicyclo[3.2.1]octyl is 1-(2-azabicyclo[3.2.1]octyl) and 6 ...

[0047] The "KRAS protein" is a protein encoded by the KRAS gene, and refers to proteins encoded by the wild-type KRAS gene and the mutant KRAS gene.

[0048] "Mutant KRAS protein" refers to the protein encoded by a mutant KRAS gene.

[0049] "Mutant KRAS" is KRAS with mutations, represented by, for example, G12D mutant KRAS, G12V mutant KRAS, and G12C mutant KRAS.

[0050] The "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.

[0051] “G12D mutant KRAS” means KRAS with a “G12D mutation”.

[0052] The "G12V 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 valine.

[0053] “G12V mutant KRAS” means KRAS with a “G12V mutation”.

[0054] The "G12C 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 cysteine.

[0055] “G12C mutant KRAS” means KRAS with a “G12C mutation”.

[0056] "Pancreatic cancer" is a malignant tumor that occurs in the pancreas. Examples of pancreatic cancer include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, and "pancreatic cancer" is pancreatic ductal carcinoma in one embodiment or pancreatic ductal adenocarcinoma in one embodiment. In addition, in one embodiment, "pancreatic cancer" is metastatic pancreatic cancer, in one embodiment, locally advanced pancreatic cancer, in one embodiment, recurrent or refractory pancreatic cancer, or in one embodiment, pancreatic cancer in patients who have not been treated and / or have a history of treatment.

[0057] "Mutated KRAS-positive pancreatic cancer" is a pancreatic cancer that is positive for mutant KRAS, in particular, a pancreatic cancer that is positive for G12V mutant, G12D mutant, and / or G12C mutant KRAS. Examples of mutant KRAS-positive pancreatic cancer include pancreatic cancers with KRAS G12V mutation, G12D mutation, and / or G12C mutation, and pancreatic cancers with a high positive rate of G12V mutant, G12D mutant, and / or G12C mutant KRAS. "Mutated KRAS-positive pancreatic cancer" is mutant KRAS-positive pancreatic ductal carcinoma, particularly G12V mutant, G12D mutant and / or G12C mutant KRAS-positive pancreatic ductal carcinoma, in one embodiment, or mutant KRAS-positive pancreatic ductal adenocarcinoma, particularly, in one embodiment, G12V mutant, G12D mutant and / or G12C mutant KRAS-positive pancreatic ductal adenocarcinoma.

[0058] Embodiments of the compound of formula (I) or a salt thereof of the present invention are shown below. (1-1) The compound or a salt thereof, wherein A is CR A or N, and R A Is H or C 1-3 alkyl. (1-2) The compound or its salt, wherein A is CR A or N, and R A It's H. (1-3) The compound or a salt thereof, wherein A is N. (1-4) The compound or a salt thereof, wherein A is CH. (2-1) The compound or a salt thereof, wherein R 1 is naphthyl optionally substituted by OH, or R 1 is a group selected from the following formula (IIa) and formula (IIb), [Chemical formula 11] R 1a and R 1b are the same as or different from each other and are H, methyl, F or Cl, and R 1c is F, Cl, methyl or ethyl. (2-2) The compound or a salt thereof, wherein R 1 is the following formula (IIa), [Chemical formula 12] R 1a is F, and R 1c It's methyl. (3-1) The compound or a salt thereof, wherein R 2 is H, halogen, optionally substituted C 1-3 Alkyl, cyclopropyl or vinyl. (3-2) The compound or a salt thereof, wherein R 2 It is cyclopropyl. (4-1) The compound or a salt thereof, wherein R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R 3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 13] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkylene-NR N1 RN2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3h is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NR N1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3k is attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, n is 1 or 2, p is 1 or 2, and k is an integer from 0 to 2. (4-2) The compound or a salt thereof, wherein R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (Va), formula (XIII-a) and formula (XXXVI), [Chemical formula 14] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c is optionally replaced by -NR N1 R N2 Substituted C 4-6 Cycloalkyl or -(CH2) p CHR 3f -NR N1 R N2 , R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O, and p is 1. (4-3) The compound or its salt, wherein R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (XXXVI) and formula (XIII-a), [Chemical formula 15] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c Yes - (CH2) pCHR 3f -NR N1 R N2 , R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 Is -O- or -N(C 1-3 alkyl)-, X 3 is O, and p is 1. (4-4) The compound or its salt, wherein R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R 3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 16] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NRN1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkylene-NR N1 R N2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3h is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NR N1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3k is attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, n is 1 or 2, p is 1 or 2, and k is an integer from 0 to 2. (4-4-1) The compound or a salt thereof, wherein R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 17] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkyl-OR 3g , C 1-3 Alkyl-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkyl-OR 3g , C 1-3 Alkyl-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkyl-OR 3g , C 1-3 Alkyl-NR N1 R N2 and-NR N1 RN2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkyl-OR 3g , C 1-3 Alkyl-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkyl-NR N1 R N2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3h is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NR N1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3kis attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, n is 1 or 2, p is 1 or 2, and k is an integer from 0 to 2. (4-5) The compound or its salt, wherein R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (Va), formula (XIII-a) and formula (XXXVI), [Chemical formula 18] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c is optionally replaced by -NR N1 R N2 Substituted C 4-6 Cycloalkyl or -(CH2) p CHR 3f -NR N1 R N2 , R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 It's O. The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV-a) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, and p is 1. (4-6) The compound or its salt, wherein R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (XIII-a) and formula (XXXVI), [Chemical formula 19] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 Is -O- or -N(C 1-3 alkyl)-, X 3 It's O. The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV) 2 is -O- or -N(C 2-3 alkyl)-, and p is 1. (5-1) The compound or a salt thereof, wherein R 4is optionally substituted C 1-6 alkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an optionally substituted 6-membered heteroaryl group containing one to three nitrogen atoms, (5-2) The compound or its salt, wherein R 4 is C optionally substituted by 1-6 Alkyl: OCH3, or tetrahydropyranyl. (5-3) The compound or its salt, wherein R 4 is C optionally substituted by 1-3 Alkyl: OCH3, or tetrahydropyranyl. (6-1) The compound or a salt thereof, wherein X 1 is a bond, -CH2-, -O-, -S- or -NR 4X -,and R 4X Is H or C 1-3 alkyl. (6-2) The compound or its salt, wherein X 1 Yes -O-. (7-1) The compound or a salt thereof, wherein Y is a phenylene group or a pyridinediyl group optionally substituted by a group selected from F and Cl, (7-2) The compound or a salt thereof, wherein Y is a phenylene group optionally substituted by F. (7-3) The compound or a salt thereof, wherein Y is a phenylene group. (8-1) The compound or a salt thereof, wherein L is -(L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 )-, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 The same or different groups are selected from the group consisting of: bond, -O-, -S-, -NR L1 -, acetylene-1,2-diyl, optionally substituted azetidinediyl, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted diazepanediyl, optionally substituted C 1-3alkylene, a saturated or unsaturated 7- or 8-membered bridged heterocyclic divalent group containing one or two nitrogen atoms, a saturated 7- to 11-membered spiro heterocyclic divalent group containing two nitrogen atoms, a saturated 8- to 10-membered bicyclic heterocyclic divalent group containing two nitrogen atoms, an optionally substituted phenylene, an optionally substituted pyridinediyl, C═O, S═O and S(═O)2, and R L1 Is H or C 1-3 alkyl. (8-2) The compound or its salt, wherein L is a group selected from the group consisting of the following formulas: (XXXX-a), (XXXX-b), (XXXXI), (XXXXII), (XXXXIII), (XXXXIV), (XXXXV), (XXXXVI), (XXXXVII) and (XXXXVIII), [Chemical formula 20] L 1 is -(CH2)-, C=O or S(=O)2, L 3 , L 4 and L 5 The same or different from each other, are bonds, -O-, C 1-3 Alkylene or C=O, R L1 Is H or C 1-3 alkyl, R L2 It is C 1-3 Alkyl or oxo, Ring B is piperazine, diazepane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.5]decane, diazaspiro[5.5]undecane or diazabicyclo[3.3.0]octane, and Ring C is azetidine, pyrrolidine or piperidine. (8-3) The compound or a salt thereof, wherein L is a group selected from the group consisting of the following formula (XXXX-a), formula (XXXX-b), formula (XXXXII), formula (XXXXIV) and formula (XXXXVIII), [Chemical formula 21] L 1 is -(CH2)- or C=O, L 3 , L 4 and L5 The same or different from each other, are bonds, -O-, C 1-3 Alkylene or C=O, R L1 and R L2 It is C 1-3 alkyl, Ring B is piperazine, diazaheptane, diazabicyclo[3.2.1]octane, diazaspiro[3.5]nonane or diazabicyclo[3.3.0]octane, and Ring C is azetidine or piperidine. (8-4) The compound or a salt thereof, wherein L is a group selected from the group consisting of the following formula (XXXX), formula (XXXX-a), formula (XXXXI), formula (XXXXII), formula (XXXXIII), formula (XXXXIV), formula (XXXXV), formula (XXXXVI), formula (XXXXVII) and formula (XXXXVIII), [Chemical formula 22] L 1 is -(CH2)-, C=O or S(=O)2, L 3 , L 4 and L 5 are the same as or different from each other and are -(CH2)- or C=O, R L1 Is H or C 1-3 alkyl, R L2 It is C 1-3 Alkyl or oxo, Ring B is piperazine, diazaheptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.5]decane, diazaspiro[5.5]undecane or diazabicyclo[3.3.0]octane, and Ring C is azetidine, pyrrolidine or piperidine. (8-5) The compound or a salt thereof, wherein L is a group selected from the group consisting of the following formula (XXXX), formula (XXXX-a), formula (XXXXI), formula (XXXXII), formula (XXXXIV) and formula (XXXXVIII), [Chemical formula 23] L 1 , L 3 , L 4and L 5 are the same as or different from each other and are -(CH2)- or C=O, R L1 and R L2 It is C 1-3 alkyl, Ring B is piperazine, diazaheptane, diazabicyclo[3.2.1]octane, diazaspiro[3.5]nonane or diazabicyclo[3.3.0]octane, and Ring C is azetidine or piperidine. (9-1) The compound or a salt thereof, wherein Z is a group selected from the group consisting of the following formulas: (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV) and (XXXV), [Chemical formula 24] Each Z 1 , are the same or different from each other, are CH or N, Z 2 is NH, NCH3, O or S, Each R 5a , which are the same or different from each other, are H, halogen, C 1-3 Alkyl or -(C=O)NH2, R 6a is C optionally substituted by F 1-6 alkyl, Each R 6b , the same or different from each other, is C 1-3 alkyl, R 6c is C optionally substituted by F 1-3 alkyl, R 6d Yes -(C=O)NR N3 R N4 , R N3 and R N4 Is H or C 1-3 Alkyl groups, identical or different from each other, R 7a is OH or -(C=O)NR N5 R N6 , R N5 and RN6 are the same as or different from each other and are H, cyclopropyl or C optionally substituted by F 1-3 Alkyl, and m is an integer from 0 to 2. (9-2) The compound or a salt thereof, wherein Z is a group selected from the following formula (XVI-a), formula (XXIII-a), formula (XIX) and formula (XXXV), [Chemical formula 25] Each Z 1 It is CH, R 5a It is H. R 6a It is C 1-3 alkyl, R 7a is OH or -(C=O)NR N5 R N6 , R N5 is H, and R N6 It is C 1-3 alkyl. (9-3) The compound or a salt thereof, wherein Z is a group selected from the following formula (XVI-a), formula (XXIII-a), formula (XIX) and formula (XXXV), [Chemical formula 26] Each Z 1 It is CH, R 5a It is H. R 6a is isopropyl, and R 7a It's OH. (9-4) The compound or its salt, wherein Z is a group selected from the following group: the following formula (XVI), formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXIV) and formula (XXXV), [Chemical formula 27] Each Z 1, are the same or different from each other, are CH or N, Z 2 is NH, NCH3, O or S, Each R 5a , which are the same or different from each other, are halogen, C 1-3 Alkyl or -(C=O)NH2, R 6a is C optionally substituted by F 1-6 alkyl, Each R 6b , the same or different from each other, is C 1-3 alkyl, R 6c is C optionally substituted by F 1-3 alkyl, R 6d Yes -(C=O)NR N3 R N4 , R N3 and R N4 Is H or C 1-3 Alkyl groups, identical or different from each other, R 7a is OH or -(C=O)NR N5 R N6 , R N5 and R N6 are the same as or different from each other and are H, cyclopropyl or C optionally substituted by F 1-3 Alkyl, and m is an integer from 0 to 2. (9-5) The compound or a salt thereof, wherein Z is a group selected from the following group: the following formula (XVI-a) and formula (XXIII-a), [Chemical formula 28] Each Z 1 It is CH, R 6a It is C 1-3 alkyl, R 7a is OH or -(C=O)NR N5 R N6 , R N5 is H, and R N6 It is C 1-3 alkyl. (9-6) The compound or a salt thereof, wherein Z is a group selected from the group consisting of formula (XVI-a) and formula (XXIII-a), Each Z1 It is CH, R 6a is isopropyl, and R 7a It's OH. (10) The compound or a salt thereof, which is a combination of any two or more of the mutually compatible embodiments described in (1-1) to (9-6) above.

