Heterocyclic compounds for inducing KRAS protein degradation

Abstract

Provided is a compound useful as an active ingredient in a pharmaceutical composition for treating cancer. The present inventors have investigated compounds useful as active ingredients in pharmaceutical compositions for cancer treatment and have found that the heterocyclic compounds represented by formula (I) and formula (II) have excellent effects of inducing the degradation of mutant KRAS proteins and wild-type KRAS proteins, particularly the effects of inducing the degradation of G12C-, G12D-, G12V-, and G13D-mutated KRAS proteins, and have inhibitory activity against mutant KRAS and KRAS in which the wild-type KRAS gene has been amplified, particularly the G12C-, G12D-, G12V-, and G13D-mutated KRAS, thereby completing the present invention. The heterocyclic compounds of the present invention or salts thereof can be used as therapeutic agents for cancer.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions and heterocyclic compounds that have an excellent effect of inducing the degradation of mutant KRAS proteins, particularly the effect of inducing the degradation of G12C-mutated, G12D-mutated, G12V-mutated, and G13D-mutated KRAS proteins and wild-type KRAS proteins, and / or an excellent inhibitory effect on mutant KRAS, particularly the inhibitory effect on G12C-mutated, G12D-mutated, G12V-mutated, and G13D-mutated KRAS, and the inhibitory effect on KRAS in which the wild-type KRAS gene has been amplified, and that are expected to be useful, for example, as an active ingredient in pharmaceutical compositions for treating cancer. [Background technology]

[0002] RAS proteins are small guanosine triphosphate (GTP)-binding proteins of approximately 21 kDa, consisting of 188–189 amino acids. There are four major RAS proteins (KRAS (KRAS4A and KRAS4B), NRAS, and HRAS) produced by three genes: KRAS, NRAS, and HRAS. RAS proteins exist in an active GTP-bound form and an inactive GDP-bound form. RAS proteins are activated by the exchange of guanosine diphosphate (GDP) for GTP upon ligand stimulation of cell membrane receptors such as EGFR. Active RAS binds to 20 effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signaling cascades. On the other hand, active RAS becomes inactive by converting GTP to GDP through its intrinsic GTP hydrolysis (GTPase) activity. This GTPase activity is enhanced by GTPase-activating proteins (GAPs). This indicates that RAS functions as an important "molecular switch" in intracellular signaling pathways such as EGFR, and plays an important role in processes such as cell growth, proliferation, and angiogenesis (Nature Rev. Cancer, 2011, 11, pp. 761-774; Nature Rev. Drug Discov., 2014, 13, pp. 828-851; Nature Rev. Drug Discov., 2016, 15, pp. 771-785).

[0003] When RAS mutations result in amino acid substitutions, RAS becomes constitutively active due to impaired GTPase function and reduced response to GAPs, resulting in continuous downstream signaling. This excessive signaling leads to carcinogenesis and accelerated cancer proliferation. For example, KRAS mutations have been observed in over 90% of patients with pancreatic ductal adenocarcinoma, and these mutations are present even in the early stages of pancreatic intraepithelial neoplasia (PanIN). KRAS mutations are also frequently observed in lung cancer and colorectal cancer. Point mutations at codon 12 in KRAS exon 2 (e.g., G12C, G12D, and G12V mutations) are commonly known (Nat. Rev. Cancer, 2018, 18, pp. 767-777).

[0004] In recent years, several selective inhibitors of G12C-mutated KRAS have been developed, including sotorasib and adagrasib, which have been approved by the FDA for the treatment of non-small cell lung cancer (J. Exp. Clin. Cancer. Res., 41 27, 2022). Approximately 14% of lung cancer patients have G12C-mutated KRAS, while G12V and G12D mutations have been reported in approximately 5% and 7%, respectively. Meanwhile, G12D and G12V mutations are common in pancreatic cancer, accounting for approximately 40% and 28%, respectively. In colorectal cancer, G12D, G12V, G12C, and G13D mutations are common in approximately 15%, 10%, 3%, and 8%, respectively. Given the high prevalence of mutations other than G12C across various cancer types, there is high hope for therapeutics that broadly target mutant KRAS (npj Precis. Onco.,6 91, 2022).

[0005] RAS inhibitors are disclosed in WO 2016 / 049565, WO 2016 / 049568, and WO 2017 / 172979, and compounds represented by the following formula (A) and formula (B) are disclosed in WO 2016 / 049568 and WO 2017 / 172979, respectively (see the publications for the meanings of the symbols in the formulas). Patent Documents 1, 2, and 3 describe that these compounds are useful for cancers with mutations in codon 12 of KRAS, including G12C and G12V mutations, but do not describe the specific effects of the compounds on G12C and G12V mutant KRAS. [ka] [ka]

[0006] Additionally, WO 2022 / 132200 discloses a pan-KRAS inhibitor.

[0007] In recent years, bifunctional compounds, collectively known as PROTACs (PROteolysis-TArgeting Chimeras) and SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers), have been discovered as a technology for inducing the degradation of targeted proteins, and are expected to be a novel drug discovery modality (Drug. Discov. Today Technol., 2019, 31, pp. 15-27). Bifunctional compounds promote the formation of a complex between the target protein and an E3 ligase in the cell, and the degradation of the target protein is induced by utilizing the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms. Proteins called E3 ligases recognize and ubiquitinate proteins to be degraded, which then leads to degradation in the proteasome.

[0008] There are over 600 types of E3 ligases in vivo, broadly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, only a limited number of E3 ligases are used in bifunctional degradation inducers, such as PROTACs and SNIPERs. Representative examples include von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). VHL and CRBN were reported in International Publication Nos. 2013 / 106643 and 2015 / 160845, respectively.

[0009] Bifunctional compounds are compounds in which a ligand for a target protein and a ligand for an E3 ligase are linked by a linker, and bifunctional compounds that degrade KRAS proteins have been reported (Cell. Chem. Biol., 2020, 27, pp. 19-31; ACS Cent. Sci., 2020, 6, pp. 1367-1375; U.S. Patent Application Publication No. 2018 / 0015087; WO 2019 / 195609; WO 2020 / 018788; WO 2021 / 051034; WO 2021 / 207172; WO 2022 / 111521; WO 2022 / 061348; WO 2022 / 061348). International Patent Publication No. 2022 / 148422, International Patent Publication No. 2022 / 228576, International Patent Publication No. 2023 / 059609, International Patent Publication No. 2023 / 077441, International Patent Publication No. 2023 / 280026, Chinese Patent Application Publication No. 113956233, Chinese Patent Application Publication No. 115785199, International Patent Publication No. 2023 / 138524). Furthermore, among PROTACs that degrade KRAS with the G12D mutation, compounds have been reported in which a substituent substituted at the 8th position of quinoline or quinazoline is linked to a ligand for E3 ligase (Patent Documents 1 and 2). In addition, pan-KRAS PROTACs have also been reported (Patent Documents 3 to 9). [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2022 / 173032 [Patent Document 2] International Publication No. 2023 / 171781 [Patent Document 3] International Publication No. 2022 / 087335 [Patent Document 4] International Publication No. 2022 / 212611 [Patent Document 5] International Publication No. 2022 / 266249 [Patent Document 6] International Publication No. 2022 / 271823 [Patent Document 7] International Publication No. 2023 / 099620 [Patent Document 8] International Publication No. 2023 / 130012 [Patent Document 9] International Publication No. 2023 / 141570 Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention provides a heterocyclic compound that is expected to be useful as an active ingredient in pharmaceutical compositions, for example, that have an effect of inducing the degradation of mutant KRAS proteins, particularly the effect of inducing the degradation of G12C-mutated, G12D-mutated, G12V-mutated, and G13D-mutated KRAS proteins and wild-type KRAS proteins, and / or an excellent inhibitory effect on mutant KRAS, particularly the inhibitory effect on G12C-mutated, G12D-mutated, G12V-mutated, and G13D-mutated KRAS, and the inhibitory effect on KRAS in which the wild-type KRAS gene has been amplified, and that is expected to be useful as an active ingredient in pharmaceutical compositions for treating cancer, particularly mutant KRAS-positive cancer, in particular G12C-mutated, G12D-mutated, G12V-mutated, and G13D-mutated KRAS-positive cancer, and wild-type KRAS gene amplification-positive cancer. [Means for solving the problem]

[0012] As a result of extensive investigations into compounds useful as active ingredients of pharmaceutical compositions for cancer treatment, the present inventors have found that heterocyclic compounds of formula (I), particularly R 1 The R of the heterocyclic compound is linked to a ligand of E3 ligase by substituting a substituent substituted at the carbon atom adjacent to the carbon atom to which R is bonded (corresponding to the 8-position in the case of quinazoline where A is N and E is CH). 1 The present inventors have discovered that a bifunctional compound of formula (I), characterized in that a substituent substituted at the carbon atom adjacent to the carbon atom to which is bonded (corresponding to the 8-position in the case of quinazoline where A is N and E is CH) and an E3 ligase ligand are linked via a linker, has excellent effects of inducing the degradation of mutant KRAS proteins and inhibiting mutant KRAS, as well as effects of inducing the degradation of wild-type KRAS proteins and inhibiting KRAS in which the wild-type KRAS gene has been amplified, and have completed the present invention. That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, A is CR A , or N, R A is H, C 1-3 Alkyl, -CN, -O-(C 1-3 alkyl), E is CH or N; X 1 is -CH2-, -O- or -NR X1 - and R X1 is H or optionally substituted C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1is represented by the following formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII), [ka] R 1a , R 1b are the same or different and are H, methyl, F or Cl, R 1c is F, Cl, methyl, ethyl, trifluoromethyl or cyclopropyl, R 1d is H, methyl, ethyl, F, Cl or —C≡CH, R 2 is H, halogen, optionally substituted C 1-3 alkyl, cyclopropyl or vinyl; R 3 is a group selected from the group consisting of the following formulas (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI) and (XVII), [ka] R 3a is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NRN1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, R 3b is H or C 1-3 is alkyl, R 3c and R 3d is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, R 3e is H, F or C 1-3 is alkyl, R 3f are the same or different and are H or C 1-3 is alkyl, R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group; R 3h is H, F or C 1-3 is alkyl, R3i are the same or different and represent H, 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 a group selected from the group consisting of alkyl, halogen, —CN, and oxo; or Two R's on the same carbon atom 3i together with the adjacent carbon atom, C 3-6 A spiro ring may be formed having a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the spiro ring may be C 1-3 Alkyl, -O-(C 1-3 may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen and oxo; R on two adjacent carbon atoms 3i together with the two carbon atoms to form C 3-6 A condensed ring may be formed with a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the condensed ring is 1-3 Alkyl, -O-(C 1-3 may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen and oxo; R on two non-adjacent carbon atoms 3i may combine with the two carbon atoms to form a bridged structure consisting of 1 to 2 carbon atoms, and the ring having the bridged structure is 1-3 Alkyl, -O-(C 1-3 optionally substituted with 1 to 2 groups selected from the group consisting of alkyl, OH, halogen, and oxo; R N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3j is H, OH, halogen, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 is a group selected from the group consisting of cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, and -CN; X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2-, -CH2-CH2-, -O-CH2-, -O- or -O-NH-, n 1 is 1 or 2, p is 1 or 2; q is 1 to 8; R 4 may be substituted C 1-6 alkyl, optionally substituted piperidinyl or optionally substituted tetrahydropyranyl; Y is phenylene or pyridinediyl, and the phenylene is optionally substituted with F; L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L Fare the same or different and represent a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A is H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle; Ring Hy is a 5- or 6-membered heterocycle; R Z1 is H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 is alkyl, R Z3 is H or C 1-3 is alkyl, R Z4 are the same or different and each represents H or C 1-3 is alkyl, R Z5 is C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; G is N or CH; However, when G is N, Z is the above formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX).

[0013] Furthermore, a compound having the effect of inducing the degradation of a target protein, particularly a mutant KRAS protein, and inhibitory activity against mutant KRAS, and / or the effect of inducing the degradation of a wild-type KRAS protein and inhibitory activity against KRAS in which the wild-type KRAS gene is amplified, may be, for example, a compound represented by the following formula (II). Furthermore, a compound having the effect of inducing the degradation of a target protein, particularly a mutant RAS protein, and inhibitory activity against mutant RAS, and / or the effect of inducing the degradation of a wild-type RAS protein and inhibitory activity against RAS in which the wild-type RAS gene is amplified, may be, for example, a compound represented by the following formula (II). That is, the present invention relates to a compound represented by formula (II) or a salt thereof, and a pharmaceutical composition comprising a compound represented by formula (II) or a salt thereof and one or more pharmaceutically acceptable excipients. [ka] (In the formula, TPB is a group capable of binding to a target protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and represent a bond, -O-, -NR L1A-, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A is H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle; Ring Hy is a 5- or 6-membered heterocycle; R Z1 is H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 is alkyl, R Z3 is H or C 1-3 is alkyl, R Z4 are the same or different and each represents H or C 1-3 is alkyl, R Z5 is C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; G is N or CH; However, when G is N, Z is the above formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX).

[0014] Unless otherwise specified, when a symbol in a chemical formula in this specification is used in other chemical formulas, the same symbol has the same meaning.

[0015] 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, a pharmaceutical composition for treating cancer, in one embodiment, a pharmaceutical composition for treating mutant KRAS-positive cancer, particularly a pharmaceutical composition for treating mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, in one embodiment, a pharmaceutical composition for treating metastatic cancer, in one embodiment, a pharmaceutical composition for treating locally advanced cancer, in one embodiment, a pharmaceutical composition for treating recurrent or refractory cancer, in one embodiment, a pharmaceutical composition for treating cancer in untreated and / or previously treated patients, and in one embodiment, a pharmaceutical composition for treating metastatic mutant KRAS-positive cancer, particularly a mutant KRAS-positive cancer having one or more mutations selected from the group consisting of metastatic G12C mutation, G12D mutation, G12V mutation, and G13D mutation. The present invention relates to a pharmaceutical composition for treating KRAS-positive cancer, and in one embodiment, the pharmaceutical composition is for treating locally advanced mutant KRAS-positive cancer, particularly a pharmaceutical composition for treating locally advanced mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. In one embodiment, the pharmaceutical composition is for treating recurrent or refractory mutant KRAS-positive cancer, particularly a pharmaceutical composition for treating recurrent or refractory mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. In one embodiment, the present invention relates to a pharmaceutical composition for treating mutant KRAS-positive cancer in untreated and / or previously treated patients, particularly a pharmaceutical composition for treating mutant KRAS-positive cancer in untreated and / or previously treated patients having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. The pharmaceutical composition for treating cancer containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients includes a therapeutic agent for cancer containing a compound of formula (I) or a salt thereof, and in one embodiment, a therapeutic agent for mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation.

[0016] 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 a pharmaceutical composition for treating cancer, in one embodiment a pharmaceutical composition for treating metastatic wild-type KRAS gene amplification-positive cancer, in one embodiment a pharmaceutical composition for treating locally advanced wild-type KRAS gene amplification-positive cancer, in one embodiment a pharmaceutical composition for treating recurrent or refractory wild-type KRAS gene amplification-positive cancer, and in one embodiment a pharmaceutical composition for treating wild-type KRAS gene amplification-positive cancer in untreated and / or previously treated patients. Note that the pharmaceutical composition for treating cancer comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients encompasses a therapeutic agent for cancer, in one embodiment a wild-type KRAS gene amplification-positive cancer, containing a compound of formula (I) or a salt thereof.

[0017] The present invention also relates to cancer, in one embodiment, mutant KRAS-positive cancer, particularly mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, in one embodiment, metastatic cancer, in one embodiment, locally advanced cancer, in one embodiment, recurrent or refractory cancer, in one embodiment, cancer in a patient who has not been previously treated and / or has been previously treated, in one embodiment, metastatic mutant KRAS-positive cancer, particularly mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. In one embodiment, the present invention relates to a mutant KRAS-positive cancer having one or more mutations selected from the group consisting of a G12C mutation, a G12D mutation, a G12V mutation, and a G13D mutation, and in one embodiment, a locally advanced mutant KRAS-positive cancer, particularly a mutant KRAS-positive cancer having one or more mutations selected from the group consisting of a G12C mutation, a G12D mutation, a G12V mutation, and a G13D mutation, and in one embodiment, a relapsed or refractory mutant KRAS-positive cancer, particularly a mutant KRAS-positive cancer having one or more mutations selected from the group consisting of a G12C mutation, a G12D mutation, a G12V mutation, and a G13D mutation, and in one embodiment, a treatment-naive and / or treatment-naive cancer. and a method for treating a patient with a mutant KRAS-positive cancer, in particular a patient with a mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. The present invention relates to a compound of formula (I) or a salt thereof for use in treating mutant KRAS-positive cancer, particularly mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, and a method for treating cancer, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject. In one embodiment, the present invention relates to a method for treating mutant KRAS-positive cancer, particularly mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation.

[0018] The present invention also relates to cancer, in one embodiment, wild-type KRAS gene amplification-positive cancer, in one embodiment, metastatic wild-type KRAS gene amplification-positive cancer, in one embodiment, locally advanced wild-type KRAS gene amplification-positive cancer, in one embodiment, relapsed or refractory wild-type KRAS gene amplification-positive cancer, in one embodiment, use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating wild-type KRAS gene amplification-positive cancer in untreated and / or previously treated patients; cancer, in one embodiment, use of a compound of formula (I) or a salt thereof for the treatment of wild-type KRAS gene amplification-positive cancer; cancer, in one embodiment, a compound of formula (I) or a salt thereof for use in the treatment of wild-type KRAS gene amplification-positive cancer; and a method for treating cancer, in one embodiment, wild-type KRAS gene amplification-positive cancer, which comprises administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0019] The present invention also relates to a compound of formula (I) or a salt thereof which is a mutant KRAS proteolysis inducer and / or a mutant KRAS inhibitor, in particular a compound of formula (I) or a salt thereof which is a mutant KRAS proteolysis inducer having one or more mutations selected from the group consisting of a G12C mutation, a G12D mutation, a G12V mutation, and a G13D mutation, and / or a mutant KRAS inhibitor having one or more mutations selected from the group consisting of a G12C mutation, a G12D mutation, a G12V mutation, and a G13D mutation.

[0020] The present invention also relates to a compound of formula (I) or a salt thereof, which is an inducer of wild-type KRAS protein degradation and / or an inhibitor of KRAS in which the wild-type KRAS gene is amplified.

[0021] The "subject" refers to a human or other animal in need of treatment, and in one embodiment, a human in need of prevention or treatment. [Effects of the Invention]

[0022] The compound of formula (I) or a salt thereof has an effect of inducing the degradation of mutant KRAS protein and inhibitory activity against mutant KRAS, particularly against mutant KRAS having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, and inhibitory activity against mutant KRAS having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, and can be used as a therapeutic agent for cancer, particularly against mutant KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. Furthermore, the compound of formula (I) or a salt thereof has the effect of inducing degradation of wild-type KRAS protein and the activity of inhibiting KRAS in which the wild-type KRAS gene is amplified, and can also be used as a therapeutic agent for cancer, particularly cancer positive for wild-type KRAS gene amplification. DETAILED DESCRIPTION OF THE INVENTION

[0023] The present invention will be described in detail below.

[0024] In this specification, "optionally substituted" means unsubstituted or having 1 to 5 substituents. In one embodiment, it means unsubstituted or having 1 to 3 substituents. When multiple substituents are present, the substituents may be the same or different from each other.

[0025] "C 1-12 The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (Hereinafter, the number of carbon atoms will be expressed in the same manner). In one embodiment, it is ethyl or dodecyl. Similarly, "C 1-6The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, dimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl; in one embodiment, methyl, ethyl, n-propyl, isopropyl, or sec-butyl; in one embodiment, methyl, ethyl, isopropyl, or tert-butyl; in one embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, or dimethylpropyl; in one embodiment, methyl, in one embodiment, ethyl, or in one embodiment, dimethylpropyl. Similarly, "C 1-3 The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, or isopropyl, and in one embodiment, it is methyl or ethyl, in one embodiment, n-propyl or isopropyl, in one embodiment, methyl or isopropyl, in one embodiment, ethyl or isopropyl, in one embodiment, methyl, in one embodiment, ethyl, in one embodiment, isopropyl, or in one embodiment, n-propyl. Similarly, "C 2-3 The term "alkyl" refers to a straight-chain alkyl having 2 to 3 carbon atoms, for example, ethyl or n-propyl, and in one embodiment, ethyl, and in another embodiment, n-propyl.

[0026] "C 3-6 "Cycloalkane" refers to a cycloalkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0027] "C 3-6"Cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, it 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, and in one embodiment, cyclohexyl.

[0028] "C 1-3 "Alkylene" means C 1-3 A divalent group formed by removing a hydrogen atom from an alkyl, and is a straight-chain or branched C 1-3 Alkylene, for example, methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. In one embodiment, a linear or branched C 1-3 It is alkylene, and in one embodiment, it is methylene, ethylene, or trimethylene, in one embodiment, it is methylene or ethylene, in one embodiment, it is methylene, in one embodiment, it is ethylene, and in one embodiment, it is trimethylene. Similarly, "C 2-3 "Alkylene" means C 2-3 It is a divalent group formed by removing a hydrogen atom from an alkyl, and in one embodiment is ethylene or trimethylene, in one embodiment is ethylene, and in one embodiment is trimethylene.

[0029] "C 3-6 "Cycloalkylene" means C 3-6 A divalent group formed by removing a hydrogen atom from cycloalkyl, such as cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, or cyclohexanediyl. In one embodiment, it is cyclopropanediyl, in one embodiment, cyclobutanediyl, in one embodiment, cyclopentanediyl, or in one embodiment, cyclohexanediyl.

