Heterocyclic compound for inducing degradation of KRAS protein

Abstract

Provided is a compound useful as an active ingredient in a pharmaceutical composition for treating cancer.　The present inventors have examined a compound useful as an active ingredient in a pharmaceutical composition for cancer treatment, and have completed the present invention by finding that: a heterocyclic compound represented by formula (I) and formula (I-I) has excellent an action of inducing degradation of a mutant KRAS protein and a wild-type KRAS protein, and in particular, an action of inducing degradation of a KRAS protein having a G12C mutation, G12D mutation, G12V mutation, or G13D mutation; and said heterocyclic compound has mutant KRAS inhibition and the inhibitory activity of KRAS amplified by a wild-type KRAS gene, and in particular, inhibitory activity of KRAS having a G12C mutation, G12D mutation, G12V mutation, or G13D mutation. The heterocyclic compound according to the present invention or a salt thereof can be used as a therapeutic agent for cancer.

Description

HETEROCYCLIC COMPOUND FOR INDUCING DEGRADATION OF KRAS PROTEIN TECHNICAL FIELD

[0001] The present invention relates to a heterocyclic compound which has excellent degradation-inducing action of mutated KRAS proteins, particularly, excellent inductive action on degradation of G12C mutated, G12D mutated, G12V mutated, and G13D mutated KRAS proteins and wild-type KRAS proteins and / or excellent inhibitory action on mutated KRAS, particularly, excellent inhibitory action on G12C mutated, G12D mutated, G12V mutated, and G13D mutated KRASs and excellent inhibitory action on KRAS in the presence of amplification of a wild-type KRAS gene, and which is expected to be useful as an active ingredient of a pharmaceutical composition such as a pharmaceutical composition for treatment of cancer. BACKGROUND ART

[0002] RAS proteins are low-molecular (about 21 kDa) guanosine triphosphate (GTP)-binding proteins each composed of 188 to 189 amino acids, and include four main proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS) generated from three genes, i.e., KRAS, NRAS, and HRAS genes. The RAS proteins include those of an GTP-binding form as an active form and a GDP-binding form as an inert form. The RAS proteins are activated by exchanging guanosine diphosphate (GDP) for GTP as a result of ligand stimulation to a cell membrane receptor such as EGFR. The active-form RASs bind to as many as 20 effector proteins such as RAF, PI3K, and RALGDS, and activates the downstream signal cascade. On the other hand, the active-form RAS becomes the inert form as a result of conversion of GTP to GDP due to endogenous GTP hydrolysis (GTPase) activity. The GTPase activity is accelerated by a GTPase activating protein (GAP). Thus, RAS has an important function as a "molecular switch" in an intracellular signaling pathway such as EGFR, and plays an important role in the processes such as growth of cells, proliferation, and generation of blood vessels (Nature Rev. Cancer, 2011, 11, p. 761-774, Nature Rev. Drug Discov., 2014, 13, p. 828-851, Nature Rev. Drug Discov., 2016, 15, p.771-785).

[0003] When spontaneous mutation of the RAS gene causes amino acid substitution, RAS is constantly activated due to its reduced function as the GTPase or a reduced reaction with GAP, and continuously transmits the signal to the downstream side. Such an excess signal causes the onset of cancers or an enhancement of proliferation of cancers. For example, mutation of the KRAS genes is observed in 90% or more of patients having pancreatic ductal adenocarcinoma, and the mutation is present from the initial state called pancreatic intraepithelial neoplasia (PanIN). In lung cancer and colorectal cancer, the mutation of the KRAS genes is also highly frequently observed. As the mutation of the KRAS genes, many examples of point mutation of codon 12 located in KRAS exon 2 (G12C mutation, G12D mutation, G12V mutation, etc.) are known (Nat. Rev. Cancer, 2018, 18, p. 767-777).

[0004] Recently, a plurality of inhibitors selective for G12C mutated KRAS has been developed, among of which Sotorasib and adagrasib are approved as curative medicines for non-small cell lung cancer by FDA (J. Exp. Clin. Cancer. Res., 41 27, 2022). About 14% of patients having lung cancer have G12C mutated KRAS, and it is reported that about 5% and about 7% of the patients have G12V mutation and G12D mutation, respectively. On the other hand, in pancreatic cancer, G12D mutation and G12V mutation are observed frequently, i.e., about 40% and about 28% of the patients, respectively, and in colon cancer, G12D mutation, G12V mutation, G12C mutation, and G13D mutation are observed in about 15%, about 10%, about 3%, and about 8% of the patients, respectively. A high proportion of mutation other than G12C mutation in a variety of cancers leads to a high expectation of a curative medicine for a wide range of mutated KRAS (npj Precis. Onco., 6 91, 2022).

[0005] WO 2016 / 049565, WO 2016 / 049568, and WO 2017 / 172979 disclose RAS inhibitors, and WO 2016 / 049568 and WO 2017 / 172979 discloses the compound represented by formula (A) and that represented by formula (B) below, respectively (for the meanings of the symbols in the formulas, see these publications). Patent Documents 1, 2, and 3 state that the compounds are useful for cancers having mutation of codon 12 in KRAS and the mutation includes G12C mutation and G12V mutation, while no specific action of the compounds against G12C mutated KRAS and G12V mutated KRAS is described. [Chemical Formula 1] (A) [Chemical Formula 2] R29 (B)

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

[0007] Recently, bifunctional compounds generally called PROTAC (PROteolysisTArgeting Chimera), SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser) and the like are found as a technique of inducing degradation of the target protein, and are expected to be one of novel drug development modalities (Drug. Discov. Today Technol., 2019, 31, p15-27). Such a bifunctional compound promotes formation of a composite form of the target protein and E3 ligase within the cell, and use of the ubiquitin-proteasome system induces degradation of the target protein. The ubiquitin-proteasome system is one of intracellular protein degradation mechanisms. The protein called E3 ligase identifies and ubiquitinizes the protein to be degraded, causing its degradation to proceed in the proteasome.

[0008] E3 ligase includes 600 or more of E3 ligases present in the living body, and is mainly classified into four subclasses, HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. Currently, the E3 ligases used in the bifunctional degradation inducing agents called PROTAC, SNIPER and the like are limited, and typical examples thereof include Von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). In particular, VHL is reported in WO 2013 / 106643, and CRBN is reported in WO 2015 / 160845.

[0009] The bifunctional compound is a compound in which the ligand of the target protein is linked to the ligand of E3 ligase via a linker, and bifunctional compounds which degrade KRAS proteins are reported so far (Cell. Chem. Biol., 2020, 27, p. 19-31, ACS Cent. Sci., 2020, 6, p. 1367-1375, U.S. Patent Application 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, China Patent Application Nos. 113956233 and 115785199, and WO 2023 / 138524). Among PROTACs which degrade KRAS having G12D mutation, compounds are reported, in which the substituent at the 8-position of quinoline and quinazoline is linked to the ligand of E3 ligase (Patent Documents 1 and 2). In addition, pan-KRAS PROTAC is also reported (Patent Documents 3 to 9). CITATION LIST PATENT DOCUMENT

[0010] PATENT DOCUMENT 1: WO 2022 / 173032 PATENT DOCUMENT 2: WO 2023 / 171781 PATENT DOCUMENT 3: WO 2022 / 087335 PATENT DOCUMENT 4: WO 2022 / 212611 PATENT DOCUMENT 5: WO 2022 / 266249 PATENT DOCUMENT 6: WO 2022 / 271823 PATENT DOCUMENT 7: WO 2023 / 099620 PATENT DOCUMENT 8: WO 2023 / 130012 PATENT DOCUMENT 9: WO 2023 / 141570 SUMMARY OF INVENTION TECHNICAL PROBLEM

[0011] Provided is a heterocyclic compound which has excellent degradation-inducing action of mutated KRAS proteins, particularly, excellent degradation-inducing action of G12C mutated, G12D mutated, G12V mutated, and G13D mutated KRAS proteins and wildtype KRAS proteins, and / or excellent inhibitory action on mutated KRAS, particularly, excellent inhibitory action on G12C mutated, G12D mutated, G12V mutated, and G13D mutated KRASs and excellent inhibitory action on KRAS in the presence of amplification of a wild-type KRAS gene, and which is expected to be useful as an active ingredient of a pharmaceutical composition such as a pharmaceutical composition for treatment of cancer, particularly, mutated KRAS-positive cancer, particularly, G12C mutated, G12D mutated, G12V mutated, and G13D mutated KRAS-positive cancers and wild-type KRAS gene amplification-positive cancer. SOLUTION TO PROBLEM

[0012] The present inventors have conducted extensive research about a compound useful as an active ingredient of a pharmaceutical composition for treatment of cancer, and as a result have completed the present invention by finding that a heterocyclic compound represented by formula (I), particularly, a bifunctional compound represented by formula (I) wherein a substituent at a carbon atom adjacent to a carbon atom bonded to R1 of a heterocyclic compound represented by formula (I) (the adjacent carbon atom corresponds to the 8-position of quinazoline that is the compound wherein A is N and E is CH) is linked to the ligand of E3 ligase or a substituent at a carbon atom adjacent to a carbon atom bonded to R1 of a heterocyclic compound (the adjacent carbon atom corresponds to the 8-position of quinazoline that is the compound wherein A is N and E is CH) is linked to the ligand of E3 ligase via a linker has excellent degradation-inducing action of mutated KRAS proteins, excellent inhibitory activity on mutated KRAS, excellent degradation-inducing action of wild-type KRAS proteins, and excellent inhibitory activity on KRAS in the presence of amplification of a wild-type KRAS gene. In other words, the present invention relates to a compound represented by formula (I) or a salt thereof, and a pharmaceutical composition including a compound represented by formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients. [Chemical Formula 3] (I) (wherein A is CRA or N, RA is H, C1-3 alkyl, -CN, or -O-(C1-3 alkyl), E is CH or N, X1 is -CH2-, -O-, or -NRX1-, RX1 is H or optionally substituted C1-3 alkyl, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11membered saturated hetero ring group, R1 is represented by the following formula (II), (III), (IV), (V), (VI), or (VII): [Chemical Formula 4] (II)               (III)              (IV)                   (V)                 (VI)              (VII) R1a and R1b are the same or different, and are each H, methyl, F, or Cl, R1c is F, Cl, methyl, ethyl, trifluoromethyl, or cyclopropyl, R1d is H, methyl, ethyl, F, Cl, or -C^C-H, R2 is H, halogen, optionally substituted C1-3 alkyl, cyclopropyl, or vinyl, R3 is a group selected from the group consisting of the following formulas (VIII), (XI), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII): [Chemical Formula 5] R3a n-r i3b (VIII) X' ^3g R y (IX) R3j .2^(7)n1 R' (X) h2n X (XI) N . (XIII) N X (XIV) X (XV) (XVI) (XVII) R3a is -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2, R3e is H, F, or C1-3 alkyl, R3f is the same or different, and is H or C1-3 alkyl, R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6membered saturated hetero ring group, R3h is H, F, or C1-3 alkyl, R3i is the same or different, and is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, or two R3is present on the same carbon atom together with the carbon atom adjacent thereto may form a spiro ring having a ring selected from the group consisting of C3-6 cycloalkane and 4- to 6-membered saturated hetero ring, wherein the spiro ring is optionally substituted with 1 to 2 groups selected from the group of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, or R3i present on two adjacent carbon atoms together with the two carbon atoms may form a fused ring having a ring selected from the group consisting of C3-6 cycloalkane and 4-to 6-membered saturated hetero ring, wherein the fused ring is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, or R3i present on two non-adjacent carbon atoms together with the two carbon atoms may form bridged structure composed of 1 to 2 carbon atoms, and ring having the bridged structure is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, RN1 and RN2 are the same or different, and are each H or C1-3 alkyl, or RN1 and RN2 together with the nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, or R3e and RN1 together with the carbon atom and the nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN, X2 is -O-, -NH-, or -N(C1-3 alkyl)-, X3 is O or S, X4 is -CH2-, -CH2-CH2-, -O-CH2-, -O-, or -O-NH-, n1 is 1 or 2, p is 1 or 2, q is 1 to 8, R4 is optionally substituted C1-6 alkyl, optionally substituted piperidinyl, or optionally substituted tetrahydropyranyl, Y is phenylene or pyridinediyl, wherein the phenylene is optionally substituted with F, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 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): [Chemical Formula 6] R 2 (XVIII) (XIX) (XX) (XXI)                    (XXII)                 (XXIII) (XXIV)               (XXV)              (XXVI)           (XXVII) (XXVIII) (XXIX) ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), r is 1 or 2, and G is N or CH, provided that when G is N, Z is the above formula (XVIII), (XXII), (XXIII), (XXIV), (XXVI), (XXVII), or (XXIX))

[0013] Further, the compound having degradation-inducing action of target proteins, particularly, mutated KRAS proteins, inhibitory activity on mutated KRAS, and / or degradation-inducing action of wild-type KRAS proteins, and inhibitory activity on KRAS in the presence of amplification of a wild-type KRAS gene, may be, for example, formula (II) below. The compound having degradation-inducing action of target proteins, particularly, mutated RAS proteins, inhibitory activity on mutated RAS, and / or degradation-inducing action of wild-type RAS proteins, and inhibitory activity on RAS in the presence of amplification of a wild-type RAS gene, may also be, for example, formula (I-I) below. In other words, the present invention relates to a compound represented by formula (I-I) or a salt thereof, and a pharmaceutical composition comprising the compound represented by formula (I-I) or a salt thereof, and one or more pharmaceutically acceptable excipients. [Chemical Formula 7] _ / 0 G NH TPB-L-Z- (I-I) (wherein TPB is a group having an ability to bind to a target protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 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): [Chemical Formula 8] (RZ1 (RZ1 (XX) (XXI) (XIX) (XXIII) (XXIV)              (XXV) (XXVI)            (XXVII) (XXVIII) (XXIX) ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), r is 1 or 2, and G is N or CH, provided that when G is N, Z is the above formula (XVIII), (XXII), (XXIII), (XXIV), (XXVI), (XXVII), or (XXIX))

[0014] When symbols in chemical formulas in this specification are also used in other chemical formulas, the same symbols indicate the same meanings unless otherwise specified.