[0059] Specific examples of the combination described in (10) above include the following embodiments. (11-1) A compound of formula (I) or a salt thereof, which is a combination of the above-mentioned embodiments (1-1), (2-1), (3-1), (4-1), (5-1), (6-1), (7-1), (8-1) and (9-1). (11-2) A compound of formula (I) or a salt thereof, which is a combination of the above-mentioned embodiments (1-2), (2-2), (3-2), (4-2), (5-2), (6-2), (7-2), (8-2) and (9-2). (11-3) A compound of formula (I) or a salt thereof, which is a combination of the above-mentioned embodiments (1-2), (2-2), (3-2), (4-3), (5-3), (6-2), (7-3), (8-3) and (9-3). (11-4) A compound of formula (I) or a salt thereof, which is a combination of the above-mentioned embodiments (1-1), (2-1), (3-1), (4-4), (5-1), (6-1), (7-1), (8-1) and (9-4). (11-5) A compound of formula (I) or a salt thereof, which is a combination of the above-mentioned embodiments (1-2), (2-2), (3-2), (4-5), (5-2), (6-2), (7-2), (8-4) and (9-5). (11-6) A compound of formula (I) or a salt thereof, which is a combination of the above-mentioned embodiments (1-3), (2-2), (3-2), (4-6), (5-3), (6-2), (7-3), (8-5) and (9-6).

[0060] The compound of formula (I) may have tautomers or geometric isomers depending on the type of substituents. In the present specification, the compound of formula (I) is sometimes described as only one of the isomers, but the present invention includes isomers other than the above isomers and includes isolated isomers or mixtures thereof. Furthermore, the compound of formula (I) may have an asymmetric carbon atom or axial chirality, and may have diastereomers based thereon. The present invention includes isolated diastereomers of the compound of formula (I) or mixtures thereof.

[0061] In addition, the present invention also includes the pharmaceutically acceptable prodrug of the compound represented by formula (I). Pharmaceutically acceptable prodrugs are compounds with groups that can be converted into amino, hydroxyl, carboxyl, etc. by solvent decomposition or under physiological conditions. Examples of prodrug formation groups include groups such as Prog.Med., 1985, 5, pp. 2157-2161 and "Pharmaceutical Research and Development", Vol. 7, Molecular Design, Hirokawa Shoten, 1990, pp. 163-198.

[0062] In addition, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and based on the type of substituent, it can be an acid addition salt or a salt formed with a base. Examples thereof include the salts shown in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use Wiley-VCH, 2008. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or acid addition salts with 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, dibenzotartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, salts with inorganic metals such as sodium, potassium, magnesium, calcium or aluminum, salts with organic bases such as methylamine, ethylamine or ethanolamine, salts with various amino acids and amino acid derivatives such as acetyleucine, lysine or ornithine, ammonium salts and the like.

[0063] In addition, the present invention also includes various hydrates, solvates and crystal polymorphs of the compound of formula (I) and its salts.

[0064] The present invention also includes all compounds of formula (I) or salts thereof labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Examples of suitable isotopes for isotopic labeling of compounds of the present invention include hydrogen ( 2 H. 3 H, etc.), carbon ( 11 C. 13 C. 14 C, etc.), nitrogen ( 13 N. 15 N, etc.), oxygen ( 15 O. 17 O. 18O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I. 125 I etc.) and sulfur ( 35 S, etc.) isotopes. The isotope-labeled compounds of the present invention of the present application can be used for research, such as tissue distribution research of drugs and / or substrates. For example, due to the ease of labeling and detection, tritium ( 3 H) and carbon 14 ( 14 C) can be used for this purpose. In certain circumstances, substitution with heavier isotopes, such as replacement of hydrogen with deuterium (2H), may be therapeutically advantageous by increasing metabolic stability (eg, increasing in vivo half-life, reducing dosage requirements or reducing drug-drug interactions). Substitution with positron emitting isotopes (11C, 18F, 15O, 13N, etc.) can be used in positron emission tomography (PET) testing to test substrate receptor occupancy. The isotope-labeled compounds of the present invention can be generally produced by conventional methods known to those skilled in the art or by the same production methods as in Examples or Production Examples etc., using an appropriate reagent labeled with an isotope instead of an unlabeled reagent.

[0065] (Production Method) Formula (I) compound and its salt can be prepared by adopting various known synthesis methods based on the characteristics of its substituent type or basic structure.Here, according to the type of functional group, in the process from raw material to intermediate, it is effective to replace the functional group with a suitable protecting group (a group that is easily converted into a functional group) as a production technology.The example of protecting group includes PGM Wuts and TW Greene, "Protective Groups in Greene's Organic Synthesis" (Greene's Protective Groups in Organic Synthesis), the 5th edition, John Wiley & Sons Inc., 2014, and the group appropriately selected from the protecting group is used according to the reaction conditions.In this method, the reaction is carried out under the condition of introducing a protecting group, and then the protecting group is removed as needed, so that the desired compound can be obtained. In addition, by introducing a specific group in the process from the raw material to the intermediate, or by further reacting using the resulting compound of formula (I), similar to the protecting group, a prodrug of the compound of formula (I) can be prepared. The reaction can be carried out by applying methods known to those skilled in the art, such as common esterification, amidation and dehydration. A typical method for preparing the compound of formula (I) will be described below. The production method can also be carried out with reference to the references attached to the specification. Note that the production method of the present invention is not limited to the examples described below.

[0066] In this manual, the following abbreviations are sometimes used. DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropyl alcohol, tBuOH: tert-butyl alcohol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, PdCl2(dppf)·CH2 Cl2: [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, iPr2O: diisopropyl ether, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, DABCO: 1,4-diazabicyclo[2.2.2 ] octane, TfOH: trifluoromethanesulfonic acid, COMU: N-[({[(1Z)-1-cyano-2-ethoxy-2-oxoethylidene]amino}oxy)(morpholin-4-yl)methylene]-N-methylmethylammonium hexafluorophosphate, NMM: N-methylmorpholine, CDI: 1,1'carbonyldiimidazole, NMO: N-methylmorpholine N-oxide, LHMDS: lithium bis(trimethylsilyl)amide, NHMDS: sodium bis(trimethylsilyl)amide , DMEDA: N,N'-dimethylethylenediamine, TritonB: benzyltrimethylammonium hydroxide, Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxydiphenyl, Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropyldiphenyl, BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.

[0067] (Production method 1) [Chemical formula 29] (In this formula, PG 1 Represents R 3 Contains NH or OH protecting groups, PG 2 Represents a hydrogen atom or R 1 Contains NH or OH protecting groups. Note that PG 1 -R 3 -R in -3 - represents a divalent group or 3 The divalent group formed by removing the hydrogen of NH or OH, PG 2 -R 1 -R in 1 - indicates that the 1 A divalent group formed by removing the hydrogen of NH and OH. The same applies to the following.)

[0068] The compound of formula (I) can be obtained by subjecting compound (1) to deprotection reaction conditions under acidic conditions. Here, examples of protecting groups that can be removed under acidic conditions include tert-butyloxycarbonyl groups, triphenylmethyl groups, tetrahydro-2H-pyran-2-yl groups, methoxymethyl groups, dimethylmethanediyl groups, tert-butylsulfinyl groups, etc. The reaction is carried out by stirring the compound (1) with an equal amount or excess amount of a deprotecting agent to the compound (1) in a solvent inert to the reaction, under cooling or heating to reflux, usually for 0.1 hour to 5 days. Examples of the deprotecting agent used herein include, but are not particularly limited to, acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid and mixtures thereof. In particular, when the deprotecting agent is trifluoroacetic acid, it is sometimes advantageous to smoothly promote the reaction by carrying out the deprotection reaction in the presence of a cation scavenger such as triisopropylsilane. Examples of the solvent used here include, but are not particularly limited to, alcohols such as MeOH or EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane or chloroform, ethers such as diethyl ether, THF, DOX or dimethoxyethane, DMF, DMSO, MeCN, TfOH or water, and mixtures thereof. By selecting a protecting group, deprotection can also be performed by catalytic hydrogenation or under alkaline conditions. Examples of protecting groups that can be removed by catalytic hydrogenation include benzyl groups, p-methoxybenzyl groups, benzyloxycarbonyl groups, etc. In addition, deprotection can also be performed with a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl (dimethyl) silyl groups, (trimethylsilyl) ethoxymethyl groups, etc. Examples of protecting groups that can be removed under alkaline conditions include acetyl, trifluoroacetyl, benzoyl, etc. In addition, by selecting a protecting group PG that can be removed under different deprotection conditions, 1 and PG 2 , deprotection can also be carried out in stages. For example, the following can be used as a reference regarding this reaction. Wuts (PGMWuts) and Greene (TWGreene), "Greene's Protective Groups in Organic Synthesis", (5th edition, 2014)". Note that when the compound (1) as a raw material has axial chirality, a stereoisomer obtained by once isolating the compound (1) can be used for the reaction.

[0069] (Raw material synthesis 1) This production method shows a method for synthesizing compound (1)-1 and compound (1)-2 contained in compound (1) which is a raw material of production method 1. [Chemical formula 30] (In the formula, ring A represents optionally C 1-3 Alkyl-substituted piperazine, ring B or ring C. R represents C 1-3 Alkyl. The same applies below.)

[0070] (first step) This step is a step of producing compound (3) by hydrolyzing compound (2)-1 contained in the raw material compound (2). The reaction is carried out by stirring compound (2)-1 and an equal amount or excess amount of a hydrolysis reagent to compound (2)-1 in a solvent inert to the reaction under cooling or heating to reflux, usually for 1 hour to 5 days. Examples of the hydrolysis reagent used herein include, but are not particularly limited to, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, aqueous lithium hydroxide solution, trimethyltin hydroxide, and the like. Examples of the solvent include, but are not particularly limited to, alcohols such as methanol, ethanol or n-propanol, ether-based solvents such as tetrahydrofuran, diethyl ether or 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, water and mixtures thereof.

[0071] (Step 2) This step is a method for preparing compound (1)-1 by amidation reaction of compound (3) and compound (4). In this reaction, compound (3) and compound (4) are used in equal amounts or one of them is used in excess, and the mixture of the compounds is stirred in a solvent inactive to the reaction in the presence of a condensing agent, from cooling to heating, preferably at -20°C to 60°C, usually for 0.1 hour to 5 days. Examples of solvents include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF or DOX, halogenated hydrocarbons such as dichloromethane, alcohols, N,N-dimethylformamide, DMSO, ethyl acetate, MeCN and mixtures thereof. Examples of condensing agents include HATU, PyBOP, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), CDI, diphenylphosphoryl azide (DPPA) and the like. It is sometimes preferred to carry out the reaction using an additive such as 1-hydroxybenzotriazole. Conducting the reaction in the presence of an organic base such as TEA, DIPEA and NMM or an inorganic base such as potassium carbonate, sodium carbonate and potassium hydroxide is sometimes beneficial to smoothly promote the reaction. Alternatively, a method of converting compound (3) into a reactive derivative and then subjecting it to an acylation reaction may be used. Examples of reactive derivatives of carboxylic acids include acid halogenated products obtained by reacting with a halogenating agent such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate and the like, and active esters obtained by condensation with 1-hydroxybenzotriazole and the like. The reaction of the reactive derivative and compound (4) may be carried out in a solvent inert to the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon and an ether, from cooling to heating, preferably at -20°C to 120°C. [References] SR Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, volume 1, Academic Press Inc., 1991 The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)", Vol. 16 (2005) (Maruzen)

[0072] (Step 3) This step is a step of producing compound (1)-2 by reductive amination reaction of compound (4) and compound (2)-2 contained in the starting compound (2). The reaction is carried out by stirring an equal amount or an excess of compound (2)-2 and compound (4) in a solvent inert to the reaction in the presence of a reducing agent and acetic acid while cooling from an ice bath to room temperature, usually for 0.1 hour to 5 days. Examples of the reducing agent used herein include, but are not particularly limited to, sodium triacetoxyborohydride (NaBH(OAc)3), 2-methylpyridine borane, sodium cyanoborohydride (NaBH3CN), and the like. Examples of the solvent used herein include, but are not particularly limited to, halogenated hydrocarbons such as dichloromethane, dichloroethane or chloroform, ether-based solvents such as tetrahydrofuran, diethyl ether or 1,4-dioxane, alcohol-based solvents such as methanol or ethanol, acetonitrile, and the like.

[0073] (Raw material synthesis 2) [Chemical formula 31-1] [Chemical formula 31-2] (In the formula, PG 3 Represents the protecting group of OH, LG 1 R represents a leaving group, and BLG represents a boronic acid group, a boronic acid group protected with a boronic acid protecting group, such as a boronic acid pinacol ester group or a trifluoroborate group (hereinafter sometimes referred to as a boronic acid group or the like). Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy, p-toluenesulfonyloxy, and the like. L Indicates OR or H. )

[0074] This preparation method is the first method for preparing the starting compound (2).

[0075] (first step) This step is a method for preparing compound (7) by ipso substitution reaction of compound (5)-1 and compound (6). In this reaction, compound (5)-1 and compound (6) are used in equal amounts or under the condition that one of the compounds is used in excess, and the mixture of the compounds is stirred in a solvent inactive to the reaction or without a solvent, and the mixture is cooled to reflux, preferably at 0°C to 80°C, and is usually continued for 0.1 hours to 5 days. Examples of the solvent used herein include, but are not particularly limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN and mixtures thereof. It is sometimes advantageous to smoothly promote the reaction by conducting 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 sodium hydride, potassium carbonate, sodium carbonate or cesium carbonate. Furthermore, compound (7) can be produced by catalytic hydrogenation of a compound obtained by Mizoroki-Heck reaction of compound (5)-1 and compound (6).

[0076] (Step 2) This step is a method for preparing compound (9) by ipso substitution reaction of compound (7) and compound (8). The reaction conditions were the same as those in the first step of the starting material synthesis 2. Furthermore, compound (9) can be prepared by Negishi coupling of a compound in which the hydrogen atom of compound (8) is converted into a halogen with compound (7).

[0077] (Step 3) This step is carried out by reacting compound (9) and PG 3 A method for preparing compound (10)-1 by ipso substitution reaction of -OH. The PG used here 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol. The reaction conditions were the same as those in the first step of the starting material synthesis 2.