[0030] "C 2-3 "Alkyndiyl" means C 2-3 It is a divalent group having a triple bond formed by removing four hydrogen atoms from an alkylene, and in one embodiment is -C≡C-, and in another embodiment is -CH2-C≡C-.

[0031] A "saturated heterocycle" is a saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. However, the saturated heterocycle may have an unsaturated bond in part. Furthermore, the sulfur atom as a ring-constituting atom of the saturated heterocycle may be oxidized. Furthermore, the saturated heterocycle may have a bridged structure, and further, the saturated heterocycle may have a spiro structure. Therefore, a "4- to 6-membered saturated heterocycle" is a 4- to 6-membered saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom, and may have a bridged structure or a spiro structure. Similarly, a "4- to 11-membered saturated heterocycle" is a 4- to 11-membered saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom, and may have a bridged structure or a spiro structure. One embodiment of the "4- to 6-membered saturated heterocycle" is a 4- to 6-membered saturated heterocycle containing, as ring-constituting atoms, 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, and one embodiment is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, or tetrahydropyridine.

[0032] A "saturated heterocyclic group" is a saturated hydrocarbon ring group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. However, the saturated heterocyclic group may have an unsaturated bond in a part of the ring. Furthermore, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized. Furthermore, the saturated heterocyclic group may have a bridged structure, and further, the saturated heterocyclic group may have a spiro structure. Therefore, the "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom, and may have a bridged structure or a spiro structure. One embodiment of the "4- to 6-membered saturated heterocyclic group" is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms. One embodiment of the 4- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms is a 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 5- to 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 4-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 5-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 6-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and one embodiment is oxetanyl, tetrahydrofuran ... and tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, or tetrahydropyridyl; in one embodiment, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl; in one embodiment, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; in one embodiment, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, or piperidinyl; in one embodiment, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, or piperidinyl; in one embodiment, it is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl; and in one embodiment, it is piperazinyl. Similarly, the term "4- to 11-membered saturated heterocyclic group" refers to a 4- to 11-membered saturated heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom, and may have a bridged structure or a spiro structure. One embodiment of the "4- to 11-membered saturated heterocyclic group" is a 4- to 11-membered saturated heterocyclic group containing one or two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 4- to 11-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 4- to 11-membered saturated heterocyclic group containing two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, one embodiment is a 4- to 11-membered saturated heterocyclic group containing one or two nitrogen atoms as ring-constituting atoms, one embodiment is a 4- to 11-membered saturated heterocyclic group containing one nitrogen atom as ring-constituting atom, and one embodiment is a 4- to 11-membered saturated heterocyclic group containing two nitrogen atoms as ring-constituting atoms.In some embodiments, the alkyl group may be oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, tetrahydropyridyl, 2,5-diazabicyclo[2.2.2]octan-2-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 3,6-diazabicyclo[3.1.1]heptan-3-yl, 3,6-diazabicyclo[3.1.1]heptan-6-yl, 2,7-diazaspiro[3.5]nonan-2-yl, or 2,7-diazaspiro[3.5]nonan-7-yl. , 2,8-diazaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl, 3,9-diazaspiro[5.5]undecan-3-yl, 3,9-diazaspiro[5.5]undecan-9-yl, 4,7-diazaspiro[2.5]octan-4-yl, or 4,7-diazaspiro[2.5]octan-7-yl, and in some embodiments, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl, or 4,7-diazaspiro[2.5]octan-7-yl.

[0033] The "divalent saturated heterocyclic group" refers to a divalent 4- to 11-membered saturated heterocyclic group containing one to two nitrogen atoms as ring-constituting atoms, and may further contain one to two oxygen atoms, or may be a divalent saturated heterocyclic group having a spiro ring or a fused ring, and the saturated heterocyclic ring may have an unsaturated bond as part of it. In one embodiment, the "divalent saturated heterocyclic group" is a divalent 4- to 11-membered saturated heterocyclic group containing one to two heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, in another embodiment, a divalent 4- to 11-membered saturated heterocyclic group containing one to two heteroatoms selected from the group consisting of oxygen and nitrogen as ring-constituting atoms, and in another embodiment, a divalent 4- to 11-membered saturated heterocyclic group containing one to two nitrogen atoms as ring-constituting atoms. An embodiment of the "divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms" is azetidinediyl, pyrrolidinediyl, imidazolidinediyl, piperidinediyl, piperazinediyl, azepanediyl, diazepanediyl, azocanediyl, diazocanediyl, azonanediyl, diazonanediyl, tetrahydropyridinediyl, or a divalent group represented by the following formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII). [ka] In one embodiment, the "divalent saturated heterocyclic group" is pyrrolidinediyl, piperazinediyl, tetrahydropyridinediyl, or a divalent group represented by the above formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII); in another embodiment, it is tetrahydropyridinediyl, or a divalent group represented by the above formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII); in another embodiment, it is a divalent group represented by the above formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII); in another embodiment, it is a divalent group represented by the above formula (XLV); and in another embodiment, it is a divalent group represented by the following formula (XLIV), (XLV), (XLV-1), (XLV-2), (XLVI), or (XLVII). [ka]

[0034] A "heterocycle" is an aromatic hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom. Therefore, a "six-membered heterocycle" is a six-membered aromatic hydrocarbon ring containing a nitrogen atom as a ring-constituting atom, and in one embodiment is a pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, or triazine ring, and in another embodiment is a pyridine ring. Furthermore, a "five- or six-membered heterocycle" refers to a five- or six-membered aromatic hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom, and in some embodiments is a pyrazole ring, triazole ring, imidazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, or triazine ring, and in some embodiments is a pyrazole ring, triazole ring, pyridine ring, or pyridazine ring. In some embodiments, it is a pyridine ring. In some embodiments, it is a pyridazine ring.

[0035] "Heteroaryl" is a heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring member. Therefore, a "5-membered heteroaryl" is a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms.

[0036] One embodiment of the "5-membered heteroaryl" is a 5-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and one embodiment is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl, one embodiment is pyrazolyl, triazolyl, or oxazolyl, and one embodiment is pyrazolyl or triazolyl.

[0037] The "6-membered heteroaryl" is a 6-membered heterocyclic group containing 1 to 3 nitrogen atoms as ring-constituting atoms. In one embodiment, the "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, in another embodiment, pyridyl or pyridazinyl, in another embodiment, pyridyl or pyrimidinyl, in another embodiment, pyridyl, and in another embodiment, pyrimidinyl.

[0038] "Halogen" means F, Cl, Br, and I. In one embodiment, it is F, Cl, or Br, in another embodiment, it is F or Cl, in another embodiment, it is F or Br, in another embodiment, it is F, in another embodiment, it is Cl, and in another embodiment, it is Br.

[0039] The term "spiro ring" refers to a polycyclic ring structure in which two ring structures are bonded by sharing a spiro atom, which is a quaternary carbon; the term "fused ring" refers to a polycyclic ring structure in which two or more ring structures are bonded by sharing two or more adjacent atoms that constitute one ring; and the term "bridged structure" refers to a divalent chain structure that links two non-adjacent atoms among the ring constituent atoms of one ring.

[0040] "Optionally substituted C 1-6 alkyl," "optionally substituted C 1-3 "Alkyl" and "Optionally substituted C 1-3 Some embodiments of the substituents allowed for "alkylene" include F, OH, OCH3, N(C optionally substituted with F), and the like. 1-3alkyl)2, optionally substituted C 3-6 In one embodiment, F, OH, OCH 3、 Cyclopropyl, N(C optionally substituted with F) 1-3 alkyl)2, (C optionally substituted with F 1-3and tetrahydrofuranyl, optionally substituted with (alkyl), and tetrahydrofuranyl, and in some embodiments, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted morpholinyl, optionally substituted pyrrolidinyl, or optionally substituted piperidinyl, and in some embodiments, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted morpholinyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, or optionally substituted pyrrolidinyl, and in some embodiments, F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, and in some embodiments, it is cyclopropyl, (dimethylaminomethyl)cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl, morpholinyl, fluoropyrrolidinyl, or methylpyrrolidinyl; in some embodiments, it is F, OH, OCH3, (methoxymethyl)cyclopropyl, (dimethylaminomethyl)cyclobutyl, tetrahydrofuranyl, morpholinyl, fluoropyrrolidinyl, or methylpyrrolidinyl; in some embodiments, it is F, OH, or cyclopropyl; in some embodiments, it is OH, OCH3, N(CH3)2, methylpyrrolidine, pyrrolidine optionally substituted with F, morpholine; in some embodiments, it is N(CH3)2; in some embodiments, it is F, OH, or OCH3; in some embodiments, it is OH or OCH3; in some embodiments, it is F or OCH3; in some embodiments, it is OH; in some embodiments, it is F; and in some embodiments, it is OCH3. In some embodiments, it is OH, OCH3, N(CH3)2, methylpyrrolidinyl, morpholinyl, fluoropyrrolidinyl, (hydroxymethyl)cyclopropyl, or (dimethylaminomethyl)cyclobutyl.

[0041] In the "optionally substituted 5-membered heteroaryl", "optionally substituted 6-membered heteroaryl", "optionally substituted 5- or 6-membered heterocycle", "optionally substituted benzene", and "optionally substituted oxazolyl", an embodiment of the permissible substituent is a C-substituted heteroaryl which may be substituted with a group selected from the group consisting of OH and OCH3. 1-3 Alkyl, -SO2CH3, halogen, OH, OCH3, or C 3-6 In one embodiment, a C alkyl group optionally substituted with a group selected from the group consisting of OH and OCH3 is used. 1-3 C is alkyl, and in one embodiment, optionally substituted with OH. 1-3 alkyl, and in one embodiment, C optionally substituted with OCH 1-3 alkyl, and in one embodiment C 1-3 It is alkyl or halogen, and in one embodiment, it is methyl, ethyl, methoxymethyl or F, in another embodiment, it is methyl, ethyl, F or Cl, and in another embodiment, it is methyl, ethyl or F.

[0042] "Optionally substituted 4- to 6-membered saturated heterocyclic group", "optionally substituted 4- to 11-membered saturated heterocyclic group", "optionally substituted pyrrolidinyl", "optionally substituted piperidinyl", "optionally substituted tetrahydropyranyl", "optionally substituted C 3-6 "cycloalkyl", "optionally substituted C 3-6 One embodiment of the substituents permitted for the "cycloalkylene" and "divalent optionally substituted saturated heterocyclic group" is a C group optionally substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. 1-3In one embodiment, it is alkyl, F, OH, OCH3, oxo, or oxetanyl. In one embodiment, it is F, OH, or OCH3, in one embodiment, it is OH or OCH3, in one embodiment, it is OH or methyl, in one embodiment, it is F, in one embodiment, it is OH, in one embodiment, it is OCH3, and in one embodiment, it is C optionally substituted with a group selected from the group consisting of F, OH, and OCH3. 1-3 C is alkyl, F, oxo, or oxetanyl, and in one embodiment, may be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. 1-3 C is alkyl or oxo, and in one embodiment, may be substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. 1-3 C is alkyl, and in one embodiment, optionally substituted with F. 1-3 C is alkyl, and in one embodiment, optionally substituted with OH. 1-3 alkyl, and in one embodiment, C optionally substituted with OCH 1-3 alkyl, and in one embodiment, optionally substituted with N(CH3)2. 1-3 alkyl, and in some embodiments, C 1-3 In one embodiment, C(CH3)2 optionally substituted with alkyl. 1-3 In one embodiment, C optionally substituted with N(CH3)2 is alkyl or oxo. 1-3 alkyl or F. In one embodiment, C optionally substituted with OCH 1-3 alkyl, dimethylaminomethyl or F.

[0043] "C optionally substituted with OH 1-3In one embodiment, "alkyl" is methyl optionally substituted with one OH group or ethyl optionally substituted with one or two OH groups. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1,2-dihydroxyethyl. In one embodiment, it is methyl, ethyl, or hydroxymethyl, in another embodiment, methyl or hydroxymethyl, in another embodiment, hydroxymethyl or hydroxyethyl, in another embodiment, hydroxymethyl, and in another embodiment, hydroxyethyl.

[0044] "C optionally substituted with OCH3 1-6 C optionally substituted with alkyl and OCH 1-3 In one embodiment, "alkyl" is methyl optionally substituted with one OCH3 or ethyl optionally substituted with one or two OCH3. For example, it is methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, or 1,2-dimethoxyethyl. In one embodiment, it is methoxymethyl or methoxyethyl, in another embodiment, methoxymethyl, or in another embodiment, methoxyethyl.

[0045] "N(C 1-3 C optionally substituted with alkyl)2 1-6 One embodiment of "alkyl" is "C optionally substituted with N(CH3)2." 1-3 alkyl" and in one embodiment, one N(C 1-3 methyl optionally substituted with one N(C alkyl)2; 1-3 ethyl or one N(C alkyl)2-substituted 1-3 In one embodiment, one N(C alkyl) is substituted with n-propyl. 1-3 Methyl optionally substituted with N(C alkyl)2 or 1-3 and ethyl optionally substituted with alkyl). "C optionally substituted with N(CH3)2 1-3In one embodiment, "alkyl" is methyl optionally substituted with one N(CH3)2 or ethyl optionally substituted with one N(CH3)2. In one embodiment, it is methyl, ethyl, dimethylaminomethyl, or dimethylaminoethyl, in one embodiment, it is methyl or dimethylaminomethyl, in one embodiment, it is dimethylaminomethyl, and in one embodiment, it is dimethylaminoethyl.

[0046] One embodiment of the "phenylene optionally substituted with F" is phenylene optionally substituted with 1 or 2 F. One embodiment is phenylene optionally substituted with one F, one embodiment is phenylene or fluorophenylene, one embodiment is phenylene, one embodiment is 2-fluoro-1,4-phenylene, and one embodiment is 3-fluoro-1,4-phenylene.

[0047] A "bond" refers to a moiety that forms a covalent bond with a specific atom or substituent. Therefore, a "bond to L" indicates that the moiety having the "bond to L" forms a covalent bond with L.

[0048] "Mutated KRAS" refers to a KRAS having a mutation, such as a G12C mutant KRAS, a G12D mutant KRAS, a G12V mutant KRAS, and / or a G13D mutant KRAS.

[0049] The term "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.

[0050] "G12C mutant KRAS" refers to KRAS having the above-mentioned "G12C mutation."

[0051] The term "G12D mutation" refers to a mutation in which the amino acid residue corresponding to codon 12 in the wild-type protein is converted from glycine to aspartic acid.

[0052] "G12D mutant KRAS" refers to KRAS having the above-mentioned "G12D mutation."

[0053] The term "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.

[0054] "G12V mutated KRAS" refers to KRAS having the above-mentioned "G12V mutation."

[0055] The term "G13D mutation" refers to a mutation in which the amino acid residue corresponding to codon 13 in the wild-type protein is converted from glycine to aspartic acid.

[0056] "G13D mutant KRAS" refers to KRAS having the above-mentioned "G13D mutation."

[0057] "Cancer" refers to a malignant tumor. In some embodiments, the cancer includes pancreatic cancer, lung cancer, colon cancer, skin cancer, uterine cancer, thyroid cancer, bladder cancer, stomach cancer, epithelial cancer, esophageal cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, kidney cancer, myeloma, lymphoma, and leukemia. In some embodiments, the cancer includes pancreatic cancer, lung cancer, colon cancer, and stomach cancer. In some embodiments, the cancer includes pancreatic cancer, lung cancer, and colon cancer. In addition, certain embodiments include pancreatic cancer, lung cancer, colon cancer, skin cancer such as melanoma, uterine cancer such as cervical cancer and endometrial cancer, thyroid cancer, bladder cancer, gastric cancer, epithelial cancer, esophageal cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma or kidney cancer, myeloma such as myelodysplastic syndrome and myeloproliferative neoplasm, lymphoma such as mature B-cell lymphoma, leukemia, esophagogastric junction cancer, head and neck cancer, glioma, hepatobiliary cancer, soft tissue sarcoma, appendix cancer, small intestine cancer, germ cell tumor, neuroendocrine cancer, gallbladder cancer, peritoneal cancer, and fallopian tube cancer. In addition, certain embodiments include germ cell tumor, esophagogastric junction cancer, ovarian cancer, and pancreatic cancer. In addition, certain embodiments include solid cancer and blood cancer, and in certain embodiments, solid cancer and blood cancer.

[0058] The term "mutated KRAS-positive cancer" refers to a cancer positive for mutant KRAS, particularly a cancer positive for G12C mutation, G12D mutation, G12V mutation, and / or G13D mutation KRAS. For example, this refers to a cancer in which KRAS G12C mutation, G12D mutation, G12V and / or G13D mutation has occurred, and in which the positive rate of G12C mutation, G12D mutation, G12V mutation, and / or G13DKRAS is high.

[0059] In some embodiments, the "mutated KRAS-positive cancer" is G12C mutation, G12D mutation, and G12V mutation KRAS positive cancer, G12C-mutated, G12D-mutated, and G13D-mutated KRAS-positive cancers, G12C-mutated, G12V-mutated, and G13D-mutated KRAS-positive cancers, and These are G12D-mutated, G12V-mutated, and G13D-mutated KRAS-positive cancers.

[0060] In some embodiments, the "mutated KRAS-positive cancer" is G12C mutation and G12D mutation KRAS positive cancer, G12C mutation and G12V mutation KRAS positive cancer, G12D mutation and G12V mutation KRAS positive cancer, G12C and G13D mutant KRAS-positive cancers, G12D-mutated and G13D-mutated KRAS-positive cancers, and This is a cancer that is positive for G12V mutation and G13D mutation of KRAS.

[0061] In some embodiments, the "mutated KRAS-positive cancer" is G12C mutant KRAS-positive cancer, G12D mutant KRAS-positive cancer, G12V mutant KRAS-positive cancer, and It is a G13D-mutated KRAS-positive cancer.

[0062] "G12C mutant KRAS positive cancer" refers to cancer that is positive for G12C mutant KRAS. For example, it is a cancer in which KRAS G12C mutation has occurred, and is a cancer with a high rate of G12C mutant KRAS positivity. In one embodiment, it is pancreatic cancer, lung cancer, or colorectal cancer, which has a high rate of G12C mutant KRAS positivity.

[0063] "G12D mutant KRAS-positive cancer" refers to cancer that is positive for G12D mutant KRAS. For example, it is a cancer in which KRAS G12D mutation has occurred, and is a cancer with a high rate of G12D mutant KRAS positivity. In one embodiment, it is pancreatic cancer, lung cancer, or colorectal cancer, which has a high rate of G12D mutant KRAS positivity.

[0064] "G12V mutant KRAS-positive cancer" refers to cancer that is positive for G12V mutant KRAS. For example, it is a cancer in which KRAS G12V mutation has occurred, and a cancer with a high rate of G12V mutant KRAS positivity. In one embodiment, it is pancreatic cancer, lung cancer, or colon cancer, which has a high rate of G12V mutant KRAS positivity.

[0065] "G13D mutant KRAS-positive cancer" refers to cancer that is positive for G13D mutant KRAS. For example, it is a cancer in which KRAS G13D mutation has occurred, and a cancer with a high rate of G13D mutant KRAS positivity. In one embodiment, it is pancreatic cancer, lung cancer, or colorectal cancer, which has a high rate of G13D mutant KRAS positivity.

[0066] "Wild-type KRAS gene amplification" refers to high-level amplification of the KRAS gene due to an abnormality in the copy number of the wild-type KRAS gene.

[0067] "Wild-type KRAS gene amplification-positive cancer" refers to cancer that has the above-mentioned "wild-type KRAS gene amplification." In some embodiments, the cancers include germ cell tumors, gastroesophageal junction cancers, ovarian cancers, and pancreatic cancers that have wild-type KRAS gene amplification.

[0068] "Pancreatic cancer" refers to malignant tumors that occur in the pancreas. Examples include pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, and in some embodiments, pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma. Furthermore, in some embodiments, the cancer is metastatic pancreatic cancer, in some embodiments, locally advanced pancreatic cancer, in some embodiments, recurrent or refractory pancreatic cancer, and in some embodiments, pancreatic cancer in untreated and / or previously treated patients.

[0069] "Lung cancer" refers to a malignant tumor that develops in the lung. For example, it refers to small cell lung cancer and non-small cell lung cancer, and in one embodiment it is small cell lung cancer and in another embodiment it is non-small cell lung cancer. Furthermore, in one embodiment it is metastatic lung cancer, in one embodiment it is locally advanced lung cancer, in one embodiment it is recurrent or refractory lung cancer, and in one embodiment it is lung cancer in patients who have not been treated and / or who have been treated previously. In one embodiment it is non-squamous non-small cell lung cancer, and in another embodiment it is squamous non-small cell lung cancer.

[0070] "Colorectal cancer" refers to malignant tumors that occur in the large intestine. For example, it refers to colon cancer and rectal cancer. In some embodiments, it refers to colon cancer and in some embodiments, it refers to rectal cancer. In some embodiments, it refers to metastatic colorectal cancer, in some embodiments, locally advanced colorectal cancer, in some embodiments, recurrent or refractory colorectal cancer, and in some embodiments, it refers to colorectal cancer in patients who have not been treated and / or who have been treated previously.

[0071] "Gastric cancer" refers to a malignant tumor that develops in the stomach. In some embodiments, it is metastatic gastric cancer, in some embodiments, locally advanced gastric cancer, in some embodiments, recurrent or refractory gastric cancer, and in some embodiments, gastric cancer in treatment-naive and / or previously treated patients.

[0072] "Esophagogastric junction cancer" refers to a malignant tumor that develops at the junction between the esophagus and stomach. In some embodiments, it is metastatic esophagogastric junction cancer, in some embodiments, locally advanced esophagogastric junction cancer, in some embodiments, recurrent or refractory esophagogastric junction cancer, and in some embodiments, esophagogastric junction cancer in treatment-naïve and / or previously treated patients.