[0015] The present invention also relates to a pharmaceutical composition including a compound represented by formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, it relates to a pharmaceutical composition for treatment of cancer. In one embodiment, it relates to a pharmaceutical composition for treatment of mutated KRAS-positive cancer, particularly a pharmaceutical composition for treatment of mutated 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, it relates to a pharmaceutical composition for treatment of metastatic cancer. In one embodiment, it relates to a pharmaceutical composition for treatment of locally advanced cancer. In one embodiment, it relates to a pharmaceutical composition for treatment of recurrent or refractory cancer. In one embodiment, it relates to a pharmaceutical composition for treatment of cancer in a patient untreated and / or having a treatment history. In one embodiment, it relates to a pharmaceutical composition for treatment of metastatic mutated KRAS-positive cancer, particularly a pharmaceutical composition for treatment of metastatic mutated 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, it relates to a pharmaceutical composition for treatment of locally advanced mutated KRAS-positive cancer, particularly a pharmaceutical composition for treatment of locally advanced mutated 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, it relates to a pharmaceutical composition for treatment of recurrent or refractory mutated KRAS-positive cancer, particularly a pharmaceutical composition for treatment of recurrent or refractory mutated 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, it relates to a pharmaceutical composition for treatment of mutated KRAS-positive cancer in a patient untreated and / or having a treatment history, particularly a pharmaceutical composition for treatment of mutated KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation in a patient untreated and / or having a treatment history. The pharmaceutical composition for treatment of cancer including a compound represented by formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients encompasses a treatment agent for cancer, and in one embodiment, the treatment agent for mutated 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 including a compound represented by formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients. In one embodiment, it relates to a pharmaceutical composition for treating cancer. In one embodiment, it relates to a pharmaceutical composition for treating metastatic wild-type KRAS gene amplification-positive cancer. In one embodiment, it relates to a pharmaceutical composition for treating locally advanced wild-type KRAS gene amplification-positive cancer. In one embodiment, it relates to a pharmaceutical composition for treating recurrent or refractory wild-type KRAS gene amplification-positive cancer. In one embodiment, it relates to a pharmaceutical composition for treating wild-type KRAS gene amplification-positive cancer in a patient untreated and / or having a treatment history. The pharmaceutical composition for treating cancer including a compound represented by formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients encompasses a treatment agent for cancer, and in one embodiment, wild-type KRAS gene amplification-positive cancer, the treatment agent containing a compound represented by formula (I) or a salt thereof.

[0017] The present invention also relates to use of a compound represented by formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating cancer, in one embodiment, mutated KRAS-positive cancer, particularly mutated 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 untreated and / or having a treatment history, in one embodiment, metastatic mutated KRAS-positive cancer, particularly mutated 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, locally advanced mutated KRAS-positive cancer, particularly mutated 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, recurrent or refractory mutated KRASpositive cancer, particularly mutated 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, mutated KRAS-positive cancer in a patient untreated and / or having a treatment history, particularly mutated 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 use of a compound represented by formula (I) or a salt thereof for treating cancer, in one embodiment, mutated KRAS-positive cancer, particularly mutated 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 represented by formula (I) or a salt thereof for use in treatment of cancer, in one embodiment, mutated KRAS-positive cancer, particularly mutated 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, in one embodiment, mutated KRAS-positive cancer, particularly mutated KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, the method including administrating an effective amount of a compound represented by formula (I) or a salt thereof to a subject.

[0018] The present invention relates to use of a compound represented by formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating 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, recurrent or refractory wild-type KRAS gene amplification-positive cancer, in one embodiment, wildtype KRAS gene amplification-positive cancer in a patient untreated and / or having a treatment history. The present invention also relates to use of a compound represented by formula (I) or a salt thereof for treating cancer, in one embodiment, wild-type KRAS gene amplification-positive cancer. The present invention also relates to a compound represented by formula (I) or a salt thereof for use in treatment of cancer, in one embodiment, wild-type KRAS gene amplification-positive cancer, and a method for treating cancer, in one embodiment, wild-type KRAS gene amplification-positive cancer, the method including administrating an effective of a compound represented by formula (I) or a salt thereof.

[0019] The present invention also relates to a compound represented by formula (I) or a salt thereof which is a mutated KRAS protein degradation inducing agent and / or a mutated KRAS inhibitor, particularly, a compound represented by formula (I) or a salt thereof which is a mutated KRAS protein degradation inducing agent having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation and / or a mutated KRAS inhibitor having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation.

[0020] The present invention also relates to a compound represented by formula (I) or a salt thereof which is a wild-type KRAS protein degradation inducing agent and / or an inhibitor of KRAS in the presence of amplification of a wild-type KRAS gene.

[0021] The "subject" indicates a person or other animals in need of the treatment, and in one embodiment, indicates a person in need of prevention or treatment. ADVANTAGEOUS EFFECTS OF INVENTION

[0022] The compound represented by formula (I) or a salt thereof has degradation-inducing action of mutated KRAS protein, inhibitory activity on mutated KRAS, particularly, inhibitory activity on mutated KRAS having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation, and inhibitory activity on mutated 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 treatment agent for cancer, particularly, mutated KRAS-positive cancer having one or more mutations selected from the group consisting of G12C mutation, G12D mutation, G12V mutation, and G13D mutation. The compound represented by formula (I) or a salt thereof has degradation-inducing action of wild-type KRAS proteins and inhibitory activity on KRAS in the presence of amplification of a wild-type KRAS gene, and can also be used as a treatment agent for cancer, particularly, wild-type KRAS gene amplification-positive cancer. DESCRIPTION OF EMBODIMENTS

[0023] Hereinafter, the present invention will be described in detail.

[0024] In this specification, "optionally substituted" indicates that the group is not substituted, or has 1 to 5 substituents. In one embodiment, it indicates that the group is not substituted, or has 1 to 3 substituents. When a plurality of substituents is present, these substituents may be the same or different.

[0025] "C1-12 alkyl" is a linear 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, or dodecyl (hereinafter, the number of carbon atoms is expressed as above). In one embodiment, it is ethyl or dodecyl. Likewise, "C1-6 alkyl" is a linear 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, it is methyl, ethyl, n-propyl, isopropyl, or secbutyl. In one embodiment, it is methyl, ethyl, isopropyl, or tert-butyl. In one embodiment, it is methyl, ethyl, n-propyl, isopropyl, n-butyl, or dimethylpropyl. In one embodiment, it is methyl. In one embodiment, it is ethyl. In one embodiment, it is dimethylpropyl. Likewise, "C1-3 alkyl" is a linear or branched alkyl having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl. In one embodiment, it is methyl or ethyl. In one embodiment, it is n-propyl or isopropyl. In one embodiment, it is methyl or isopropyl. In one embodiment, it is ethyl or isopropyl. In one embodiment, it is methyl. In one embodiment, it is ethyl. In one embodiment, it is isopropyl. In one embodiment, it is n-propyl. Likewise, "C2-3 alkyl" is a linear alkyl having 2 to 3 carbon atoms, such as ethyl or n-propyl. In one embodiment, it is ethyl. In one embodiment, it is n-propyl.

[0026] "C3-6 cycloalkane" is a cycloalkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane.

[0027] "C3-6 cycloalkyl" is a cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, it is a cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, it is cyclobutyl or cyclopentyl. In one embodiment, it is cyclopentyl or cyclohexyl. In one embodiment, it is cyclopropyl or cyclobutyl. In one embodiment, it is cyclopropyl. In one embodiment, it is cyclobutyl. In one embodiment, it is cyclopentyl. In one embodiment, it is cyclohexyl.

[0028] "C1-3 alkylene" is a divalent group formed by removing a hydrogen atom from a C1-3 alkyl, and is a linear or branched C1-3 alkylene, such as methylene, ethylene, trimethylene, methylmethylene, or 1,1-dimethylmethylene. In one embodiment, it is a linear or branched C1-3 alkylene. 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. In one embodiment, it is trimethylene. Likewise, "C2-3 alkylene" is a divalent group formed by removing a hydrogen atom from C2-3 alkyl, and in one embodiment, is ethylene or trimethylene. In one embodiment, it is ethylene. In one embodiment, it is trimethylene.

[0029] "C3-6 cycloalkylene" is a divalent group formed by removing a hydrogen atom from C3-6 cycloalkyl, such as cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, or cyclohexanediyl. In one embodiment, it is cyclopropanediyl. In one embodiment, it is cyclobutanediyl. In one embodiment, it is cyclopentanediyl. In one embodiment, it is cyclohexanediyl.

[0030] "C2-3 alkynediyl" is a divalent group having a triple bond in which four hydrogen atoms are removed from C2-3 alkylene. In one embodiment, it is -C=C-. In one embodiment, it is -CH2-C-C-.

[0031] "Saturated hetero ring" is a saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring forming atom. Here, part of the saturated hetero ring may have an unsaturated bond. The sulfur atom as a ring forming atom of the saturated hetero ring may be oxidized. Furthermore, the saturated hetero ring may have a bridged structure, and further, the saturated hetero ring may have a spiro structure. Accordingly, the "4- to 6-membered saturated hetero ring" is a 4- to 6membered saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom, and may have a bridged structure, and may have a spiro structure. Likewise, the "4- to 11-membered saturated hetero ring" is a 4- to 11-membered saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom, and may have a bridged structure, and may have a spiro structure. One aspect of the "4- to 6membered saturated hetero ring" is a 4- to 6-membered saturated hetero ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine, or tetrahydropyridine.

[0032] The "saturated hetero ring group" is a saturated hydrocarbon ring group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. Here, part of the ring of the saturated hetero ring group may have an unsaturated bond. The sulfur atom as the ring forming atom of the saturated hetero ring group may be oxidized. Furthermore, the saturated hetero ring group may have a bridged structure, and further, the saturated hetero ring group may have a spiro structure. Accordingly, the "4- to 6-membered saturated hetero ring group" is a 4- to 6membered saturated hetero ring group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom, and may have a bridged structure, and may have a spiro structure. One embodiment of the "4- to 6-membered saturated hetero ring group" is a 4- to 6-membered saturated hetero ring group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. One embodiment of the 4- to 6-membered saturated hetero ring group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom is a 4- to 6-membered saturated hetero ring group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a 5- to 6-membered saturated hetero ring group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a 4-membered saturated hetero ring group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a 5-membered saturated hetero ring group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a 6membered saturated hetero ring group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is oxetanyl, 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, or tetrahydropyranyl. In one embodiment, it is piperazinyl. Likewise, the "4- to 11-membered saturated hetero ring group" is a 4- to 11membered saturated hetero ring group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom, and may have a bridged structure, and may have a spiro structure. One embodiment of the "4- to 11-membered saturated hetero ring group" is a 4- to 11-membered saturated hetero ring group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a 4- to 11-membered saturated hetero ring group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a 4- to 11-membered saturated hetero ring group containing 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is 4- to 11-membered saturated hetero ring group containing 1 to 2 nitrogen atoms as the ring forming atom. In one embodiment, it is 4- to 11-membered saturated hetero ring group containing one nitrogen atom as the ring forming atom. In one embodiment, it is 4- to 11-membered saturated hetero ring group containing 2 nitrogen atoms as the ring forming atom. In one embodiment, it is 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, 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. In one embodiment, it is 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 group of saturated hetero ring" is a divalent group of a 4- to 11membered saturated hetero ring group containing 1 to 2 nitrogen atoms as the ring forming atom, and may further contain 1 to 2 oxygen atoms, may be a divalent group of a saturated hetero ring having spiro ring and fused ring, or may have an unsaturated bond in part of the saturated hetero ring. One embodiment of the "divalent group of a saturated hetero ring" is a divalent group of a 4- to 11-membered saturated hetero ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is a divalent group of a 4- to 11-membered saturated hetero ring containing 1 to 2 heteroatoms selected from the group consisting of oxygen and nitrogen as the ring forming atom. In one embodiment, it is a divalent group of a 4- to 11-membered saturated hetero ring containing 1 to 2 nitrogen atoms as the ring forming atom. One embodiment of the "divalent group of saturated hetero ring containing 1 to 2 nitrogen atoms" is azetidinediyl, pyrrolidinediyl, imidazolidinediyl, piperidinediyl, piperazinediyl, azepanediyl, diazepanediyl, azocanediyl, diazocanediyl, azonanediyl, diazonanediyl, tetrahydropyridinediyl, or divalent group represented by formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII) below: [Chemical Formula 9] (XLIV) (XLVI I) (XLVIII) One embodiment of the "divalent group of saturated hetero ring" is pyrrolidinediyl, piperazinediyl, tetrahydropyridinediyl, or divalent group represented by formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII) above. In one embodiment, it is tetrahydropyridinediyl or a divalent group represented by formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII) above. In one embodiment, it is a divalent group represented by formula (XLIV), (XLV), (XLVI), (XLVII), or (XLVIII) above. In one embodiment, it is divalent group represented by formula (XLV) above. In one embodiment, it is divalent group represented by the following formula (XLIV), (XLV-1), (XLV-2), (XLVI), or (XLVII): [Chemical Formula 10] (XLIV)           (XLV)         (XLV-1)          (XLV-2)          (XLVI)          (XLVI I)