[0078] (Step 4) This step is a method for preparing compound (11) by 2Suzuki-Miyaura coupling reaction of a boronic acid group or other boronic acid derivative with compound (10) (including both compound (10)-1 obtained in the third step of the synthesis method and compound (10)-2 obtained in (Starting Material Synthesis 9) described below). Examples of the boronic acid group and the like used herein include, but are not particularly limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triol borate salt group, and a trifluoroborate salt group. In this reaction, compound (10) and R 2 -boronic acid group and the like are used in equal amounts or under the condition that one of the compounds is in excess, and the mixture of the compounds is stirred in a solvent inactive to the reaction in the presence of a base and a palladium catalyst, from room temperature to heating reflux, preferably at 20°C to 140°C, usually for 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, alcohols such as MeOH, EtOH, isopropanol, butanol or pentanol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water and mixtures thereof. Examples of the base include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide. Examples of palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane additive, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]methanesulfonatepalladium(II), palladium(II) acetate, etc. Conducting the reaction in the presence of a ligand such as dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine or 1,1'-bis(diphenylphosphino)ferrocene is sometimes beneficial for smoothly promoting the reaction. Furthermore, heating the mixture by microwave radiation is sometimes advantageous to smoothly promote the reaction. [References] J. Am. Chem. Soc., 2005, 127, pp. 4685-4696 Org.Lett.2011,13,pp.3948-3951 Org.Lett.2012,14,pp.1278-1281 Compound (11) (wherein R 2 is hydrogen) can be prepared by dehydrogenation reaction of compound (10) with a Pd catalyst and a reducing agent. [References] J.Org.Chem.,1977,42,pp.3491-3494 Tetrahedron Letters 2013,54,5207-5210

[0079] (Step 5) This step is a method for preparing compound (13) by Suzuki-Miyaura coupling reaction of compound (11) and compound (12). The reaction conditions are the same as those in the fourth step of the starting material synthesis 2. When compound (13) has axial chirality, compound (13) is obtained in the form of a stereoisomer mixture, and each stereoisomer can be separated by using a conventional separation operation (eg, ODS column chromatography or silica gel column chromatography).

[0080] (Step 6) This step is a method for preparing compound (14) by deprotecting compound (13) through catalytic hydrogenation reaction. The reaction can be carried out by stirring compound (13) under a hydrogen atmosphere in the presence of a metal catalyst in a reaction-inactive solvent such as MeOH, EtOH or ethyl acetate, from normal pressure to pressure, from cooling to heating, preferably at room temperature, for 1 hour to 5 days. As the metal catalyst, a palladium catalyst such as Pd / C or palladium black, a platinum catalyst such as platinum plate or platinum oxide, a nickel catalyst such as reduced nickel or Raney nickel, etc. are used.

[0081] (Step 7) This step is a method for preparing compound (2) by reacting compound (14) and compound (15). The reaction is carried out by reacting equal amounts of compound (14) and compound (15) or a mixture in which one of the compounds is in excess in the presence of a base in a solvent inert to the reaction, from cooling to heating to reflux, preferably at 0°C to 80°C, usually for 0.1 hour to 5 days. The solvent used here is not particularly limited, and examples thereof include aromatic hydrocarbons such as benzene, toluene or xylene, alcohols such as MeOH or EtOH, ethers such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, DMF, DMSO, ethyl acetate, MeCN and mixtures thereof. Examples of bases include, but are not particularly limited to, organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium or tBuOK, and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate or sodium hydride. It is sometimes advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride. For example, the following can be used as a reference regarding this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry), 5th edition, Vol. 14, Maruzen, 2005 Compound (2) sometimes has axial chirality and is obtained as a mixture of stereoisomers by 2 Each stereoisomer can be separated by subjecting the compound (2) having a protecting group or a compound obtained by subjecting the compound (2) to a common separation operation such as ODS column chromatography or silica gel column chromatography. The reaction conditions of the deprotection reaction used here are the same as those in the step described in Production Method 1. In addition, LG 1 Compound (15) which is a halogen atom can be prepared by halogenation of the atom with LG 1 Examples of the halogenating agent used herein include, but are not particularly limited to, thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, and the like. For example, the following can be used as a reference regarding this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry), 5th edition, Vol. 13, Maruzen, 2004 Among them, LG 1 The compound (15) which is a sulfonyloxy group can be prepared by reacting it with LG in the presence of a base. 1 The corresponding part is a hydroxyl compound and is prepared by sulfonylation. Examples of the sulfonylating agent used herein include, but are not particularly limited to, methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, etc. Examples of the base include, but are not particularly limited to, TEA, DIPEA, pyridine, tetramethylethylenediamine, etc. For example, the following can be used as a reference regarding this reaction. Synthesis, 1999, 9, pp. 1633-1636 In this step, the LG of compound (15) can be reacted with 1 The compound (2) can be prepared by Mitsunobu reaction of the corresponding compound having a hydroxyl group and the compound (14). For example, the following can be used as reference with respect to the Mitsunobu reaction described herein. Chem. Asian J. 2007, 2, pp. 1340-1355

[0082] (Raw material synthesis 3) [Chemical formula 32-1] [Chemical formula 32-2] (Where R LG Represents C 1-12 Alkyl, q represents 1 or 2. )

[0083] This preparation method is a second method for preparing the starting compound (13).

[0084] (first step) This step is carried out by reacting compound (7) and R LG A method for preparing compound (16) by ipso substitution reaction of -SH. R used herein LG -SH examples include C 1-12 Alkyl mercaptans such as ethyl mercaptan and dodecanethiol. The reaction conditions were the same as those in the first step of the starting material synthesis 2.

[0085] (Step 2) This step is carried out by reacting compound (16) with PG 3 Method for preparing compound (17)-1 by ipso substitution reaction of -OH. PG used herein 3 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol. The reaction conditions were the same as those in the first step of the starting material synthesis 2.

[0086] (Step 3) This step is a method for preparing compound (18) by 2 Suzuki-Miyaura coupling reaction of a boronic acid group or other boronic acid derivative with compound (17) (including both compound (17)-1 obtained in the second step of this synthesis method and compound (17)-2 obtained in (Starting Material Synthesis 8) described below). The reaction conditions are the same as those in the fourth step of the starting material synthesis 2. Compound (18) (wherein R 2 is hydrogen) can be prepared by dehydrogenation reaction of compound (17) with a Pd catalyst and a reducing agent. [References] J.Org.Chem.,1977,42,pp.3491-3494 Tetrahedron Letters 2013,54,5207-5210

[0087] (Step 4) This step is a method for preparing compound (19) by Suzuki-Miyaura coupling reaction of compound (18) and compound (12). The reaction conditions are the same as those in the fourth step of the starting material synthesis 2. Compound (19) sometimes has axial chirality and is obtained as a mixture of stereoisomers by 19 Each stereoisomer can be separated by subjecting the compound (19) having a protecting group or a compound obtained by subjecting the compound (19) to a deprotection reaction to a common separation operation such as ODS column chromatography or silica gel column chromatography. The reaction conditions of the deprotection reaction used here are the same as those in the step described in Production Method 1. The subsequent conversion of PG 2 Examples of the protecting group include a tetrahydro-2H-pyran-2-yl group and the like.

[0088] (Step 5) This step is a method for producing compound (20) by oxidation reaction of compound (19). In this reaction, compound (19) is treated with an equal amount or an excess of an oxidant in a solvent inactive to the reaction, from cooling to heating, preferably at -20°C to 80°C, usually for 0.1 hour to 3 days. In this reaction, meta-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is appropriately used for oxidation. Examples of solvents include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN and mixtures thereof. Other examples of oxidants include cumene hydroperoxide, Oxone, active manganese dioxide, chromic acid, potassium permanganate, sodium periodate and the like. [References] The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry), 5th edition, Vol. 17, Maruzen, 2004

[0089] (Step 6) This step is a method for preparing compound (13) by ipso substitution reaction of compound (20) and compound (8). The reaction conditions were the same as those in the first step of the starting material synthesis 2. When compound (13) has axial chirality, compound (13) is obtained in the form of a stereoisomer mixture, and each stereoisomer can be separated by using a conventional separation operation (eg, ODS column chromatography or silica gel column chromatography).

[0090] (Raw material synthesis 4) [Chemical formula 33]

[0091] This preparation method is a second method for preparing the starting compound (2).

[0092] (first step) This step is a method for preparing compound (21) by deprotection through catalytic hydrogenation of compound (20)-1. The reaction conditions are the same as those in the sixth step of the starting material synthesis 2.

[0093] (Step 2) This step is a method for preparing compound (22) by reacting compound (21) with compound (15). The reaction conditions are the same as those in the seventh step of the starting material synthesis 2.

[0094] (Step 3) This step is a method for preparing compound (2) by ipso substitution reaction of compound (22) and compound (8). The reaction conditions were the same as those in the first step of the starting material synthesis 2. Compound (2) sometimes has axial chirality and is obtained as a mixture of stereoisomers by 2 Each stereoisomer can be separated by subjecting the compound (2) having a protecting group or a compound obtained by subjecting the compound (2) to a common separation operation such as ODS column chromatography or silica gel column chromatography. The reaction conditions of the deprotection reaction used here are the same as those in the step described in Production Method 1.

[0095] (Raw material synthesis 5) [Chemical formula 34] (In the formula, PG 4 represents a tert-butyl group, R 3A represents X attached to a compound represented by formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (XII) or formula (XIII) 2 In the formula, PG 1Represents R 3A The protective group of NH or OH contained in

[0096] This production method is a method for producing compound (2)-3 contained in the raw material compound (2).

[0097] (first step) This step is a method for preparing compound (23) by hydrolysis of compound (5)-1. The reaction is carried out by stirring compound (5)-1, cooling to heating reflux, usually for 0.1 hour to 5 days. Examples of solvents used herein include but are not particularly limited to alcohols, acetone, DMF, THF, etc. In addition, a mixed solvent of the above solvents and water is sometimes suitable for the reaction. Examples of hydrolysis reagents include but are not particularly limited to aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, etc. For example, the following can be used as a reference regarding this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)", Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, pp. 1378-1382.

[0098] (Step 2) This step is a method for producing compound (24) by protecting the hydroxyl group of compound (23) with a tert-butyl group. The reaction is carried out by stirring compound (23), cooling to heating reflux, usually for 0.1 hour to 5 days. Examples of solvents used herein include but are not particularly limited to ethers such as THF or DOX, halogenated hydrocarbons such as dichloromethane, tBuOH, DMF, etc. Examples of tert-butyl protecting agents include but are not particularly limited to isobutylene, 2-tert-butyl-1,3-diisopropylisourea, etc. Furthermore, compound (24) can be prepared by a dehydration condensation reaction of compound (23) and tBuOH. For example, the following can be used as a reference regarding this reaction. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014 Org.Lett.,2012,14,17,pp.4678-4681

[0099] (Step 3) This step is carried out by reacting compound (24) and R LG A method for preparing compound (25) by ipso substitution reaction of -SH. The reaction conditions were the same as those in the first step of the starting material synthesis 3.

[0100] (Step 4) This step is carried out by reacting compound (25) with PG 3 A method for preparing compound (26) by ipso substitution reaction of -OH. The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0101] (Step 5) This step is carried out by reacting compound (26) with R 2 A method for preparing compound (27) by Suzuki-Miyaura coupling reaction of boronic acid derivatives composed of -boronic acid groups and the like. The reaction conditions are the same as those in the fourth step of the starting material synthesis 2. Compound (27) (wherein R 2 is hydrogen) can be prepared by dehydrogenation reaction of compound (26) with a Pd catalyst and a reducing agent. [References] J.Org.Chem.,1977,42,pp.3491-3494 Tetrahedron Letters 2013,54,5207-5210

[0102] (Step 6) This step is a method for preparing compound (28) by Suzuki-Miyaura coupling reaction of compound (27) and compound (12). The reaction conditions are the same as those in the fifth step of the starting material synthesis 2.

[0103] (Step 7) This step is a method for producing compound (29) by oxidation reaction of compound (28). The reaction conditions are the same as those in the fifth step of the starting material synthesis 3. When compound (29) has axial chirality, compound (29) can be obtained as a mixture of stereoisomers, and each stereoisomer can be separated by using a conventional separation operation (eg, ODS column chromatography or silica gel column chromatography) or by fractional crystallization. In addition, compound (29) sometimes converts PG 2The compound (28) can be converted to another protecting group and then deprotected, thereby reacting the protecting group PG introduced later under different conditions. 1 Deprotection. The reaction conditions of the deprotection reaction used here are the same as those in the step described in Production Method 1. The subsequent conversion of PG 2 Examples of the protecting group include a tetrahydro-2H-pyran-2-yl group and the like. For example, the following can be used as a reference regarding this reaction. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014

[0104] (Step 8) This step is a method for preparing compound (30) by deprotecting compound (29) through catalytic hydrogenation reaction. The reaction conditions are the same as those in the sixth step of the starting material synthesis 2.

[0105] (Step 9) This step is a method for preparing compound (31) by reacting compound (30) with compound (15). The reaction conditions are the same as those in the seventh step of the starting material synthesis 2.

[0106] (Step 10) This step is a method for preparing compound (32) by ipso substitution reaction of compound (31) and compound (8). The reaction conditions are the same as those in the sixth step of the starting material synthesis 3.

[0107] (Step 11) This step is a method for preparing compound (33) by subjecting compound (32) to a deprotection reaction. The reaction conditions are the same as those in the step described in Preparation Method 1.

[0108] (Step 12) This step is a method for preparing compound (2)-3 by reacting compound (33) with compound (6)-1. In this reaction, compound (33) and compound (6)-1 are used in equal amounts or one of them is used in excess, and the mixture of the compounds is stirred in a solvent inert to the reaction in the presence of a condensing agent, from cooling to heating, preferably at -20°C to 60°C, usually for 0.1 hour to 5 days. Examples of solvents include aromatic hydrocarbons such as toluene, ethers such as THF or DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN and mixtures thereof. Examples of condensing agents include PyBOP, HATU, CDI and the like. It is sometimes advantageous to smoothly promote the reaction by conducting 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 cesium carbonate.