[0073] "Ovarian cancer" refers to a malignant tumor that develops in the ovaries. In some embodiments, the cancer is metastatic, in some embodiments, locally advanced, in some embodiments, recurrent or refractory ovarian cancer, and in some embodiments, ovarian cancer in untreated and / or previously treated patients.

[0074] A "germ cell tumor" is a tumor formed when germ cells change for some reason, and in one embodiment is a metastatic germ cell tumor, in one embodiment is a locally advanced germ cell tumor, in one embodiment is a recurrent or refractory germ cell tumor, or in one embodiment is a germ cell tumor in a patient who has not been treated and / or has been treated before.

[0075] "Solid cancer" refers to cancer other than blood cancer. In some embodiments, the solid cancer is pancreatic cancer, lung cancer, colon cancer, skin cancer such as melanoma, uterine cancer such as endometrial cancer, thyroid cancer, bladder cancer, stomach cancer, epithelial cancer, esophageal cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma or kidney cancer, esophagogastric junction cancer, head and neck cancer, glioma, hepatobiliary cancer, soft tissue sarcoma, appendix cancer, small intestine cancer, germ cell tumor, neuroendocrine cancer, gallbladder cancer, peritoneal cancer, or fallopian tube cancer.

[0076] "Blood cancer" refers to a disease in which blood cells become cancerous and proliferate abnormally. Examples of blood cancer include leukemias such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia, malignant lymphomas such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and mature B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

[0077] "Binding ability to RAS protein" refers to the ability of a compound to bind to RAS protein. In one embodiment, this refers to the ability to bind to KRAS protein, HRAS protein, and / or NRAS protein, which are members of the RAS family. In another embodiment, this refers to the ability to inhibit KRAS protein, HRAS protein, and / or NRAS protein, which are members of the RAS family. The RAS protein referred to here includes mutant RAS proteins, such as G12C, G12D, G12V, and G13D mutant KRAS proteins. The binding ability to RAS protein can be evaluated by the methods described in Patent Document 1 and Patent Document 2, or methods similar thereto.

[0078] One embodiment of the "group capable of binding to RAS protein" is a group capable of binding to KRAS protein, HRAS protein, and / or NRAS protein, which belong to the RAS family, and another embodiment is a group in which any hydrogen atom on a compound having inhibitory activity against KRAS protein, HRAS protein, and / or NRAS protein, which belong to the RAS family, is substituted with a bond.

[0079] One embodiment of the "group capable of binding to RAS protein" is a group in which any hydrogen atom on a compound having inhibitory activity against KRAS protein is substituted with a bond, such as a group in which any hydrogen atom on a compound having inhibitory activity against KRAS protein described in the following document is substituted with a bond: International Publication No. 2022 / 132200, International Publication No. 2022 / 133038, International Publication No. 2022 / 047260, International Publication No. 2022 / 173870, International Publication No. 2022 / 061251, International Publication No. 2022 / 250170, International Publication No. 2023 / 001123, International Publication No. 2023 / 287896, International Publication International Publication No. 2023 / 287896, International Publication No. 2023 / 099623, International Publication No. 2023 / 099608, International Publication No. 2023 / 099592, International Publication No. 2023 / 099624, International Publication No. 2023 / 137223, International Publication No. 2023 / 138589, International Publication No. 2023 / 154766, International Publication No. 202 3 / 114733, WO 2023 / 172737, WO 2023 / 183585, WO 2023 / 244599, WO 2023 / 244604, WO 2023 / 232776, WO 2023 / 244615, WO 2024 / 041621, WO 2024 / 04 1589, WO 2024 / 044667, WO 2024 / 086061, WO 2024 / 104425, WO 2023 / 230190, WO 2016 / 049568, WO 2017 / 172979, WO 2018143315, WO 2022173033.

[0080] One embodiment of the "group capable of binding to a RAS protein" is a group that serves as a ligand for a target protein in a bifunctional compound such as a PROTAC that degrades a KRAS protein, for example, a group that serves as a ligand for a target protein in a bifunctional compound such as a PROTAC that degrades a KRAS protein described in the following document: Cell. Chem. Biol., 2020, 27, p19-31, ACS Cent. Sci., 2020, 6, p1367-1375, U.S. Patent Application Publication No. 2018 / 0015087, WO 2019 / 195609, WO 2020 / 018788, WO 2021 / 051034, WO 2021 / 207172, WO 2022 / 111521, WO 2022 / 061348, WO 2022 / 148422, WO 2022 / 228576, WO 2023 / 059609, WO 2023 / 077441, WO 2023 / 280026, Chinese Patent Application Publication No. 113956233, Chinese Patent Application Publication No. International Publication No. 115785199, International Publication No. 2023 / 138524, International Publication No. 2022 / 173032, International Publication No. 2023 / 171781, International Publication No. 2022 / 087335, International Publication No. 2022 / 212611, International Publication No. 2022 / 266249, International Publication No. 2022 / 271823, International Publication No. 2023 / 099620, International Publication No. 2023 / 130012, International Publication No. 2023 / 141570, International Publication No. 2024019103, International Publication No. 2024034591, International Publication No. 2024029613, International Publication No. 2024034593.

[0081] Certain embodiments of the compound of formula (I) or a salt thereof according to the present invention are shown below.

[0082] (1-1) A is CR A , or N and R A But H, C 1-3 Alkyl, -CN, -O-(C 1-3 A compound of formula (I) or a salt thereof, wherein (1-2) A is CR A , or N and R A But H or C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (1-3) A is CR A , or N and R Ais H, or a salt thereof. (1-4) A is CR A , or N and R A But C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (1-5) A compound of formula (I) or a salt thereof, wherein A is N. (1-6) A is CR A and R A But H, C 1-3 Alkyl, -CN, -O-(C 1-3 A compound of formula (I) or a salt thereof, wherein (1-7) A is CR A and R A is H, or a salt thereof.

[0083] (1A-1) A compound of formula (I) or a salt thereof, wherein E is CH or N. (1A-2) A compound of formula (I) or a salt thereof, wherein E is CH. (1A-3) A compound of formula (I) or a salt thereof, wherein E is N.

[0084] (2-1) X 1 is -CH2-, -O- or -NR X1 - and R X1 is H or optionally substituted C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may be taken together with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, or a salt thereof. (2-1-1) X 1 is -CH2-, -O- or -NR X1- and R X1 is H or optionally substituted C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or a salt thereof. (2-2) X 1 is -O- or -NR X1 - and R X1 But H or C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may be taken together with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, or a salt thereof. (2-2-1) X 1 is -O- or -NR X1 - and R X1 But H or C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or a salt thereof. (2-3) X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4together with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, or a salt thereof. (2-3-1) X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or a salt thereof. (2-4) X 1 is -O- or -NR X1 - and R X1 But H or C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (2-5) X 1 is -O- or a salt thereof. (2-6) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, or a salt thereof. (2-6-1) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or a salt thereof. (2-7) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 C, which may be substituted with N(CH3)2 together with the adjacent nitrogen atom 1-3A compound of formula (I) or a salt thereof, which forms a 4- to 11-membered saturated heterocyclic group optionally substituted with alkyl or F. (2-7-1) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 C, which may be substituted with N(CH3)2 together with the adjacent nitrogen atom 1-3 A compound of formula (I) or a salt thereof, which forms a 4- to 6-membered saturated heterocyclic group optionally substituted with alkyl or F. (2-8) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom, C 1-3 A compound of formula (I) or a salt thereof, which forms a 4- to 11-membered saturated heterocyclic group which may be substituted with alkyl. (2-8-1) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom, C 1-3 A compound of formula (I) or a salt thereof, which forms a 4- to 6-membered saturated heterocyclic group optionally substituted with alkyl. (2-9) X 1 But, -NR X1 - and R present on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom, C 1-3 A compound of formula (I) or a salt thereof, which forms a piperazinyl group which may be substituted with alkyl.

[0085] (3-1) R 1 is represented by the following formula (II), formula (III), formula (IV), formula (V), formula (VI), or formula (VII), [ka] R 1a , R 1b are the same or different and are H, methyl, F or Cl, R 1c is F, Cl, methyl, ethyl, trifluoromethyl or cyclopropyl; R 1d is H, methyl, ethyl, F, Cl or —C≡CH or a salt thereof. (3-1-1) R 1 is represented by the following formula (II), formula (III), formula (IV), formula (V), formula (VI), or formula (VII), [ka] R 1a are the same or different and are H, methyl, F or Cl, R 1b is H, methyl, F or Cl, R 1c is F, Cl, methyl, ethyl, trifluoromethyl or cyclopropyl; R 1d is H, methyl, ethyl, F, Cl or —C≡CH or a salt thereof. (3-2) R 1 is represented by the following formula (II), formula (III), or formula (IV): [ka] R 1a are the same or different and are H or F, R 1b is H, R 1c is methyl or cyclopropyl, R 1d is H, or a salt thereof. (3-3) R 1 is the following formula (II): [ka] R 1a is H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl, or a salt thereof. (3-4) R 1 is the following formula (II): [ka] R 1a But F, R 1c is methyl or a salt thereof. (3-5) R 1 is the following formula (III): [ka] R 1a is H or F, R 1b is H, R 1c is methyl or cyclopropyl, or a salt thereof. (3-6) R 1 is the following formula (IV): [ka] R 1a are the same or different and are H or F, R 1d is H, or a salt thereof.

[0086] (4-1) R 2 is H, halogen, optionally substituted C 1-3 A compound of formula (I) or a salt thereof, wherein: (4-2) R 2 But H, halogen, C 1-3 alkyl, cyclopropyl, or vinyl, 1-3The compound of formula (I) or a salt thereof, wherein the alkyl is optionally substituted with a group selected from the group consisting of OH and OCH3. (4-3) R 2 is cyclopropyl, or vinyl, or a salt thereof. (4-4) R 2 is cyclopropyl; or a salt thereof.

[0087] (5-1) R 3 is a group selected from the group consisting of the following formulas (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI) and (XVII), [ka] R 3a But -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, R 3b But H or C 1-3is alkyl, R 3c and R 3d But -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, R 3e But H, F or C 1-3 is alkyl, R 3f are the same or different and are H or C 1-3 is alkyl, R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group; R 3h But H, F or C 1-3 is alkyl, R 3i are the same or different and are H, OH, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, -NH- optionally substituted C 1-3Alkyl, -N-(optionally substituted C 1-3 a group selected from the group consisting of alkyl, halogen, —CN, and oxo; or Two R's on the same carbon atom 3i together with the adjacent carbon atom, C 3-6 A spiro ring may be formed having a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the spiro ring may be C 1-3 Alkyl, -O-(C 1-3 may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen and oxo; R on two adjacent carbon atoms 3i together with the two carbon atoms to form C 3-6 A condensed ring may be formed with a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the condensed ring is 1-3 Alkyl, -O-(C 1-3 may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen and oxo; R on two non-adjacent carbon atoms 3i may combine with the two carbon atoms to form a bridged structure consisting of 1 to 2 carbon atoms, and the ring having the bridged structure is 1-3 Alkyl, -O-(C 1-3 optionally substituted with 1 to 2 groups selected from the group consisting of alkyl, OH, halogen, and oxo; R N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1may form an optionally substituted 4- to 6-membered saturated heterocyclic group together with the carbon atom and nitrogen atom to which they are bonded, R 3j H, OH, halogen, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 is a group selected from the group consisting of cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, and -CN; X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is -CH2-, -CH2-CH2-, -O-CH2-, -O- or -O-NH-, n 1 is 1 or 2, p is 1 or 2, A compound of formula (I) or a salt thereof, wherein q is 1 to 8. (5-2) R 3 is a group represented by the following formula (XII), formula (XIII), formula (XIV) or formula (XVII), [ka] R 3f are the same or different and are H or C 1-3 is alkyl, R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group; R 3j H, OH, halogen, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, optionally substituted C 3-6is a group selected from the group consisting of cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, and -CN; X 2 is -O-, -NH-, or -N(C 1-3 A compound of formula (I) or a salt thereof, wherein R is 1 or 2; (5-3) R 3 is a group represented by formula (XIV) or a salt thereof. [ka]

[0088] (6-1) R 4 may be substituted C 1-6 A compound of formula (I) or a salt thereof, which is alkyl, optionally substituted piperidinyl or optionally substituted tetrahydropyranyl. (6-2) R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is F;OH;OCH 3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a may be substituted C 1-3 is alkyl, R 4b may be substituted C 1-3 alkyl or halogen; A compound of formula (I) or a salt thereof. (6-3) R 4 But C 1-6 alkyl or piperidinyl,1-6 Alkyl is OH; OCH3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a But C 1-3 is alkyl, R 4b But -O-(C 1-3 alkyl) or -N(C 1-3 C optionally substituted with alkyl)2 1-3 A compound of formula (I) or a salt thereof, wherein: (6-3-1) R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is OH; OCH3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a But C 1-3 is alkyl, R 4b OH, -O-(C 1-3 alkyl) and -N(C 1-3 C optionally substituted with a group selected from the group consisting of alkyl)2 1-3 A compound of formula (I) or a salt thereof, wherein: (6-4) R 4 But N(C 1-3 C optionally substituted with alkyl)2 1-6A compound of formula (I) or a salt thereof, wherein R is alkyl. (6-5) R 4 C optionally substituted with N(Me) 1-6 A compound of formula (I) or a salt thereof, wherein R is alkyl.

[0089] (7-1) A compound of formula (I) or a salt thereof, wherein Y is phenylene or pyridinediyl, and the phenylene may be substituted with F. (7-2) A compound of formula (I) or a salt thereof, wherein Y is phenylene optionally substituted with F. (7-3) A compound of formula (I) or a salt thereof, wherein Y is phenylene. (7-4) A compound of formula (I) or a salt thereof, wherein Y is phenylene or pyridinediyl.

[0090] (8-1) L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (8-2) L is the following formula (XXX-L), formula (XXXI-L), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 a divalent group of alkynediyl, -C≡C-, or an optionally substituted saturated heterocyclic ring, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (8-2-1) L is the following formula (XXX-L), formula (XXXI-LX), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 a divalent group of alkynediyl, -C≡C-, or an optionally substituted saturated heterocyclic ring, R LX is H or OH, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (8-3) L is the following formula (XXX-L), formula (XXXI-L), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 alkylene-O- or tetrahydropyridinediyl, L 2 is —CH—C≡C— or —CHCH—O—, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (8-3-1) L is the following formula (XXX-L), formula (XXXI-LX), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3alkylene-O- or tetrahydropyridinediyl, R LX is H or OH, L 2 is —CH—C≡C— or —CHCH—O—, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (8-4) L is a group represented by the following formula (XXXI-L): [ka] L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 A compound of formula (I) or a salt thereof, which is alkylene-O- or tetrahydropyridinediyl. (8-4-1) L is a group represented by the following formula (XXXI-LX), [ka] L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 alkylene-O- or tetrahydropyridinediyl, R LXis H or OH, or a salt thereof. (8-5) L is a group represented by the following formula (XXXI-L): [ka] L 1 is —CH2CH2—O— or —CH2—C≡C—, or a salt thereof. (8-6) L is a group represented by the following formula (XXXI-L): [ka] L 1 is —CH2CH2—O—, or a salt thereof. (8-7) L is a group represented by the following formula (XXXI-L): [ka] L 1 is —CH2—C≡C—, or a salt thereof.

[0091] (9-1) Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 But H or C 1-3 is alkyl, R Z3 But H or C 1-3 is alkyl, R Z4 are the same or different and are H or C 1-3 is alkyl, R Z5 But C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; A compound of formula (I) or a salt thereof. (9-2) Z is a group selected from the group consisting of formula (XXII), formula (XXIV), formula (XXVI), and formula (XXVII), [ka] Ring B is a benzene ring or a 6-membered heterocycle, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 But H or C 1-3 is alkyl, R Z4 are the same or different and are H or C 1-3 is alkyl, R Z5 But C 1-3 is alkyl, r is 1 or 2; The compound of formula (I) or a salt thereof, wherein L is bonded to the ring B of formula (XXII), formula (XXVI), the benzene ring of formula (XXIV), and ring Hy of formula (XXVII). (9-3) Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z), and formula (XXXII-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3 are the same or different and are CH or N, R Z2 But C 1-3 is alkyl, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, halogen, C 1-3 Alkyl, -O-(C 1-3 A compound of formula (I) or a salt thereof, wherein - is -C, ... (9-4) Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z), and formula (XXXII-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C1-3 is alkyl, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, C 1-3 A compound of formula (I) or a salt thereof, wherein: (9-5) Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z1), formula (XXXII-Z2), and formula (XXXIV-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] Ring Hy2 is represented by the following formula (XLIII): [ka] R Z1 But H, C 1-3 alkyl or halogen; R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Hy2 But H, C 1-3 A compound of formula (I) or a salt thereof, wherein: (9-5-1) Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z1), formula (XXXII-Z2), and formula (XXXIV-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] Ring Hy2 is represented by the following formula (XLIII): [ka] R Z1 But H, C 1-3 alkyl or halogen; R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Hy2 But H, C 1-3 A compound of formula (I) or a salt thereof, wherein: (9-6) Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z1), formula (XXXII-Z2), and formula (XXXIV-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] Ring Hy2 is represented by the following formula (XLIII): [ka] R Z1 is H or a halogen, R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Hy2 But H or C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (9-6-1) Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z1), formula (XXXII-Z2), and formula (XXXIV-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] Ring Hy2 is represented by the following formula (XLIII): [ka] R Z1 is H or a halogen, R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Hy2 But H or C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (9-7) Z is formula (XXXI-Z1), [ka] Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI), [ka] R Hy1a But H, C 1-3 A compound of formula (I) or a salt thereof, wherein: (9-8) Z is formula (XXXI-Z1), [ka] Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI), [ka] R Hy1a is H, or a salt thereof.

[0092] (10-1) L and Z together form a group selected from the group consisting of formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3 are the same or different and are CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; Ring Hy is a 5- or 6-membered heterocycle, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R Z1 But H, halogen, C 1-3 Alkyl, -O-(C 1-3 alkyl) or -CN; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (10-1-1) L and Z together form a group selected from the group consisting of formula (XXX), formula (XXXI-X), formula (XXXII), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3 are the same or different and are CH or N, R Z2 But C1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R Z1 But H, halogen, C 1-3 Alkyl, -O-(C 1-3 alkyl) or -CN; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (10-2) L and Z together represent a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy is a 5- or 6-membered heterocycle, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-2-1) L and Z together represent a group selected from the group consisting of formula (XXX), formula (XXXI-X), formula (XXXII), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-3) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-3-1) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z Ais a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-4) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 is H or a halogen, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, R L4 and R L5 are both H or the R L4 and R L5may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-4-1) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 is H or a halogen, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-5) L and Z together form a group selected from the group consisting of formula (XXX), formula (XXXI), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3 are the same or different and are CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (10-5-1) L and Z together form a group selected from the group consisting of formula (XXX), formula (XXXI-X), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3 are the same or different and are CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (10-6) L and Z together represent a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXIII-A), (XXXIII-B), (XXXIV) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-6-1) L and Z together represent a group selected from the group consisting of formula (XXX), formula (XXXI-X), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and RL5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-7) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 But H, C 1-3 alkyl or halogen; A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-7-1) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 But H, C 1-3 alkyl or halogen; A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-8) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 is H or a halogen, A1 is CH or N, R L2 and RL3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-8-1) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, RZ2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 is H or a halogen, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, RL4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-9) L and Z together represent a group represented by formula (XXXI-1), [ka] L 1 is —CHCH—O— or —CH—C≡C—, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI), [ka] R Hy1a But H, C 1-3 A compound of formula (I) or a salt thereof, wherein: (10-9-1) L and Z together represent a group represented by formula (XXXI-1X), [ka] L 1 is —CHCH—O— or —CH—C≡C—, R LX is H, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI), [ka] R Hy1a But H, C 1-3 A compound of formula (I) or a salt thereof, wherein: (10-10) L and Z together represent a group represented by formula (XXXI-1A) or formula (XXXI-1B), [ka] R LX is H, L 1A is -CH2CH2-O-, L 1B is —CHCH—O— or —CH—C≡C—, R Hy1a But H or C 1-3 A compound of formula (I) or a salt thereof, wherein R is alkyl. (10-11) L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1bBut H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 is H or a halogen, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-12) L and Z together form a group selected from the group consisting of formula (XXXI-X), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (10-13) L and Z together represent a group selected from the group consisting of formula (XXXI-X), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-14) L and Z together represent a group selected from the group consisting of the following formulae (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] RHy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 But H, C 1-3 alkyl or halogen; A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-15) L and Z together represent a group selected from the group consisting of the following formulae (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 is H or a halogen, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, RL4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (10-16) L and Z together represent a group selected from the group consisting of the following formulae (XXXI-1X), (XXXIII-A1), (XXXIII-B1) and (XXXIV-1), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 is H or a halogen, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof.

[0093] (11-1) G is N or CH; A compound of formula (I) or a salt thereof, wherein when G is N, Z is formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX). (11-2) G is N, A compound of formula (I) or a salt thereof, wherein Z is formula (XXII), formula (XXIV), formula (XXVI) or formula (XXVII). (11-3) A compound of formula (I) or a salt thereof, wherein G is N.

[0094] (12) A compound or a salt thereof, which is any combination of two or more of the above-mentioned embodiments (1-1) to (1-7), (1A-1) to (1A-3), (2-1) to (2-8-1), (3-1) to (3-4), (4-1) to (4-4), (5-1) to (5-3), (6-1) to (6-4), (7-1) to (7-4), (8-1) to (8-6), (9-1) to (9-7), (10-1) to (10-16), and (11-1) to (11-3) that are not contradictory.