[0034] The "hetero ring" is an aromatic hydrocarbon ring containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. Accordingly, the "6-membered hetero ring" is 6-membered aromatic hydrocarbon ring containing nitrogen atom as the ring forming atom. In one embodiment, it is pyridine ring, a pyridazine ring, a pyrimidine ring, pyrazine ring, or triazine ring. In one embodiment, it is pyridine ring. The "5- or 6-membered hetero ring" is a 5- or 6-membered aromatic hydrocarbon ring containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. In one embodiment, it is pyrazole ring, triazole ring, imidazole ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, oxadiazole ring, thiadiazole ring, tetrazole ring, pyridine ring, pyridazin ring, pyrimidine ring, pyrazine ring, or triazine ring. In one embodiment, it is pyrazole ring, triazole ring, pyridine ring, or pyridazine ring. In one embodiment, it is pyridine ring. In one embodiment, it is pyridazine ring.

[0035] The "heteroaryl" is a hetero ring group containing heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom. Accordingly, the "5-membered heteroaryl" is 5-membered hetero ring group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as the ring forming atom.

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

[0037] The "6-membered heteroaryl" is a 6-membered hetero ring group containing 1 to 3 nitrogen atoms as the ring forming atom. One aspect of the "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In one embodiment, it is pyridyl or pyridazinyl. In one embodiment, it is pyridyl or pyrimidinyl. In one embodiment, it is pyridyl. In one embodiment, it is pyrimidinyl.

[0038] The "halogen" indicate F, Cl, Br, and I. In one embodiment, it is F, Cl, or Br. In one embodiment, it is F or Cl. In one embodiment, it is F or Br. In one embodiment, it is F. In one embodiment, it is Cl. In one embodiment, it is Br.

[0039] The "spiro ring" indicates polycyclic ring structure in which two ring structures are bonded with one shared spiro atom as a quaternary carbon, and the "fused ring" indicates a polycyclic ring structure in which two or more ring structures are bonded with two or more adjacent atoms comprising one of the rings being shared. The "bridged structure" is divalent chain structure linked to two non-adjacent atoms among the ring forming atoms in one ring.

[0040] One embodiment of acceptable substituents in "optionally substituted C1-6 alkyl ", "optionally substituted C1-3 alkyl ", and "optionally substituted C1-3 alkylene " is F, OH, OCH3, N(C1-3 alkyl optionally substituted with F)2, optionally substituted C3-6 cycloalkyl, azabicyclo[3.3.0]octanyl, or optionally substituted 4- to 6-membered saturated hetero ring group. In one embodiment, it is F, OH, OCH3, cyclopropyl, N(C1-3 alkyl optionally substituted with F)2, pyrrolidinyl optionally substituted with (C1-3 alkyl optionally substituted with F), and tetrahydrofuranyl. In one embodiment, it is 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. In one embodiment, it is 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. In one embodiment, it is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, (dimethylaminomethyl)cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyranyl, pyrrolidinyl, morpholinyl, fluoropyrrolidinyl, or methylpyrrolidinyl. In one embodiment, it is F, OH, OCH3, (methoxymethyl)cyclopropyl, (dimethylaminomethyl)cyclobutyl, tetrahydrofuranyl, morpholinyl, fluoropyrrolidinyl, or methylpyrrolidinyl. In one embodiment, it is F, OH, or cyclopropyl. In one embodiment, it is OH, OCH3, N(CH3)2, methylpyrrolidine, pyrrolidine optionally substituted with F, or morpholine. In one embodiment, it is N(CH3)2. In one embodiment, it is F, OH, or OCH3. In one embodiment, it is OH or OCH3. In one embodiment, it is F or OCH3. In one embodiment, it is OH. In one embodiment, it is F. In one embodiment, it is OCH3. In one embodiment, it is OH, OCH3, N(CH3)2, methylpyrrolidinyl, morpholinyl, fluoropyrrolidinyl, (hydroxymethyl)cyclopropyl, or (dimethylaminomethyl)cyclobutyl.

[0041] One embodiment of acceptable substituents in the "optionally substituted 5membered heteroaryl", "optionally substituted 6-membered heteroaryl", "optionally substituted 5- or 6-membered hetero ring", "optionally substituted benzene", and "optionally substituted oxazolyl" is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, -SO2CH3, halogen, OH, OCH3, or C3-6 cycloalkyl. In one embodiment, it is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3. In one embodiment, it is C1-3 alkyl optionally substituted with OH. In one embodiment, it is C1-3 alkyl optionally substituted with OCH3. In one embodiment, it is C1-3 alkyl or halogen. In one embodiment, it is methyl, ethyl, methoxymethyl, or F. In one embodiment, it is methyl, ethyl, F, or Cl. In one embodiment, it is methyl, ethyl, or F.

[0042] One embodiment of acceptable substituents in the "optionally substituted 4- to 6membered saturated hetero ring group", "optionally substituted 4- to 11-membered saturated hetero ring group", "optionally substituted pyrrolidinyl", "optionally substituted piperidinyl", "optionally substituted tetrahydropyranyl", "optionally substituted C3-6 cycloalkyl", "optionally substituted C3-6 cycloalkylene", and "divalent group of optionally substituted saturated hetero ring" is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, 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. In one embodiment, it is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, and OCH3, F, oxo, or oxetanyl. In one embodiment, it is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2, or oxo. In one embodiment, it is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, and N(CH3)2. In one embodiment, it is C1-3 alkyl optionally substituted with F. In one embodiment, it is C1-3 alkyl optionally substituted with OH. In one embodiment, it is C1-3 alkyl optionally substituted with OCH3. In one embodiment, it is C1-3 alkyl optionally substituted with N(CH3)2. In one embodiment, it is C1-3 alkyl. In one embodiment, it is C1-3 alkyl optionally substituted with N(CH3)2, or oxo. In one embodiment, it is C1-3 alkyl optionally substituted with N(CH3)2, or F. In one embodiment, it is C1-3 alkyl optionally substituted with OCH3, dimethylaminomethyl, or F.

[0043] One embodiment of "C1-3 alkyl optionally substituted with OH" is methyl optionally substituted with one OH group, or ethyl optionally substituted with 1 to 2 OH groups. Examples thereof include methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1,2-dihydroxyethyl. In one embodiment, it is methyl, ethyl, or hydroxymethyl. In one embodiment, it is methyl or hydroxymethyl. In one embodiment, it is hydroxymethyl or hydroxyethyl. In one embodiment, it is hydroxymethyl. In one embodiment, it is hydroxyethyl.

[0044] One aspect of the "C1-6 alkyl optionally substituted with OCH3" and "C1-3 alkyl optionally substituted with OCH3" is methyl optionally substituted with one OCH3 group or ethyl optionally substituted with 1 to 2 OCH3 groups. Examples thereof include methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 1,2-dimethoxyethyl. In one embodiment, it is methoxymethyl or methoxyethyl. In one embodiment, it is methoxymethyl. In one embodiment, it is methoxyethyl.

[0045] One aspect of "C1-6 alkyl optionally substituted with N(C1-3 alkyl)2" is "C1-3 alkyl optionally substituted with N(CH3)2". In one embodiment, it is methyl optionally substituted with one N(C1-3 alkyl)2, ethyl optionally substituted with one N(C1-3 alkyl)2, or n-propyl optionally substituted with one N(C1-3 alkyl)2. In one embodiment, it is methyl optionally substituted with one N(C1-3 alkyl)2, or ethyl optionally substituted with one N(C1-3 alkyl)2. One embodiment of "C1-3 alkyl optionally substituted with N(CH3)2" 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. In one embodiment, it is dimethylaminoethyl.

[0046] One embodiment of "phenylene optionally substituted with F" is phenylene optionally substituted with 1 to 2 F atoms. In one embodiment, it is phenylene optionally substituted with one F atom. In one embodiment, it is phenylene or fluorophenylene. In one embodiment, it is phenylene. In one embodiment, it is 2-fluoro-1,4-phenylene. In one embodiment, it is 3-fluoro-1,4-phenylene.

[0047] The "attachment point" indicates a site which forms covalent bond with a specific atom or a substituent. Accordingly, "attachment point to L" indicates that the site having the "attachment point to L" and L form covalent bond.

[0048] The "mutated KRAS" is KRAS having mutation, and indicates G12C mutated KRAS, G12D mutated KRAS, G12V mutated KRAS, and / or G13D mutated KRAS, for example.

[0049] "G12C mutation" indicates a mutation in a wild-type protein in which the amino acid residue corresponding to codon 12 is converted from glycine to cysteine.

[0050] "G12C mutated KRAS" indicates KRAS having the "G12C mutation" above.

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

[0052] "G12D mutated KRAS" indicates KRAS having the "G12D mutation" above.

[0053] "G12V mutation" indicates a mutation in a wild-type protein in which the amino acid residue corresponding to codon 12 is converted from glycine to valine.

[0054] "G12V mutated KRAS" indicates KRAS having the "G12V mutation" above.

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

[0056] "G13D mutated KRAS" indicates KRAS having the "G13D mutation" above.

[0057] The "cancer" indicates a malignant tumor. In one embodiment, it is pancreatic cancer, lung cancer, colon cancer, skin cancer, uterus cancer, thyroid cancer, bladder cancer, gastric cancer, epithelia cancer, esophagus cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, kidney cancer, myeloma, lymphoma, or leukemia. In one embodiment, it is pancreatic cancer, lung cancer, colon cancer, or gastric cancer. In one embodiment, it is pancreatic cancer, lung cancer, or colon cancer. In one embodiment, it is also pancreatic cancer, lung cancer, colon cancer, skin cancer such as melanoma, cervical cancer, uterus cancer such as endometrial cancer, thyroid cancer, bladder cancer, gastric cancer, epithelia cancer, esophagus cancer, liver cancer, breast cancer, ovarian cancer, prostate cancer, renal cell carcinoma or kidney cancer, myelodysplastic syndrome, myeloma such as 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 intestinal cancer, germ cell tumor, neuroendocrine carcinoma, gallbladder cancer, peritoneal cancer, or fallopian tube cancer. In one embodiment, it is also germ cell tumor, esophagogastric junction cancer, ovarian cancer, and pancreatic cancer. In one embodiment, it is also solid cancer and hematological cancer. In one embodiment, it is solid cancer. In one embodiment, it is hematological cancer.

[0058] The "mutated KRAS-positive cancer" is mutated KRAS-positive cancer, particularly G12C mutated, G12D mutated, G12V mutated, and / or G13D mutated KRAS-positive cancer. For example, it is a cancer wherein KRAS G12C mutation, G12D mutation, G12V, mutation, and / or G13D mutation occur, and is a cancer showing high positive rates of G12C mutation, G12D mutation, G12V mutation, and / or G13DKRAS.

[0059] One embodiment of the "mutated KRAS-positive cancer" is: G12C mutated, G12D mutated, and G12V mutated KRAS-positive cancer, G12C mutated, G12D mutated, and G13D mutated KRAS-positive cancer, G12C mutated, G12V mutated, and G13D mutated KRAS-positive cancer, and G12D mutated, G12V mutated, and G13D mutated KRAS-positive cancer.

[0060] One embodiment of the "mutated KRAS-positive cancer" is: G12C mutated and G12D mutated KRAS-positive cancer, G12C mutated and G12V mutated KRAS-positive cancer, G12D mutated and G12V mutated KRAS-positive cancer, G12C mutated and G13D mutated KRAS-positive cancer, G12D mutated and G13D mutated KRAS-positive cancer, and G12V mutated and G13D mutated KRAS-positive cancer.

[0061] One embodiment of the "mutated KRAS-positive cancer" is: G12C mutated KRAS-positive cancer, G12D mutated KRAS-positive cancer, G12V mutated KRAS-positive cancer, and G13D mutated KRAS-positive cancer.