[0109] (Raw material synthesis 6) [Chemical formula 35]

[0110] This production method is a method for producing compound (13)-1 contained in the raw material compound (13).

[0111] This step is a method for preparing compound (34) by ipso substitution reaction of compound (29)-1 and compound (8). The reaction conditions are the same as those in the sixth step of the starting material synthesis 3.

[0112] (Step 2) This step is a method for preparing compound (35) by subjecting compound (34) to a deprotection reaction. The reaction conditions are the same as those in the step described in Preparation Method 1.

[0113] (Step 3) This step is a method for preparing compound (13)-1 by reacting compound (35) and compound (6). The reaction conditions are the same as those in step 12 of the starting material synthesis 5.

[0114] (Raw material synthesis 7) [Chemical formula 36]

[0115] This preparation method is a second method for preparing the starting compound (34).

[0116] (first step) This step is a method for preparing compound (36) by ipso substitution reaction of compound (24) and compound (8). The reaction conditions are the same as those in the second step of the starting material synthesis 2.

[0117] (Step 2) This step is carried out by reacting compound (36) with PG 3 A method for preparing compound (37) by ipso substitution reaction of -OH. The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0118] (Step 3) This step is carried out by reacting compound (37) with R 2 A method for preparing compound (38) by Suzuki-Miyaura coupling reaction of boronic acid derivatives composed of -boronic acid groups and the like. The reaction conditions are the same as those in the fourth step of the starting material synthesis 2. Compound (38) (wherein R 2 is hydrogen) can be prepared by dehydrogenation reaction of compound (37) with a Pd catalyst and a reducing agent. [References] J.Org.Chem.,1977,42,pp.3491-3494 Tetrahedron Letters 2013,54,5207-5210

[0119] (Step 4) This step is a method for preparing compound (34) by Suzuki-Miyaura coupling reaction of compound (38) and compound (12). The reaction conditions are the same as those in the fifth step of the starting material synthesis 2.

[0120] (Raw material synthesis 8) [Chemical formula 37]

[0121] This production method is a method for producing compound (17)-2 contained in the raw material compound (17).

[0122] (first step) This step is a method for preparing compound (5)-2 by chlorination reaction of compound (39). The reaction is carried out by stirring an equal amount of compound (39) and a chlorinating agent or a mixture of one of the compounds in excess in a solvent inert to the reaction or in the absence of a solvent, from cooling to heating to reflux, preferably at 60° C. to heating to reflux, usually for 0.1 hour to 5 days. Examples of the solvent used herein include but are not particularly limited to aromatic hydrocarbons such as toluene, ethers such as THF or DOX, halogenated hydrocarbons such as dichloromethane, etc. Examples of the chlorinating agent include phosphorus oxychloride, thionyl chloride, etc. It is sometimes beneficial to smoothly promote the reaction in the presence of an organic base such as TEA, DIPEA or NMM.

[0123] (Step 2) This step is to react compound (5)-2 with R LG A method for preparing compound (40) by ipso substitution reaction of -SH. The reaction conditions were the same as those in the first step of the starting material synthesis 3.

[0124] (Step 3) This step is carried out by reacting compound (40) with PG 3 A method for preparing compound (41) by ipso substitution reaction of -OH. The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0125] (Step 4) This step is a method for preparing compound (17)-2 by ipso substitution reaction of compound (41) and compound (6)-1. The reaction conditions were the same as those in the first step of the starting material synthesis 2.

[0126] (Raw material synthesis 9) [Chemical formula 38]

[0127] This production method is a method for producing compound (10)-2 contained in the raw material compound (10).

[0128] (first step) This step is a method for preparing compound (42) by ipso substitution reaction of compound (5)-2 and compound (8). The reaction conditions are the same as those in the second step of the starting material synthesis 2. Alternatively, compound (42) can be prepared by Negishi coupling of a compound in which the hydrogen atom of compound (8) is converted into a halogen with compound (5)-2.

[0129] (Step 2) This step is carried out by reacting compound (42) and PG 3 A method for preparing compound (43) by ipso substitution reaction of -OH. The reaction conditions are the same as those in the third step of the starting material synthesis 2.

[0130] (Step 3) This step is a method for preparing compound (10)-2 by ipso substitution reaction of compound (43) and compound (6)-1. The reaction conditions were the same as those in the first step of the starting material synthesis 2.

[0131] The compound of formula (I) is isolated and purified as a free compound, its salt, hydrate, solvate or a crystalline polymorphic substance or a substance in the form of an amorphous solid. The salt of the compound of formula (I) can also be prepared by subjecting the compound to a salt-forming reaction, which is a common method. Isolation and purification are performed by applying common chemical manipulations such as extraction, fractional crystallization, or various types of fractional chromatography. Various types of isomers can be produced by selecting appropriate raw material compounds, or can be separated by utilizing the differences in physical and chemical properties between isomers. For example, optical isomers can be obtained by general optical analysis methods of racemates (e.g., fractional crystallization, inducing racemates into diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), or can be prepared from appropriate optically active raw material compounds. In addition, the compound of formula (I) or its intermediate sometimes has axial chirality and is obtained as a mixture of stereoisomers, each of which can be separated by using a conventional separation operation (e.g., octadecylsilyl (ODS) column chromatography or silica gel column chromatography) or by fractional crystallization.

[0132] The pharmacological activity of the compounds of formula (I) was demonstrated by the following tests.

[0133] Test Example 1: Evaluation of KRAS degradation activity in human G12D mutant KRAS-positive pancreatic cancer line AsPC-1 (CRL-1682; ATCC) The KRAS degradation activity of the test compounds was assessed by measuring the expression level of KRAS G12D by cell ELISA. AsPC-1 cells were seeded in 384-well plates (Greinerbio-one) at 20 μL per well, with 2.0 x 10 4 As for the cell culture conditions, RPMI 1640 (from Sigma-Aldrich) medium containing 10% fetal bovine serum (from Cytiva) was used at 37°C in the presence of 5% CO2. The next day, the test compound (10 points, final concentrations ranging from 10 μM to 0.3 nM) and DMSO (from FUJIFILM Wako Pure Chemical Corporation) as a solvent for the test compound as a negative control were diluted 500-fold with fresh culture medium and 20 μL was added to each well. The cells were cultured overnight. The next day, the culture supernatant was removed and 4% paraformaldehyde phosphate buffer (from Fujifilm Wako Pure Chemical Industries, Ltd.) was added, 20 μL per well. The plate was allowed to stand at room temperature for 30 minutes to fix the cells. Then, the supernatant was removed and phosphate-buffered saline (PBS; from Fujifilm Wako Pure Chemical Industries, Ltd.) containing 0.1% TritonX-100 (from Amersham Biosciences) was added, 20 μL per well. After standing at room temperature for 10 minutes, the supernatant was removed. 25 μL PBS was added to each well, and the supernatant was removed to wash each well. Washing was performed twice in total. Next, the supernatant was removed and PBS containing 0.5% sodium dodecyl sulfate (SDS; from Invitrogen) was added, 20 μL per well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation (using a centrifugal dehydrator, the supernatant was removed by the same method as below). 25 μL of PBS was added to each well, and the supernatant was removed to wash each well. Washing was performed twice in total. The supernatant was removed, and a blocking solution (Intercept Blocking Buffer; from Li-COR Biosciences) was added, 20 μL per well. After standing at room temperature for 30 minutes, the supernatant was removed, and the following solutions were added to the positive control well and other wells at 15 μL / well, respectively, as primary antibodies: a solution in which the anti-β-actin antibody (anti-β-Actin antibody [mAbcam8226]-loading control; from abcam) was diluted 1,000 times with a blocking solution, a solution in which the anti-rat (G12D mutant-specific) antibody (Ras (G12D mutant-specific) (D8H7) rabbit mAb #14429; from Cell Signaling Technology) was diluted 1,000 times with a blocking solution, and a solution in which the anti-β-actin antibody (from abcam) was diluted 1,000 times. The plates were placed at 4°C overnight. The next day, the supernatant was removed. 25 μL of PBS was added to each well, and the supernatant was removed to wash each well. Washing was performed twice in total. The supernatant was removed, and 15 μL of the following solution was added to each well as a secondary antibody: a solution obtained by diluting donkey anti-mouse IgG H&L (IRDye680RD) (from Li-COR Biosciences) and goat anti-rabbit IgG H&L (IRDye 800CW) (from Li-CORBiosciences) 1,000 times with blocking solution. After standing at room temperature for 1 hour, the supernatant was removed. 25 μL of PBS was added to each well, and the supernatant was removed to wash each well. Washing was performed twice in total. After removing the supernatant, the plate was air-dried at room temperature for 2 hours or more, and the 700nm and 800nm ​​fluorescence signals were measured with Aerius (from Li-COR Biosciences). After correcting the RAS signal value measured at a fluorescence wavelength of 800 nm with the β-actin signal value measured at a fluorescence wavelength of 700 nm, the degradation rate at 10 μM (the highest concentration evaluated) was calculated, with the signal value when DMSO was added as 0% and the signal value when stained only with anti-β-actin antibody as 100%. The table below shows the results for some of the tested compounds of formula (I).

[0134] In the following table, Ex represents the instance number.

[0135] [Table 1] Ex Degradation % Ex Degradation % 1 43 10 37 2 44 11 51 3 46 12 20 4 15 13 57 5 46 14 58 6 25 15 17 7 20 16 30 8 53 17 37 18 20

[0136] Test Example 2: Evaluation of the anchorage-independent cell growth inhibitory effect on human G12D mutant KRAS-positive pancreatic cancer line AsPC-1 The anchorage-independent cell growth inhibitory effects of the test compounds were evaluated by 3D cell culture. AsPC-1 cells were seeded in a low cell adhesion round-bottom 384-well plate (PrimeSurface: from Sumitomo Bakelite) at 5 x 10 cells per well. 2 cells, 36 μL / well. Regarding cell culture conditions, RPMI 1640 medium containing 10% fetal bovine serum was used at 37°C in the presence of 5% CO2. The next day, the test compound (6 points, final concentration in the range of 10 μM to 30 nM) and DMSO (which is the solvent of the test compound) as a negative control were diluted 100 times with fresh culture medium, and 4 μL was added to each well. After culturing for 6 days at 37°C and 5% CO2, 20 μL CellTiter Glo 2.0 (from Promega) was added to each well. After stirring for 1 hour at room temperature with a plate mixer (from FINEPCR), the luminescent signal was measured with ARVO X3 (from PerkinElmer). The signal value of DMSO treatment was taken as 100% and the signal value of medium without cells was taken as 0%. The 50% inhibitory concentration (IC 50 The following table shows the results for some test compounds of formula (I).

[0137] In the following table, Ex represents the instance number.

[0138] [Table 2] Ex <![CDATA[IC 50 (μM)]]> Ex <![CDATA[IC 50 (μM)]]> 1 3.3 10 3.7 2 1.9 11 2.9 3 2.8 12 3.5 4 5.1 13 2.0 5 2.2 14 1.2 6 3.6 15 3.9 8 3.1 17 2.6 9 3.4 18 7.4 19 2.3

[0139] Test Example 3: Evaluation of the inhibitory effect on KRAS G12D / SOS / c-Raf complex formation The inhibitory effect of the test compounds on protein complex formation was detected by time-resolved fluorescence resonance energy transfer (TR-FRET) method using human recombinant KRAS G12D, SOS and c-Raf proteins. Biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5 μL; 400 nM) and test compounds dissolved in assay buffer (50 mM HEPES [from Jena], 150 mM NaCl [from Nacalai Tesque], 5 mM MgCl2 [from Thermo Fisher Scientific], 0.05% Tween20 [from Sigma-Aldrich], pH 7.0) were added to a 384-well plate (from Corning) in a liquid volume of 2.5 μL at 40,000 nM to 40 nM. c-Raf (amino acid region 51-131) GST (2.5 μL; 130 nM) and Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 μL; 1.3 μM) containing GTP (from Sigma-Aldrich; 2 μM) were added to the plate, and the plate was left to stand at room temperature for 1 hour. Then, a mixture (10 μL) of LANCE Ulight-anti-GST (from PerkinElmer; 120 nM) and LANCE Eu-W1024-labeled streptavidin (from PerkinElmer; 100 ng / mL) was added, and the fluorescence intensity at 620-nm and 665-nm was measured using EnVision 2104 (from PerkinElmer) under the condition of excitation wavelength of 337 nm. After the values ​​were normalized with the fluorescence intensity at the reference wavelength of 620 nm, the 50% inhibitory concentration (IC) was calculated by Sigmoid-Emax nonlinear regression analysis. 50 ), where the signal value of solvent treatment was taken as 0% inhibition, and the signal value without addition of GTP was taken as 100% inhibition.

[0140] The results of the above tests show that some compounds of formula (I) have G12D mutant KRAS degradation activity (Test Example 1). In addition, an inhibitory effect on complex formation (G12D mutant KRAS inhibitory effect) was also observed (Test Example 3). In addition, some compounds of formula (I) were observed to have a cell growth inhibitory effect on human G12D mutant KRAS positive pancreatic cancer cell lines (Test Example 2). Therefore, the compounds of formula (I) can be used to treat cancer, in particular pancreatic cancer, such as G12D mutant KRAS positive pancreatic cancer, etc.

[0141] The pharmaceutical composition containing one or two or more compounds of formula (I) or their salts as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, ie, pharmaceutical excipients, pharmaceutical carriers, etc. The administration method can be oral administration, such as tablets, pills, capsules, granules, powders, liquids or other agents, or parenteral administration, such as intra-articular injection, intravenous injection, intramuscular injection or other injection, transmucosal agent, inhalation agent, etc.