[0095] Specific examples of the combination described in (12) above include the following. (12-1) A compound of formula (I) or a salt thereof. [ka] (In the formula, A is CR A , or N, R A is H, C 1-3 Alkyl, -CN, -O-(C 1-3 alkyl), E is CH or N; X 1 is -CH2-, -O- or -NR X1 - and R X1 is H or optionally substituted C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1 is represented by the following formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII), [ka] R 1a , R 1b are the same or different and are H, methyl, F or Cl, R 1c is F, Cl, methyl, ethyl, trifluoromethyl or cyclopropyl, R 1d is H, methyl, ethyl, F, Cl or —C≡CH, R 2 is H, halogen, optionally substituted C 1-3 alkyl, cyclopropyl or vinyl; R 3is a group selected from the group consisting of the following formulas (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI) and (XVII), [ka] R 3a is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, R 3b is H or C 1-3 is alkyl, R 3c and R 3d is -(CH2) p CHR 3e -NR N1 R N2 ;-(CH2) p CHR 3e -OR 3f ;C 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2, and -NR N1 R N2 a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of: 1-3 Alkyl, -C 1-3 Alkylene-OR 3f , -C 1-3 Alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 C optionally substituted with a group selected from the group consisting of 3-6 is cycloalkyl, R 3e is H, F or C 1-3 is alkyl, R 3f are the same or different and are H or C 1-3 is alkyl, R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group; R 3h is H, F or C 1-3 is alkyl, R 3i are the same or different and represent H, 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 a group selected from the group consisting of alkyl, halogen, —CN, and oxo; or Two R's on the same carbon atom 3i together with the adjacent carbon atom, C 3-6 A spiro ring may be formed having a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the spiro ring may be C 1-3 Alkyl, -O-(C 1-3may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen and oxo; R on two adjacent carbon atoms 3i together with the two carbon atoms to form C 3-6 A condensed ring may be formed with a ring selected from the group consisting of cycloalkanes and 4- to 6-membered saturated heterocycles, and the condensed ring is 1-3 Alkyl, -O-(C 1-3 may be substituted with one or two groups selected from the group consisting of alkyl, OH, halogen and oxo; R on two non-adjacent carbon atoms 3i may combine with the two carbon atoms to form a bridged structure consisting of 1 to 2 carbon atoms, and the ring having the bridged structure is 1-3 Alkyl, -O-(C 1-3 optionally substituted with 1 to 2 groups selected from the group consisting of alkyl, OH, halogen, and oxo; R N1 and R N2 are the same or different and are H or C 1-3 alkyl, or R N1 and R N2 may combine with the nitrogen atom to which they are attached to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may form, together with the carbon atom and nitrogen atom to which they are attached, an optionally substituted 4- to 6-membered saturated heterocyclic group, R 3j is H, OH, halogen, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 is a group selected from the group consisting of cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, and -CN; X 2 is -O-, -NH-, or -N(C1-3 alkyl)-, X 3 is O or S, X 4 is -CH2-, -CH2-CH2-, -O-CH2-, -O- or -O-NH-, n 1 is 1 or 2, p is 1 or 2; q is 1 to 8; R 4 may be substituted C 1-6 alkyl, optionally substituted piperidinyl or optionally substituted tetrahydropyranyl; Y is phenylene or pyridinediyl, and the phenylene is optionally substituted with F; L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and represent a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A is H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle; Ring Hy is a 5- or 6-membered heterocycle; R Z1 is H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 is alkyl, R Z3 is H or C 1-3 is alkyl, R Z4 are the same or different and each represents H or C 1-3 is alkyl, R Z5 is C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; G is N or CH; However, when G is N, Z is the above formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX).

[0096] (12-2) E is CH; R 3 is a group represented by the following formula (XII), formula (XIII), formula (XIV) or formula (XVII), [ka] R 3f are the same or different and are H or C1-3 is alkyl, R 3g may be substituted C 3-6 cycloalkyl, an optionally substituted 5-membered heteroaryl, an optionally substituted 6-membered heteroaryl, or an optionally substituted 4- to 6-membered saturated heterocyclic group; R 3j is H, OH, halogen, optionally substituted C 1-3 Alkyl, -O-optionally substituted C 1-3 Alkyl, optionally substituted C 3-6 is a group selected from the group consisting of cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, and -CN; X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is a group selected from the group consisting of formula (XXII), formula (XXIV), formula (XXVI) and formula (XXVII), [ka] Ring B is a benzene ring or a 6-membered heterocycle, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 But H or C 1-3 is alkyl, R Z4 are the same or different and are H or C 1-3 is alkyl, R Z5 But C 1-3 is alkyl, r is 1 or 2; L is bonded to the ring B in the above formula (XXII) and formula (XXVI), to the benzene ring in formula (XXIV), and to the ring Hy in formula (XXVII), G is N, The compound or salt thereof according to (12-1) above.

[0097] (12-2-1) X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1 is represented by the following formula (II), formula (III), or formula (IV): [ka] R 1a are the same or different and are H or F, R 1b is H, R 1c is methyl or cyclopropyl, R 1d is H, R 2 is cyclopropyl, R 3 is a group represented by formula (XIV), [ka] R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is OH; OCH3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a But C 1-3 is alkyl, R 4b But -O-(C 1-3 alkyl) or -N(C 1-3 C optionally substituted with alkyl)2 1-3 alkyl or halogen; Y is phenylene; L is the following formula (XXX-L), formula (XXXI-L), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 alkylene-O- or tetrahydropyridinediyl, L 2 is —CH—C≡C— or —CHCH—O—, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may be combined with the carbon atom to which it is attached to form a cyclopropane. Z is a group selected from the group consisting of formula (XXX-Z), formula (XXXI-Z), and formula (XXXII-Z), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, C 1-3 alkyl or halogen; The compound or salt thereof according to (12-2) above.

[0098] (12-3) E is CH; R 3 is a group represented by formula (XIV), [ka] Y is phenylene; L and Z together form a group selected from the group consisting of formula (XXX), formula (XXXI), formula (XXXII), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3 are the same or different and are CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; Ring Hy is a 5- or 6-membered heterocycle, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R Z1 But H, halogen, C 1-3 Alkyl, -O-(C 1-3 alkyl) or -CN; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and RL3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is attached, G is N, The compound or salt thereof according to (12-1) above.

[0099] (12-3-1) E is CH; X 1 is -O- or -NR X1 - and R X1 But H or C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1 is represented by the following formula (II), formula (III), or formula (IV): [ka] R 1a are the same or different and are H or F, R 1b is H, R1c is methyl or cyclopropyl, R 1d is H, R 3 is a group represented by formula (XIV), [ka] R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is F;OH;OCH 3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a may be substituted C 1-3 is alkyl, R 4b may be substituted C 1-3 alkyl or halogen; Y is phenylene; L and Z together form a group selected from the group consisting of formula (XXX), formula (XXXI-X), formula (XXXII), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-1), [ka] R Z11 is H or a halogen, Z 1 , Z 2 , and Z 3are the same or different and are CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R Z1 But H, halogen, C 1-3 Alkyl, -O-(C 1-3 alkyl) or -CN; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is attached, G is N, The compound or salt thereof according to (12-1) above.

[0100] (12-4) A is N, X 1 is -O- or -NR X1 - and R X1 But H or C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is F;OH;OCH 3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a may be substituted C 1-3 is alkyl, R 4b may be substituted C 1-3 alkyl or halogen; The compound or salt thereof according to (12-3) above.

[0101] (12-4-1) A is N, X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1-, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is F;OH;OCH 3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a may be substituted C 1-3 is alkyl, R 4b may be substituted C 1-3 alkyl or halogen; The compound or salt thereof according to (12-3-1) above.

[0102] (12-5) A is N, X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1 is represented by the following formula (II), formula (III), or formula (IV): [ka] R 1a are the same or different and are H or F, R 1bis H, R 1c is methyl or cyclopropyl, R 1d is H, R 2 is cyclopropyl, R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is OH; OCH3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a But C 1-3 is alkyl, R 4b But -O-(C 1-3 alkyl) or -N(C 1-3 C optionally substituted with alkyl)2 1-3 alkyl or halogen; L and Z together represent a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy is a 5- or 6-membered heterocycle, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may be taken together with the carbon atom to which it is attached to form a cyclopropane; The compound or salt thereof according to (12-1).

[0103] (12-5-1) A is N, X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1 is represented by the following formula (II), formula (III), or formula (IV): [ka] R 1a are the same or different and are H or F, R 1b is H, R 1c is methyl or cyclopropyl, R 1d is H, R 2 is cyclopropyl, R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is OH; OCH3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a But C 1-3 is alkyl, R 4b OH, -O-(C 1-3 alkyl) and -N(C 1-3 C optionally substituted with a group selected from the group consisting of alkyl)2 1-3 alkyl or halogen; L and Z together represent a group selected from the group consisting of formula (XXX), formula (XXXI-X), formula (XXXII), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may be taken together with the carbon atom to which it is attached to form a cyclopropane; The compound or salt thereof according to (12-3-1).

[0104] (12-6) X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4together with the adjacent nitrogen atom form an optionally substituted 4- to 6-membered saturated heterocyclic group, L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, RL2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof, according to (12-5) above.

[0105] (12-6-1) X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, L and Z together represent a group selected from the group consisting of the following formulae (XXX), (XXXI-1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] Z A is a group represented by the following formula (XXII-1) or formula (XXVI-2), [ka] R Z11 is a halogen, Z 1 is CH or N, R Z2 But C 1-3 is alkyl, L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, L 2 is —CH—C≡C— or —CHCH—O—, R Z1 But H, C 1-3 alkyl or halogen; R L1 is H or methyl, A1 is CH or N, RL2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof according to the above (12-5-1).

[0106] (12-7) L and Z together represent a group represented by formula (XXXI-1), [ka] L 1 is —CHCH—O— or —CH—C≡C—, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI), [ka] R Hy1a But H, C1-3 The compound or salt thereof according to (12-6) above, wherein the aryl is alkyl or halogen.

[0107] (12-7-1) L and Z together represent a group represented by formula (XXXI-1X), [ka] L 1 is —CHCH—O— or —CH—C≡C—, R LX is H, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI), [ka] R Hy1a But H, C 1-3 The compound or salt thereof according to (12-6-1) above, wherein the aryl is alkyl or halogen.

[0108] (12-8) R 1 is the following formula (II): [ka] R 1a But F, R 1c is methyl, R 4 C optionally substituted with N(Me) 1-6 is alkyl, L and Z together represent a group represented by formula (XXXI-1A) or formula (XXXI-1B), [ka] R LX is H, L 1A is -CH2CH2-O-, L 1B is —CHCH—O— or —CH—C≡C—, R Hy1a But H or C 1-3 is alkyl, The compound or salt thereof according to (12-7-1) above.

[0109] (12-9) E is CH; R 3 is a group represented by formula (XIV), [ka] Y is phenylene; L and Z together form a group selected from the group consisting of formula (XXXI-X), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 alkynediyl or -C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is attached, G is N, The compound or salt thereof according to (12-1) above.

[0110] (12-10) A is N, X 1 is -O- or -NR X1 - and R X1 But H or C 1-3 is alkyl, However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 may combine with the adjacent nitrogen atom to form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is F;OH;OCH 3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a may be substituted C 1-3 is alkyl, R 4b may be substituted C 1-3 alkyl or halogen; The compound or salt thereof according to (12-9) above.

[0111] (12-11) A is N, X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4 together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, R 1 is represented by the following formula (II), formula (III), or formula (IV): [ka] R 1a are the same or different and are H or F, R 1b is H, R 1c is methyl or cyclopropyl, R 1d is H, R 2 is cyclopropyl, R 4 But C 1-6 alkyl or piperidinyl, 1-6 Alkyl is OH; OCH3; N(R 4a )2;R 4b C optionally substituted with 3-6 Cycloalkyl; R 4b Pyrrolidinyl optionally substituted with R 4b and morpholinyl optionally substituted by R 4b may be substituted with R 4a But C 1-3 is alkyl, R 4b OH, -O-(C 1-3 alkyl) or -N(C 1-3 C optionally substituted with alkyl)21-3 alkyl or halogen; L and Z together represent a group selected from the group consisting of formula (XXXI-X), formula (XXXIII-A), formula (XXXIII-B), formula (XXXIV) and formula (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy is a 5- or 6-membered heterocycle, A1 is CH or N, and R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, R Z1 But H, C 1-3 alkyl or halogen; m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may be taken together with the carbon atom to which it is attached to form a cyclopropane; The compound or salt thereof according to (12-9).

[0112] (12-12) X 1 is -O- or -NR X1 - and However, X 1 Ga-NR X1 -, R on the same nitrogen atom X1 and R 4together with the adjacent nitrogen atom form an optionally substituted 4- to 11-membered saturated heterocyclic group, L and Z together represent a group selected from the group consisting of the following formulae (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1) and (XXXI-A), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulae (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 But H, C 1-3 alkyl or halogen, A1 is CH or N; R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 But H, C 1-3alkyl or halogen; m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H, C 1-3 alkyl or halogen; R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof, according to (12-11) above.

[0113] (12-13) L and Z together represent a group selected from the group consisting of the following formulae (XXXI-1X), (XXXIII-A1), (XXXIII-B1) and (XXXIV-1), [ka] L 1 But, bond, C 1-3 Alkylene, -C 1-3 alkylene -O- or -CH2-C≡C-; R LX is H or OH, Ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII) and (XXXIX), [ka] R Hy1a But H, C 1-3 alkyl or halogen; R Hy1b But H or C 1-3 is alkyl, R Z1 is H or a halogen, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, Ring Hy3 is a ring selected from the group consisting of the following formulae (XL) and (XLI): [ka] R Hy3 is H or a halogen, m and n are both 1 or both 2, Ring Hy2 is represented by the following formula (XLIII): [ka] R Hy2 But H or C 1-3 is alkyl, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof, according to (12-12) above.

[0114] (12-14) The compound or salt thereof according to (12-1), wherein the compound of formula (I) is any of Examples 1 to 41 below.

[0115] (12-15) The compound of formula (I) (2S)-1-[(7M)-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-({4-[9-(2-{[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-{[4-(9-{3-[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]prop-2-yn-1-yl}-3-azaspiro[5.5]undecane-3-carbonyl)phenyl]methoxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)-4-methylpyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, and (2S)-1-[(7M)-6-cyclopropyl-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-2-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, The compound or salt thereof according to (12-1), selected from the group consisting of:

[0116] (12-16) The compound of formula (I) (2S)-1-[(7M)-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-({4-[9-(2-{[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, and (2S)-1-[(7M)-6-cyclopropyl-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-2-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, The compound or salt thereof according to (12-1), selected from the group consisting of:

[0117] Certain embodiments of the compound of formula (II) or a salt thereof according to the present invention are shown below.

[0118] (13-1) A compound of formula (II) or a salt thereof, wherein TPB is a group capable of binding to a target protein. (13-1-1) A compound of formula (II) or a salt thereof, wherein TPB is a group capable of binding to a RAS protein. (13-2) TPB is represented by the following formula (I-II), (I-III) or (I-IV): [ka] In the formula, A, R A , E, X 1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X3 , X 4 , n 1 , p, q, R 4 and Y are defined as in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 4L may be substituted C 1-6 is a divalent alkylene group or an optionally substituted saturated heterocyclic group, R 1L is represented by the following formula (II-I), formula (III-I), formula (IV-I), formula (VI), formula (VI-I) or formula (VII-I), [ka] R 1aL and R 1bLare the same or different and are bonds to H, methyl, F, Cl or L, R 1cL is a bond to F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl or L, R 1dL is a bond to H, methyl, ethyl, F, Cl, —C≡CH or L, R 1LL is a bond to H or L, A compound of formula (II) or a salt thereof, wherein there is only one bond to L in each of the above formulas (II-I), (III-I), (IV-I), (VI), (VI-I) and (VII-I). (13-2-1) TPB is represented by the following formula (I-II), formula (I-III-1) or formula (I-IV-1), [ka] In the formula, A, R A , E, X 1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q and R 4 is the same as defined in formula (I), R 8 H, halogen, -OC 1-3 Alkyl or -O-CH2-YR 5 and Y is as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 4L may be substituted C 1-6 is a divalent alkylene group or an optionally substituted saturated heterocyclic group, R 1L is represented by the following formula (II-I), formula (III-I), formula (IV-I), formula (VI), formula (VI-I) or formula (VII-I), [ka] R 1aL are the same or different and are bonds to H, methyl, F, Cl or L, R 1bL is a bond to H, methyl, F, Cl or L, R1cL is a bond to F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl or L, R 1dL is a bond to H, methyl, ethyl, F, Cl, —C≡CH or L, R 1LL are the same or different and are bonds to H or L, A compound of formula (II) or a salt thereof, wherein there is only one bond to L in each of the above formulas (II-I), (III-I), (IV-I), (VI), (VI-I) and (VII-I). (13-3) TPB is represented by the following formula (I-II): [ka] In the formula, A, R A , E, X 1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q, R 4 and Y is the same as defined in formula (I), or a salt thereof. (13-4) TPB is represented by the following formula (I-III): [ka] In the formula, A, R A , E, X1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q and Y are the same as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6may be substituted with alkyl, R 4L may be substituted C 1-6 A compound of formula (II) or a salt thereof, wherein R is a divalent group of alkylene or an optionally substituted saturated heterocycle. (13-4-1) TPB is represented by the following formula (I-III-1): [ka] In the formula, A, R A , E, X 1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p and q are the same as defined in formula (I), R 8 H, halogen, -OC 1-3 Alkyl or -O-CH2-YR 5 and Y is as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 4L may be substituted C 1-6 A compound of formula (II) or a salt thereof, wherein R is a divalent group of alkylene or an optionally substituted saturated heterocycle. (13-5) TPB is represented by the following formula (I-IV): [ka] In the formula, A, R A , E, X 1 , R X1 , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q, R 4 and Y are defined as in formula (I), R5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 1L is represented by the following formula (II-I), formula (III-I), formula (IV-I), formula (VI), formula (VI-I) or formula (VII-I), [ka] R 1aL and R 1bL are the same or different and are bonds to H, methyl, F, Cl or L, R 1cL is a bond to F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl or L, R 1dL is a bond to H, methyl, ethyl, F, Cl, —C≡CH or L, R 1LL is a bond to H or L, A compound of formula (II) or a salt thereof, wherein there is only one bond to L in each of the above formulas (II-I), (III-I), (IV-I), (VI), (VI-I) and (VII-I). (13-5-1) TPB is represented by the following formula (I-IV-1): [ka] In the formula, A, R A , E, X 1 , R X1 , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q and R 4 is the same as defined in formula (I), R 8 H, halogen, -OC 1-3 Alkyl or -O-CH2-YR 5 and Y is as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5bare the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 1L is represented by the following formula (II-I), formula (III-I), formula (IV-I), formula (VI), formula (VI-I) or formula (VII-I), [ka] R 1aL are the same or different and are bonds to H, methyl, F, Cl or L, R 1bL is a bond to H, methyl, F, Cl or L, R 1cL is a bond to F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl or L, R 1dL is a bond to H, methyl, ethyl, F, Cl, —C≡CH or L, R 1LL are the same or different and are bonds to H or L, A compound of formula (II) or a salt thereof, wherein there is only one bond to L in each of the above formulas (II-I), (III-I), (IV-I), (VI), (VI-I) and (VII-I).

[0119] (14-1) L is -(L A -L B -L C -LD -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 A compound of formula (II) or a salt thereof, wherein R is alkyl. (14-2) L is the following formula (XXX-L), formula (XXXI-L), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 a divalent group of alkynediyl, -C≡C-, or an optionally substituted saturated heterocyclic ring, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (14-2-1) L is the following formula (XXX-L), formula (XXXI-LX), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-C 2-3 a divalent group of alkynediyl, -C≡C-, or an optionally substituted saturated heterocyclic ring, R LX is H or OH, L 2 But -C 1-3 Alkylene-C 2-3 Alkynediyl or -C 1-3 alkylene-O-; R L1 But H or C 1-3 is alkyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are the same or different and are 1 or 2; R L4 and R L5 are the same or different and are H or C 1-3 alkyl or the R L4 and R L5 Together with the carbon atom to which it is bonded, C 3-6 may form a cycloalkane, or the R L4 and R L5 may form a carbonyl together with the carbon atom to which it is bonded, or a salt thereof. (14-3) L is the following formula (XXX-L), formula (XXXI-L), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 alkylene-O- or tetrahydropyridinediyl, L 2 is —CH—C≡C— or —CHCH—O—, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (14-3-1) L is the following formula (XXX-L), formula (XXXI-LX), formula (XXXII-L), formula (XXXIII-L), and formula (XXXIV-L), [ka] is a group selected from the group consisting of L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 alkylene-O- or tetrahydropyridinediyl, R LX is H or OH, L 2 is —CH—C≡C— or —CHCH—O—, R L1 is H or methyl, A1 is CH or N, R L2 and R L3 are the same or different and are H, OH or C 1-3 alkyl, provided that R L2 and R L3 cannot be simultaneously OH, and R L2 and R L3 And it doesn't become H at the same time, m and n are both 1 or both 2, R L4 and R L5 are both H or the R L4 and R L5 may form cyclopropane together with the carbon atom to which it is bonded, or a salt thereof. (14-4) L is a group represented by the following formula (XXXI-L): [ka] L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 A compound of formula (II) or a salt thereof, which is alkylene-O- or tetrahydropyridinediyl. (14-4-1) L is a group represented by the following formula (XXXI-LX), [ka] L 1 But, bond, C 1-3 Alkylene, -CH2-C≡C-, -C 1-3 alkylene-O- or tetrahydropyridinediyl, R LX is H or OH, or a salt thereof. (14-5) L is a group represented by the following formula (XXXI-L): [ka] L 1 is —CH2CH2—O—, or a salt thereof. (14-6) L is a group represented by the following formula (XXXI-L): [ka] L 1 is —CH2—C≡C—, or a salt thereof.