[0062] The "G12C mutated KRAS-positive cancer" is G12C mutated KRAS-positive cancer. For example, it is a cancer wherein KRAS G12C mutation occurs, and is a cancer showing a high positive rate of G12C mutated KRAS. In one embodiment, it is pancreatic cancer, lung cancer, or colon cancer showing a high positive rate of G12C mutated KRAS.

[0063] The "G12D mutated KRAS-positive cancer" is G12D mutated KRAS-positive cancer. For example, it is a cancer wherein KRAS G12D mutation occurs, and is a cancer showing a high positive rate of G12D mutated KRAS. In one embodiment, it is pancreatic cancer, lung cancer, or colon cancer showing a high positive rate of G12D mutated KRAS.

[0064] The "G12V mutated KRAS-positive cancer" is G12V mutated KRAS-positive cancer. For example, it is a cancer wherein KRAS G12V mutation occurs, and is a cancer showing a high positive rate of G12V mutated KRAS. In one embodiment, it is pancreatic cancer, lung cancer, or colon cancer showing a high positive rate of G12V mutated KRAS.

[0065] The "G13D mutated KRAS-positive cancer" is G13D mutated KRAS-positive cancer. For example, it is a cancer wherein KRAS G13D mutation occurs, and is a cancer showing a high positive rate of G13D mutated KRAS. In one embodiment, it is pancreatic cancer, lung cancer, or colon cancer showing a high positive rate of G13D mutated KRAS.

[0066] The "wild-type KRAS gene amplification" indicates that the KRAS gene is amplified to a high level due to copy number alterations of the wild-type KRAS gene.

[0067] The "wild-type KRAS gene amplification-positive cancer" is a cancer having the "wild-type KRAS gene amplification" above. In one embodiment, it is germ cell tumor, esophagogastric junction cancer, ovarian cancer, and pancreatic cancer having the wild-type KRAS gene amplification.

[0068] The "pancreatic cancer" is a malignant tumor formed in a pancreas. For example, it is pancreatic ductal cancer and pancreatic ductal adenocarcinoma. In one embodiment, it is pancreatic ductal cancer. In one embodiment, it is pancreatic ductal adenocarcinoma. Furthermore, in one embodiment, it is metastatic pancreatic cancer. In one embodiment, it is locally advanced pancreatic cancer. In one embodiment, it is recurrent or refractory pancreatic cancer. In one embodiment, it is pancreatic cancer in a patient untread and / or having a treatment history.

[0069] The "lung cancer" is a malignant tumor formed in a lung. For example, it is small cell lung cancer and non-small cell lung cancer. In one embodiment, it is small cell lung cancer. In one 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. In one embodiment, it is lung cancer in a patient untread and / or having a treatment history. In one embodiment, it is non-squamous non-small cell lung cancer. As another aspect, it is squamous non-small cell lung cancer.

[0070] The "colon cancer" is a malignant tumor formed in a colon. For example, it is colonic cancer and rectal cancer. In one embodiment, it is colonic cancer. In one embodiment, it is rectal cancer. Furthermore, in one embodiment, it is metastatic colon cancer. In one embodiment, it is locally advanced colon cancer. In one embodiment, it is recurrent or refractory colon cancer. In one embodiment, it is colon cancer in a patient untread and / or having a treatment history.

[0071] The "gastric cancer" is a malignant tumor formed in a stomach. In one embodiment, it is metastatic gastric cancer. In one embodiment, it is locally advanced gastric cancer. In one embodiment, it is recurrent or refractory gastric cancer. In one embodiment, it is gastric cancer in a patient untread and / or having a treatment history.

[0072] The "esophagogastric junction cancer" is a malignant tumor formed in a junction of an esophagus and a stomach. In one embodiment, it is metastatic esophagogastric junction cancer. In one embodiment, it is locally advanced esophagogastric junction cancer. In one embodiment, it is recurrent or refractory esophagogastric junction cancer. In one embodiment, it is esophagogastric junction cancer in a patient untread and / or having a treatment history.

[0073] The "ovarian cancer" is a malignant tumor formed in an ovary. In one embodiment, it is metastatic ovarian cancer. In one embodiment, it is locally advanced ovarian cancer. In one embodiment, it is recurrent or refractory ovarian cancer. In one embodiment, it is ovarian cancer in a patient untread and / or having a treatment history.

[0074] The "germ cell tumor" is a tumor into which germ cells have been transformed for some reason. In one embodiment, it is a metastatic germ cell tumor. In one embodiment, it is a locally advanced germ cell tumor. In one embodiment, it is a recurrent or refractory germ cell tumor. In one embodiment, it is a germ cell tumor in a patient untread and / or having a treatment history.

[0075] The "solid cancer" is a cancer other than hematological cancer. In one embodiment, it is, pancreatic cancer, lung cancer, colon cancer, skin cancer such as melanoma, uterus cancer such as endometrial cancer, thyroid cancer, bladder cancer, gastric cancer, epithelia cancer, esophagus 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 intestinal cancer, germ cell tumor, neuroendocrine carcinoma, gallbladder cancer, peritoneal cancer, or fallopian tube cancer.

[0076] The "hematological cancer" is a disease in which blood cells become cancerous and abnormally proliferate. In one embodiment, it includes leukemia such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia, malignant lymphoma such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and mature B-cell lymphoma, multiple myeloma, myelodysplastic syndrome, polycythemia vera, essential thrombocythemia, primary myelofibrosis and the like.

[0077] The "ability to bind to a RAS protein" indicates that the compound can bond to the RAS protein. In one embodiment, it indicates that the compound can bond to the KRAS protein, HRAS protein, and / or NRAS protein contained in the RAS family. In one embodiment, it indicates that the compound shows inhibitory activity on the KRAS protein, HRAS protein, and / or NRAS protein contained in the RAS family. The RAS protein shown here includes mutated RAS proteins, such as G12C, G12D, G12V, and G13D mutated KRAS proteins. The ability to bind to a RAS protein can be evaluated by the methods described in Patent Document 1 and Patent Document 2 above or by a similar method thereof.

[0078] One embodiment of the "group having an ability to bind to a RAS protein" is a group having an ability to bind to the KRAS protein, HRAS protein, and / or NRAS protein contained in the RAS family. In one embodiment, it indicates that the group is a group formed by replacing any hydrogen atom on the compound having inhibitory activity on the KRAS protein, HRAS protein, and / or NRAS protein contained in the RAS family by an attachment point.

[0079] One embodiment of the "group having an ability to bind to a RAS protein" is a group formed by replacing any hydrogen atom on the compound having inhibitory activity on the KRAS protein by an attachment point, such as a group formed by replacing any hydrogen atom on the compound having inhibitory activity on the KRAS protein described in the following literatures by an attachment point: WO 2022 / 132200, WO 2022 / 133038, WO 2022 / 047260, WO 2022 / 173870, WO 2022 / 061251, WO 2022 / 250170, WO 2023 / 001123, WO 2023 / 287896, WO 2023 / 287896, WO 2023 / 099623, WO 2023 / 099608, WO 2023 / 099592, WO 2023 / 099624, WO 2023 / 137223, WO 2023 / 138589, WO 2023 / 154766, WO 2023 / 114733, WO 2023 / 172737, WO 2023 / 183585, WO 2023 / 244599, WO 2023 / 244604, WO 2023 / 232776, WO 2023 / 244615, WO 2024 / 041621, WO 2024 / 041589, WO 2024 / 044667, WO 2024 / 086061, WO 2024 / 104425, WO 2023 / 230190, WO 2016 / 049568, WO 2017 / 172979, WO 2018143315, and WO 2022173033.

[0080] One embodiment of the "group having an ability to bind to a RAS protein" is a group serving as the ligand of the target protein in bifunctional compounds such as PROTACs which degrade KRAS proteins, such as a group serving as the ligand of the target protein in bifunctional compounds such as PROTACs which degrade KRAS proteins described in the following literatures: Cell. Chem. Biol., 2020, 27, p. 19-31, ACS Cent. Sci., 2020, 6, p. 1367-1375, U.S. Patent Application 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, China Patent Application Nos. 113956233 and 115785199, WO 2023 / 138524, WO 2022 / 173032, WO 2023 / 171781, WO 2022 / 087335, WO 2022 / 212611, WO 2022 / 266249, WO 2022 / 271823, WO 2023 / 099620, WO 2023 / 130012, WO 2023 / 141570, WO 2024019103, WO 2024034591, WO 2024029613, and WO 2024034593.

[0081] One embodiment of the compound represented by formula (I) or a salt thereof according to the present invention is shown below.

[0082] (1-1) A compound represented by formula (I) or a salt thereof, wherein A is CRA or N, and RA is H, C1-3 alkyl, -CN, or -O-(C1-3 alkyl). (1-2) A compound represented by formula (I) or a salt thereof, wherein A is CRA or N, and RA is H or C1-3 alkyl. (1-3) A compound represented by formula (I) or a salt thereof, wherein A is CRA or N, and RA is H. (1-4) A compound represented by formula (I) or a salt thereof, wherein A is CRA or N, and RA is C1-3 alkyl. (1-5) A compound represented by formula (I) or a salt thereof, wherein A is N. (1-6) A compound represented by formula (I) or a salt thereof, wherein A is CRA, and RA is H, C1-3 alkyl, -CN, or -O-(C1-3 alkyl). (1-7) A compound represented by formula (I) or a salt thereof, wherein A is CRA, and RA is H.

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

[0084] (2-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -CH2-, -O-, or -NRX1-, RX1 is H or optionally substituted C1-3 alkyl, and provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11membered saturated hetero ring group. (2-1-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -CH2-, -O-, or -NRX1-, RX1 is H or optionally substituted C1-3 alkyl, and provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 6membered saturated hetero ring group. (2-2) A compound represented by formula (I) or a salt thereof, wherein X1 is -O- or - NRX1-, RX1 is H or C1-3 alkyl, and provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11membered saturated hetero ring group. (2-2-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -O- or - NRX1-, RX1 is H or C1-3 alkyl, and provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 6membered saturated hetero ring group. (2-3) A compound represented by formula (I) or a salt thereof, wherein X1 is -O- or - NRX1-, and provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11- membered saturated hetero ring group. (2-3-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -O- or -NRX1-, and provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 6membered saturated hetero ring group. (2-4) A compound represented by formula (I) or a salt thereof, wherein X1 is -O- or -NRX1-, and RX1 is H or C1-3 alkyl. (2-5) A compound represented by formula (I) or a salt thereof, wherein X1 is -O-. (2-6) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11-membered saturated hetero ring group. (2-6-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 6-membered saturated hetero ring group. (2-7) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form 4- to 11-membered saturated hetero ring group optionally substituted with C1-3 alkyl optionally substituted with N(CH3)2, or F. (2-7-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form 4- to 6-membered saturated hetero ring group optionally substituted with C1-3 alkyl optionally substituted with N(CH3)2, or F. (2-8) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form a 4- to 11-membered saturated hetero ring group optionally substituted with C1- 3 alkyl. (2-8-1) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form a 4- to 6-membered saturated hetero ring group optionally substituted with C1- 3 alkyl. (2-9) A compound represented by formula (I) or a salt thereof, wherein X1 is -NRX1-, and RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form piperazinyl group optionally substituted with C1-3 alkyl.

[0085] (3-1) A compound represented by formula (I) or a salt thereof, wherein R1 is represented by the following formula (II), (III), (IV), (V), (VI), or (VII): [Chemical Formula 11] (II)               (III)              (IV)                   (V)                 (VI)              (VII) R1a and R1b are the same or different, and are each H, methyl, F, or Cl, R1c is F, Cl, methyl, ethyl, trifluoromethyl, or cyclopropyl, and R1d is H, methyl, ethyl, F, Cl, or -C-C-H. (3-1-1) A compound represented by formula (I) or a salt thereof, wherein R1 is represented by the following formula (II), (III), (IV), (V), (VI), or (VII): [Chemical Formula 12] (II)               (III)              (IV)                   (V)                 (VI)              (VII) R1a is the same or different, and is H, methyl, F, or Cl, R1b is H, methyl, F, or Cl, R1c is F, Cl, methyl, ethyl, trifluoromethyl, or cyclopropyl, and R1d is H, methyl, ethyl, F, Cl, or -C C-H. (3-2) A compound represented by formula (I) or a salt thereof, wherein R1 is represented by the following formula (II), (III), or (IV): [Chemical Formula 13] R1a is the same or different, and is H or F, R1b is H, R1c is methyl or cyclopropyl, and R1d is H. (3-3) A compound represented by formula (I) or a salt thereof, wherein R1 is represented by the following formula (II): [Chemical Formula 14] (II) R1a R1a is H, methyl, F, or Cl, and R1c is F, Cl, methyl, or ethyl. (3-4) A compound represented by formula by the following formula (II): [Chemical Formula 15] hOa XXric (II) R1a R1a is F, and R1c is methyl. (3-5) A compound represented by formula by the following formula (III): [Chemical Formula 16] (I) or a salt thereof, wherein R1 is represented (I) or a salt thereof, wherein R1 is represented (III) R1a is H or F, R1b is H, and R1c is methyl or cyclopropyl. (3-6) A compound represented by formula (I) or a salt thereof, wherein R1 is represented by the following formula (IV): [Chemical Formula 17] HCL X (IV) R1a is the same or different, and is H or F, and R1d is H.