[0142] As solid compositions for oral administration, tablets, powders, granules, etc. can be used. In such solid compositions, one or two or more active ingredients are mixed with at least one inactive excipient. The composition may contain inactive additives such as lubricants, disintegrants, stabilizers or dissolution aids according to conventional methods. As required, tablets or pills may be coated with sugar coating or gastric or intestinal soluble films. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inactive diluents, such as purified water or EtOH. In addition to inactive diluents, liquid compositions may also include adjuvants, such as solubilizers, wetting agents or suspending agents, sweeteners, flavoring agents, aromatics or preservatives.

[0143] Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of aqueous solvents include distilled water for injection or physiological saline. Examples of non-aqueous solvents are alcohols, such as EtOH. Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. These may be filtered, microbicides added or sterilized by radiation through a bacteria-retaining filter. In addition, such compositions may be made into sterile solid compositions, dissolved or suspended in sterile water or a sterile injection solvent before use.

[0144] Transmucosal agents such as inhalants or nasal agents are used in solid, liquid or semisolid forms and can be produced according to conventional known methods. For example, known excipients can be appropriately added, and in addition, pH adjusting agents, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. Suitable suction or insufflation devices can be used for administration. For example, known devices such as metering and administration inhalation devices or nebulizers can be used to administer the powder of a single compound or a prepared mixture, or in the form of a solution or suspension combined with a medically acceptable carrier. Dry powder inhalers, etc. can be administered in a single or multiple administrations, and dry powders or powder-containing capsules can be used. Alternatively, suitable propellants can be used, for example, suitable gases such as chlorofluorocarbons or carbon dioxide, in the form of pressurized aerosol sprayers.

[0145] In the case of conventional oral administration, a daily dose of about 0.001 to 100 mg / kg body weight is appropriate, preferably 0.1 to 30 mg / kg body weight, further preferably 0.1 to 10 mg / kg body weight, and the dose is given once a day or divided into 2 to 4 times. In the case of intravenous administration, a daily dose of about 0.0001 to 10 mg / kg body weight is appropriate, and it is given once a day or divided into multiple administrations within a day. In addition, the daily dose of the transmucosal agent is about 0.001 to 100 mg / kg body weight, which is given once a day or divided into multiple administrations within a day. The dosage is appropriately determined according to individual circumstances, taking into account symptoms, age, gender, etc.

[0146] Depending on the administration route, dosage form, administration site and the types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, in one embodiment, 0.01 to 50% by weight of one or more compounds of formula (I) or salts thereof as active ingredients.

[0147] The compounds of formula (I) may be used in combination with various therapeutic or prophylactic agents for the treatment of diseases for which the compounds of formula (I) are believed to be effective. The combination may be administered simultaneously or separately, sequentially or at desired intervals. The preparations administered simultaneously may be prepared as a combined preparation or may be prepared separately. Example

[0148] The preparation method of the compound of formula (I) will be described in more detail below based on the examples. Note that the present invention is not limited to the compounds described in the following examples. The preparation method of the raw material compound is also shown in the preparation examples. The preparation method of the compound of formula (I) is not limited to the preparation method of the specific embodiment described below, and the compound of formula (I) can also be prepared by a combination of preparation methods or methods obvious to those skilled in the art.

[0149] Note that in this specification, compounds are sometimes named using naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.).

[0150] For convenience, the concentration mol / L is shown as M. For example, 1M sodium hydroxide aqueous solution means 1 mol / L sodium hydroxide aqueous solution.

[0151] The “amorphous solid form” described in the present specification includes a form having no peak in a powder X-ray diffraction (XRD) pattern and a form having low crystallinity.

[0152] Preparation Example 1 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100g), DOX (1000mL) and THF (500mL) was cooled with an ice bath, followed by addition of DIPEA (240mL) and (1S, 4S)-2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (48g). The mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure until the total amount of the solution became about 400mL. A mixed solvent (hexane / ethyl acetate = 4 / 1, 1000mL) was added to the resulting solution, and the mixture was stirred at room temperature. The precipitated solid was filtered to obtain tert-butyl (1S,4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (123 g) as a solid.

[0153] Preparation Example 2 At room temperature, ethyl mercaptan (5.3 mL) and DABCO (10.6 g) were added to a mixture of (1S, 4S)-5-(7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-yl)-2,5-diazabicyclo [2.2.1] heptane-2-tert-butyl carboxylate (38.4 g) and CH2Cl2 (500 mL), and the mixture was stirred at room temperature for 17 hours under an argon atmosphere. Ethyl mercaptan (1 mL) was added, and the mixture was further stirred at room temperature for 6 hours. Then, DABCO (1.5 g) was added thereto and stirred at room temperature for 3 days, cesium carbonate (2.1 g) was added thereto and stirred at room temperature for 22 hours. Ice water was poured into the reaction mixture, and the mixture was extracted twice with CHCl3. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl (1S,4S)-5-[7-bromo-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (43.2 g) as a foamy solid.

[0154] Preparation Example 3 A mixture of (1S,4S)-5-[7-bromo-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (40.2 g), dehydrated THF (400 mL) and (1S)-1-phenylethan-1-ol (10 mL) was stirred thoroughly in an ice / MeOH bath under cooling, tBuOK (15.3 g) was added, and the mixture was stirred under cooling for 30 minutes under an argon atmosphere and at room temperature for 30 minutes. Ice and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain (1S,4S)-5-{7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (45.94 g) as a foamy solid.

[0155] Preparation Example 4 A mixture of (1S,4S)-5-{7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (45.93 g), cyclopropylboronic acid (9.8 g), tripotassium phosphate (55 g), PdCl2(dppf)·CH2Cl2 (5.4 g), MeCN (360 mL), DOX (240 mL) and water (120 mL) was degassed and then purged with argon, and the mixture was stirred at 90° C. for 5 hours under an argon atmosphere. The cooled reaction mixture was concentrated to about half the volume under reduced pressure, and a saturated aqueous sodium bicarbonate solution (100 mL) and water (300 mL) were poured into the residue, and extracted twice with ethyl acetate. After washing the combined organic layer with a saturated sodium chloride aqueous solution, thiol-modified silica gel (about 10 g) and alkaline silica gel (about 10 g) were added, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S, 4S)-5-{7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (27.74 g) as a foamy solid.

[0156] Preparation Example 5 A mixture of (1S,4S)-5-{7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (17.7 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (19.6 g), palladium(II) acetate (0.7 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (2.7 g), barium hydroxide (14.6 g), DOX (500 mL) and water (50 mL) was degassed and then purged with argon, and the mixture was stirred at 50° C. under argon atmosphere for 6 hr. The reaction suspension after cooling was filtered with a diatomaceous earth (registered trademark) pad and washed with ethyl acetate. After the filtrate was concentrated under reduced pressure to about 1 / 4, water was added and extracted twice with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified twice by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain (1S, 4S)-5-{6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (derived from a mixture of diastereomers of about 4.5:1 of axial chirality, 20.64g), which was a foamy solid.

[0157] Preparation Example 6 A mixture of (1S, 4S)-5-{6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (derived from an approximately 4.5:1 diastereoisomer mixture of axial chirality, 20.63 g) and EtOH (250 mL) was stirred at room temperature and 4-methylbenzene-1-sulfonic acid monohydrate (4.8 g) was added, and the mixture was stirred at room temperature for 1 hour under an argon atmosphere. Ice and saturated aqueous sodium bicarbonate solution were poured into the reaction mixture, and the resulting white insoluble matter was dissolved in ethyl acetate and extracted twice with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (derived from a single diastereomer of axial chirality, 11.17 g). The low polar fraction was a foamy solid, and (1S,4S)-5-{(7P)-6-cyclopropyl-2-(ethylsulfanyl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (derived from a single diastereomer of axial chirality, 1.92 g) was a high polar fraction, a foamy solid.

[0158] Preparation Example 7 To a mixture of (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.1 g) and THF (150 mL) was added 3,4-dihydro-2H-pyran (10 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (0.7 g) with stirring at room temperature, and the mixture was stirred at room temperature for 14 hours under an argon atmosphere. 3,4-dihydro-2H-pyran (5 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (0.3 g) were added, and the mixture was stirred at room temperature for another 5 hours. After adding TEA (2 mL) to quench the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline-4-yl 1-[4-(4-(4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.15 g) as a foamy solid.

[0159] Preparation Example 8 Under ice-cooling, to a mixture of (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (11.14 g) and CH2Cl2 (170 mL) was added m-chloroperbenzoic acid (about 30% water content, 7.9 g), and the mixture was stirred at room temperature for 1.5 hours under an argon atmosphere. Ice, a saturated aqueous sodium thiosulfate solution, and a saturated aqueous sodium bicarbonate solution were added, and the mixture was stirred at room temperature for about 20 minutes. The reaction solution was then diluted with CH2Cl2 and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (1S,4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (9.02 g) as a foamy solid.

[0160] Preparation Example 9 To a mixture of (1S, 4S)-5-{(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-(oxacyclohexane-2-yl)-1H-indazole-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (4.5 g) and MeOH (100 mL), 10% Pd / C (52% water content, 1 g) was added, and the mixture was stirred at room temperature overnight under a normal pressure hydrogen atmosphere. Celite (registered trademark) was added, the mixture was filtered, and washed with ethyl acetate and CHCl3 at the same time. Toluene (about 20 mL) was added to the filtrate, and the mixture was concentrated under reduced pressure. MeOH (80mL) and 10% Pd / C (52% water content, 1.4g) are added to the obtained solid, and stirred at room temperature for 3 hours under normal pressure hydrogen atmosphere. Celite (registered trademark) is added, the mixture is filtered, and washed with ethyl acetate and CHCl3 at the same time. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (1S, 4S) -5-{(7M) -6- cyclopropyl -2- (ethylsulfonyl) -7- [6- fluoro-5-methyl -1- (oxacyclohexane -2- base) -1H- indazole -4- base] -8- hydroxyquinazoline -4- base} -2,5- diazabicyclo [2.2.1] heptane -2- carboxylic acid tert-butyl ester (3.42g), which is a foamy solid.

[0161] Preparation Example 10 To (1S, 4S) -5- { (7M) -6- cyclopropyl -2- (ethylsulfonyl) -7- [6- fluoro -5- methyl -1- (oxacyclohexane -2- base) -1H- indazole -4- base] -8- hydroxyquinazoline -4- base} -2,5- diazabicyclo [2.2.1] heptane -2- carboxylic acid tert-butyl ester (3.01g), DMF (30mL) and 4- (chloromethyl) benzoic acid methyl ester (1g) mixture at room temperature stirring and adding cesium carbonate (4g), and under argon atmosphere at room temperature stirring mixture overnight. Ice water and saturated aqueous ammonium chloride solution are added to the reaction mixture, and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S,4S)-5-[(7M)-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinazolin-4-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (3.32 g) as a foamy solid.

[0162] Preparation Example 11 Under ice / MeOH bath cooling, to (1S, 4S) -5- [(7M) -6- cyclopropyl -2- (ethylsulfonyl) -7- [6- fluoro -5- methyl -1- (oxacyclohexane -2- base) -1H- indazole -4- base] -8- { [4- (methoxycarbonyl) phenyl] methoxy} quinazoline -4- base] -2,5- diazabicyclo [2.2.1] heptane -2- carboxylic acid tert-butyl ester (200mg), tetrahydro -2H- pyran -4- alcohol (32mg) and THF (4mL) mixture was added tBuOK (56mg), and the mixture was stirred at the same temperature for 30 minutes under argon atmosphere. Ice water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to give (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (144 mg) as a foamy solid.

[0163] Preparation Example 12 Under ice-bath cooling, to a mixture of (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (142 mg), MeOH (1 mL) and THF (1 mL), an aqueous sodium hydroxide solution (1M, 1 mL) was added, and the mixture was stirred at room temperature for 6 hours. Under ice-bath cooling, hydrochloric acid (1M, 1 mL) was added, and the mixture was extracted twice with CHCl3 / MeOH (9 / 1). The combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 4-[({(7M)-4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoic acid (132 mg) as a solid.

[0164] Preparation Example 13 7-Bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (40 g) was suspended in THF (400 mL), and an aqueous sodium hydroxide solution (1 M, 190 mL) was added dropwise under ice bath cooling to make the internal temperature 10°C or lower, and then the mixture was stirred for 2 hours. The reaction solution was poured into a conical flask filled with hydrochloric acid (1 M, 190 mL) and ice water (about 900 g) at one time, and the mixture was stirred at room temperature for about 30 minutes (until the ice melted). The insoluble matter was filtered, washed with water, and dried under reduced pressure to obtain 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (33.56 g) as a solid.

[0165] Preparation Example 14 Under a nitrogen stream, a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazoline-4-ol (24.6 g) and THF (260 mL) was heated to 60 ° C, and 2-tert-butyl-1,3-diisopropylisourea (73.4 g) was added dropwise over 15 minutes. The mixture was stirred at the same temperature for 2.5 hours. After cooling to room temperature, the colorless solid was separated by filtration and washed with THF (about 500 mL). The filtrate was concentrated, MeOH (210 mL) was added to the resulting solid, and the mixture was suspended and washed by stirring at room temperature for 1 hour. The solid was filtered with MeOH (100 mL) to obtain 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

[0166] Preparation Example 15 Ethanethiol (3.6 mL) and DABCO (7.7 g) were added to a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (21 g) in CH2Cl2 (200 mL) at room temperature, and the mixture was stirred at room temperature overnight under an argon atmosphere. The reaction was quenched with water under ice bath cooling. CHCl3 was added, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted three times with CHCl3. The collected organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, thereby obtaining 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazoline (23.4 g) as a solid.

[0167] Preparation Example 16 To a solution of 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazoline (32 g) and (1S)-1-phenylethan-1-ol (11 mL) in THF (400 mL) was added tBuOK (10 g) under ice-bath cooling, and the mixture was stirred for 1 hour under ice-bath cooling in an argon atmosphere. The reaction was quenched with a saturated aqueous solution of ammonium chloride under ice-bath cooling. Water and ethyl acetate were added, the organic layer and the aqueous layer were separated, the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g) as an oil.