[0120] (15-1) Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle, Ring Hy is a 5- or 6-membered heterocycle, R Z1 But H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 But H or C 1-3 is alkyl, R Z3 But H or C 1-3 is alkyl, R Z4 are the same or different and are H or C 1-3 is alkyl, R Z5 But C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; A compound of formula (II) or a salt thereof: (15-2) Z is the following formula (XXVII-1), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 and do not simultaneously become CH. (15-3) Z is the following formula (XXVII-1), [ka] E 1 is CH and E 2 is N, or a salt thereof. (15-4) Z is the following formula (XXVII-1), [ka] E 1 is N and E 2 is CH or a salt thereof.

[0121] (16-1) G is N or CH; A compound of formula (II) or a salt thereof, wherein when G is N, Z is formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX). (16-2) G is N or CH; However, when G is N, Z is formula (XXVII), or a salt thereof. (16-3) A compound of formula (II) or a salt thereof, wherein G is N and Z is formula (XXVII).

[0122] (17) A compound of formula (II) or a salt thereof, which is a combination of any two or more of the above-mentioned embodiments (13-1) to (13-5-1), (14-1) to (14-6), (15-1) to (5-4), and (16-1) to (16-3) that are not contradictory.

[0123] Specific examples of the combination described in (17) above include the following. (17-0) A compound of formula (II) or a salt thereof: [ka] (In the formula, TPB is a group capable of binding to a target protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and represent a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A is H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle; Ring Hy is a 5- or 6-membered heterocycle; R Z1 is H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 is alkyl, R Z3 is H or C 1-3 is alkyl, R Z4are the same or different and each represents H or C 1-3 is alkyl, R Z5 is C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; G is N or CH; However, when G is N, Z is the above formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX).

[0124] (17-1) A compound of formula (II) or a salt thereof: [ka] (In the formula, TPB is a group capable of binding to RAS proteins, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and represent a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1Ais H or C 1-3 is alkyl, Z is a group selected from the group consisting of the following formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), and (XXIX), [ka] Ring B is a benzene ring or a 6-membered heterocycle; Ring Hy is a 5- or 6-membered heterocycle; R Z1 is H, C 1-3 Alkyl, halogen, -O-(C 1-3 alkyl), -NR Z4 2, -CN, -CONR Z4 2 or -NR Z4 COR Z5 and R Z2 is H or C 1-3 is alkyl, R Z3 is H or C 1-3 is alkyl, R Z4 are the same or different and are H or C 1-3 is alkyl, R Z5 is C 1-3 is alkyl, L is bonded to ring B in the above formula (XVIII), formula (XIX), formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXVI), formula (XXVIII) and formula (XXIX), to the benzene ring in formula (XXIV) and formula (XXV), and to ring Hy in formula (XXVII), r is 1 or 2; G is N or CH; However, when G is N, Z is the above formula (XVIII), formula (XXII), formula (XXIII), formula (XXIV), formula (XXVI), formula (XXVII) or formula (XXIX).

[0125] (17-2) TPB is represented by the following formula (I-II): [ka] In the formula, A, R A , E, X 1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q, R 4 and Y are defined as in formula (I), Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, G is N, The compound or salt thereof according to (17-1) above.

[0126] (17-3) TPB is represented by the following formula (I-III): [ka] In the formula, A, R A , E, X 1 , R X1 , R1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q and Y are the same as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R4L may be substituted C 1-6 is a divalent alkylene group or an optionally substituted saturated heterocyclic group, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, G is N, The compound or salt thereof according to (17-1) above.

[0127] (17-3-1) TPB is represented by the following formula (I-III-1): [ka] In the formula, A, R A , E, X 1 , R X1 , R 1 , R 1a , R 1b , R 1c , R 1d , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p and q are the same as defined in formula (I), R 8 H, halogen, -OC 1-3 Alkyl or -O-CH2-YR 5 and Y is as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 4L may be substituted C 1-6 is a divalent alkylene group or an optionally substituted saturated heterocyclic group, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, G is N, The compound or salt thereof according to (17-1) above.

[0128] (17-4) TPB is represented by the following formula (I-IV): [ka] In the formula, A, R A , E, X 1 , R X1 , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q, R 4 and Y are defined as in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6and R 7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 1L is represented by the following formula (II-I), formula (III-I), formula (IV-I), formula (VI), formula (VI-I) or formula (VII-I), [ka] R 1aL and R 1bL are the same or different and are bonds to H, methyl, F, Cl or L, R 1cL is a bond to F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl or L, R 1dL is a bond to H, methyl, ethyl, F, Cl, —C≡CH or L, R 1LL is a bond to H or L, provided that there is only one bond to L in each of the above formulas (II-I), (III-I), (IV-I), (VI), (VI-I) and (VII-I), Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, G is N, The compound or salt thereof according to (17-1) above.

[0129] (17-4-1) TPB is represented by the following formula (I-IV-1): [ka] In the formula, A, R A , E, X 1 , R X1 , R 2 , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R N1 , R N2 , R 3j , X 2 , X 3 , X 4 , n 1 , p, q and R 4 is the same as defined in formula (I), R 8 H, halogen, -OC 1-3 Alkyl or -O-CH2-YR 5 and Y is as defined in formula (I), R 5 But, H, CONR 6 R 7 or a group selected from the group consisting of the following formulas (IV), (I-VI), (I-VII), (I-VIII), (I-IX), (IX), (I-XI), (I-XII), (I-XIII), (I-XIV), (I-XV) and (I-XVI), [ka] R 5a and R 5b are the same or different and are H, optionally substituted C 1-3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl or pyrazinyl; R 6 and R 7 are the same or different and are H or optionally substituted C 1-6 alkyl, or R 6 and R7 form a 4- to 6-membered saturated heterocyclic group together with the nitrogen atom to which they are bonded, and the 4- to 6-membered saturated heterocyclic group is an optionally substituted C 1-6 may be substituted with alkyl, R 1L is represented by the following formula (II-I), formula (III-I), formula (IV-I), formula (VI), formula (VI-I) or formula (VII-I), [ka] R 1aL are the same or different and are bonds to H, methyl, F, Cl or L, R 1bL is a bond to H, methyl, F, Cl or L, R 1cL is a bond to F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl or L, R 1dL is a bond to H, methyl, ethyl, F, Cl, —C≡CH or L, R 1LL are the same or different and are bonds to H or L, provided that there is only one bond to L in each of the above formulas (II-I), (III-I), (IV-I), (VI), (VI-I) and (VII-I), Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, G is N, The compound or salt thereof according to (17-1) above.

[0130] (17-5-0) TPB is a group capable of binding to a target protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, The compound or salt thereof according to (17-0) above, wherein G is N.

[0131] (17-5) TPB is a group capable of binding to a RAS protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L Fare the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 and E 2 are the same or different and are CH or N, with the proviso that E 1 and E 2 does not become CH at the same time, The compound or salt thereof according to (17-1) above, wherein G is N.

[0132] (17-6-0) TPB is a group capable of binding to a target protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 is CH and E 2 is N, The compound or salt thereof according to (17-0) above, wherein G is N.

[0133] (17-6) TPB is a group capable of binding to a RAS protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 is CH and E 2 is N, The compound or salt thereof according to (17-1) above, wherein G is N.

[0134] (17-7-0) TPB is a group capable of binding to a target protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , L D , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 is N and E 2 is CH, The compound or salt thereof according to (17-0) above, wherein G is N.

[0135] (17-7) TPB is a group capable of binding to a RAS protein, L is -(L A -L B -L C -L D -L E -L F )- and L A , L B , L C , LD , L E and L F are the same or different and are a bond, -O-, -NR L1A -, a divalent group of an optionally substituted saturated heterocyclic ring, an optionally substituted C 1-3 Alkylene, optionally substituted C 3-6 Cycloalkylene, C 1-3 C optionally substituted with alkyl 2-3 is a group selected from the group consisting of alkynediyl and C═O; R L1A But H or C 1-3 is alkyl, Z is the following formula (XXVII-1) in formula (XXVII), [ka] E 1 is N and E 2 is CH, The compound or salt thereof according to (17-1) above, wherein G is N.

[0136] The compounds of formula (I) and formula (II) may exist as tautomers or geometric isomers depending on the type of substituents. In this specification, the compounds of formula (I) and formula (II) may be described in only one isomeric form, but the present invention also includes other isomers, and also includes isolated isomers or mixtures thereof. Furthermore, the compounds of formula (I) and formula (II) may have asymmetric carbon atoms or axial asymmetry, and therefore may exist as diastereomers. The present invention also encompasses separated diastereomers of the compounds of formula (I) and formula (II) or mixtures thereof.

[0137] Furthermore, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formula (I) and formula (II). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198.

[0138] The salts of the compounds of formula (I) and formula (II) are pharmaceutically acceptable salts of the compounds of formula (I) and formula (II), which may form acid addition salts or salts with bases depending on the types of substituents. Examples include salts described in Handbook of Pharmaceutical Salts Properties, Selection, and Use by P. Heinrich Stahl, Wiley-VCH, 2008. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, and ornithine; and ammonium salts.

[0139] Furthermore, the present invention also encompasses various hydrates and solvates of the compounds of formula (I) and formula (II) and salts thereof, as well as crystalline polymorphic substances.

[0140] The present invention also encompasses all compounds of formula (I) and formula (II) or salts thereof that are labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Suitable examples of isotopes used to isotopic label the compounds of the present invention include hydrogen ( 2 H and 3 H, etc.), carbon ( 11 C. 13 C and 14 C, etc.), nitrogen ( 13 N and 15 N etc.), oxygen ( 15 O, 17 O and 18 O etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I etc.), sulfur ( 35 Isotopes of sulphur (e.g., sulphur) are included. It can be used for research such as tissue distribution studies of the compounds, drugs and / or substrates of the present invention labeled with isotopes. For example, tritium ( 3 H), carbon-14 ( 14 Radioisotopes such as C may be used for this purpose because of their ease of labeling and convenience of detection. Substitution of heavier isotopes, e.g., deuterium for hydrogen ( 2 H) may be therapeutically advantageous due to increased metabolic stability (e.g., increased in vivo half-life, reduced dosage requirements, and reduced drug interactions). Positron-emitting isotopes ( 11 C, 18 F, 15 O and 13 Substitutions to 2,4-diaminobenzyl- ... The isotopically labeled compounds of the present invention can generally be produced by conventional methods known to those skilled in the art, or by a process similar to that described in the Examples or Preparations, using an appropriate isotopically labeled reagent instead of an unlabeled reagent.

[0141] (Manufacturing method) The compounds of formula (I) and formula (II) and salts thereof can be produced by various known synthetic methods, taking advantage of characteristics based on their basic structure or the type of substituents. In this case, depending on the type of functional group, it may be effective from a manufacturing technology perspective to replace the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 5th Edition, by P.G.M. Wuts and T.W. Greene, John Wiley & Sons Inc., 2014, and the like. These protecting groups may be appropriately selected and used depending on the reaction conditions. In such methods, the desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group, if necessary. A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design, 163-198. Furthermore, prodrugs of the compounds of formula (I) and formula (II) can be produced by introducing a specific group at the stage leading from the raw material to the intermediate, as in the case of the above-mentioned protecting group, or by further reacting the obtained compounds of formula (I) and formula (II). The reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, etc. Representative methods for producing the compounds of formula (I) and formula (II) are described below. Each method can be performed by referring to the references attached to the description. However, the production methods of the present invention are not limited to the examples shown below.

[0142] In this specification, the following abbreviations may be used. DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH or IPA: isopropyl alcohol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, Et3N or TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tert-butoxide, tBuONa: sodium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd / C: palladium on carbon, PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium Hexafluorophosphate, PyAOP: (7-azabenzotriazol-1-yloxy)trispyrrolizinophosphonium hexafluorophosphate, SFC: supercritical fluid chromatography, NMM: N-methylmorpholine, CDI: 1,1'-carbonyldiimidazole, HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DABCO: 1,4-diazabicyclo[2.2.2]octane, TFA: trifluoroacetic acid, DBU: 1,8-diazabicyclo[5.4.0]-7-Undecene, TBAF: tetra-n-butylammonium fluoride, Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0), Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0), XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, NMP: N-methyl-2-pyrrolidone, mCPBA: m-chloroperbenzoic acid, RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, RuPhos Pd G3: (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate, PdCl2(PPh3)2: dichlorobis(triphenylphosphine) palladium(II), DMP: Dess-Martin periodinane, EPhos: dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane, Ephos Pd G4: [dicyclohexyl[3-(1-methylethoxy)-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine-κP](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]palladium(II), XPhos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, LHMDS: lithium bis(trimethylsilyl)amide, KHMDS: potassium bis(trimethylsilyl)amide, LAH: lithium aluminum hydride, HOBt: 1-hydroxybenzotriazole, EDC·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EtOAc: Ethyl acetate, AcOH: acetic acid, TfOH: trifluoromethanesulfonic acid, TMEDA: N,N,N',N'-tetramethylethylenediamine, SPhos: dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine, ODS: octadecylsilyl, MW: microwave.

[0143] (Manufacturing method 1) [ka] (In the formula, -L CF - is -L-contained in -L C -L D -L E -L F - indicates that. The same applies below.) This production method is for the compound of formula (I) where A is N and -L is included in -L-. A - is CO, -L B -Ga-N(R L1A )- or a divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted, C -L D -L E -L F -Ga-L CF - and R L1A is H or C 1-3 A method for producing a compound of formula (I-1), wherein the compound is alkyl. This reaction involves using equal amounts of compound (1) and compound (2), or an excess of either, and stirring the mixture in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at temperatures between -20°C and 60°C, typically for 0.1 hours to 5 days, to obtain an amide compound. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include PyBOP, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride (EDC·HCl), N,N'-dicyclohexylcarbodiimide (DCC), CDI, diphenylphosphoryl azide (DPPA), and PyAOP. The use of an additive (e.g., HOBt or dimethylaminopyridine) may be advantageous in some cases. In some cases, it is advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, in order to ensure that the reaction proceeds smoothly. Alternatively, a method can be used in which compound (1) is converted into a reactive derivative and then acylated. Examples of reactive derivatives of carboxylic acids include acid halides obtained by reaction with a halogenating agent such as phosphorus oxychloride or thionyl chloride, mixed acid anhydrides obtained by reaction with isobutyl chloroformate, and activated esters obtained by condensation with 1-hydroxybenzotriazole. The reaction of these reactive derivatives with compound (2) can be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling or heating, preferably at -20°C to 120°C. [Literature] S.R. Sandler and W. Karo, Organic Functional Group Preparations, 2nd ed., Vol. 1, Academic Press Inc., 1991 "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen)

[0144] (Manufacturing method 2) [ka] (PG 71 is R 1 represents the NH protecting group contained in 11 is R 1 represents a divalent group in which H is eliminated from NH contained in the formula (hereinafter the same).

[0145] This process is an alternative method for preparing the compound of formula (I). The compound of formula (I) can also be obtained by deprotecting compound (3). Examples of the protecting group include tert-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethanediyl, and tert-butylsulfinyl. This deprotection reaction is carried out under cooling or reflux with stirring, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols such as MeOH and EtOH; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as diethyl ether, THF, DOX, and dimethoxyethane; DMF, DMSO, MeCN, water, and mixtures thereof. Examples of deprotection reagents include, but are not limited to, hydrogen chloride (DOX solution), and acids such as trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. By selecting a protecting group, deprotection can also be carried out by catalytic hydrogenation. Examples of protecting groups include a benzyl group, a p-methoxybenzyl group, and a benzyloxycarbonyl group. Deprotection can also be carried out using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include a tert-butyl(dimethyl)silyl group and a (trimethylsilyl)ethoxymethyl group. Furthermore, examples of protecting groups that can be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, and a benzoyl group. For reference, the following can be referred to, for example: PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014 A.R. Katritzky and R.J.K. Taylor, Comprehensive Organic Functional Group Transformations II, Vol. 2, Elsevier Pergamon, 2005

[0146] (Manufacturing method 3) [ka] This production method is a method for producing a compound of formula (I-2) in which A is N and E is CH, among compounds of formula (I), by reacting compound (4) with compound (5). This reaction involves using equal amounts of compound (4) and compound (5), or an excess of either, and stirring the mixture in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at temperatures between -20°C and 60°C, typically for 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include PyBOP, HATU, CDI, and PyAOP. Carrying out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, may be advantageous for smooth reaction progression. Alternatively, the compound of formula (I-2) can be obtained by converting compound (4) to a reactive derivative in which the hydroxyl group at the 4-position of compound (4) is converted to a chloro group using a chlorinating reagent such as phosphorus oxychloride or thionyl chloride, and then adding compound (5) in the presence of an organic base such as TEA, DIPEA, or pyridine, or an inorganic base such as potassium carbonate, cesium carbonate, or potassium acetate. The reaction of these reactive derivatives with compound (5) can be carried out in a reaction-inert solvent such as halogenated hydrocarbons, aromatic hydrocarbons, or ethers, under cooling or heating, preferably at -20°C to 120°C. (Manufacturing method 4) [ka] This production method is a second method for producing a compound of formula (I-2), in which A is N and E is CH, among the compounds of formula (I), by subjecting compound (115) to an oxidation reaction in the first step and then reacting it with compound (18) in the second step. In the first step of this reaction, the oxidation reaction can be carried out under the same conditions as in the seventh step of Raw Material Synthesis 1 described below. In the second step, an ipso substitution reaction with compound (18) is carried out under the same conditions as in the third step of Raw Material Synthesis 1 described below, thereby producing a compound of formula (I-2).

[0147] (Raw material synthesis 1) [ka] (In the formula, LG 2 , L.G. 4 , L.G. 6 , L.G. 7 , L.G. 8 and L.G. 81 are the same or different and each represents a leaving group. PG 4 is the protecting group for OH, PG 7 and P.G. 71 are R 1 The protecting group of NH contained in R 11 is R 1 A divalent group formed by removing H from NH contained in PG 8 denotes a protecting group that can be removed under catalytic hydrogenation conditions, PG 81 indicates a protecting group for COOH. 4 , P.G. 7 , P.G. 71 , P.G. 8 and P.G. 81 In the case of R, protecting groups that can be deprotected under different deprotection conditions can be selected and deprotection can be carried out stepwise. LG2 is C 1-12 BLG represents a boronic acid group, a boronic acid group protected by 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, etc.). Examples of leaving groups shown here include Cl, Br, I, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, etc. (The same applies hereinafter.)

[0148] This production method is a first method for producing compound (1)-1, which is a starting compound of production method 1, in which A is N and E is CH.

[0149] (first step) This step is a method for producing compound (7) from compound (6). This reaction is carried out by stirring compound (6) under cooling or refluxing, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols, acetone, DMF, THF, etc. Mixing the above solvents with water may also be suitable for the reaction. Examples of reagents used in this reaction include, but are not limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, etc. As references for this reaction, for example, the following can be referred to. "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0150] (Second process) This step is a method for producing compound (8) by protecting the hydroxyl group of compound (7) with a protecting group. For example, when protecting with a tert-butyl group, this reaction is carried out by stirring compound (7) in the presence of a tert-butyl protecting reagent, usually under cooling to reflux, for 0.1 hours to 5 days. Examples of the solvent used here include, but are not limited to, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, tBuOH, DMF, etc. Examples of the tert-butyl protecting reagent include, but are not limited to, isobutene, 2-tert-butyl-1,3-diisopropylisourea, etc. Compound (8) can also be produced by a dehydration condensation reaction between compound (7) and tBuOH. As references for this reaction, for example, the following can be referred to. PGM Wuts and TW Greene, "Greene's Protective Groups in Organic Synthesis," 5th ed., John Wiley & Sons Inc., 2014 Org. Lett., 2012, 14, 17, p.4678-4681

[0151] (Third step) This step involves the synthesis of compound (8) and compound (9), R LG2 This method involves the production of compound (10) by ipso substitution reaction with -SH. The R used here LG2 An example of -SH is C 1-12 Alkyl thiols such as ethanethiol and dodecanethiol are included. This reaction involves using equal amounts of compound (8) and compound (9), or an excess of either compound. The mixture is stirred in a reaction-inert solvent, or without solvent, under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, MeCN, NMP, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK, or KHMDS, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction progress.

[0152] (Fourth step) This process involves the synthesis of compound (10) and compound (11), PG 8 This method produces compound (12) by ipso substitution reaction with -OH. 8 Examples of -OH include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol. The reaction conditions were the same as those in the third step of the present Raw Material Synthesis 1.

[0153] (Fifth step) This step involves the synthesis of compound (12) and compound (13), R 2 This is a method for producing compound (14) by Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like. Examples of the boronic acid group used herein include, but are not limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triol borate base, and a trifluoroborate base. This reaction is carried out by reacting compound (12) with R 2 A mixture of these compounds is stirred in the presence of a base and a palladium catalyst in an inert solvent at room temperature to reflux, preferably at 20°C to 140°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide. Palladium catalysts include tetrakis(triphenylphosphine)palladium, PdCl2(PPh3)2, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. The reaction can be carried out in the presence of ligands such as SPhos, RuPhos, and 1,1'-bis(diphenylphosphino)ferrocene. Microwave heating of the mixture can also be beneficial for smooth reaction. [Literature] J. Am. Chem. Soc., 2005, 127, p.4685-4696 Org. Lett. 2011, 13, p.3948-3951 Org. Lett. 2012, 14, p.1278-1281 Also, LG 6 When R is a halogen, compound (12) is dehalogenated using a Pd catalyst and a reducing agent to give compound (14) (where R 2 can produce hydrogen). [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210

[0154] (Sixth step) This step is a method for producing compound (16) by Suzuki-Miyaura coupling reaction between compound (14) and compound (15). The reaction conditions were the same as those in the fifth step of the present Raw Material Synthesis 1. When compound (16) has axial chirality, it is obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0155] (Seventh step) This step is a method for producing compound (17) by oxidation of compound (16). In this reaction, compound (16) is treated with an equivalent or excess amount of an oxidizing agent in a reaction-inert solvent under cooling to heating, preferably at -20°C to 80°C, for typically 0.1 hours to 3 days. In this reaction, oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used. Examples of solvents include halogenated hydrocarbons such as dichloromethane, DMF, ethyl acetate, MeCN, and mixtures thereof. Examples of other oxidizing agents include cumene hydroperoxide, oxone, activated manganese dioxide, chromic acid, potassium permanganate, and sodium periodate. [Literature] Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 17, Maruzen, 2004 When compound (17) has axial chirality, it may be obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography, or resolution by SFC using a chiral column.