[0086] (4-1) A compound represented by formula (I) or a salt thereof, wherein R2 is H, halogen, optionally substituted C1-3 alkyl, cyclopropyl, or vinyl. (4-2) A compound represented by formula (I) or a salt thereof, wherein R2 is H, halogen, C1-3 alkyl, cyclopropyl, or vinyl, and the C1-3 alkyl is optionally substituted with a group selected from the group consisting of OH and OCH3. (4-3) A compound represented by formula (I) or a salt thereof, wherein R2 is cyclopropyl or vinyl. (4-4) A compound represented by formula (I) or a salt thereof, wherein R2 is cyclopropyl.

[0087] (5-1) A compound represented by formula (I) or a salt thereof, wherein R3 is a group selected from the group consisting of the following formulas (VIII), (XI), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII): [Chemical Formula 18] R3a n-r i3b (VIII) ^3g R y (IX) R3j r-N X2^)n1 R' (X) H2N X (XI) N . (XIII) N X (XIV) X (XV) (XVI) (XVII) R3a is -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2, R3e is H, F, or C1-3 alkyl, R3f is the same or different, and is H or C1-3 alkyl, R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6membered saturated hetero ring group, R3h is H, F, or C1-3 alkyl, R3i is the same or different, and is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, or two R3is present on the same carbon atom, together with the carbon atom adjacent thereto, may form a spiro ring having a ring selected from the group consisting of C3-6 cycloalkane and 4- to 6-membered saturated hetero ring, and the spiro ring is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, or R3i present on two carbon atoms adjacent thereto, together with the two carbon atoms, may form a fused ring having a ring selected from the group consisting of C3-6 cycloalkane and 4- to 6-membered saturated hetero rings, and the fused ring is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, R3i present on two carbon atoms not adjacent thereto, together with the two carbon atoms, may form a bridged structure composed of 1 to 2 carbon atoms, or the ring having the bridged structure is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, RN1 and RN2 are the same or different, and are each H or C1-3 alkyl, or RN1 and RN2 together with a nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, or R3e and RN1 together with a carbon atom and a nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN, X2 is -O-, -NH-, or -N(C1-3 alkyl)-, X3 is O or S, X4 is -CH2-, -CH2-CH2-, -O-CH2-, -O-, or -O-NH-, n1 is 1 or 2, p is 1 or 2, and q is 1 to 8. (5-2) A compound represented by formula (I) or a salt thereof, wherein R3 is a group represented by the following formula (XII), (XIII), (XIV), or (XVII): [Chemical Formula 19] „3g R 9 2J\„3f X R (xii)X R3j h2n N . (XIII) ........ /         2 O N       X2 X(xiv) X H N Xo (XVII) R3f is the same or different, and is H or C1-3 alkyl, R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6membered saturated hetero ring group, R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN, and X2 is -O-, -NH-, or -N(C1-3 alkyl)-. (5-3) A compound represented by formula (I) or a salt thereof, wherein R3 is a group represented by (XIV): [Chemical Formula 20] H2N / )...... > 0 N X (xiv) A compound represented by formula (I) or a salt thereof, wherein R4 is optionally substituted C1-6 alkyl, optionally substituted piperidinyl, or optionally substituted tetrahydropyranyl. (6-2) A compound represented by formula (I) or a salt thereof, wherein R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of F; OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is optionally substituted C1-3 alkyl, and R4b is optionally substituted C1-3 alkyl or halogen. (6-3) A compound represented by formula (I) or a salt thereof, wherein R4 is C1-6 alkyl or piperidinyl, the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is C1-3 alkyl, and R4b is C1-3 alkyl optionally substituted with -O-(C1-3 alkyl) or -N(C1-3 alkyl)2, or halogen. (6-3-1) A compound represented by formula (I) or a salt thereof, wherein R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is C1-3 alkyl, and R4b is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH, -O-(C1-3 alkyl), and -N(C1-3 alkyl)2, or halogen. (6-4) A compound represented by formula (I) or a salt thereof, wherein R4 is C1-6 alkyl optionally substituted with N(C1-3 alkyl)2. (6-5) A compound represented by formula (I) or a salt thereof, wherein R4 is C1-6 alkyl optionally substituted with N(Me)2.

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

[0090] (8-1) A compound represented by formula (I) or a salt thereof, wherein L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, and RL1A is H or C1-3 alkyl. A compound represented by formula (I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-L), (XXXIIL), (XXXIII-L), and (XXXIV-L): [Chemical Formula 21] 0 (XXX-L) (XXXI-L) (XXXII-L) (XXXIII-L) (XXXIV-L) L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, -C=C-, or divalent group of optionally substituted saturated hetero ring, L2 is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (8-2-1) A compound represented by formula (I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-LX), (XXXII-L), (XXXIII-L), and (XXXIV-L): [Chemical Formula 22] 0 (XXX-L) (XXXII-L) (XXXIV-L) L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, -C=C-, or divalent group of optionally substituted saturated hetero ring, RLX is H or OH, L2 is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (8-3) A compound represented by formula (I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-L), (XXXIIL), (XXXIII-L), and (XXXIV-L): [Chemical Formula 23] 0 (XXX-L) (XXXI-L) (XXXII-L) n (XXXIII-L) (XXXIV-L) L1 is bond, C1.3 alkylene, -CH2-C=C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, L2 is -C b-C C- or -CH2CH2-O-, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (8-3-1) A compound represented by formula (I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-LX), (XXXII-L), (XXXIII-L), and (XXXIV-L): [Chemical Formula 24] 0 (XXX-L) (XXXI-LX) (XXXII-L) n (XXXIII-L) (XXXIV-L) L1 is bond, C1-3 alkylene, -CH2-C=C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, RLX is H or OH, L2 is -CH2-C C- or -CH2CH2-O-, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (8-4) A compound represented by formula (I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 25] (XXXI-L) wherein L1 is bond, C1-3 alkylene, -CH2-C-C-, -C1.3 alkylene-O-, or tetrahydropyridinediyl. (8-4-1) A compound represented by formula (I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-LX): [Chemical Formula 26] (XXXI-LX) wherein L1 is bond, C1.3 alkylene, -CHi-C^C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, and RLX is H or OH. (8-5) A compound represented by formula (I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 27] (XXXI-L) 0 wherein L1 is -CH2CH2-O- or -CH2-C C-. (8-6) A compound represented by formula (I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 28] (XXXI-L) wherein L1 is -CH2CH2-O-. (8-7) A compound represented by formula (I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 29] (XXXI-L) wherein L1 is -CHi-C^C-.

[0091] (9-1) A compound represented by formula (I) or a salt thereof, wherein 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): [Chemical Formula 30] R 2 (XVIII) (XIX) (XX) (XXI)                    (XXII)                 (XXIII) (XXIV)               (XXV)              (XXVI)           (XXVII) (XXVIII) (XXIX) wherein ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or - NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), and r is 1 or 2. (9-2) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXII), (XXIV), (XXVI), and (XXVII): [Chemical Formula 31] (XXII) (XXIV)           (XXVI)            (XXVII) ring B is benzene ring or a 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or - NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, r is 1 or 2, and L is bonded to ring B in the above formulas (XXII) and (XXVI), to the benzene ring in formula (XXIV), and to ring Hy in formula (XXVII). (9-3) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z), and (XXXII-Z): [Chemical Formula 32] (XXXII-Z) (XXX-Z) (XXXI-Z) ZA is a group represented by the following formula (XXII-1) or (XXVI-1): [Chemical Formula 33] (XXII-1)          (XXVI-1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, ring Hy is 5- or 6-membered hetero ring, and RZ1 is H, halogen, C1-3 alkyl, -O-(C1-3 alkyl), or -CN. (9-4) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z), and (XXXII-Z): [Chemical Formula 34] I Hu (XXX-Z)    ^RZ1 (XXXI-Z) (XXXI I -Z) ZA is a group selected from the group consisting of the following formula (XXII-1) or (XXVI-2): [Chemical Formula 35] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, ring Hy is 5- or 6-membered hetero ring, and RZ1 is H, C1-3 alkyl, or halogen. (9-5) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z1), (XXXII-Z2), and (XXXIV-Z): [Chemical Formula 36] (XXX-Z)    (XXXI-Z1)      (XXXII-Z2)     (XXXIV-Z) ZA is a group represented by formula (XXII-1) or (XXVI-2): [Chemical Formula 37] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 38] RHy1a        RHy1a (XXXV)         (XXXVI) RHy1a (XXXVII) (XXXVIII) (XXXIX) ring Hy2 is of the following formula (XLIII): [Chemical Formula 39] RHY2 (XLI II ) RZ1 is H, C1-3 alkyl, or halogen, RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, and RHy2 is H, C1-3 alkyl, or halogen. (9-5-1) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z1), (XXXII-Z2), and (XXXIV-Z): [Chemical Formula 40] (XXXI-Z1)      (XXXII-Z2)     (XXXIV-Z) (XXX-Z) ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 41] ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII), and (XXXIX): [Chemical Formula 42] (XXXV) RHy1a (XXXVII-2) (XXXVI) RHy1b < N.A II N-N (XXXVIII) (XXXVII) RHy1a (XXXIX) ring Hy2 is of the following formula (XLIII): [Chemical Formula 43] RHy2 (XLI II ) RZ1 is H, C1-3 alkyl, or halogen, RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, and RHy2 is H, C1-3 alkyl, or halogen. (9-6) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z1), (XXXII-Z2), and (XXXIV-Z): [Chemical Formula 44] (XXX-Z) (XXXI-Z1)      (XXXII-Z2) (XXXIV-Z) ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 45] ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 46] (XXXV)          (XXXVI)        (XXXVII) ring Hy2 is of the following formula (XLIII): [Chemical Formula 47] RHy2 (XLI II ) RZ1 is H or halogen, RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, and RHy2 is H or C1-3 alkyl. (9-6-1) A compound represented by formula (I) or a salt thereof, wherein Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z1), (XXXII-Z2), and (XXXIV-Z): [Chemical Formula 48] (XXX-Z) (XXXI-Z1)      (XXXII-Z2) (XXXIV-Z) ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 49] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVII-2), (XXXVIII), and (XXXIX): [Chemical Formula 50] (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) ring Hy2 is of the following formula (XLIII): [Chemical Formula 51] RHy2 (XLI II ) RZ1 is H or halogen, RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, and RHy2 is H or C1-3 alkyl. (9-7) A compound represented by formula (I) or a salt thereof, wherein Z is formula (XXXI-Z1): [Chemical Formula 52] ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI): [Chemical Formula 53] (XXXV)         (XXXVI) RHy1a is H, C1-3 alkyl, or halogen. (9-8) A compound represented by formula (I) or a salt thereof, wherein Z is formula (XXXI-Z1): [Chemical Formula 54] (XXXI-Z1) ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI): [Chemical Formula 55] (XXXV)         (XXXVI) RHy1a is H.