[0168] Preparation Example 17 At room temperature, 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinazoline (36.6 g), cyclopropylboronic acid (7.5 g), PdCl2(dppf)·CH2Cl2 (7.6 g), tripotassium phosphate (53 g), MeCN (440 mL) and water (80 mL) were mixed and stirred at 90° C. for 4 hours under an argon atmosphere. After the temperature returned to room temperature, the reaction solution was diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline (22.9 g) as an oil.

[0169] Preparation Example 18 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (19.3 g), palladium (II) acetate (0.67 g), dicyclohexyl (2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl) phosphine (2.67 g), anhydrous barium hydroxide (14.6 g) and DOX (500 mL) / water (100 mL) were added to 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline (14.21 g), and degassing and argon replacement were performed several times. Then, the mixture was heated and stirred at 50° C. overnight under an argon atmosphere. The reaction suspension after cooling was filtered through a diatomaceous earth (registered trademark) pad, washed with ethyl acetate, and the gray insoluble matter was removed by filtration. After the filtrate was concentrated to about 1 / 4 under reduced pressure, water was added and the mixture was extracted twice with ethyl acetate. The collected organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (derived from an axial chiral diastereoisomer mixture of about 3.3:1, 16.44g) as a solid.

[0170] Preparation Example 19 Under nitrogen flow, 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (about 3.3:1 diastereoisomer mixture derived from axial chirality, 33.71 g) was dissolved in CH2Cl2 (500 mL), and m-chloroperbenzoic acid (about 30% water content, 22.4 g) was added under ice-cooling (internal temperature: 5 to 10°C). The mixture was stirred at room temperature for 2 hours. Under ice-cooling, an aqueous solution (300 mL) of sodium thiosulfate pentahydrate (11 g) and a saturated aqueous sodium bicarbonate solution (300 mL) were poured into the reaction solution, stirred at room temperature for 30 minutes, and then extracted twice with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (derived from a mixture of diastereomers with axial chirality). iPrOH (1000 mL) was added to the obtained residue, and the mixture was stirred at room temperature overnight. The obtained solid was filtered, washed with iPrOH, and dried under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (derived from a mixture of diastereomers with axial chirality, about 1:1, 11.52 g) as a solid. The filtrate was concentrated under reduced pressure to give the desired (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4-yl] 1-[(1S)-1-phenylethoxy]quinazoline (single diastereomer, 23.29 g) as a solid.

[0171] Preparation Example 23 To a mixture of methyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (2.51 g) and THF (30 mL) were added 3,4-dihydro-2H-pyran (2.7 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (270 mg) at room temperature, and the mixture was stirred at 60°C for 2 hrs. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to give methyl 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (1.79 g) as a foamy solid.

[0172] Preparation Example 24 Under nitrogen atmosphere, cesium carbonate (85 mg) and PyBOP (120 mg) were added to a solution of methyl 4-[({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (100 mg) in THF (2 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. (3S)-tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (76 mg) and cesium carbonate (100 mg) were added at room temperature, and the mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, ethyl acetate was added to the reaction solution, and filtered through a Celite (registered trademark) pad. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (hexane / ethyl acetate) to give (3S)-3-[{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (123 mg) as an oil.

[0173] Preparation Example 29 To a mixture of methyl 4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoate (45 mg) and dichloroethane (2 mL) was added trimethyltin hydroxide (50 mg) at room temperature, and the mixture was stirred at 80° C. for 16 hours. After the mixture was cooled to room temperature, trimethyltin hydroxide (50 mg) was added, and the mixture was stirred at 80° C. for 48 hours. After the mixture was cooled to room temperature, hydrochloric acid (1 M) was added, and the mixture was extracted twice with CHCl3 / MeOH (9 / 1). The combined organic layers were washed with hydrochloric acid (1 M), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 4-[({(7M)-6-cyclopropyl-4-[(1-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (74 mg, purity: about 60%) as a solid.

[0174] Preparation Example 30 To a mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (10 g) and N-methyl-2-pyrrolidone (20 mL) was added trimethyl orthoacetate (10.5 mL), and the mixture was stirred for 12 hours at 110° C. After the mixture was cooled to room temperature, MeOH (20 mL) was added, and the resulting solid was filtered and washed with ice-cold methanol (about 60 mL), and dried under reduced pressure to obtain methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (6.67 g) as a solid.

[0175] Preparation Example 31 Under argon atmosphere, under water bath cooling, 2-acetamido-4-bromo-3-fluoro-5-iodobenzoic acid methyl ester (18g) was added in batches to a mixture of lithium bis(trimethylsilyl)amide (1.3M THF solution, 100mL) and THF (150mL). The mixture was stirred at 40°C for 1 hour, then cooled to room temperature, water was added, and the mixture was washed twice with ethyl acetate. Under ice bath cooling, the water layer was acidified and stirred for a while with hydrochloric acid (1M, 140mL) and ice water. The precipitated solid was filtered and dried under reduced pressure. The gained solid was filtered and washed with methanol, dried under reduced pressure to obtain 7-bromo-8-fluoro-4-hydroxy-6-iodoquinoline-2 (1H) -one (13.6g) solid.

[0176] Preparation Example 32 Under an argon atmosphere, phosphoryl chloride (24 mL) was added to 7-bromo-8-fluoro-4-hydroxy-6-iodoquinoline-2(1H)-one (5 g), and DIPEA (7 mL) was slowly added under ice bath cooling. The mixture was stirred at 110°C for 1 hour. The reaction solution was cooled to room temperature and dried at room temperature under reduced pressure. Ice water was added to the residue and stirred for 30 minutes. The precipitated solid was filtered, washed with water, and then dried under reduced pressure to obtain 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (5.03 g).

[0177] Preparation Example 33 Under an argon atmosphere, DABCO (1.8 g) was added to a mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (6.4 g) and DMAc (70 mL), and the mixture was stirred at 40° C. for 2 hours. Ethyl mercaptan (1.4 mL) was added, and the mixture was stirred at 60° C. for 1 hour. After the mixture was cooled to room temperature, water was added, and the mixture was stirred for 5 minutes. The obtained solid was filtered and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (hexane / ethyl acetate), thereby obtaining solid 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (5.76 g).

[0178] Preparation Example 34 Under an argon atmosphere, a mixture prepared by adding tBuOK (1.39 g) to a solution of (1S)-1-phenylethan-1-ol (1.56 mL) in dehydrated THF (40 mL) and stirring at room temperature for 30 minutes was added dropwise to a mixture of 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (5.5 g) and dehydrated THF (40 mL) under ice-bath cooling over 20 minutes, and the mixture was stirred at the same temperature for 10 minutes. Separately, under an argon atmosphere, tBuOK (415 mg) was added to a solution of (1S)-1-phenylethan-1-ol (0.45 mL) in dehydrated THF (10 mL), stirred at room temperature for 10 minutes, and then the mixture was slowly added dropwise to the above reaction mixture under ice-bath cooling, and the mixture was stirred at the same temperature for 10 minutes. Saturated aqueous ammonium chloride solution, ice, and ethyl acetate were added to separate the layers, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 7-bromo-4-chloro-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (4.9 g) as an oil. The slightly impure fractions were concentrated to give 7-bromo-4-chloro-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (1.56 g) as an oil.

[0179] Preparation Example 35 Under an argon atmosphere, to a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2.7 g) in DMAc (20 mL) was added tBuOK (1.59 g) and stirred at room temperature for 10 minutes to prepare a mixture, which was added dropwise to a mixture of 7-bromo-4-chloro-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (6.46 g) and DMAc (40 mL) under ice-bath cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution, ice and ethyl acetate were added, and the mixture was stirred to separate layers. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain tert-butyl (3S)-3-({7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (4.6 g) as a solid.

[0180] Preparation Example 36 Under an argon atmosphere, to a mixture of tert-butyl (3S)-3-({7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (1.38 g), cyclopropylboronic acid (255 mg), PdCl2(dppf)·CH2Cl2 (162 mg), MeCN (15 mL) and water (3 mL) was added tripotassium phosphate (1.52 g), and the mixture was stirred at 90°C for 6 hours. After the mixture was cooled to room temperature, ethyl acetate and water were added. The two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3S)-3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (589 mg) as a foamy solid.

[0181] Preparation Example 37 Under argon protection, a mixture of tert-butyl (3S)-3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (2.71 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (3.44 g), dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (531 mg), palladium(II) acetate (106 mg) and anhydrous barium hydroxide (2.29 g) was suspended in DOX (110 mL) and water (22 mL), and the suspension was stirred at 50° C. for 15 minutes. 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1.6 g) was added and the mixture was stirred at 50°C for 15 minutes. After the mixture was cooled to room temperature, ethyl acetate and water were added and the insoluble matter was removed by filtration through a diatomaceous earth (registered trademark) pad. The two layers of filtrate were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. After separating the desiccant by filtration, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (basic silica gel, hexane / ethyl acetate) to obtain tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (derived from a 5:1 diastereoisomer mixture of axial chirality, 3.88 g) as an oil. To tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (derived from a mixture of approximately 5:1 diastereomers of axial chirality, 100 mg) was added MeOH (2 mL), and the mixture was heated to 70° C. for dissolution. The mixture was stirred at room temperature overnight and then for 3 days. Solid precipitation was observed (pale yellow suspension). The solid was filtered and washed with a small amount of MeOH to give a powder of (3S)-tert-butyl 3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (derived from a mixture of approximately 1:1 diastereomers with axial chirality, 21 mg). The filtrate was concentrated to give the desired (3S)-tert-butyl 3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (derived from a single diastereomer with axial chirality, 70 mg) as a solid. Similarly, to tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (derived from an approximately 5:1 diastereoisomer mixture of axial chirality, 2.95 g) was added EtOH (6 mL), and the mixture was heated to 70° C. for dissolution. A trace amount of the axial chiral diastereoisomer mixture (obtained above) powder was added at room temperature, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered and washed with a small amount of EtOH to obtain tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfonyl)-7-(6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (derived from an approximately 1:1 diastereoisomer mixture of axial chirality, 699 mg) as a colorless powder. The filtrate was concentrated to obtain the desired (3S)-3-[{6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate 4-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (derived from a single diastereomer of axial chirality, 2.33 g) as a foamy solid.

[0182] Preparation Example 38 Under argon protection, to a solution of tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (2.70 g) in CH2Cl2 (30 mL) was added m-chloroperbenzoic acid (about 30% water content, 1.6 g) under ice-bath cooling, and the mixture was stirred at the same temperature for 1 hour. Under ice-bath cooling, an aqueous solution (10 mL) containing sodium thiosulfate pentahydrate (1.7 g) and a saturated aqueous sodium bicarbonate solution (40 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinolin-4-yl}oxy)pyrrolidine-1-carboxylate (2.68 g) as a foamy solid.

[0183] Preparation Example 39 Under nitrogen atmosphere, to MeOH (15mL) and THF (15mL) solution of (3S)-3-({6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinoline-4-yl}oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.3g) was added 10% Pd / C (50% water content, 300mg) and sodium bicarbonate (600mg), and then the mixture was stirred at room temperature for 4 hours under normal pressure hydrogen atmosphere. The reaction mixture was covered with nitrogen, then filtered through a diatomaceous earth (registered trademark) pad using MeOH, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give tert-butyl (3S)-3-({6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxyquinolin-4-yl}oxy)pyrrolidine-1-carboxylate (1.16 g) as a foamy solid.

[0184] Preparation Example 40 To a mixture of (3S)-tert-butyl 3-({6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxyquinolin-4-yl}]oxy)pyrrolidine-1-carboxylate (1.16 g), methyl 4-(chloromethyl)benzoate (375 mg) and DMF (12 mL) was added cesium carbonate (2 g) at room temperature, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate and water were added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (hexane / ethyl acetate) to give (3S)-tert-butyl 3-({6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinolin-4-yl}]oxy}pyrrolidine-1-carboxylate (1.22 g) as a foamy solid.

[0185] Preparation Example 41 Under ice bath cooling, to (3S)-3-{[6-cyclopropyl-2-(ethylsulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}quinolin-4-yl]oxy}pyrrolidine-1-carboxylic acid tert-butyl ester (835 mg) and (2S)-2-methoxypropan-1-ol (97 μL) in THF (10 mL) solution, tBuOK (114 mg) was added, and the mixture was stirred at the same temperature for 2 hours. Ice water and aqueous ammonium chloride solution were added to the reaction solution to quench the reaction, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3S)-3-({6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole-4- yl]-tert-butyl 8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}]oxy}pyrrolidine-1-carboxylate (374 mg) as a foamy solid.

[0186] Preparation Example 42 A solution of (3S)-tert-butyl 3-({6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-{[4-(methoxycarbonyl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4-yloxy)pyrrolidine-1-carboxylate (250 mg) in MeOH (2 mL) and THF (2 mL) was added to an aqueous sodium hydroxide solution (1 M, 1.2 mL) at room temperature, and the mixture was stirred at room temperature for 6 hours. Ethyl acetate and a saturated aqueous ammonium chloride solution were added under ice cooling, the organic layer was extracted, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. iPr2O was added to the resulting residue, and the precipitated solid was filtered and washed with iPr2O to give 4-{[(4-{[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]benzoic acid (216 mg) as a solid.

[0187] Preparation Example 43 To a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL) and CH2Cl2 (1880 mL) was added 1,1',1"-(chloromethanetriyl)triphenyl (335 g) at room temperature, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into ice water (1.5 L), and the organic layer and the aqueous layer were separated. The aqueous layer was extracted three times with CH2Cl2 (400 mL). The combined organic layers were dried over anhydrous sodium sulfate. Subsequently, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the resulting residue and triturated (0°C, 2 hours), and then 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid was obtained by filtration collection and drying under reduced pressure.