[0156] (Eighth process) This step is a method for producing compound (19) by ipso substitution reaction between compound (17) and compound (18). The reaction conditions were the same as those in the third step of the present Raw Material Synthesis 1.

[0157] (Ninth step) This step is a method for producing compound (20) by deprotecting compound (19) through catalytic hydrogenation. This reaction can be carried out by stirring compound (19) under a hydrogen atmosphere in a reaction-inert solvent such as MeOH, EtOH, ethyl acetate, or THF under normal to elevated pressure in the presence of a metal catalyst, with stirring for 1 hour to 5 days, preferably at room temperature. Examples of suitable metal catalysts include palladium catalysts such as Pd / C or palladium black, platinum catalysts such as platinum plate or platinum oxide, and nickel catalysts such as reduced nickel or Raney nickel. PG 4 and PG 7 In order to prevent the protecting group of from being deprotected, the reaction may be favored by adding an inorganic base such as NaHCO3.

[0158] (10th step) This step is a method for producing compound (22) from compound (20) and compound (21). This reaction is carried out by reacting a mixture of compound (20) and compound (21) in the presence of a base in a reaction-inert solvent under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of bases include, but are not limited to, organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, and tBuOK; and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. It may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride. As references for this reaction, for example, the following can be referred to. Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 14, Maruzen, 2005 Compound (21) is also a LG 81 By halogenating a compound in which the moiety corresponding to LG is a hydroxy group, 81 is a halogen. Examples of the halogenating agent used here include, but are not limited to, thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, etc. As references for this reaction, for example, the following can be referred to. Chemical Society of Japan, "Experimental Chemistry Lectures," 5th edition, Vol. 13, Maruzen, 2004 Furthermore, compound (21) can be prepared by the reaction of LG 81 The compound having a hydroxy group in the corresponding position is sulfonylated in the presence of a base to give LG 81is a sulfonyloxy group. Examples of the sulfonylation reagent used here include, but are not limited to, methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, etc. Examples of the base include, but are not limited to, TEA, DIPEA, pyridine, tetramethylethylenediamine, etc. As references for this reaction, for example, the following can be referred to. Synthesis 1999, 9, p.1633-1636

[0159] (Eleventh step) This step involves the PG protecting group of compound (22) 4 and P.G. 7 Deprotection of R 11 The deprotected NH group contained in 71 This is a method for producing compound (23) by protecting the compound with The reaction conditions were the same as those in the process described in Production Method 2, and compound (22) and a deprotection reagent were added, and the NH group was converted to PG. 71 The reaction can be carried out by adding a protecting reagent for protecting with a group.

[0160] (12th step) This step is a method for producing compound (24) by reacting compound (23) with compound (5). The reaction conditions are the same as in Production Method 3.

[0161] (13th process) This step is a method for producing compound (1) by subjecting compound (24) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0162] (Raw material synthesis 2) [ka] (In the formula, PG 82 is C 1-3 (The same applies below.)

[0163] In this production method, in the compound (3) which is the raw material compound in Production Method 2, A is N, and in -L-, -L A - is CO, -L B -Ga-N(R L1A )- or a divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted, C -L D -L E -L F -Ga-L CF -wherein R L1A is H or C 1-3 This is the first method for producing compound (3-1), which is an alkyl.

[0164] (first step) This step is a method for producing compound (26) by reacting compound (25) with compound (5). The reaction conditions were the same as in Production Method 3.

[0165] (Second process) This step is a method for producing compound (27) by hydrolyzing compound (26) under basic conditions. This reaction is carried out by stirring compound (26) under cooling or reflux, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols, acetone, DMF, and THF. Mixing the above solvents with water may also be suitable for the reaction. Examples of hydrolysis reagents include, but are not limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, and trimethyltin hydroxide. As references for this reaction, for example, the following can be referred to. "Experimental Chemistry Lectures (5th Edition)" edited by the Chemical Society of Japan, Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.

[0166] (Third step) This step is a method for producing compound (3-1) by subjecting compound (27) and compound (2) to an amidation reaction. The reaction conditions are the same as those in the process described in Production Method 1.

[0167] (Raw material synthesis 3) [ka]

[0168] In this production method, in the compound (3) which is the raw material compound in Production Method 2, A is N, and in -L-, -L A - is CO, -L B -Ga-N(R 1A )- or a divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted, C -L D -L E -L F -Ga-L CF -wherein R L1A is H or C 1-6 This is the second method for producing compound (3-1), which is an alkyl group.

[0169] (first step) This step is a method for producing compound (29) from compound (20) and compound (28). The reaction conditions were the same as those in the tenth step of Raw Material Synthesis 1.

[0170] (Second process) This step is a method for producing compound (30) by subjecting compound (29) to a deprotection reaction. The reaction conditions were the same as those in the second step of Raw Material Synthesis 2.

[0171] (Third step) This step is a method for producing compound (31) by subjecting compound (30) and compound (2) to an amidation reaction. The reaction conditions are the same as those in the process described in Production Method 1.

[0172] (Fourth step) This step involves the PG protecting group of compound (31) 4 and P.G. 7 Deprotection of R 11 The deprotected NH group contained in 71 This is a method for producing compound (32) by protecting the compound with The reaction conditions were the same as those in the process described in Production Method 2, and compound (31) and a deprotection reagent were added, and the NH group was converted to PG 71 The reaction can be carried out by adding a protecting reagent for protecting with a group.

[0173] (Fifth step) This step is a method for producing compound (3-1) by reacting compound (32) with compound (5). The reaction conditions were the same as in Production Method 3.

[0174] (Raw material synthesis 4) [ka] (In the formula, -L'- is -L included in -L-. A -L B -L C -L D - indicates PG 83 represents a protecting group for NH bonded to L'. L ' is H or C 1-3 It may be alkyl, or may combine with the adjacent nitrogen atom and L' to form a divalent saturated heterocyclic group containing 1 or 2 nitrogen atoms.

[0175] This production method is a method for producing compound (4), which is a raw material compound of production method 3, by removing -L contained in -L-. E -Ga-N(R L’ )- and -L F This is a method for producing a compound (4-1) in which - is -CH2-.

[0176] (first step) This step is a method for producing compound (34) from compound (20) and compound (33). The reaction conditions were the same as those in the tenth step of Raw Material Synthesis 1.

[0177] (Second process) This step is a method for producing compound (35) by subjecting compound (34) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0178] (Third step) In this step, compound (35) and compound (36) are converted into -R Z When -CHO is used, it is converted by reductive amination, and when -R Z Ga-CH2-LG 81 In the case of (1), the compound (4-1) is obtained by alkylation. -R Z When is -CHO, the reaction is carried out by using equal equivalents of compound (35) and compound (36), or an excess equivalent of either, in the presence of a reducing agent and acetic acid in a reaction-inert solvent, stirring at ice-cooling to room temperature for typically 1 hour to 5 days. Examples of the reducing agent used here include, but are not limited to, NaBH(OAc)3, 2-picoline borane, NaBH3CN, etc. The solvent used here is also not limited to, but includes halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc., ether solvents such as THF, diethyl ether, DOX, etc., alcoholic solvents such as MeOH, EtOH, etc., and MeCN, etc. -R Z Ga-CH2-LG 81 The reaction conditions in this case are the same as those in the tenth step of Raw Material Synthesis 1.

[0179] (Raw material synthesis 5) [ka] (In the formula, PG 41 represents a protecting group for NH, and R 31 is R 3a -N(R 3b )CO-, R 3c -OCO- or R 3d -CO-.)

[0180] This production method is a compound (1) which is a raw material compound of Production Method 1, in which E is CH, R 3 is represented by formula (VIII), formula (IX) or formula (X), and X 3 is O.

[0181] (first step) This step involves the synthesis of compound (6) and compound (9), R LG2 This method involves the preparation of compound (37) by ipso substitution reaction with -SH. The reaction conditions were the same as those in the third step of Raw Material Synthesis 1.

[0182] (Second process) This step is a method for producing compound (38) by ipso substitution reaction between compound (37) and compound (11). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 1.

[0183] (Third step) This step involves the reaction of compound (38) with the protecting group PG 41 This method involves the ipso substitution reaction of compound (39) having an amino group protected by the formula (I) to produce compound (40). This reaction uses equal amounts of compound (38) and compound (39), or an excess of either, and the mixture is stirred in a reaction-inert solvent under cooling to heating, preferably at -20°C to 60°C, for typically 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction.

[0184] (Fourth step) This step involves the reaction of compound (40) with compound (13), R 2This is a method for producing compound (41) by Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like. The reaction conditions were the same as those in the fifth step of Raw Material Synthesis 1.

[0185] (Fifth step) This step is a method for producing compound (42) by Suzuki-Miyaura coupling reaction of compound (41) and compound (15). The reaction conditions were the same as those in the fifth step of Raw Material Synthesis 1. When compound (42) has axial chirality, it is obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0186] (Sixth step) This step is a method for producing compound (43) by oxidation of compound (42). The reaction conditions were the same as those in the seventh step of Raw Material Synthesis 1. When compound (43) has axial asymmetry, it may be obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography, or resolution by SFC using a chiral column.

[0187] (Seventh step) This step is a method for producing compound (44) by ipso substitution reaction between compound (43) and compound (18). The reaction conditions were the same as those in the third step of Raw Material Synthesis 1.

[0188] (Eighth process) This step is a method for producing compound (45) by deprotecting compound (44) through catalytic hydrogenation. The reaction conditions were the same as those in the ninth step of Raw Material Synthesis 1.

[0189] (Ninth step) This step is a method for producing compound (46) from compound (45) and compound (21). The reaction conditions were the same as those in the tenth step of Raw Material Synthesis 1.

[0190] (10th step) This step is a method for producing compound (47) by subjecting compound (46) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0191] (Eleventh step) This step is a step of obtaining compound (51) by subjecting compound (47) to a urea reaction using compound (48), a carbamate reaction using compound (49), and an amidation reaction using compound (50). The urea formation reaction using compound (48) and the carbamate formation reaction using compound (49) are carried out by using an equivalent amount of compound (48) or compound (49) relative to compound (47), or an excess amount of either compound. The mixture is stirred in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at temperatures between -20°C and 60°C, typically for 0.1 hours to 5 days. Examples of solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. Examples of condensing agents include CDI, triphosgene, bis(4-nitrophenyl)carbonate, and 4-nitrophenyl chloroformate. The use of an additive (e.g., HOBt or dimethylaminopyridine) may be preferable for the reaction. In some cases, it is advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, in order to ensure that the reaction proceeds smoothly. The reaction conditions for the amidation reaction using compound (50) are the same as those in the process described in Production Method 1.

[0192] (12th step) This step is a method for producing compound (52) by subjecting compound (51) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0193] (Raw material synthesis 6) [ka]

[0194] This production method is a second method for producing compound (1)-1, which is the starting compound of production method 1, in which A is N and E is CH.

[0195] (first step) This step is a method for producing compound (53) by deprotecting compound (17) through catalytic hydrogenation. The reaction conditions were the same as those in the ninth step of Raw Material Synthesis 1.

[0196] (Second process) This step is a method for producing compound (54) from compound (53) and compound (21). The reaction conditions were the same as those in the tenth step of Raw Material Synthesis 1.

[0197] (Third step) This step is a method for producing compound (55) by ipso substitution reaction between compound (54) and compound (18). The reaction conditions were the same as those in the third step of Raw Material Synthesis 1. Alternatively, the reaction in the fourth step can be carried out without isolating compound (55) in this step.

[0198] (Fourth step) This step is a method for producing compound (56) by subjecting compound (55) to a deprotection reaction. The reaction conditions were the same as those in the process described in Production Method 2, and compound (55) and a deprotection reagent were added, and the NH group was converted to PG. 71 The reaction can be carried out by adding a protecting reagent such as dihydropyran for protecting with a group.

[0199] (Fifth step) This step is a method for producing compound (57) by reacting compound (56) with compound (5). The reaction conditions were the same as in Production Method 3.

[0200] (Sixth step) This step is a method for producing compound (1)-1 by subjecting compound (57) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0201] (Raw material synthesis 7) [ka]

[0202] This production method is a method for producing a compound (3) which is a raw material compound of Production Method 2, in which A is N and -L is included in -L-. A - is CO, -L B -Ga-N(R L1A )- or a divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted, C -L D -L E -L F -Ga-L CF - and R L1A is H or C 1-6 This is a method for producing compound (61), which is an alkyl.

[0203] (first step) This step is a method for producing compound (58) by subjecting compound (29) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0204] (Second process) This step is a method for producing compound (59) by reacting compound (58) with compound (5). The reaction conditions were the same as in Production Method 3.

[0205] (Third step) This step is a method for producing compound (60) by subjecting compound (59) to a deprotection reaction. The reaction conditions were the same as those in the second step of Raw Material Synthesis 2.

[0206] (Fourth step) This step is a method for producing compound (61) by subjecting compound (60) and compound (2) to an amidation reaction. The reaction conditions are the same as those in the process described in Production Method 1.

[0207] (Raw material synthesis 8) [ka]

[0208] This production method is a method for producing compound (69), which is a starting compound for Production Method 4.

[0209] (first step) This step is a method for producing compound (62) by ipso substitution reaction between compound (38) and compound (5). The reaction conditions were the same as those in the third step of Raw Material Synthesis 5.

[0210] (Second process) This step involves the synthesis of compound (62) and compound (13), R 2 This is a method for producing compound (63) by Suzuki-Miyaura coupling reaction with a boronic acid derivative comprising a -boronic acid group or the like. The reaction conditions were the same as those in the fifth step of Raw Material Synthesis 1.

[0211] (Third step) This step is a method for producing compound (64) by Suzuki-Miyaura coupling reaction of compound (63) and compound (15). The reaction conditions were the same as those in the fifth step of Raw Material Synthesis 1. When compound (64) has axial chirality, it is obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0212] (Fourth step) This step is a method for producing compound (65) by oxidation of compound (64). The reaction conditions were the same as those in the seventh step of Raw Material Synthesis 1. When compound (65) has axial chirality, it may be obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography, or resolution by SFC using a chiral column.

[0213] (Fifth step) This step is a method for producing compound (66) by ipso substitution reaction between compound (65) and compound (18). The reaction conditions were the same as those in the third step of Raw Material Synthesis 1.

[0214] (Sixth step) This step is a method for producing compound (67) by deprotecting compound (66) through catalytic hydrogenation. The reaction conditions were the same as those in the ninth step of Raw Material Synthesis 1.

[0215] (Seventh step) This step is a method for producing compound (68) from compound (67) and compound (21). The reaction conditions were the same as those in the tenth step of Raw Material Synthesis 1.

[0216] (Eighth process) This step is a method for producing compound (69) by subjecting compound (68) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0217] (Raw material synthesis 9) [ka]

[0218] This production method is a third method for producing compound (1)-1, which is the starting compound of production method 1, in which A is N and E is CH.

[0219] (first step) This step is a method for producing compound (70) by oxidation of compound (14). The reaction conditions were the same as those in the seventh step of Raw Material Synthesis 1.

[0220] (Second process) This step is a method for producing compound (71) by ipso substitution reaction between compound (70) and compound (18). The reaction conditions were the same as those in the third step of Raw Material Synthesis 1.

[0221] (Third step) This step is a method for producing compound (72) by deprotection reaction of compound (71). The reaction conditions were the same as in Production Method 2.

[0222] (Fourth step) This step is a method for producing compound (73) by reacting compound (72) with compound (5). The reaction conditions are the same as in Production Method 3.

[0223] (Fifth step) This step is a method for producing compound (74) by Suzuki-Miyaura coupling reaction of compound (73) and compound (15). The reaction conditions were the same as those in the fifth step of the present Raw Material Synthesis 1. When compound (74) has axial chirality, it is obtained as a mixture of stereoisomers. However, each stereoisomer can be isolated by a conventional resolution procedure, for example, resolution using ODS column chromatography or silica gel column chromatography.

[0224] (Sixth step) This step is a method for producing compound (75) by deprotecting compound (74) through catalytic hydrogenation. The reaction conditions were the same as those in the ninth step of Raw Material Synthesis 1.

[0225] (Seventh step) This step is a method for producing compound (76) from compound (75) and compound (21). The reaction conditions are the same as those in the tenth step of Raw Material Synthesis 1.

[0226] (Eighth process) This step is a method for producing compound (1)-1 by subjecting compound (76) to a deprotection reaction. The reaction conditions are the same as those in the process described in Production Method 2.

[0227] (Raw material synthesis 10) [ka] (In the formula, LG CB indicates a leaving group, and PG CB L 2 The protecting group for NH contained therein is shown.)

[0228] This production method is carried out by using -L 2 - is a divalent saturated heterocyclic group containing two nitrogen atoms which may be substituted, and -L 35 The compound (2-1) is produced by the method of claim 1, wherein - is -CH2-.

[0229] (first step) This step is a method for producing compound (79) by Suzuki-Miyaura coupling reaction between compound (77) and compound (78). The reaction conditions were the same as those in the fifth step of Raw Material Synthesis 1.

[0230] (Second process) This step is a method for producing an aldehyde compound (80) from compound (79). In this reaction, compound (79) is reacted with osmium tetroxide in a reaction-inert solvent in the presence of an organic base at room temperature or under cooling to obtain the corresponding 1,2-diol compound. Subsequently, a periodic acid is added to the reaction mixture to oxidize the 1,2-diol to obtain the aldehyde compound (80). Examples of solvents that can be used include alcohols such as tBuOH, ethers such as THF, DOX, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetone, and mixtures of these with water. Examples of organic bases that can be used include pyridine and 2,6-lutidine. Examples of periodic acids that can be used include sodium periodate and periodic acid. Alternatively, this reaction can be carried out by carrying out an oxidative cleavage reaction using ozone instead of osmium tetroxide and periodates to produce compound (80). References for this reaction include, for example, the following: Chem. Rev. 1958, 58, 5, p.925-1010.

[0231] (Third step) This step is a method for producing compound (82) by reductive amination using compound (80) and compound (81), which is an amine compound. The reaction conditions are the third step of raw material synthesis 4 -R Z is the same as in the case of -CHO.

[0232] (Fourth step) In this step, compound (82) is subjected to a deprotection reaction to obtain compound (2-1). The reaction conditions are the same as in Production Method 2.

[0233] (Raw material synthesis 11) [ka] (PG L1represents a protecting group for the amino group contained in compound (2)-2, such as a tert-butoxycarbonyl group. L1 represents a leaving group, for example, a halogen, and in one embodiment, Br.

[0234] This production method is a method for producing a compound (2) containing L B is expressed by the following formula (XXX-L B ) and L CF is a bond, Z is a group represented by the following formula (XXII), and G is N. [ka]

[0235] (first step) This step is a method for producing compound (85) by reacting compound (83) with compound (84). This reaction involves using equal amounts of compound (83) and compound (84), or an excess of either, and stirring the mixture in a reaction-inert solvent in the presence of a base and a palladium catalyst at room temperature to reflux, preferably at 20°C to 140°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water, and mixtures thereof. Examples of bases include inorganic bases such as tBuONa, tBuOK, cesium carbonate, tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide. Palladium catalysts include Pd(t-Bu3P)2, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. The reaction may be carried out in the presence of a ligand such as SPhos, RuPhos, 1,1'-bis(diphenylphosphino)ferrocene, or XPhos. Microwave heating of the mixture may also be beneficial for smooth reaction.

[0236] (Second process) This step is a method for producing compound (2)-2 by a deprotection reaction of compound (85). The reaction conditions are the same as those in the process described in Production Method 2.

[0237] (Raw material synthesis 12) [ka] (LG L2 represents a leaving group, for example, halogen, and in one embodiment, F.

[0238] This production method is a method for producing a compound (2) containing L B is expressed by the following formula (XXX-L B ) and L CF is a bond, Z is a group represented by formula (XXVI), and G is N. [ka]

[0239] (first step) This step is a method for producing compound (87) by ipso substitution reaction of compound (86) with compound (84). The reaction conditions are the same as those in the third step of Raw Material Synthesis 5.

[0240] (Second process) This step is a method for producing compound (88) by reducing compound (87). The reduction is carried out by using compound (87) and a reducing agent in equivalent amounts, or an excess of one, in a reaction-inert solvent, with stirring under cooling to heating, preferably at temperatures between -20°C and 100°C, typically for 1 hour to 5 days. Examples of reducing agents that can be used include, but are not limited to, BH3·THF, LAH, and LiBH4. The solvent that can be used includes, but is not limited to, halogenated hydrocarbons such as dichloromethane and dichloroethane; ether solvents such as THF, diethyl ether, and DOX; and aromatic hydrocarbons such as toluene and benzene. Alternatively, compound (88) can be produced by reducing compound (87) by hydrogenation in the presence of a metal catalyst. In this case, Raney nickel or the like can be used as the metal catalyst, and MeOH or the like can be used as the solvent. In some cases, the addition of aqueous ammonia may be beneficial for the reaction.