[0092] (10-1) A compound represented by formula (I) or a salt thereof, wherein L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 56] ZA is a group represented by the following formula (XXII-1) or (XXVI-1): [Chemical Formula 57] (XXII-1)          (XXVI-1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, ring Hy is 5- or 6-membered hetero ring, L2is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RZ1 is H, halogen, C1-3 alkyl, -O-(C1-3 alkyl), or -CN, RL1 is H or C1-3 alkyl, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, and the RL4 and RL5 together with a carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with a carbon atom bonded thereto may form carbonyl. (10-1-1) A compound represented by formula (I) or a salt thereof, wherein L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXI X), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 58] ZA is a group represented by the following formula (XXII-1) or (XXVI-1): (XXII-1)          (XXVI -1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, L2 is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RZ1 is H, halogen, C1-3 alkyl, -O-(C1-3 alkyl), or -CN, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (10-2) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 61] £. / ' ’ (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1.3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, ring Hy is 5- or 6-membered hetero ring, L2 is -CH;-C-C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-2-1) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-X), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 62] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 63] ,N-N (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1.3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, L2 is -C b-C C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-3) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 64] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 65] £. / ' ’ (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, L2 is -CIM' C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 67] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-3-1) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI- 1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 69] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1.3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, RLX 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): [Chemical Formula 71] (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, L2 is -CH;-C-C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 72] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 73] RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-4) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 74] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 75] £. / ' ’ (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, L2 is -CIM' C- or -CH2CH2-O-, RZ1 is H or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 77] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-4-1) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI- 1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 79] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1.3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, RLX is H or OH, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 81] (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, L2 is -CH;-C-C- or -CH2CH2-O-, RZ1 is H or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 82] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 83] RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-5) A compound represented by formula (I) or a salt thereof, wherein L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 84] ZA is a group represented by the following formula (XXII-1) or (XXVI-1): [Chemical Formula 85] (XXII-1)          (XXVI -1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (10-5-1) A compound represented by formula (I) or a salt thereof, wherein L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXIX), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 86] ZA is a group represented by the following formula (XXII-1) or (XXVI-1): [Chemical Formula 87] (XXII-1)          (XXVI-1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (10-6) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 89] R (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-6-1) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-X), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 90] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 91] ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-7) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 92] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 93] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 94] (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H, C1-3 alkyl, or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 95] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 96] RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-7-1) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 97] LX (XXX) (XXXI-1X) 0 ZA is a group represented by the following formula (XXII-1) or (XXVI-2): ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, RLX is H or OH, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 99] (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3 alkyl, RZ1 is H, C1-3 alkyl, or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 101] RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-8) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 102] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 103] ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 104] (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 105] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 106] RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-8-1) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 107] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 108] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, RLX is H or OH, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): [Chemical Formula 109] (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 110] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 111] RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-9) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group represented by the formula (XXXI-1): [Chemical Formula 112] L1 is -CH2CH2-O- or -CH2-C=C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI): [Chemical Formula 113] Hy1a        RHy1a (XXXV)         (XXXVI) RHy1a is H, C1-3 alkyl, or halogen. A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group represented by the formula (XXXI-1X): [Chemical Formula 114] L1 is -CH2CH2-O- or -Clb-C C-, RLX is H, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI): [Chemical Formula 115] (XXXV)         (XXXVI) RHy1a is H, C1-3 alkyl, or halogen. (10-10) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group represented by formula (XXXI-1A) or (XXXI-1B): [Chemical Formula 116] O       (XXXI-1A) RLX is H, L1A is -CH2CH2-O-, L1B is -CH2CH2-O- or -CH2-C=C-, and RHy1a is H or C1-3 alkyl. (10-11) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI- 1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 117] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 118] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1.3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-, RLX 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): [Chemical Formula 119] (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, L2 is -Clb-C C- or -CH2CH2-O-, RZ1 is H or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 120] (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, and ring Hy2 is of the following formula (XLIII): [Chemical Formula 121] RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-12) A compound represented by formula (I) or a salt thereof, wherein L together with Z forms a group selected from the group consisting of the following formulas (XXXI-X), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 122] (XXXIII-A) (XXXIV) Hy (XXXI-X) Hy n (XXXIII-B)      RZ1 (XXXI-A) Hy L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (10-13) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXXI-X), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 123] (XXXIII-A) (XXXIV) Hy (XXXI-X) Hy (XXXIII-B) (XXXI-A) Hy L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-14) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 124] (XXXIII-A1) (XXXIV-1) Hy2 (XXXI-1X) Hy1 (XXXI-A) (XXXIII-B1) Hy3 L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX 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): [Chemical Formula 125] (XXXV) ,Hy1a Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) RHy1a (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H, C1-3 alkyl, or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 126] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): [Chemical Formula 127] RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-15) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 128] L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX 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): [Chemical Formula 129] (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 130] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (10-16) A compound represented by formula (I) or a salt thereof, wherein L and Z together are a group selected from the group consisting of the following formulas (XXXI-1X), (XXXIII-A1), (XXXIII-B1), and (XXXIV-1): [Chemical Formula 132] L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX 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): (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 134] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

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

[0094] (12) A compound or a salt thereof which is any noncontradictory combination of two or more of the embodiments according to (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 (97), (10-1) to (10-16), and (11-1) to (11-3).

[0095] Examples of the combination according to (12) above specifically include the following embodiments. (12-1) A compound represented by formula (I) or a salt thereof: [Chemical Formula 136] (I) wherein A is CRA or N, RA is H, C1-3 alkyl, -CN, or -O-(C1-3 alkyl), E is CH or N, X1 is -CH2-, -O-, or -NRX1-, RX1 is H or optionally substituted C1-3 alkyl, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11- membered saturated hetero ring group, R1 is represented by the following formula (II), (III), (IV), (V), (VI), or (VII): [Chemical Formula 137] (II)               (III)              (IV)                   (V)                 (VI)              (VII) R1a and R1b are the same or different, and are each H, methyl, F, or Cl, R1c is F, Cl, methyl, ethyl, trifluoromethyl, or cyclopropyl, R1d is H, methyl, ethyl, F, Cl, or -C-C-H, R2 is H, halogen, optionally substituted C1-3 alkyl, cyclopropyl, or vinyl, R3 is a group selected from the group consisting of the following formulas (VIII), (XI), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII): [Chemical Formula 138] R3a n-r i3b (VIII) ^3g R y (IX) R3j r-N X2^)n1 R' (X) H2N X (XI) N . (XIII) N X (XIV) X (XV) (XVI) (XVII) R3a is -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; a 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2, R3e is H, F, or C1-3 alkyl, R3f is the same or different, and is H or C1-3 alkyl, R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6membered saturated hetero ring group, R3h is H, F, or C1-3 alkyl, R3i is the same or different, and is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, or two R3is present on the same carbon atom together with the carbon atom adjacent thereto may form a spiro ring having a ring selected from the group consisting of C3-6 cycloalkane and 4- to 6-membered saturated hetero ring, wherein the spiro ring is optionally substituted with 1 to 2 groups selected from the group of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, or R3i present on two adjacent carbon atoms together with the two carbon atoms may form a fused ring having a ring selected from the group consisting of C3-6 cycloalkane and 4-to 6-membered saturated hetero ring, wherein the fused ring is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, or R3i present on two non-adjacent carbon atoms together with the two carbon atoms may form a bridged structure composed of 1 to 2 carbon atoms, and a ring having the bridged structure is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, RN1 and RN2 are the same or different, and are each H or C1-3 alkyl, or RN1 and RN2 together with the nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, or R3e and RN1 together with the carbon atom and the nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN, X2 is -O-, -NH-, or -N(C1-3 alkyl)-, X3 is O or S, X4 is -CH2-, -CH2-CH2-, -O-CH2-, -O-, or -O-NH-, n1 is 1 or 2, p is 1 or 2, q is 1 to 8, R4 is optionally substituted C1-6 alkyl, optionally substituted piperidinyl, or optionally substituted tetrahydropyranyl, Y is phenylene or pyridinediyl, wherein the phenylene is optionally substituted with F, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3- 6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 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): [Chemical Formula 139] R 2 (XVIII) (XIX) (XX) (XXI)                    (XXII)                 (XXIII) (XXIV)               (XXV)              (XXVI)           (XXVII) (XXVIII) (XXIX) ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), r is 1 or 2, and G is N or CH, provided that when G is N, Z is the above formula (XVIII), (XXII), (XXIII), (XXIV), (XXVI), (XXVII), or (XXIX).

[0096] (12-2) The compound or a salt thereof according to (12-1) above, wherein E is CH, R3 is a group represented by the following formula (XII), (XIII), (XIV), or (XVII): [Chemical Formula 140] „3g R 9 2J\„3f X R (xii)X R3j h2n N . (XIII) ........ /         2 O N       X2 (xiv) X H N )=O (XVII) R3f is the same or different, and is H or C1-3 alkyl, R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6membered saturated hetero ring group, R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN, X2 is -O-, -NH-, or -N(C1-3 alkyl)-, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is a group selected from the group consisting of formulas (XXII), (XXIV), (XXVI), and (XXVII): [Chemical Formula 141] (XXII) (XXIV)           (XXVI)            (XXVII) ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, r is 1 or 2, L is bonded to ring B in the above formulas (XXII) and (XXVI), to the benzene ring in formulas (XXIV), and to ring Hy in formula (XXVII), and G is N.

[0097] (12-2-1) The compound or a salt thereof according to (12-2) above, wherein X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group, R1 is represented by the following formula (II), (III), or (IV): [Chemical Formula 142] (II) (III) (IV) R1a is the same or different, and is H or F, R1b is H, R1c is methyl or cyclopropyl, R1d is H, R2 is cyclopropyl, R3 is a group represented by formula (XIV): [Chemical Formula 143] h2n ....... o I X (xiv) R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is C1-3 alkyl, and R4b is C1-3 alkyl optionally substituted with -O-(C1-3 alkyl) or -N(C1-3 alkyl)2, or halogen, Y is phenylene, L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-L), (XXXII-L), (XXXIII-L), and (XXXIV-L): [Chemical Formula 144] 0 (XXX-L) (XXXI-L) (XXXII-L) n (XXXIII-L) (XXXIV-L) L1 is bond, C1-3 alkylene, -CH2-C=C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, L2 is -CIM' C- or -CH2CH2-O-, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z), and (XXXII-Z): [Chemical Formula 145] Hy (XXX-Z) (XXXI-Z)       (XXXII-Z) ZA is a group represented by the following formula (XXII-1) or (XXVI-2): ,N—N (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, ring Hy is 5- or 6-membered hetero ring, and RZ1 is H, C1-3 alkyl, or halogen.

[0098] (12-3) The compound or a salt thereof according to (12-1) above, wherein E is CH, R3 is a group represented by formula (XIV): [Chemical Formula 147] h2n 0 N X (xiv) Y is phenylene, L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 148] ZA is a group represented by the following formula (XXII-1) or (XXVI-1): [Chemical Formula 149] (XXII-1)          (XXVI-1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, ring Hy is 5- or 6-membered hetero ring, L2is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RZ1 is H, halogen, C1-3 alkyl, -O-(C1-3 alkyl), or -CN, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl, and G is N.

[0099] (12-3-1) The compound or a salt thereof according to (12-1) above, wherein E is CH, X1 is -O- or -NRX1-, RX1 is H or C1-3 alkyl, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11membered saturated hetero ring group, R1 is represented by the following formula (II), (III), or (IV): [Chemical Formula 150] (II)                 (III)               (IV) R1a is the same or different, and is H or F, R1b is H, R1c is methyl or cyclopropyl, R1d is H, R3 is a group represented by the formula (XIV): h2n 0 N X (xiv) R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of F; OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is optionally substituted C1-3 alkyl, R4b is optionally substituted C1-3 alkyl, or halogen, Y is phenylene, L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXI-X), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 152] ZA is a group represented by the following formula (XXII-1) or (XXVI-1): (XXII-1)          (XXVI -1) RZ11 is H or halogen, Z1, Z2, and Z3 are the same or different, and are each CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, L2 is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RZ1 is H, halogen, C1-3 alkyl, -O-(C1-3 alkyl), or -CN, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl, and G is N.

[0100] (12-4) The compound or a salt thereof according to (12-3) above, wherein A is N, X1 is -O- or -NRX1-, RX1 is H or C1-3 alkyl, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11- membered saturated hetero ring group, R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of F; OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is optionally substituted C1-3 alkyl, R4b is optionally substituted C1-3 alkyl, or halogen.

[0101] (12-4-1) The compound or a salt thereof according to (12-3-1) above, wherein A is N, X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group, R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of F; OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is optionally substituted C1-3 alkyl, and R4b is optionally substituted C1-3 alkyl, or halogen.

[0102] (12-5) The compound or a salt thereof according to (12-3), wherein A is N, X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group, R1 is represented by the following formula (II), (III), or (IV): R1a is the same or different, H or F, R1b is H, R1c is methyl or cyclopropyl, R1d is H, R2 is cyclopropyl, R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is C1-3 alkyl, R4b is C1-3 alkyl optionally substituted with -O-(C1-3 alkyl) or -N(C1-3 alkyl)2, or halogen, L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 155] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 156] £. / ' ’ (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1.3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, ring Hy is 5- or 6-membered hetero ring, L2 is -CH;-C-C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

[0103] (12-5-1) The compound or a salt thereof according to (12-3-1), wherein A is N, X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group, R1 is represented by the following formula (II), (III), or (IV): [Chemical Formula 157] (II)                 (III)               (IV) R1a is the same or different, and is H or F, R1b is H, R1c is methyl or cyclopropyl, R1d is H, R2 is cyclopropyl, R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is C1-3 alkyl, R4b is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH, -O-(C1-3 alkyl) and -N(C1-3 alkyl)2, or halogen, L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-X), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 158] (XXXII) ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 159] (XXVI -2) (XXII -1) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, L2 is -CH2-C-C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

[0104] (12-6) The compound or a salt thereof according to (12-5) above, wherein X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 6membered saturated hetero ring group, L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 160] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 161] R (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV), (XXXVI), (XXXVII), (XXXVIII), and (XXXIX): (XXXV)          (XXXVI)        (XXXVII) (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, L2 is -CIM' C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 163] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

[0105] (12-6-1) The compound or a salt thereof according to (12-5-1) above, wherein X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group, L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 165] ZA is a group represented by the following formula (XXII-1) or (XXVI-2): [Chemical Formula 166] R (XXII-1)        (XXVI -2) RZ11 is halogen, Z1 is CH or N, RZ2 is C1-3 alkyl, L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX 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): [Chemical Formula 167] Hy1a          Hy1a           Hy1a rx                    rx                    lx (XXXV)         (XXXVI)        (XXXVII) (XXXVII-2)      (XXXVIII)       (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, L2 is -CIM' C- or -CH2CH2-O-, RZ1 is H, C1-3 alkyl, or halogen, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 168] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

[0106] (12-7) The compound or a salt thereof according to (12-6) above, wherein L and Z together are a group represented by the formula (XXXI-1): [Chemical Formula 170] L1 is -CH2CH2-O- or -CH2-C=C-, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI): [Chemical Formula 171] Hy1a        RHy1a (XXXV)         (XXXVI) RHy1a is H, C1-3 alkyl, or halogen.