[0188] Preparation Example 44 At -78 ℃, under nitrogen atmosphere, diisopropylamide lithium (2M THF solution, 214.28mL) was added to the mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100g) and 2-methyltetrahydrofuran (1000mL), and the mixture was stirred at -78 ℃ for 2.5 hours. Methyl iodide (26.68mL) was added at -78 ℃, and the mixture was stirred at 25 ℃ for 2.5 hours. Water (2000mL) was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (800mL). The combined organic layer was dried over anhydrous sodium sulfate. Subsequently, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (50mL) / petroleum ether (50mL) was added to the obtained residue and ground, then collected by filtration and dried under reduced pressure to obtain a solid of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81g).

[0189] Preparation Example 45 To a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g) and DOX (1000 mL) was added palladium acetate (4.52 g) at room temperature under a nitrogen atmosphere. After the reaction mixture was degassed and filled with nitrogen three times, the mixture was stirred at 100 ° C for 12 hours under a nitrogen atmosphere. After cooling, water (1500 mL) was added and the mixture was extracted three times with ethyl acetate (900 mL). The combined organic layer was dried over anhydrous sodium sulfate and then filtered to remove insoluble matter. Activated carbon (50 g) was added to the resulting solution, the solution was stirred at 20 ° C for 1 hour, filtered, and washed three times with ethyl acetate (50 mL). The filtrate was concentrated. MeOH (200 mL) was added to the obtained residue and triturated, collected by filtration and dried under reduced pressure to give 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (110 g) as a solid.

[0190] Preparation Example 48 To (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexane-2- To a mixture of tert-butyl ester (200 mg), 4-(chloromethyl)benzaldehyde (60 mg) and DMF (4 mL) was added cesium carbonate (160 mg), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added, the two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3 / MeOH) to give (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-8-[(4-formylphenyl)methoxy]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (165 mg) as an oil.

[0191] Preparation Example 49 (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxacyclohexane-2- A mixture of {{2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindol-5-yl}(piperazin-1-yl)methanone monohydrochloride (salt) (55 mg), MeOH (1 mL) and acetic acid (0.1 mL) was stirred at room temperature for 30 minutes. Then 2-methylpyridine borane (15 mg) was added, and the mixture was stirred at room temperature for 2 hours. Hydrochloric acid (1 M) was added at room temperature, and the mixture was stirred at room temperature for 15 minutes. Then water and saturated sodium bicarbonate aqueous solution were added, and the mixture was extracted twice with CHCl3 / MeOH (9 / 1). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (1S, 4S)-5-{(7M)-6-cyclopropyl-8-({4-[(4-{2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carbonyl}piperazin-1-yl)methyl]phenyl}methoxy)-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-carboxylic acid tert-butyl ester (20 mg) as a solid.

[0192] Preparation Example 50 To a mixture of 4-[({(7M)-4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoic acid (60 mg), {2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindol-5-yl}(piperazin-1-yl)methanone monohydrochloride (38 mg), DIPEA (50 μL) and DMF (1 mL) was added HATU (35 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-8-{[4-(4-{2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carbonyl}piperazine-1-carbonyl)phenyl}methoxy}-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-carboxylic acid tert-butyl ester (74 mg) as an oil.

[0193] Preparation Example 67 Under ice bath cooling, HATU (35 mg) was added to a mixture of 2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carboxylate (100 mg), piperazine-1-carboxylic acid tert-butyl ester (65 mg), DIPEA (100 μL) and DMF (1 mL), and the mixture was stirred at room temperature for 4 hours. Ethyl acetate, water and saturated sodium bicarbonate aqueous solution were added to separate the aqueous layer. The organic layer was washed twice with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to obtain 4-{2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carbonyl}piperazine-1-carboxylic acid tert-butyl ester (147 mg) as an oil.

[0194] Preparation Example 70 Under ice-cooling, to a mixture of tert-butyl 4-{2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carbonyl}piperazine-1-carboxylate (145 mg) and CH2Cl2 (2 mL) was added hydrogen chloride (4M DOX solution, 1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain {2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-yl}(piperazin-1-yl)methanone monohydrochloride (salt) (136 mg) as a solid.

[0195] Preparation Example 73 To a solution of (2S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester (90 mg) and 2-[2,4-bis(benzyloxy)-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carboxaldehyde (120 mg) in CH2Cl2 (2 mL) was added acetic acid (10 μL) at room temperature, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (100 mg) was then added, and the mixture was stirred at room temperature for 2 hours. Water and a saturated aqueous sodium bicarbonate solution were added at room temperature, the mixture was stirred for a while, and extracted with CHCl3. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (2S)-4-({2-[2,4-bis(benzyloxy)-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindol-5-yl}methyl)-2-methylpiperazine-1-carboxylate (159 mg) as an oil.

[0196] Preparation Example 81 To tert-butyl (2S)-4-({2-[2,4-bis(benzyloxy)-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindol-5-yl}methyl)-2-methylpiperazine-1-carboxylate (70 mg) were added trifluoroacetic acid (2 mL) and trifluoromethanesulfonic acid (0.2 mL) at room temperature, and the mixture was stirred at 60° C. for 2 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, CHCl3 / MeOH) to obtain [2,4-dihydroxy-5-(propan-2-yl)phenyl](5-{[(3S)-3-methylpiperazin-1-yl]methyl}-1,3-dihydro-2H-isoindol-2-yl)methanone (58 mg) as a solid.

[0197] Preparation Example 86 A solution of tert-butyl 4-({2-[2,4-bis(benzyloxy)-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindol-5-yl}methyl)piperazine-1-carboxylate (2.80 g) in trifluoroacetic acid (10 mL) and trifluoromethanesulfonic acid (1 mL) was stirred at 60° C. for 12 hours. The solution was concentrated under reduced pressure, and the resulting crude product was purified by reverse phase HPLC (40% MeCN aqueous solution / 0.1% hydrochloric acid) to give [2,4-dihydroxy-5-(propan-2-yl)phenyl]{5-[(piperazin-1-yl)methyl]-1,3-dihydro-2H-isoindol-2-yl}methanone trifluoromethanesulfonate (376 mg) as a solid.

[0198] Preparation Example 90 To a mixture of benzyl 4-{[1-(tert-butoxycarbonyl)azetidin-3-yl]methyl}piperazine-1-carboxylate (649 mg) and CH2Cl2 (7 mL) was added trifluoroacetic acid (1 mL) under ice-cooling, the mixture was stirred overnight at room temperature and concentrated under reduced pressure to give benzyl 4-[(azetidin-3-yl)methyl]piperazine-1-carboxylate (1.12 g) as an oil.

[0199] Preparation Example 92 To a mixture of 4-{[1-({2-[2,4-bis(benzyloxy)-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindol-5-yl}methyl)azetidin-3-yl]methyl}piperazine-1-carboxylic acid benzyl ester (98 mg) and 10% Pd / C (50% water content, 45 mg) was added MeOH (2 mL) at room temperature, and the mixture was stirred for 2 hours under a hydrogen atmosphere. 10% Pd / C (50% water content, 30 mg) was added, and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The mixture was filtered through a Celite (registered trademark) pad and washed with MeOH. The filtrate was concentrated under reduced pressure to obtain [2,4-dihydroxy-5-(propan-2-yl)phenyl][5-({3-[(piperazin-1-yl)methyl]azetidin-1-yl}methyl)-1,3-dihydro-2H-isoindol-2-yl]methanone (51 mg) as a solid.

[0200] Preparation Example 93 Under ice-bath cooling, 1,1'-carbonylbis-1H-imidazole (8.9 g) was added to a solution of 2-(dimethylamino)ethylamine (6 mL) in THF (50 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, iPrOH (50 mL) and azetidin-3-ol monohydrochloride (5 g) were added to the residue, and the mixture was stirred at 80° C. for 3 hours under an argon atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH / ammonia water) to obtain N-[2-(dimethylamino)ethyl]-3-hydroxyazetidine-1-carboxamide (9.67 g) as a liquid.

[0201] Preparation Example 94 Under ice bath cooling, bis (4-nitrophenyl) carbonate (450mg) is added to the mixture of 2- (dimethylamino) second -1- alcohol (120mg), DMF (5mL) and DIPEA (1.7mL), and the mixture is stirred at room temperature for 2 hours.At room temperature, azetidin-3-yl (methyl) carbamic acid benzyl hydrochloride (260mg) is added in the reaction solution, and stirred at room temperature overnight under argon atmosphere.Ice and aqueous ammonium chloride solution are added to the reaction aqueous solution, and the mixture is extracted with ethyl acetate twice.The organic layer is dried over anhydrous magnesium sulfate, and the solvent is concentrated under reduced pressure.Residue is passed through silica gel column chromatography (basic silica gel, CHCl3) purified, so as to obtain 2- (dimethylamino) ethyl 3-{ [(benzyloxy) carbonyl] (methyl) amino} azetidin-1-carboxylates (320mg), it is an oil.

[0202] Preparation Example 95 A mixture of 2-(dimethylamino)ethyl 3-{[(benzyloxy)carbonyl](methyl)amino}azetidine-1-carboxylate (313 mg), MeOH (6 mL) and 10% Pd / C (52% water content, 110 mg) was stirred at room temperature for 3 hours under a hydrogen atmosphere. Celite (registered trademark) was added, and the mixture was filtered through a celite (registered trademark) pad and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (basic silica gel, CHCl3) to obtain 2-(dimethylamino)ethyl 3-(methylamino)azetidine-1-carboxylate (134 mg) as an oil.

[0203] Preparation Example 96 Under ice bath cooling, sodium hydride (45 mg, about 60% by weight mineral oil dispersion) was added to a solution of 4-(3-hydroxypropyl)piperazine-1-carboxylic acid benzyl ester (311 mg) in THF (4 mL), and the mixture was warmed to room temperature and stirred for 30 minutes under an argon atmosphere. The reaction mixture was cooled with an ice bath, and 2-chloro-7,8-dihydropyrido [4,3-d] pyrimidine-6 ​​(5H) -carboxylic acid tert-butyl ester (200 mg) was added. The mixture was stirred for 30 minutes under ice bath cooling and stirred at room temperature for 48 hours. The reaction was quenched with saturated aqueous ammonium chloride solution under ice bath cooling. Water and ethyl acetate were added to separate the organic layer and the aqueous layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 / MeOH) to obtain tert-butyl 2-(3-{4-[(benzyloxy)carbonyl]piperazin-1-yl}propoxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (265 mg) as an oil.

[0204] The compounds shown in the following tables were prepared in the same manner as the preparation methods of the above-mentioned preparation examples. In addition, the preparation methods, structures and physicochemical data of the compounds of the preparation examples are shown in the following tables.

[0205] Example 1 To a mixture of (1S,4S)-5-{(7M)-6-cyclopropyl-8-{[4-(4-{2-[2,4-dihydroxy-5-(propan-2-yl)benzoyl]-2,3-dihydro-1H-isoindole-5-carbonyl}piperazine-1-carbonyl)phenyl]methoxy}-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-carboxylic acid tert-butyl ester (72 mg) and CH2Cl2 (1 mL) was added trifluoroacetic acid (0.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (0.1% formic acid in MeCN / 0.1% formic acid in water). Saturated aqueous sodium bicarbonate solution was added to the fraction containing the target compound, and the mixture was extracted twice with CHCl3 / MeOH (9 / 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with Et2O and dried under reduced pressure to give [5-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]benzoyl}piperazine-1-carbonyl)-1,3-dihydro-2H-isoindol-2-yl][2,4-dihydroxy-5-(propan-2-yl)phenyl]methanone (15 mg) as a solid.

[0206] Example 5 Under argon atmosphere and ice-cooling, (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-{4-[(4-{3-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-5-hydroxy-4H-1,2,4-triazol-4-yl}phenyl)methyl]piperazine-1-carbonyl}phenyl)methoxy]-7-[6-fluoro-5-methyl-1-(oxane-2-yl)phenyl]-1-[(4-{3-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-5-hydroxy-4H-1,2,4-triazol-4-yl}phenyl)methyl]piperazine-1-carbonyl}phenyl)methoxy]-1-[( ...piperazine-1-carbonyl}phenyl)methoxy]piperazine-1-carbonyl}phenyl)methoxy]piperazine-1-carbonyl}phenyl)methoxy]piperazine-1-carbonyl} To a solution of tert-butyl ester (53 mg)-1H-indazol-4-yl]-2-[(oxacyclohexane-4-yl)oxy]quinazoline-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (53 mg) and triisopropylsilane (20 μL) in CH2Cl2 (2 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at room temperature for three hours and then concentrated under reduced pressure. The residue was purified by ODS column chromatography (0.1% formic acid in MeCN solution / 0.1% formic acid aqueous solution). Under ice cooling, saturated aqueous sodium bicarbonate solution was added to the fraction containing the target compound, and the mixture was diluted with water and CHCl3 / iPrOH (4 / 1). The two layers were separated and the aqueous layer was extracted with CHCl3 / iPrOH (4 / 1). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with Et2O to give {4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}{4-[(4-{3-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-5-hydroxy-4H-1,2,4-triazol-4-yl}phenyl)methyl]piperazin-1-yl}methanone (17.6 mg) as a solid.

[0207] The compounds shown in the following tables were prepared in the same manner as the preparation methods of the above examples. In addition, the preparation methods and physicochemical data of the compounds of the examples are shown in the following tables.

[0208] In the following tables, the following abbreviations are sometimes used. PEx: Preparation Example No., Ex: Example No., PSyn: Preparation Example No. prepared in the same manner, Syn: Example No. prepared in the same manner (e.g., Syn:9 indicates preparation in the same manner as Example 9), Str: Chemical Structural Formula (a compound with "*" in the chemical structural formula indicates that the compound has a single structure in terms of axial chirality or central chirality), n HCl: n hydrochloride (a compound with a Preparation Example No. indicates that the compound is mono- to tetra-hydrochloride), nTfOH: trifluoromethanesulfonate (a compound with a Preparation Example No. indicates that the compound is mono- to tri-trifluoromethanesulfonate), n TFA: n trifluoroacetate (a compound with a Preparation Example No. indicates that the compound is mono- to tri-trifluoroacetate), DAT: physicochemical data, ESI+: m / z value in mass spectrum (ionization method ESI, [M+H] + (unless otherwise stated), ESI-: m / z values ​​in mass spectra (ionization method ESI, [MH] -(Unless otherwise stated, NMR: DMSO-d6 at 27°C 1 δ value (ppm) of the peak in H-NMR (500 MHz), NMR (400 MHz): in DMSO-d6 at 27°C 1 δ value of the peak in H-NMR (400 MHz), NMR (90°C): 90°C in DMSO-d6 1 δ value of peak in H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: double of doublets (spectrum), t: triplet (spectrum), tt: triplet of triplet (spectrum), dq: double of quartet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad peak (spectrum) (e.g.: brs).