[0241] (Third step) This step is a method for producing compound (89) by reacting compound (88) with an acrylic acid ester. The reaction is carried out by using equal amounts of compound (88) and an acrylic ester, or an excess of either one, in a reaction-inert solvent, with stirring under cooling or heating, preferably at temperatures between -20°C and 150°C, typically for 1 hour to 5 days. Examples of the acrylic ester used here include methyl acrylate and ethyl acrylate. The solvent used here is not particularly limited, but examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and ether solvents such as THF, diethyl ether, and DOX.

[0242] (Fourth step) This step is a method for producing compound (90) by reacting compound (89) with a urea-forming reagent. The reaction is carried out by using compound (89) and a urea-forming reagent in equivalent amounts or an excess equivalent of either one in a reaction-inert solvent, with stirring under cooling to heating, preferably at temperatures between -20°C and 150°C, typically for 1 hour to 5 days. Examples of the urea-forming reagent used here include trimethylsilyl isocyanate and chlorosulfonyl isocyanate. The solvent used here is not particularly limited, but examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and ether solvents such as THF, diethyl ether, and DOX. Alternatively, compound (90) can be produced by reacting compound (89) with triphosgene or 1,1'-carbonyldiimidazole, followed by treatment with aqueous ammonia.

[0243] (Fifth step) This step is a method for producing compound (91) from compound (90). The reaction is carried out by using equal equivalents of compound (90) and a weak base, or an excess equivalent of either one, in a reaction-inert solvent, with stirring under cooling to heating, preferably at temperatures between -20°C and 100°C, usually for 1 hour to 5 days. Examples of the weak base used here include benzyltrimethylammonium hydroxide, potassium carbonate, potassium trimethylsilanolate, etc. The solvent used here is not particularly limited, but examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as THF, diethyl ether, and DOX, and MeCN.

[0244] (Sixth step) This step is a method for producing compound (2)-3 by deprotecting compound (91). The reaction conditions are the same as in Production Method 2.

[0245] (Raw material synthesis 13) [ka] (LG L3 represents a leaving group, for example, a halogen, and in one embodiment, I. PG Z1 represents a protecting group for NH contained in compound (95), and examples thereof include a p-methoxybenzyl group.

[0246] This production method is a method for producing a compound (2) containing L B is represented by the following formula (XXXIII-L B2 ) and A 2 is CH or N, and L CF Ga-L C1 -O- and L C1 Ha-L C -L D -L E -, Z is a group represented by the following formula (XXVII), and G is N. [ka]

[0247] (first step) This step is a method for producing compound (94) by Mitsunobu reaction between compound (92) and compound (93). The reaction is carried out by using equal amounts of compound (92) and compound (93), or an excess equivalent of either, with a phosphine reagent and an azodicarboxylate ester in a reaction-inert solvent, under cooling to heating, preferably at -20°C to 100°C, and stirring for typically 1 hour to 5 days. Examples of the phosphine reagent used here include triphenylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, etc. Examples of the azodicarboxylate ester used here include dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc. The solvent used here is not particularly limited, but includes ether solvents such as THF, diethyl ether, and DOX, as well as benzene and toluene. Instead of azodicarboxylic acid ester, azodicarboxylic acid amide such as N,N,N',N'-tetramethylazodicarboxamide or bis(piperidinocarbonyl)diimide can also be used. Alternatively, compound (93) in which OH is halogen can be subjected to an ipso substitution reaction with compound (92) in the presence of a base to produce compound (94). In this case, sodium hydride or tBuOK can be used as the base, and the other conditions are the same as those for the third step of Starting Material Synthesis 1.

[0248] (Second process) This step is a method for producing compound (96) by reacting compound (94) with compound (95). This reaction is carried out by stirring equimolar amounts of compound (94) and compound (95), or an excess equivalent of the reagent, in a reaction-inert solvent in the presence of copper halide, a ligand, and a base, under ice-cooling to reflux, typically for 1 hour to 5 days. Examples of copper halides and ligands used here include copper(I) iodide, 1,10-phenanthroline, and N,N,N',N'-tetramethylethylenediamine. Examples of bases used here include, but are not limited to, tripotassium phosphate and potassium carbonate. Examples of solvents used here include, but are not limited to, ethereal solvents such as THF and DOX, as well as benzene, toluene, and DOX. In addition, it may be advantageous to heat the mixture by microwave irradiation in order to ensure smooth progress of the reaction. This step can also be carried out using a palladium catalyst under the same reaction conditions as in the third step of Raw Material Synthesis 16 described below.

[0249] (Third step) This step is a method for producing compound (2)-4 by deprotecting compound (96). The reaction conditions are the same as in Production Method 2.

[0250] (Raw material synthesis 14) [ka]

[0251] This production method is a method for producing a compound (2) containing L B is represented by the formula (XXXIII-L B2 ) and A 2 is CH or N, and L CF Ga-L C1 -O- and L C1 Ha-L C -L D -L E -, Z is a group represented by formula (XXVII), and G is N. [ka]

[0252] (first step) This step is a method for producing compound (97) by reacting compound (93) with compound (95). The reaction conditions were the same as those in the second step of Raw Material Synthesis 13.

[0253] (Second process) This step is a method for producing compound (96) by Mitsunobu reaction between compound (97) and compound (92). The reaction conditions were the same as those in the first step of Raw Material Synthesis 13.

[0254] (Third step) This step is a method for producing compound (2)-4 by deprotecting compound (96). The reaction conditions are the same as in Production Method 2.

[0255] (Raw material synthesis 15) [ka]

[0256] This production method is a method for producing a compound (2) containing L B is represented by the following formula (XXXIII-L B2 ) and A 2 is CH or N, and L CF Ga-L C1 - and L C1 Ha-L C -L D -L E -L F -, Z is a group represented by the following formula (XXVII)-1, and G is N. [ka]

[0257] (first step) This step is a method for producing compound (99) by Mitsunobu reaction between compound (92) and compound (98). The reaction conditions were the same as those in the first step of Raw Material Synthesis 13.

[0258] (Second process) This step is a method of producing compound (100) by reducing compound (99) by catalytic hydrogenation. The reaction conditions were the same as those in the ninth step of Raw Material Synthesis 1.

[0259] (Third step) This step is a method for producing compound (101) from compound (100). The reaction conditions are the same as those in the third step of Raw Material Synthesis 12.

[0260] (Fourth step) This step is a method for producing compound (102) from compound (101). The reaction conditions are the same as those in the fourth step of Raw Material Synthesis 12.

[0261] (Fifth step) This step is a method for producing compound (103) from compound (102). The reaction conditions are the same as those in the fifth step of Raw Material Synthesis 12.

[0262] (Sixth step) This step is a method for producing compound (2)-5 by deprotecting compound (103). The reaction conditions are the same as in Production Method 2.

[0263] (Raw material synthesis 16) [ka] (LG L5 represents a leaving group, for example, a halogen, and in one embodiment, Br. Similarly, LG L6 represents a leaving group, for example, halogen, and in one embodiment, I.

[0264] This production method is a method for producing a compound (2) containing L B is represented by the formula (XXXIII-L B2 ) and A 2 is CH or N, and L CF Ga-L C1 -C≡C-, and L C1 Ha-L C -L D -L E -, Z is a group represented by formula (XXVII), and G is N. [ka]

[0265] (first step) This step is a method of oxidizing the hydroxyl group of compound (104) to obtain compound (105). This reaction is carried out by stirring the compound (104) and an oxidizing agent in equimolar amounts or in excess of either in an inert solvent at room temperature or under ice cooling for typically 1 hour to 5 days. Examples of the oxidizing agent used here include Dess-Martin periodinane. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as benzene and halogenated hydrocarbons such as dichloromethane.

[0266] (Second process) This step is a method for producing compound (106) from compound (105) using an ethynyl group-introducing reagent. This reaction is carried out by stirring the compound (105) and an ethynyl group-introducing reagent in equimolar amounts or in excess of either in an inert solvent, typically for 1 hour to 5 days, at ice-cooling to room temperature. Examples of the ethynyl group-introducing reagent used here include dimethyl (1-diazo-2-oxopropyl)phosphonate. Examples of the solvent include, but are not limited to, alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, ethers such as THF, DOX, and dimethoxyethane, DMF, DMSO, MeCN, water, and mixtures thereof.

[0267] (Third step) This step is a method for producing compound (108) by reacting compound (107) with compound (95). This reaction involves using equal amounts of compound (107) and compound (95), or an excess of either, and stirring the mixture in a reaction-inert solvent in the presence of a base and a palladium catalyst at room temperature to reflux, preferably at 20°C to 150°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as cesium carbonate, tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide. Palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. The reaction can be carried out in the presence of ligands such as SPhos, RuPhos, 1,1'-bis(diphenylphosphino)ferrocene, and XPhos. Microwave heating of the mixture can also be beneficial for smooth reaction.

[0268] (Fourth step) This step is a method for producing compound (109) by reacting compound (106) with compound (108). This reaction involves using equal amounts of compound (106) and compound (108), or an excess of either compound. A mixture of these compounds is stirred in a reaction-inert solvent in the presence of a base and palladium and copper catalysts at room temperature to reflux, preferably at 20°C to 140°C, typically for 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, and amyl alcohol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one; water; and mixtures thereof. Examples of bases include inorganic bases such as cesium carbonate, tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide. Palladium catalysts include tetrakis(triphenylphosphine)palladium, PdCl2(PPh3)2, PdCl2(dppf)·CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. Copper catalysts include copper(I) iodide. Bases include TEA and DIPEA.

[0269] (Fifth step) This step is a method for producing compound (2)-6 by deprotecting compound (109). The reaction conditions are the same as in Production Method 2.

[0270] (Raw material synthesis 17) [ka] (LG L4 represents a leaving group, for example, a halogen, and in one embodiment, Cl.

[0271] This production method is a method for producing L B is represented by the formula (XXXIII-L B1 ) and LCF -C(R L2 )(R L3 )-C≡C-, Z is a group represented by formula (XXIV), and G is N. [ka]

[0272] (first step) This step is a method for producing compound (112) from compound (110) and compound (111). This reaction is carried out by stirring equal amounts of compound (110) and compound (111) or an excess of either in an equivalent amount in a reaction-inert solvent in the presence of a base at ice-cooling to room temperature, typically for 1 hour to 5 days. Examples of the base used here include TEA. Examples of the solvent include, but are not limited to, aromatic hydrocarbons such as toluene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; ethers such as THF, DOX, and dimethoxyethane; DMF, DMSO, and MeCN. In some cases, the addition of a copper salt such as copper(I) chloride may be beneficial to the reaction. However, R L2 and R L3 When both are H, compound (110) and compound (111) can be subjected to a nucleophilic substitution reaction in the presence of a base to produce compound (112). The reaction conditions in this case are the same as those in the tenth step of Starting Material Synthesis 1.

[0273] (Second process) This step is a method for producing compound (114) by reacting compound (112) with compound (113). The reaction conditions were the same as those in the fourth step of Raw Material Synthesis 16. (Third step) This step is a method for producing compound (2)-7 by deprotecting compound (114). The reaction conditions are the same as in Production Method 2.

[0274] (Raw material synthesis 18) [ka]

[0275] In this production method, among the compound (115) which is a raw material compound of Production Method 4, -L-, -L A - is CO, -L B -Ga-N(R L1A )- or a divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms which may be substituted, C -L D -L E -L F -Ga-L CF - a method for producing compound (120)

[0276] (first step) This step is a step of obtaining compound (116) by reacting compound (54) with compound (9). The reaction conditions were the same as those in the third step of Raw Material Synthesis 1.

[0277] (Second process) This step is a step of obtaining compound (117) by carrying out a deprotection reaction of compound (116). The reaction conditions are the same as those in the eleventh step of Raw Material Synthesis 1.

[0278] (Third step) This step is a step of obtaining compound (118) by reacting compound (117) with compound (5). The reaction conditions are the same as those in the twelfth step of Raw Material Synthesis 1.

[0279] (Fourth step) This step is a step of obtaining compound (119) by carrying out a deprotection reaction of compound (118). The reaction conditions are the same as those in the thirteenth step of Raw Material Synthesis 1.

[0280] (Fifth step) This step is a step of obtaining compound (120) by reacting compound (119) with compound (2). The reaction conditions were the same as those in the third step of Raw Material Synthesis 2.

[0281] The pharmacological activities of the compounds of formula (I) and formula (II) were confirmed by the following tests.

[0282] Test Example 1 Evaluation of KRAS degradation activity against human G12V mutant KRAS-positive pancreatic cancer line PA-TU-8902 The KRAS expression level was measured by Cell ELISA to evaluate the KRAS degradation activity of the test compounds. PA-TU-8902 cells (DSMZ, ACC 179) were plated at 1.5 x 10 per well. 4 36 μL of each solution was seeded onto a 384-well plate (Greiner Bio-One) to form cells. Cell culture was performed at 37°C in the presence of 5% CO2 using DMEM medium (Sigma-Aldrich) containing 10% fetal bovine serum (Cytiva). The next day, the test compounds (10 points with final concentrations ranging from 1 μM to 0.03 nM) and dimethyl sulfoxide (DMSO), the solvent for the test compounds as a negative control, were diluted 100-fold with fresh medium, and 4 μL each was added to each well, followed by incubation for 24 hours. The next day, the culture supernatant was removed, and 20 μL of 4% paraformaldehyde phosphate buffer (FUJIFILM Wako) was added to each well. The cells were fixed by incubating at room temperature for 30 minutes. The supernatant was then removed, and 20 μL of phosphate-buffered saline (PBS) containing 0.1% Polyoxyethylene(10) Octylphenyl Ether (FUJIFILM Wako) was added to each well. After incubating at room temperature for 10 minutes, the supernatant was removed, and 25 μL of PBS was added to each well. Each well was washed twice by removing the supernatant. Subsequent washing procedures were performed in the same manner. Next, 20 μL of PBS containing 0.5% sodium dodecyl sulfate (SDS; ThermoFisher Scientific) was added to each well. After incubating at room temperature for 10 minutes, the plate was centrifuged to remove the supernatant. After washing with PBS, the supernatant was removed by centrifugation, and 20 μL of Intercept Blocking Buffer (LI-COR Biosciences) was added to each well. After allowing the plate to stand at room temperature for 30 minutes, the supernatant was removed by centrifugation. A mixture of anti-KRAS antibody (EPR23474-76; Rabbit mAb; Abcam; 1:1,000 dilution) and anti-β-Actin antibody (Anti-β Actin antibody; Mouse mAb; Abcam; 1:1,000 dilution) diluted with Intercept Blocking Buffer was added to each well (15 μL). The plate was then allowed to stand overnight at 4°C. The next day, the supernatant was removed by centrifugation and the plates were washed with PBS. The supernatant was then removed by centrifugation, and 15 μL of a mixture of anti-rabbit IgG antibody (IRDye 800CW Goat anti-Rabbit IgG; LI-COR Biosciences) and anti-mouse IgG antibody (IRDye 680RD Donkey anti-Mouse IgG; LI-COR Biosciences) diluted 1:1,000 in Intercept Blocking Buffer was added to each well. After incubation at room temperature for 1 hour, the supernatant was removed by centrifugation and the plates were washed with PBS. After removing the supernatant, the plates were air-dried at room temperature for at least 2 hours, and the fluorescence signals at 721-740 nm and 816-840 nm were measured using an Odyssey M Imaging System (LI-COR Biosciences). The KRAS signal value corrected by the β-Actin signal value was set to 0% when DMSO was added, and 100% when stained with anti-β-Actin antibody alone. The KRAS degradation rate was calculated using the 50% degradation value (DC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) and formula (II) are shown in the table below.

[0283] [Table 1-1]

[0284] [Table 1-2]

[0285] Test Example 2 Evaluation of the anchorage-independent cell growth inhibitory effect on the human G12V mutant KRAS-positive pancreatic cancer line PA-TU-8902, the human G12D mutant KRAS-positive pancreatic cancer line PK-59, the human G12C mutant KRAS-positive pancreatic cancer line MIA PaCa-2, the human G12C mutant KRAS-positive lung cancer line NCI-H358, the human G12D mutant KRAS-positive colon cancer line GP2d, the human G13D mutant KRAS-positive colon cancer line LoVo, or the human wild-type KRAS gene amplification-positive gastric cancer line MKN1 The inhibitory effect of test compounds on anchorage-independent cell growth was evaluated using three-dimensional spheroid culture. PA-TU-8902 cells or GP2d cells (ECACC, 95090714), PK-59 cells (RIKEN BRC, RCB1901), MIA PaCa-2 cells (RIKEN BRC, RCB2094), NCI-H358 cells (ATCC, CRL-5807), LoVo cells (ATCC, CCL-229), or MKN1 cells (JCRB, JCRB0252) were cultured at 5x10 per well. 2 The cells were seeded in a low-cell-adsorption U-bottom 384-well plate (Prime Surface, Sumitomo Bakelite Co., Ltd.) at 36 μL / well, but the culture of PA-TU-8902 cells was carried out under the same conditions as in Test Example 1. GP2d cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. PK-59 cells, MIA PaCa-2 cells, LoVo cells, NCI-H358 cells, and MKN1 cells were cultured in RPMI-1640 medium (Sigma-Aldrich) containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. The next day, test compounds (10 concentrations ranging from 10 μM to 0.03 nM) and DMSO (the solvent for the test compounds) were diluted 100-fold with fresh medium and added in 4 μL aliquots to each well containing PA-TU-8902, PK-59, MIA PaCa-2, LoVo, NCI-H358, or MKN1 cells. After incubation at 37°C in the presence of 5% CO for 6 days, 20 μL of CellTiter-Glo 2.0 (Promega) was added to each well. After stirring for 1 hour at room temperature, luminescence signals were measured using an ARVO X3 (PerkinElmer). The signal value in DMSO treatment was defined as 100% viability, and the signal value in the absence of cells and medium alone was defined as 0% viability. The 50% inhibition value (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) and formula (II) are shown in the table below.

[0286] [Table 2-1]

[0287] [Table 2-2]

[0288] Test Example 3: Evaluation of antitumor activity in mice bearing the human G12D mutant KRAS-positive colon cancer line GP2d GP2d cells were cultured under the same conditions as in Test Example 2. GP2d cells were collected and suspended in PBS, and a 2-fold volume of VitroGel Hydrogel Matrix (The Well Biosciences) was added to give a 4.0 x 10 7A 100 μL volume of cell suspension prepared at cells / mL was inoculated subcutaneously into 4-5 week-old male nude mice (BALB / c-nu (nu / nu), Jackson Laboratories Japan). Approximately two weeks after inoculation, the mice were divided into groups so that tumor volume and body weight were approximately equal, and the test compound was administered the following day. The test consisted of five mice in each of the vehicle control and test compound groups. The test compound was dissolved in a solvent containing ethanol (FUJIFILM Wako), 5% glucose solution (Otsuka Pharmaceutical), 1 M hydrochloric acid, 50% aqueous solution of (2-hydroxypropyl)-β-cyclodextrin (HP-βCD) (ROQUETTE), HCO-40 (Nikko Chemicals), and 1 M aqueous sodium hydroxide solution in a volume ratio of 4:8, 4.4: 1.1: 1: 9: 0.5. The test compound or vehicle control was administered intravenously into the tail vein. The administration was performed twice a week. Tumor diameter and body weight were measured twice a week. The tumor volume was calculated using the following formula: [Tumor volume (mm 3 )] = [Tumor long diameter (mm)] x [Tumor short diameter (mm)] 2 x 0.5 The tumor growth inhibition rate (%) of the test compound was calculated by setting the tumor volume of the test compound administration group on the day before the start of administration as 100% inhibition, and the tumor volume of the vehicle group 2 weeks after the grouping date as 0% inhibition. In addition, when the tumor volume of the test compound administration group was lower than the tumor volume on the day before the start of administration, the tumor volume on the day before the start of administration was set as 0% regression, and a tumor volume of 0 was set as 100% regression, and the tumor regression rate (%) of the test compound was calculated. The results of several test compounds of formula (I) and formula (II) are shown in the table below.

[0289] [Table 3]

[0290] Test Example 4: Evaluation of antitumor activity in mice bearing the human G12V mutant KRAS-positive pancreatic cancer line PA-TU-8988S PA-TU-8988S cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2. PA-TU-8988S cells were harvested and suspended in PBS. Cultrex Basement Membrane Extract (R&D Systems) was added to a final concentration of 5.0 mg / mL, and 5.0 x 10 7 A cell suspension adjusted to cells / mL was inoculated subcutaneously in 100 μL into 4-5 week-old male nude mice (BALB / c-nu (nu / nu), Jackson Laboratory Japan). Approximately two weeks after inoculation, the mice were divided into groups so that tumor volume and body weight were approximately equivalent between groups, and administration of the test compound began the following day. The test was conducted with five mice in each of the solvent control group and the test compound administration group. The test compound was dissolved in the same solvent as in Test Example 3. The test compound or solvent control was administered into the tail vein. Administration was once a week for 2-3 doses. Tumor diameter and body weight were measured twice a week. Tumor volume, tumor growth inhibition rate (%) by the test compound, and tumor regression rate (%) by the test compound were calculated as in Test Example 3.

[0291] Test Example 5: Evaluation of antitumor activity in mice bearing the human G12C mutant KRAS-positive lung cancer strain NCI-H358 NCI-H358 cells were cultured in the same manner as in Test Example 2. NCI-H358 cells were collected and suspended in PBS, and a 2-fold volume of VitroGel Hydrogel Matrix (The Well Biosciences) was added to give a 5.0 x 10 7A cell suspension adjusted to cells / mL was inoculated subcutaneously in 100 μL into 4-5 week-old male nude mice (BALB / c-nu (nu / nu), Jackson Laboratory Japan). Approximately 3 weeks after inoculation, the mice were divided into groups so that tumor volume and body weight were approximately equivalent between groups, and administration of the test compound began the following day. The test was conducted with 5 mice in each of the solvent control group and the test compound administration group. The test compound was dissolved in the same solvent as in Test Example 3. The test compound or solvent control was administered into the tail vein. Administration was once a week for 2-3 times. Tumor diameter and body weight were measured 2-3 times a week. Tumor volume, tumor growth inhibition rate (%) by the test compound, and tumor regression rate (%) by the test compound were calculated as in Test Example 3.