[0107] (12-7-1) The compound or a salt thereof according to (12-6-1) above, wherein L and Z together are a group represented by the formula (XXXI-1X): L1 is -CH2CH2-O- or -CH2-C-C-, RLX is H, ring Hy1 is a ring selected from the group consisting of the following formulas (XXXV) and (XXXVI): [Chemical Formula 173] Hy1a        RHy1a (XXXV)         (XXXVI) RHy1a is H, C1-3 alkyl, or halogen.

[0108] (12-8) The compound or a salt thereof according to (12-7-1) above, wherein R1 is represented by the following formula (II): [Chemical Formula 174] R1a is F, R1c is methyl, R4 is C1-6 alkyl optionally substituted with N(Me)2, L and Z together are a group represented by formula (XXXI-1A) or (XXXI-1B): 0       (XXXI-1A) RLX is H, L1A is -CH2CH2-O-, L1B is -CH2CH2-O- or -CH2-C^C-, and RHy1a is H or C1-3 alkyl.

[0109] (12-9) The compound or a salt thereof according to (12-1) above, wherein E is CH, R3 is a group represented by formula (XIV): [Chemical Formula 176] H2N ....... O । X (xiv) Y is phenylene, L together with Z forms a group selected from the group consisting of the following formulas (XXXI-X), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 177] L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are the same or different, and are each 1 or 2, RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl, and G is N.,

[0110] (12-10) The compound or a salt thereof according to (12-9) above, wherein A is N, X1 is -O- or -NRX1-, RX1 is H or C1-3 alkyl, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11membered saturated hetero ring group, R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of F; OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is optionally substituted C1-3 alkyl, and R4b is optionally substituted C1-3 alkyl, or halogen.

[0111] (12-11) The compound or a salt thereof according to (12-9), wherein A is N, X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group, R1 is represented by the following formula (II), (III), or (IV): [Chemical Formula 178] (II)                 (III)               (IV) R1a is the same or different, and is H or F, R1b is H, R1c is methyl or cyclopropyl, R1d is H, R2 is cyclopropyl, R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b, R4a is C1-3 alkyl, R4b is C1-3 alkyl optionally substituted with OH, -O-(C1-3 alkyl), or -N(C1-3 alkyl)2, or halogen, L and Z together are a group selected from the group consisting of the following formulas (XXXI-X), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 179] L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX is H or OH, ring Hy is 5- or 6-membered hetero ring, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, RZ1 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

[0112] (12-12) The compound or a salt thereof according to (12-11) above, wherein X1 is -O- or -NRX1-, provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11- membered saturated hetero ring group, L and Z together are a group selected from the group consisting of the following formulas (XXXI-1X), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A): [Chemical Formula 180] L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX 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): [Chemical Formula 181] (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H, C1-3 alkyl, or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 182] RHy3         RHy3 (XL)              (XLI) RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H, C1-3 alkyl, or halogen, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

[0113] (12-13) The compound or a salt thereof according to (12-12) above, L and Z together are a group selected from the group consisting of the following formulas (XXXI-1X), (XXXIII-A1), (XXXIII-B1), and (XXXIV-1): [Chemical Formula 184] L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-, RLX 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): (XXXV) ,Hy1a (XXXVII) RHy1a (XXXVII-2) (XXXVI) RHy1b N-N (XXXVIII) (XXXIX) RHy1a is H, C1-3 alkyl, or halogen, RHy1b is H or C1-3alkyl, RZ1 is H or halogen, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI): [Chemical Formula 186] RHy3         RHy3 (XL)              (XLI) RHy3 is H or halogen, m and n are both 1 or both 2, ring Hy2 is of the following formula (XLIII): RHy2 (XLIII) RHy2 is H or C1-3 alkyl, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

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

[0115] (12-15) The compound or a salt thereof according to (12-1), wherein the compound represented by formula (I) is selected from the group consisting of: (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.

[0116] (12-16) The compound or a salt thereof according to (12-1), wherein the compound represented by formula (I) is selected from the group consisting of: (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.

[0117] One aspect of the compound represented by formula (I-I) or a salt thereof according to the present invention will be shown below.

[0118] (13-1) A compound represented by formula (I-I) or a salt thereof, wherein TPB is a group having an ability to bind to target protein. (13-1-1) The compound represented by formula (I-I) or a salt thereof, wherein TPB is a group having an ability to bind to RAS protein. (13-2) The compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-II), (I-III), or (I-IV): [Chemical Formula 188] (I-II)                            (I-III) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, R4, and Y are defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (IXV), and (I-XVI): [Chemical Formula 189] (I-VI)               (I-VII)                (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1-6 alkyl; or R6 and R7 together with a nitrogen atom bonded thereto form a 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R4L is optionally substituted C1-6 alkylene, or divalent group of optionally substituted saturated hetero ring, R1L is the following formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I): [Chemical Formula 190] (II-I)                    (III-I)                    (IV-I) R1aL and R1bL are the same or different, and are each H, methyl, F, Cl, or an attachment point to L, R1cL is F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, or an attachment point to L, R1dL is H, methyl, ethyl, F, Cl, -C C-H, or an attachment point to L, and R1LL is H or an attachment point to L, provided that only one attachment point to L is present in the above formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I). (13-2-1) A compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-II), (I-III-1), or (I-IV-1): [Chemical Formula 191] (I-II) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, and R4 are defined as in formula (I), R8 is H, halogen, -O-C1-3 alkyl, or -O-CH2-Y-R5, Y is defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I- XV), and (I-XVI): [Chemical Formula 192] (I-VI)               (I-VII) (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1- 6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R4L is optionally substituted C1-6 alkylene, or divalent group of optionally substituted saturated hetero ring, R1L is the following formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I): [Chemical Formula 193] (II-I)                    (III-I)                    (IV-I) R1aL is the same or different, and is H, methyl, F, Cl, or an attachment point to L, R1bL is H, methyl, F, Cl, or an attachment point to L, R1cL is F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, or an attachment point to L, R1dL is H, methyl, ethyl, F, Cl, -C-C-H, or an attachment point to L, and R1LL is the same or different, and is H or an attachment point to L, provided that only one attachment point to L is present in the above formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I). (13-3) A compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-II): [Chemical Formula 194] (I-II) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, R4, and Y are defined as in formula (I). (13-4) A compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-III): [Chemical Formula 195] (I-III) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, and Y are defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (IXV), and (I-XVI): [Chemical Formula 196] (I-VI)               (I-VII)                (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1-6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, and R4L is optionally substituted C1-6 alkylene, or divalent group of optionally substituted saturated hetero ring. (13-4-1) A compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-III-1): (I-III-1) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, and q are defined as in formula (I), R8 is H, halogen, -O-C1-3 alkyl, or -O-CH2-Y-R5, Y is defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I- XV), and (I-XVI): [Chemical Formula 198] (I-VI)               (I-VII) (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1- 6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, and R4L is optionally substituted C1-6 alkylene, or divalent group of optionally substituted saturated hetero ring. (13-5) A compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-IV): [Chemical Formula 199] (I-IV) wherein A, RA, E, X1, RX1, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, R4, and Y are defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (IXV), and (I-XVI): [Chemical Formula 200] (I-VI)               (I-VII)                (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1-6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R1L is the following formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I): [Chemical Formula 201] (II-I)                    (III-I)                    (IV-I) R1aL and R1bL are the same or different, and are each H, methyl, F, Cl, or an attachment point to L, R1cL is F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, or an attachment point to L, R1dL is H, methyl, ethyl, F, Cl, -C C-H, or an attachment point to L, and R1LL is H or an attachment point to L, provided that only one attachment point to L is present in the above formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I). (13-5-1) A compound represented by formula (I-I) or a salt thereof, wherein TPB is the following formula (I-IV-1): [Chemical Formula 202] wherein A, RA, E, X1, RX1, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, and R4 are defined as in formula (I), R8is H, halogen, -O-C1-3alkyl, or -O-CH2-Y-R5, Y is defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I- XV), and (I-XVI): [Chemical Formula 203] (I-VIII) (I-V) (I-VI) (I-VII) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionallysubstituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1-6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R1L is the following formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I): [Chemical Formula 204] (II-I)                    (III-I)                    (IV-I) R1aL is the same or different, and is H, methyl, F, Cl, or an attachment point to L, R1bL is H, methyl, F, Cl, or an attachment point to L, R1cL is F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, or an attachment point to L, R1dL is H, methyl, ethyl, F, Cl, -C C-H, or an attachment point to L, and R1LL is the same or different, and is H or an attachment point to L, provided that only one attachment point to L is present in the above formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I).

[0119] (14-1) A compound represented by formula (I-I) or a salt thereof, wherein L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, and RL1A is H or C1-3 alkyl. A compound represented by formula (I-I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-L), (XXXII- L), (XXXIII-L), and (XXXIV-L): [Chemical Formula 205] 0 (XXX-L) 0 (XXXII-L) N. (XXXIV-L) L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, -C=C-, or divalent group of optionally substituted saturated hetero ring, L2 is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (14-2-1) A compound represented by formula (I-I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-LX), (XXXII-L), (XXXIII-L), and (XXXIV-L): [Chemical Formula 206] 0 (XXX-L) (XXXII-L) (XXXIV-L) L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, -C=C-, or divalent group of optionally substituted saturated hetero ring, RLX is H or OH, L2 is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-, RL1 is H or C1-3 alkyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2, and RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl. (14-3) A compound represented by formula (I-I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-L), (XXXIIL), (XXXIII-L), and (XXXIV-L): 0 (XXX-L) (XXXI-L) (XXXII-L) n (XXXIII-L) (XXXIV-L) L1 is bond, C1.3 alkylene, -CH2-C=C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, L2 is -C b-C C- or -CH2CH2-O-, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (14-3-1) A compound represented by formula (I-I) or a salt thereof, wherein L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-LX), (XXXII-L), (XXXIII-L), and (XXXIV-L): [Chemical Formula 208] 0 (XXX-L) (XXXI-LX) (XXXII-L) n (XXXIII-L) (XXXIV-L) L1 is bond, C1-3 alkylene, -CH2-C=C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, RLX is H or OH, L2 is -CH2-C C- or -CH2CH2-O-, RL1 is H or methyl, A1 is CH or N, RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, and RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane. (14-4) A compound represented by formula (I-I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 209] (XXXI-L) wherein L1 is bond, C1-3 alkylene, -CH2-C-C-, -C1.3 alkylene-O-, or tetrahydropyridinediyl. (14-4-1) A compound represented by formula (I-I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-LX): [Chemical Formula 210] (XXXI-LX) wherein L1 is bond, C1.3 alkylene, -CHi-C^C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl, and RLX is H or OH. (14-5) A compound represented by formula (I-I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 211] (XXXI-L) wherein L1 is -CH2CH2-O-. (14-6) A compound represented by formula (I-I) or a salt thereof, wherein L is a group represented by the following formula (XXXI-L): [Chemical Formula 212] wherein L1 is -CH^-C^C-.

[0120] (15-1) A compound represented by formula (I-I) or a salt thereof, wherein 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): [Chemical Formula 213] (RZ1 0^2 (XVIII) * (RZ1) (XIX) (RZ1 0 (XX) (XXI) (XXII)                 (XXIII) (XXIV)               (XXV)              (XXVI)           (XXVII) (XXVIII) (XXIX) wherein ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or - NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), and r is 1 or 2. (15-2) A compound represented by formula (I-I) or a salt thereof, wherein Z is the following formula (XXVII-1): [Chemical Formula 214] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time. (15-3) A compound represented by formula (I-I) or a salt thereof, wherein Z is the following formula (XXVII-1): [Chemical Formula 215] (XXVII-1) E1 is CH, and E2 is N. (15-4) A compound represented by formula (I-I) or a salt thereof, wherein Z is the following formula (XXVII-1): [Chemical Formula 216] (XXVII-1) E1is N, and E2is CH.

[0121] (16-1) A compound represented by formula (I-I) or a salt thereof, wherein G is N or CH, and provided that when G is N, Z is formula (XVIII), (XXII), (XXIII), (XXIV), (XXVI), (XXVII), or (XXIX). (16-2) A compound represented by formula (I-I) or a salt thereof, wherein G is N or CH, and provided that when G is N, Z is formula (XXVII). (16-3) A compound represented by formula (I-I) or a salt thereof, wherein G is N, and Z is formula (XXVII).

[0122] (17) A compound represented by formula (I-I) or a salt thereof which is any noncontradictory combination of two or more of the aspects according to (13-1) to (13-5-1), (14-1) to (14-6), (15-1) to (5-4), and (16-1) to (16-3) above.