[0209] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] [Table 3-22] [Table 3-23] [Table 3-24] [Table 3-25] [Table 3-26] [Table 3-27] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-5] [Table 5-6] [Table 5-7]

[0212] [Table 6] Ex Syn DAT 1 1 ESI+: 1056.7 2 1 ESI+: 1070.7 3 1 ESI+: 1070.6 4 1 ESI+: 1068.8 5 5 ESI+: 1056.9 6 1 ESI+: 1042.9 7 1 ESI+: 1056.7 8 1 ESI+: 1056.8 9 1 ESI+: 1069.0 10 1 ESI+: 1082.9 11 1 ESI+: 1125.7 12 1 ESI+: 1111.7 13 1 ESI+: 1060.9 14 1 ESI+: 1161.8 15 1 ESI+: 1042.8 16 1 ESI+: 1046.8 17 1 ESI+: 1147.7 18 1 ESI+: 1084.9 19 5 ESI+: 1102.6

[0213] As examples of specific compounds of formula (I) included in the present invention, compounds with any of the following structures are shown. These compounds are also prepared by the above-mentioned typical preparation methods, preparation examples and preparation methods of examples, combinations of preparation methods or methods obvious to those skilled in the art. In addition, the G12D mutant KRAS protein degradation activity and cell growth inhibitory effect of these compounds on human G12D mutant KRAS positive pancreatic cancer lines were observed by the test method of the above test example. Therefore, these compounds can be used as active ingredients of pharmaceutical compositions, for example, pharmaceutical compositions for treating pancreatic cancer.

[0214] [Table 7] Industrial Applicability

[0215] The compound or salt thereof of the present invention has an excellent effect of inducing KRAS protein degradation and / or can be used as a KRAS inhibitor, and can be used as an active ingredient of a pharmaceutical composition for treating cancer, particularly a pharmaceutical composition for treating pancreatic cancer.

Claims

1. A compound of formula (I) or a salt thereof, [Chemical formula 1] (wherein in the formula, A is for CR A or N, R A Is H or C 1-3 alkyl; R 1 is naphthyl optionally substituted by OH, or R 1 is a group selected from the following formula (IIa) and formula (IIb), [Chemical formula 2] R 1a and R 1b are the same as or different from each other and are H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl, R 2 is H, halogen, optionally substituted C 1-3 Alkyl, cyclopropyl or vinyl, R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R 3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 3] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkylene-NR N1 R N2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3h is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NR N1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3k is attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, n is 1 or 2, p is 1 or 2, k is an integer from 0 to 2, R 4 is optionally substituted C 1-6 alkyl, an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl group containing one to four heteroatoms selected from oxygen, sulfur and nitrogen, or an optionally substituted 6-membered heteroaryl group containing one to three nitrogen atoms, X 1 is a bond, -CH2-, -O-, -S- or -NR 4X -, R 4X Is H or C 1-3 alkyl, Y is phenylene or pyridinediyl optionally substituted by a group selected from F and Cl, L is -(L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 )-, L 1 , L 2 , L 3 , L 4 , L 5 , L 6 and L 7 The same or different groups are selected from the group consisting of: bond, -O-, -S-, -NR L1 -, acetylene-1,2-diyl, optionally substituted azetidinediyl, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted diazepanediyl, optionally substituted C 1-3 alkylene, a saturated or unsaturated 7- or 8-membered bridged heterocyclic divalent group containing one or two nitrogen atoms, a saturated 7- to 11-membered spiro heterocyclic divalent group containing two nitrogen atoms, a saturated 8- to 10-membered bicyclic heterocyclic divalent group containing two nitrogen atoms, an optionally substituted phenylene, an optionally substituted pyridinediyl, C=O, S=O and S(=O)2, R L1 Is H or C 1-3 alkyl, Z is a group selected from the following formula (XVI), formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXIV) and formula (XXXV), [Chemical formula 4] Each Z 1 , are the same or different from each other, are CH or N, Z 2 is NH, NCH3, O or S, Each R 5a , which are the same or different from each other, are H, halogen, C 1-3 Alkyl or -(C=O)NH2, R 6a is C optionally substituted by F 1-6 alkyl, Each R 6b , the same or different from each other, is C 1-3 alkyl, R 6c is C optionally substituted by F 1-3 alkyl, R 6d Yes -(C=O)NR N3 R N4 , R N3 and R N4 Is H or C 1-3 Alkyl groups, identical or different from each other, R 7a is OH or -(C=O)NR N5 R N6 , R N5 and R N6 are the same as or different from each other and are H, cyclopropyl or C optionally substituted by F 1-3 Alkyl, and m is an integer from 0 to 2).

2. The compound or salt thereof according to claim 1, Where A is CR A or N, R A It is H. R 1 is the following formula (IIa), [Chemical formula 5] R 1a It's F. R 1c It is methyl, R 2 is cyclopropyl, R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (Va), formula (XIII-a) and formula (XXXVI), [Chemical formula 6] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c Yes - (CH2) p CHR 3f -NR N1 R N2 or optionally -NR N1 R N2 Substituted C 3-6 Cycloalkyl, R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 It's O. p is 1, R 4 is C optionally substituted by 1-6 Alkyl: OCH3, or tetrahydropyranyl, X 1 Yes-O-, Y is phenylene optionally substituted by F, L is a group selected from the group consisting of formula (XXXX-a), formula (XXXX-b), formula (XXXXI), formula (XXXXII), formula (XXXXIII), formula (XXXXIV), formula (XXXXV), formula (XXXXVI), formula (XXXXVII) and formula (XXXXVIII), [Chemical formula 7] L 1 is -(CH2)-, C=O or S(=O)2, L 3 , L 4 and L 5 The same or different from each other, are bonds, -O-, C 1-3 Alkylene or C=O, R L1 Is H or C 1-3 alkyl, R L2 It is C 1-3 Alkyl or oxo, Ring B is piperazine, diazaheptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.5]decane, diazaspiro[5.5]undecane or diazabicyclo[3.3.0]octane, Ring C is azetidine, pyrrolidine or piperidine, Z is a group selected from the following group: the following formula (XVI-a), formula (XXIII-a), formula (XIX) and formula (XXXV), [Chemical formula 8] Each Z 1 It is CH, R 5a It is H. R 6a It is C 1-3 alkyl, R 7a is OH or -(C=O)NR N5 R N6 , R N5 is H, and R N6 It is C 1-3 alkyl.

3. The compound or salt thereof according to claim 2, wherein R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (XXXVI) and formula (XIII-a), [Chemical formula 9] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 Is -O- or -N(C 1-3 alkyl)-, X 3 It's O. p is 1, R 4 is C optionally substituted by 1-3 Alkyl: OCH3, or tetrahydropyranyl, Y is phenylene, L is a group selected from the following formula (XXXX-a), formula (XXXX-b), formula (XXXXII), formula (XXXXIV) and formula (XXXXVIII), [Chemical formula 10] L 1 is -(CH2)- or C=O, L 3 , L 4 and L 5 The same or different from each other, are bonds, -O-, C 1-3 Alkylene or C=O, R L1 and R L2 It is C 1-3 alkyl, Ring B is piperazine, diazaheptane, diazabicyclo[3.2.1]octane, diazaspiro[3.5]nonane or diazabicyclo[3.3.0]octane, Ring C is azetidine or piperidine, Z is a group selected from the following group: the following formula (XVI-a), formula (XXIII-a), formula (XIX) and formula (XXXV), [Chemical formula 11] Each Z 1 It is CH, R 5a It is H. R 6a is isopropyl, and R 7a It's OH.

4. The compound or salt thereof according to claim 1, wherein R 3 is a group selected from the following formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV) and formula (XV), or R 3 is a saturated or unsaturated 7- or 8-membered bridged heterocyclic group containing one or two nitrogen atoms, which is optionally substituted by OH, wherein when the bridged heterocyclic group is substituted by OH, OH is only attached to carbon atoms which are atoms forming the bridged heterocyclic ring, [Chemical formula 12] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 5-membered or 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3b Is H or C 1-3 alkyl, R 3c and R 3d Yes - (CH2) p CHR 3f -NR N1 R N2 ; -(CH2) p CHR 3f -OR 3g ; A 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 and-NR N1 R N2 ; or C 3-6 Cycloalkyl, which is optionally substituted by a group selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkylene-OR 3g , C 1-3 Alkylene-NR N1 R N2 、-OR 3g and-NR N1 R N2 , R 3e Yes-OC 2-3 Alkylene-NR N1 R N2 or -NR N1 R N2 , R 3f is H, F or C 1-3 alkyl, R 3g Is H or C 1-3 alkyl, R 3h is an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or an optionally substituted -NR N1 R N2 Substituted cyclobutyl, R N1 and R N2 Is H or C 1-3 alkyl groups, which are the same or different from each other, or R N1 and R N2 together with the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group comprising one or two heteroatoms selected from oxygen, sulfur and nitrogen, or R 3f and R N1 Together with the carbon atom and the nitrogen atom to which it is attached, optionally form an optionally substituted 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, Each R 3k are identical or different from each other and are selected from the group consisting of OH, optionally substituted C 1-3 Alkyl, -O-(optionally substituted C 1-3 alkyl), -NH-(optionally substituted C 1-3 alkyl), -N-(optionally substituted C 1-3 alkyl)2, halogen, -CN and oxo, wherein R 3k is attached only to carbon atoms that are atoms forming a ring, the ring being represented by formula (XI), formula (XII), formula (XIII) or formula (XIV), X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2- or -NH-, X 5 is a bond, -CH2- or C=O, X 6 is -CH2- or -O-, The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, n is 1 or 2, p is 1 or 2, k is an integer from 0 to 2, Z is a group selected from the following formula (XVI), formula (XVII), formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), formula (XXVIII), formula (XXIX), formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII), formula (XXXIV) and formula (XXXV), [Chemical formula 13] Each Z 1 , are the same or different from each other, are CH or N, Z 2 is NH, NCH3, O or S, Each R 5a , which are the same or different from each other, are halogen, C 1-3 Alkyl or -(C=O)NH2, R 6a is C optionally substituted by F 1-6 alkyl, Each R 6b , the same or different from each other, is C 1-3 alkyl, R 6c is C optionally substituted by F 1-3 alkyl, R 6d Yes -(C=O)NR N3 R N4 , R N3 and R N4 Is H or C 1-3 Alkyl groups, identical or different from each other, R 7a is OH or -(C=O)NR N5 R N6 , R N5 and R N6 are the same as or different from each other and are H, cyclopropyl or C optionally substituted by F 1-3 Alkyl, and m is an integer from 0 to 2.

5. The compound or salt thereof according to claim 4, Where A is CR A or N, R A It is H. R 1 is the following formula (IIa), [Chemical formula 14] R 1a It's F. R 1c It is methyl, R 2 is cyclopropyl, R 3 is a group selected from the following group: the following formula (III-a), formula (IV-a), formula (Va), formula (XIII-a) and formula (XXXVI), [Chemical formula 15] R 3a Yes - (CH2) p CHR 3f -NR N1 R N2 , R 3b It is H. R 3c Yes - (CH2) p CHR 3f -NR N1 R N2 or optionally -NR N1 R N2 Substituted C 3-6 Cycloalkyl, R 3f It is H. R N1 and R N2 All C 1-3 alkyl, X 2 is -O-, -NH- or -N(C 1-3 alkyl)-, X 3 It's O. The condition is that when R 3c -(CH2) p CHR 3f -NR N1 R N2 When X in formula (IV-a) 2 is -O-, -NH- or -N(C 2-3 alkyl)-, p is 1, R 4 is C optionally substituted by 1-6 Alkyl: OCH3, or tetrahydropyranyl, X 1 Yes-O-, Y is phenylene optionally substituted by F, L is a group selected from the group consisting of formula (XXXX), formula (XXXX-a), formula (XXXXI), formula (XXXXII), formula (XXXXIII), formula (XXXXIV), formula (XXXXV), formula (XXXXVI), formula (XXXXVII) and formula (XXXXVIII), [Chemical formula 16] L 1 is -(CH2)-, C=O or S(=O)2, L 3 , L 4 and L 5 are the same as or different from each other and are -(CH2)- or C=O, R L1 Is H or C 1-3 alkyl, R L2 It is C 1-3 Alkyl or oxo, Ring B is piperazine, diazaheptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, diazaspiro[3.5]nonane, diazaspiro[4.5]decane, diazaspiro[5.5]undecane or diazabicyclo[3.3.0]octane, Ring C is azetidine, pyrrolidine or piperidine, Z is a group selected from the following group: the following formula (XVI-a) and formula (XXIII-a), [Chemical formula 17] Each Z 1 It is CH, R 6a It is C 1-3 alkyl, R 7a is OH or -(C=O)NR N5 R N6 , R N5 is H, and R N6 It is C 1-3 alkyl.

6. A pharmaceutical composition comprising the compound or salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

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

8. Use of the compound or salt thereof according to claim 1 in preparing a pharmaceutical composition for treating pancreatic cancer.

9. The compound or salt thereof according to claim 1, for use in treating pancreatic cancer.

10. Use of the compound or a salt thereof according to claim 1 for treating pancreatic cancer.

11. A method for treating pancreatic cancer, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

Images