[0292] As a result of the above test, some compounds of formula (I) and formula (II) were confirmed to have the effect of inducing the degradation of G12V mutant KRAS. In addition, some compounds of formula (I) and formula (II) were confirmed to have cell proliferation inhibitory effects on human G12V mutant KRAS-positive cancer, human G12D mutant KRAS-positive cancer, human G12C mutant KRAS-positive cancer, and human G13D mutant KRAS-positive cancer. Furthermore, some compounds of formula (I) and formula (II) were confirmed to have antitumor effects in mice bearing human G12D mutant KRAS-positive colon cancer. Therefore, the compounds of formula (I) and formula (II) can be used for the treatment of cancer, particularly G12C mutant, G12D mutant, G12V mutant, and G13D mutant KRAS-positive cancer.

[0293] Pharmaceutical compositions containing one or more of the compounds of formula (I) and formula (II) or salts thereof as active ingredients can be prepared by commonly used methods using excipients commonly used in the art, i.e., pharmaceutical excipients and pharmaceutical carriers. Administration may be in the form of oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration using injections such as intra-articular, intravenous, or intramuscular injections, transmucosal agents, or inhalants.

[0294] Solid compositions for oral administration include tablets, powders, granules, etc. In such solid compositions, one or more active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with sugar or a film of a gastric or enteric substance, if necessary. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and contain commonly used inert diluents such as purified water or EtOH. In addition to the inert diluents, the liquid compositions may contain adjuvants such as solubilizing agents, wetting agents, and suspending agents, as well as sweeteners, flavors, aromatics, and preservatives.

[0295] Injectable preparations for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include alcohols such as EtOH. Such compositions may further contain an isotonic agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These are sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizer, or irradiation. Alternatively, sterile solid compositions can be prepared and dissolved or suspended in sterile water or a sterile injectable solvent before use.

[0296] Transmucosal agents such as inhalants and nasal agents may be in solid, liquid, or semisolid form and may be prepared according to conventional methods. For example, known excipients, as well as pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc., may be added as appropriate. Administration can be performed using a suitable inhalation or insufflation device. For example, known devices such as metered-dose inhalers or nebulizers can be used to administer the compound alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. Dry powder inhalers and the like may be for single or multiple doses and may utilize a dry powder or powder-containing capsule. Alternatively, the compound may be in the form of a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as a chlorofluoroalkane or carbon dioxide.

[0297] In general, for oral administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, preferably 0.1 to 30 mg / kg, and more preferably 0.1 to 10 mg / kg, and is administered once or in two to four divided doses. For intravenous administration, the daily dosage is approximately 0.0001 to 10 mg / kg of body weight, and is administered once or in multiple divided doses. For transmucosal administration, the daily dosage is approximately 0.001 to 100 mg / kg of body weight, and is administered once or in multiple divided doses. The dosage is determined appropriately for each individual case, taking into account symptoms, age, sex, etc.

[0298] Although the amount varies depending on the route of administration, dosage form, administration site, and types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment, 0.01 to 50% by weight, of the active ingredient, one or more compounds of formula (I) and formula (II) or salts thereof.

[0299] The compounds of formula (I) and formula (II) can be used in combination with various therapeutic or preventive agents for diseases for which the compounds of formula (I) and formula (II) are considered to be effective. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately. [Example]

[0300] The methods for producing the compounds of formula (I) and formula (II) are explained in more detail below with reference to examples. It should be noted that the present invention is not limited to the compounds described in the following examples. Furthermore, the methods for producing the starting compounds are shown in the respective production examples. Furthermore, the methods for producing the compounds of formula (I) and formula (II) are not limited to the production methods of the specific examples shown below, and the compounds of formula (I) and formula (II) can also be produced by a combination of these production methods or by methods that would be obvious to one skilled in the art.

[0301] In the present specification, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.

[0302] For convenience, the concentration in mol / L is expressed as M. For example, a 1M aqueous solution of sodium hydroxide means a 1 mol / L aqueous solution of sodium hydroxide.

[0303] Manufacturing Example 1 Under an argon atmosphere, a solution of (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazoline (3 g) in MeOH (70 mL) and THF (70 mL) was added with sodium bicarbonate (1551 mg) and 10% Pd / C (approximately 50% water content, 994 mg) at room temperature. The mixture was stirred overnight under a hydrogen atmosphere at ambient temperature and pressure. After purging with argon, the reaction mixture was filtered through Celite® using CHCl3 / IPA (4 / 1, 100 mL) and EtOH / water (10 / 1, 100 mL). The filtrate was concentrated under reduced pressure. EtOAc and water were added, and the separated organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure gave (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (2705 mg) as a foamy solid.

[0304] Manufacturing Example 2 To a solution of (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (10.3 g) in DMF (150 mL), tert-butyl 4-(chloromethyl)benzoate (5.5 g) and cesium carbonate (18 g) were added under ice cooling, and the mixture was stirred overnight at 40°C under an argon atmosphere. The reaction was quenched by adding saturated aqueous ammonium chloride solution under ice cooling. EtOAc and water were added, and the organic and aqueous layers were separated. The organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane / Et0Ac) to give tert-butyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (11.8 g) as a foamy solid.

[0305] Manufacturing Example 3 To a solution of tert-butyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (1 g) and 3-dimethylamino-2,2-dimethyl-1-propanol (0.36 mL) in THF (10 mL) was added tBuOK (160 mg) and stirred for 30 minutes under ice-cooling. The reaction was quenched by adding saturated aqueous ammonium chloride solution under ice-cooling. EtOAc and water were added, and the organic and aqueous layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc) to give tert-butyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (790 mg) as a foamy solid.

[0306] Manufacturing Example 4 To a solution of tert-butyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (790 mg) in THF (10 mL) was added 3,4-dihydro-2H-pyran (0.5 mL) and p-toluenesulfonic acid monohydrate (270 mg) under ice-cooling, and the mixture was stirred at room temperature under an argon atmosphere overnight. EtN (1.3 mL) was added under ice-cooling, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl 4-[({(7M)-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxyquinazolin-8-yl}oxy)methyl]benzoate (520 mg) as a foamy solid.

[0307] Production Example 5 To a suspension of tert-butyl 4-[({(7M)-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxyquinazolin-8-yl}oxy)methyl]benzoate (520 mg) and (2S)-azetidine-2-carboxamide (170 mg) in MeCN (10 mL) was added DIPEA (0.9 mL) and PyAOP (720 mg) under ice cooling, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH / 28% aqueous ammonia) to give tert-butyl 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (660 mg) as a foamy solid.

[0308] Manufacturing Example 6 To a solution of tert-butyl 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (660 mg) in CHCl (10 mL) was added TFA (2.4 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and then THF (3 mL) and saturated aqueous sodium bicarbonate were added under ice cooling. The mixture was stirred for 1 minute under ice cooling. CHCl / IPA (4 / 1) and water were added, and the pH was adjusted to 8-9 with 1M hydrochloric acid. The aqueous layer was extracted four times with CHCl / IPA (4 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)benzoic acid (600 mg) as a solid.

[0309] Manufacturing Example 7 3-[(4-Methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (616 mg), 4-iodopyridin-2-ol (450 mg), CuI (402 mg), and tripotassium phosphate (900 mg) were suspended in DOX (6 mL) and TMEDA (316 μL) at room temperature and stirred at 150 °C for 1 h under MW irradiation. CuI (400 mg), tripotassium phosphate (450 mg), and TMEDA (0.31 mL) were added at room temperature and stirred at 150 °C for 1.5 h under MW irradiation. Water and EtOAc were added to the reaction mixture at room temperature, filtered, and the filtrate was extracted three times with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give 1-(2-hydroxypyridin-4-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (204 mg) as a foamy solid.

[0310] Manufacturing Example 8 1-(2-Hydroxypyridin-4-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (794 mg) and tert-butyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylate (938 mg) were suspended in toluene (12 mL) at room temperature. N,N,N',N'-Tetramethylazodicarboxamide (1253 mg) and tri-n-butylphosphine (1.97 mL) were added under ice cooling, and the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Saturated aqueous sodium bicarbonate was added to the reaction mixture at room temperature, and the mixture was extracted three times with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / EtOAc) to give tert-butyl 9-{2-[(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}pyridin-2-yl)oxy]ethyl}-3-azaspiro[5.5]undecane-3-carboxylate (666 mg) as an oil.

[0311] Manufacturing Example 9 Tert-butyl 9-{2-[(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}pyridin-2-yl)oxy]ethyl}-3-azaspiro[5.5]undecane-3-carboxylate (1750 mg) was dissolved in TFA (28 mL) at room temperature. TfOH (1.51 mL) was added at room temperature, and the mixture was stirred at 60 °C under an argon atmosphere for 4 hours. The reaction mixture was concentrated under reduced pressure, and EtN (4 mL) was added to the resulting residue under ice cooling. The mixture was purified by basic silica gel column chromatography (CHCl / MeOH / 28% aqueous ammonia) to give 1-{2-[2-(3-azaspiro[5.5]undecan-9-yl)ethoxy]pyridin-4-yl}-1,3-diazinan-2,4-dione (1451 mg) as a solid.

[0312] Manufacturing Example 10 To a solution of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)-1,3-diazinan-2,4-dione (300 mg), tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (340 mg), and Pd(tBuP) (46 mg) in DMSO (3 mL), tBuONa (170 mg) was added at room temperature. The mixture was stirred at 100°C under argon atmosphere and MW irradiation for 1 hour. Water was added at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (hexane / CHCl3 / MeOH) to give tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indazol-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (205 mg) as a solid.

[0313] Manufacturing Example 11 Tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indazol-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (200 mg) was dissolved in CHCl (3 mL), TFA (1 mL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane / CHCl / MeOH) to give 1-[5-fluoro-1-methyl-6-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-1H-indazol-3-yl]-1,3-diazinan-2,4-dione (130 mg) as a solid.

[0314] Manufacturing Example 12 2,6-Dichloro-5-fluoropyridine-3-carbonitrile (400 mg) and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (540 mg) were dissolved in NMP (4 mL), and DIPEA (720 μL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. Ethylhydrazine dihydrochloride (835 mg) and DIPEA (3.5 mL) were then added, and the mixture was stirred at room temperature for 1 hour, at 60 °C for 2 hours, and at 120 °C overnight. The reaction mixture was poured into ice water and stirred at room temperature for 30 minutes. The resulting powder was collected by filtration and dried under reduced pressure to give tert-butyl 4-(3-amino-1-ethyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (604 mg) as a solid.

[0315] Manufacturing Example 13 A mixture of tert-butyl 4-(3-amino-1-ethyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (600 mg), ethyl acrylate (2 mL), DBU (200 μL), and DL-lactic acid (100 μL) was stirred under MW irradiation at 120 °C for 4 h and at 130 °C for 2 h. The reaction mixture was poured into EtOAc / water and extracted three times with EtOAc. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc). The resulting residue was dissolved in AcOH (4.5 mL) and water (1.5 mL). Sodium cyanate (150 mg) was added in several portions under ice cooling. The mixture was stirred for 10 min under ice cooling and then for 1 h at room temperature. Sodium cyanate (90 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with EtOAc. The organic layer was washed once with water, twice with 1M aqueous sodium hydroxide, once with saturated aqueous sodium bicarbonate, and once with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was filtered and concentrated under reduced pressure. The resulting residue was dissolved in MeCN (10 mL), and benzyltrimethylammonium hydroxide (40% in MeOH, 250 μL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-ethyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (273 mg) as a foamy solid.

[0316] Manufacturing Example 14 Tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-ethyl-5-fluoro-1H-pyrazolo[3,4-b]pyridin-6-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (272 mg) was dissolved in CHCl (3 mL), TFA (500 μL) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and EtOAc (3 mL) was added to the residue. HCl / EtOAc (4 M, 500 μL) was added at room temperature, and the mixture was stirred at room temperature for 20 minutes. The mixture was then concentrated under reduced pressure. The residue was suspended in EtOAc, filtered, and dried under reduced pressure to give 1-[1-ethyl-5-fluoro-6-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,3-diazinan-2,4-dione hydrochloride (204 mg) as a solid.

[0317] Manufacturing Example 15 7-Bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline (4.7 g) and CHCl (90 mL) were added, and mCPBA (approximately 30% water content, 4.8 g) was added while stirring in an ice bath, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with CHCl and washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate, followed by separation. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. 3-Dimethylamino-2,2-dimethyl-1-propanol (1.6 mL) and THF (50 mL) were added to the residue. tBuOK (2 g) was added while stirring in a MeOH / ice bath, followed by stirring in the same bath for 0.5 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and then ice and saturated aqueous ammonium chloride were poured into it. The mixture was extracted twice with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (hexane / EtOAc) to give 3-({7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}oxy)-N,N,2,2-tetramethylpropan-1-amine (2.35 g) as an oil.

[0318] Manufacturing Example 16 3-({7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}oxy)-N,N,2,2-tetramethylpropan-1-amine (3.4 g) was dissolved in THF (50 mL) and p-toluenesulfonic acid monohydrate (1.4 g) was added with stirring at room temperature. The mixture was then stirred at room temperature under an argon atmosphere for 3 hours. EtN (3 mL) was added to the reaction mixture, and the solvent was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl / MeOH) to give 7-bromo-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-ol (2.97 g) as a foamy solid.

[0319] Manufacturing Example 18 (2S)-1-{7-bromo-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}azetidine-2-carboxamide (200 mg), 2-[7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (160 mg), RuPhos (25 mg), RuPhos Pd G3 (45 mg), tripotassium phosphate (250 mg), DOX (5 mL), and water (1 mL) were added to the reaction mixture. The mixture was degassed under reduced pressure and refilled with argon several times, and then stirred at 80°C for 2 hours under an argon atmosphere. The cooled reaction mixture was poured into ice water and extracted twice with EtOAc. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (hexane / Et0Ac) to give (2S)-1-{6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}azetidine-2-carboxamide (a mixture of diastereomers resulting from axial asymmetry, 189 mg) as a foamy solid.

[0320] Manufacturing Example 19 (2S)-1-{6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}azetidine-2-carboxamide (186 mg) was added to MeOH (5 mL) and 20% Pd(OH) / C (approximately 50% water content, 60 mg) and stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 1 hour. Celite® was added to the reaction mixture, and the mixture was filtered through Celite®, washing with EtOAc and CHCl3. Toluene (approximately 5 mL) was added to the filtrate, and the solvent was evaporated under reduced pressure to give (2S)-1-{6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-8-hydroxyquinazolin-4-yl}azetidine-2-carboxamide (164 mg) as a foamy solid.

[0321] Manufacturing Example 21 Triisopropylsilane (0.12 mL) and CHCl (3 mL) were added to tert-butyl 4-[({4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-[7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]quinazolin-8-yl}oxy)methyl]benzoate (159 mg). TFA (1 mL) was added dropwise with stirring in a MeOH / ice bath, and the mixture was stirred overnight at room temperature under an argon atmosphere. The solvent was concentrated under reduced pressure, and a small amount of ice water was poured into the residue. The pH was adjusted to 5-6 with saturated aqueous sodium bicarbonate. After extraction with CHCl3 / MeOH (5 / 1) three times, the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 4-[({4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(7-fluoro-3-hydroxynaphthalen-1-yl)quinazolin-8-yl}oxy)methyl]benzoic acid (67 mg) as a solid.

[0322] Manufacturing Example 26 tert-Butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1400 mg) and 4-chloro-5-fluoropyridine-2-carbonitrile (780 mg) were suspended in MeCN (10 mL) and DIPEA (1.7 mL) at room temperature and stirred under MW irradiation at 150 °C under an argon atmosphere for 1.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture at room temperature, and the mixture was extracted three times with EtOAc. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / EtOAc) to give tert-butyl 4-(4-chloro-6-cyanopyridin-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1501 mg) as a foamy solid.

[0323] Manufacturing Example 27 tert-Butyl 4-(4-chloro-6-cyanopyridin-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1450 mg) was dissolved in THF (16 mL) at room temperature. Under ice-cooling, BH3-THF complex (0.9 M THF solution, 16 mL) was added and stirred at 60 °C for 1 hour under an argon atmosphere. MeOH was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (hexane / EtOAc) to give tert-butyl 4-[6-(aminomethyl)-4-chloropyridin-3-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (293 mg) as a foamy solid.

[0324] Manufacturing Example 28 Tert-butyl 4-[6-(aminomethyl)-4-chloropyridin-3-yl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (293 mg) was dissolved in EtOH (7 mL) at room temperature, and ethyl acrylate (0.15 mL) was added at room temperature. The mixture was stirred overnight at room temperature under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (7 mL) at room temperature. Trimethylsilyl isocyanate (1.5 mL) was added at room temperature, and the mixture was stirred at 60°C over the weekend under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl 4-(4-chloro-6-{[carbamoyl(3-ethoxy-3-oxopropyl)amino]methyl}pyridin-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (296 mg) as a foamy solid.

[0325] Manufacturing Example 29 tert-Butyl 4-(4-chloro-6-{[carbamoyl(3-ethoxy-3-oxopropyl)amino]methyl}pyridin-3-yl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (296 mg) was dissolved in MeCN (5.5 mL) at room temperature, and benzyltrimethylammonium hydroxide (40% in MeOH, 0.27 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH) to give tert-butyl 4-{4-chloro-6-[(2,4-dioxo-1,3-diazinan-1-yl)methyl]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (259 mg) as a foamy solid.

[0326] Manufacturing Example 30 Tert-butyl 4-{4-chloro-6-[(2,4-dioxo-1,3-diazinan-1-yl)methyl]pyridin-3-yl}-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (259 mg) was dissolved in CHCl (5 mL) at room temperature. HCl / DOX (4 M, 2.6 mL) was added at room temperature and stirred overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure to give 1-{[4-chloro-5-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pyridin-2-yl]methyl}-1,3-diazinan-2,4-dione hydrochloride (255 mg) as a foamy solid.

[0327] Manufacturing Example 31 At room temperature, tert-butyl 4-[({(7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (160 mg), NMP (2 mL), (S)-1,2-dimethylpiperazine (120 mg), and DIPEA (300 μL) were added and stirred at 150 °C for 3 hours under MW irradiation. EtOAc and water were added, and the organic and aqueous layers were separated by liquid separation. The organic layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in THF (5 mL), and 3,4-dihydro-2H-pyran (280 μL) and p-toluenesulfonic acid monohydrate (200 mg) were added under ice-cooling. The mixture was stirred overnight at room temperature under an argon atmosphere. EtN (1.5 mL) was added under ice-cooling, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH) to give tert-butyl 4-[({(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxyquinazolin-8-yl}oxy)methyl]benzoate (150 mg) as an oil.

[0328] Manufacturing Example 32 To a suspension of tert-butyl 4-[({(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxyquinazolin-8-yl}oxy)methyl]benzoate (150 mg) and (2S)-azetidine-2-carboxamide (95 mg) in MeCN (5 mL) was added DIPEA (400 μL) and PyAOP (430 mg) under ice cooling, and the mixture was stirred at 50° C. under an argon atmosphere for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH / 28% aqueous ammonia) to give tert-butyl 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (100 mg) as a foamy solid.

[0329] Manufacturing Example 33 To a solution of tert-butyl 4-[({(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]quinazolin-8-yl}oxy)methyl]benzoate (72 mg) in CHCl (3 mL) was added TFA (0.25 mL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and THF (3 mL) and saturated aqueous sodium bicarbonate were added under ice cooling. The mixture was stirred for 1 minute under ice cooling. CHCl / IPA (4 / 1) and water were added, and the pH was adjusted to 8-9 with 1M hydrochloric acid. The aqueous layer was extracted four times with CHCl / IPA (4 / 1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-({[(7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl]oxy}methyl)benzoic acid (60 mg) as a solid.

[0330] Manufacturing Example 34 To a suspension of tert-butyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylate (1.3 g) and 5-iodopyridin-3-ol (750 mg) in toluene (10 mL) and THF (10 mL), tri-n-butylphosphine (2 mL) and N,N,N',N'-tetramethylazodicarboxamide (1.4 g) were added under ice cooling. The mixture was stirred at room temperature under argon for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / Et0Ac) to give tert-butyl 9-{2-[(5-iodop...

Claims

(2S)-1-[(7M)-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-({4-[9-(2-{[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-{[4-(9-{3-[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]prop-2-yn-1-yl}-3-azaspiro[5.5]undecane-3-carbonyl)phenyl]methoxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)-4-methylpyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, (2S)-1-[(7M)-6-cyclopropyl-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-2-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide, or These salts.

2. (2S)-1-[(7M)-6-Cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-({4-[9-(2-{[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide or a salt thereof.

3. (2S)-1-[(7M)-6-Cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide or a salt thereof.

4. (2S)-1-[(7M)-6-Cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-{[4-(9-{3-[4-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-2-yl]prop-2-yn-1-yl}-3-azaspiro[5.5]undecane-3-carbonyl)phenyl]methoxy}-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide or a salt thereof.

5. (2S)-1-[(7M)-6-Cyclopropyl-2-[(3S)-3,4-dimethylpiperazin-1-yl]-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)-4-methylpyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide or a salt thereof.

6. (2S)-1-[(7M)-6-Cyclopropyl-8-({4-[9-(2-{[5-(2,4-dioxo-1,3-diazinan-1-yl)pyridin-3-yl]oxy}ethyl)-3-azaspiro[5.5]undecane-3-carbonyl]phenyl}methoxy)-2-[(3S)-4-ethyl-3-methylpiperazin-1-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl]azetidine-2-carboxamide or a salt thereof.