[0123] Examples of the combinations according to (17) specifically include the following aspects. (17-0) A compound represented by formula (I-I) or a salt thereof: [Chemical Formula 217] £ NH TPB-L-Z^ (I-I) (wherein TPB is a group having an ability to bind to a target protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 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): [Chemical Formula 218] (RZ1 (XX) (XIX) (XXI)                    (XXII)                 (XXIII) (XXIV)               (XXV)               (XXVI)           (XXVII) (XXVIII) (XXIX) ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or - NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), r is 1 or 2, and G is N or CH, provided that when G is N, Z is the above formula (XVIII), (XXII), (XXIII), (XXIV), (XXVI), (XXVII), or (XXIX))

[0124] (17-1) A compound represented by formula (I-I) or a salt thereof: [Chemical Formula 219] _ / 0 G NH TPB-L-Z- (I-I) (wherein TPB is a group having an ability to bind to a RAS protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 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): [Chemical Formula 220] (RZ1 (RZ1 (XX) (XXI) (XIX) (XXIII) (XXIV)              (XXV) (RZ1)r Hy (XXVII ) (XXVIII) (XXIX) ring B is benzene ring or 6-membered hetero ring, ring Hy is 5- or 6-membered hetero ring, RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5, RZ2 is H or C1-3 alkyl, RZ3 is H or C1-3 alkyl, RZ4 is the same or different, and is H or C1-3 alkyl, RZ5 is C1-3 alkyl, L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII), r is 1 or 2, and G is N or CH, provided that when G is N, Z is the above formula (XVIII), (XXII), (XXIII), (XXIV), (XXVI), (XXVII), or (XXIX))

[0125] (17-2) The compound or a salt thereof according to (17-1) above, wherein TPB is the following formula (I-II): [Chemical Formula 221] (I-II) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, R4, and Y are defined as in formula (I), Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 222] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N.

[0126] (17-3) The compound or a salt thereof according to (17-1) above, wherein TPB is the following formula (I-III): [Chemical Formula 223] (I-III) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, and Y are defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I- XV), and (I-XVI): [Chemical Formula 224] (I-VIII) (I-V) (I-VI) (I-VII) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1- 6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R4L is optionally substituted C1-6 alkylene, or divalent group of optionally substituted saturated hetero ring, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 225] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N.

[0127] (17-3-1) The compound or a salt thereof according to (17-1) above, wherein TPB is the following formula (I-III-1): [Chemical Formula 226] (I-III-1) wherein A, RA, E, X1, RX1, R1, R1a, R1b, R1c, R1d, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, and q are defined as in formula (I), R8 is H, halogen, -O-C1-3 alkyl, or -O-CH2-Y-R5, Y is defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (IXV), and (I-XVI): [Chemical Formula 227] (I-VI)               (I-VII)                (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1- 6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R4L is optionally substituted C1-6 alkylene, or divalent group of optionally substituted saturated hetero ring, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 228] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N.

[0128] (17-4) The compound or a salt thereof according to (17-1) above, wherein TPB is the following formula (I-IV): [Chemical Formula 229] (I-IV) wherein A, RA, E, X1, RX1, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, R4, and Y are defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (I- XV), and (I-XVI): [Chemical Formula 230] o p5a WN       N-R u (I-V)                   (I-VI) R5a N-N      , N-N^ X / / A_5b YY     ' (I-IX)                   (I-X) < N^N R5a v / x Y <  / n^^n T R5b (I-XIII)                (I-XIV) °V^ R5a 0 Gn  vJo (I-VII)                (I-VIII) An x / n=n 5 ^-N^r51’ -UNK-Ra (I-XI)                 (I-XII) <XQ X N^N > (I-XV)              (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1- 6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R1L is the following formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I): [Chemical Formula 231] (II-I)                    (III-I)                    (IV-I) R1aL and R1bL are the same or different, and are each H, methyl, F, Cl, or an attachment point to L, R1cL is F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, or an attachment point to L, R1dL is H, methyl, ethyl, F, Cl, -C-C-H, or an attachment point to L, R1LL is H or an attachment point to L, provided that only one attachment point to L is present in the above formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I), Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 232] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N.

[0129] (17-4-1) The compound or a salt thereof according to (17-1) above, wherein TPB is the following formula (I-IV-1): [Chemical Formula 233] wherein A, RA, E, X1, RX1, R2, R3, R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h, R3i, RN1, RN2, R3j, X2, X3, X4, n1, p, q, and R4 are defined as in formula (I), R8 is H, halogen, -O-C1-3 alkyl, or -O-CH2-Y-R5, Y is defined as in formula (I), R5 is H, CONR6R7, or a group selected from the group consisting of the following formulas (I-V), (I-VI), (I-VII), (I-VIII), (I-IX), (I-X), (I-XI), (I-XII), (I-XIII), (I-XIV), (IXV), and (I-XVI): [Chemical Formula 234] (I-VI)               (I-VII)                (I-VIII) (I-V) (I-XI) (I-XII) (I-XV) (I-XVI) R5a and R5b are the same or different, and are each H, optionally substituted C1- 3 alkyl, cyclopropyl, cyclopropylmethyl, oxetanyl, tetrahydropyranyl, optionally substituted oxazolyl, thiazolyl, or pyrazinyl, R6 and R7 are the same or different, and are each H or optionally substituted C1-6 alkyl, or R6 and R7, together with a nitrogen atom bonded thereto, form 4- to 6-membered saturated hetero ring group, and the 4- to 6-membered saturated hetero ring group is optionally substituted with optionally substituted C1-6 alkyl, R1L is the following formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I): [Chemical Formula 235] (II-I)                    (III-I)                    (IV-I) R1aL is the same or different, and is H, methyl, F, Cl, or an attachment point to L, R1bL is H, methyl, F, Cl, or an attachment point to L, R1cL is F, Cl, methyl, ethyl, trifluoromethyl, cyclopropyl, or an attachment point to L, R1dL is H, methyl, ethyl, F, Cl, -C C-H, or an attachment point to L, R1LL is the same or different, and is H or an attachment point to L, provided that only one attachment point to L is present in the above formula (II-I), (III-I), (IV-I), (V-I), (VI-I), or (VII-I), Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 236] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N. The compound or a salt thereof according to (17-0) above, wherein TPB is a group having an ability to bind to a target protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 237] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N.

[0131] (17-5) The compound or a salt thereof according to (17-1) above, wherein TPB is a group having an ability to bind to a RAS protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 238] (XXVII-1) E1 and E2 are the same or different, and are each CH or N, provided that E1 and E2 are never CH at the same time, and G is N.

[0132] (17-6-0) The compound or a salt thereof according to (17-0) above, wherein TPB is a group having an ability to bind to a target protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 239] (XXVII-1) E1 is CH, and E2 is N, and G is N.

[0133] (17-6) The compound or a salt thereof according to (17-1) above, wherein TPB is a group having an ability to bind to a RAS protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 240] (XXVII-1) E1 is CH, and E2 is N, and G is N.

[0134] (17-7-0) The compound or a salt thereof according to (17-0) above, wherein TPB is a group having an ability to bind to a target protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 241] (XXVII-1) E1 is N, and E2 is CH, and G is N. The compound or a salt thereof according to (17-1) above, wherein TPB is a group having an ability to bind to a RAS protein, L is -(LA-LB-LC-LD-LE-LF)-, LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O, RL1A is H or C1-3 alkyl, Z is the following formula (XXVII-1) as (XXVII): [Chemical Formula 242] (XXVII-1) E1 is N, and E2 is CH, and G is N.

[0136] In the compounds represented by formulas (I) and (I-I), tautomers and / or geometric isomers can be present depending on the type of the substituent. In this specification, although the compounds represented by formulas (I) and (I-I) are described as only one form of isomers in some cases, the present invention encompasses other isomers, and also encompasses separated isomers or a mixture thereof. In some cases, the compounds represented by formulas (I) and (I-I) may have an asymmetric carbon atom or axial chirality, and a diastereomer based on this can be present. The present invention also encompasses the separated diastereomers of the compounds represented by formulas (I) and (I-I) or mixtures thereof.

[0137] Further, the present invention also encompasses pharmaceutically acceptable prodrugs of the compounds represented by formulas (I) and (I-I). The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under a physiological condition. Examples of groups forming a prodrug include those described in Prog. Med., 5, 2157-2161 (1985) and "Iyakuhin no Kaihatsu" (Hirokawa Shoten, 1990) vol. 7, Bunshi Sekkei, 163-198.

[0138] Salts of the compounds represented by formulas (I) and (I-I) are pharmaceutically acceptable salts of the compounds represented by formulas (I) and (I-I), and depending on the type of substituents, these compounds may form an acid addition salt or a salt with a base in some cases. Examples of the salts include salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specifically, examples thereof include acid addition salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, or phosphoric acid or an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, aspartic acid, or glutamic acid; salts with a inorganic metal such as sodium, potassium, magnesium, calcium, or aluminum; salts with an organic base such as methylamine, ethylamine, or ethanolamine; salts with a variety of amino acids such as acetyl leucine, lysine, or ornithine or an amino acid derivative; and ammonium salts.

[0139] Further, the present invention also encompasses a variety of hydrates of the compounds represented by formulas (I) and (I-I) and salts thereof, solvates thereof, and crystal polymorphic substances thereof.

[0140] The present invention also encompasses all the pharmaceutically acceptable compounds represented by formulas (I) and (I-I) or salts thereof which are labelled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes. Examples of suitable isotopes used for isotopic labelling of the compound of the present invention include isotopes of hydrogen (such as 2H and 3H), carbon (such as 11C, 13C, and 14C), nitrogen (such as 13N and 15N), oxygen (such as 15O, 17O, and 18O), fluorine (such as 18F), chlorine (such as 36Cl), iodine (such as 123I and 125I), and sulfur (such as35S). The compounds according to the present invention labelled with an isotope can be used for research such as research on tissue distribution of drugs and / or substrates. For example, the radioactive isotopes such as tritium (3H) and carbon 14 (14C) can be used for this purpose because of easy labelling and convenience of detection. In some cases, replacement by a heavier isotope, such as replacement by hydrogen deuterium (2H), improves metabolic stability, and thus may lead to therapeutic advantageous (e.g., an increase in half-life in vivo, a reduction in necessary amount, a reduction in drug interaction). Replacement by a positron emitting isotope (such as 11C, 18F, 15O, or 13N) can be used in a test using positron emission tomography (PET) in order to examine substrate receptor occupancy. The isotope-labeled compound of the present invention can be generally produced by a conventional method known to persons skilled in the art, or by the same production method as in Examples or Production Examples or the like, using an appropriate isotopically-labelled reagent instead of a non-labelled reagent.

[0141] (Production method) Utilizing characteristics based on the basic structure of the compound or the type of substituent, the compounds represented by formulas (I) and (I-I) and salts thereof can be produced using a variety of known synthetic methods. In the production, depending on the type of functional group, it may be technically effective in the production to substitute the functional group by an appropriate protecting group (a group easily convertible to the functional group) in a stage in which the raw material is formed into an intermediate product. Examples of such a protecting group include protecting groups described in P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", the 5th edition, John Wiley & Sons Inc., 2014, and these protecting groups can be appropriately selected according to the reaction conditions thereof for use. In such a method, a desired compound can be obtained by introducing the protecting group, performing the reaction, and then removing the protecting group as needed. The pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under a physiological condition. Examples of groups forming a prodrug include those described in Prog. Med., 5, 2157-2161 (1985) and "Iyakuhin no Kaihatsu" (Hirokawa Shoten, 1990) vol. 7, Bunshi Sekkei, 163-198. The prodrugs of the compounds represented by formulas (I) and (I-I) can be produced by introducing a specific group in a stage in which the raw material is formed into an intermediate product as in the production of the protecting group above or by further reacting the obtained compounds represented by formulas (I) and (I-I). The reaction can be performed using a method known by persons skilled in the art, such as standard esterification, amidation, or dehydration. Hereinafter, representative methods for producing the compounds represented by formulas (I) and (I-I) will be described. The production methods can also be performed by referring to the reference attached to the description. The production method according to the present invention is not limited to the examples shown below.

[0142] In the present specification, the following abbreviations are sometimes 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, PdCb(dppf)-CH2Cb: [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)trispyrrolidinophosphonium 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-ethyl-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-KP](methanesulfonato-KO)[2'-(methylamino-KN)[1,1'-biphenyl]-2-yl-KC]palladium(II), XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, LHMDS: lithium bis(trimethylsilyl)amide, KHMDS: potassium bis(trimethylsilyl)amide, LAH: lithium aluminium 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, and MW: microwave.

[0143] (Production Method 1) [Chemical Formula 243] b, cf ^NH (2) 3 R‘ N R4 NH O (I-1) (wherein -LCF- represents -LC-LD-LE-LF- contained in -L-. The same shall apply hereinafter) This production method is a method for producing a compound of formula (I-1) included in the compound of formula (I), wherein A is N, -LA- contained in -L- is CO, -LB- is -N(RL1A)- or a saturated heterocyclic divalent group containing 1 or 2 nitrogen atoms optionally substituted, -LC-LD-LE-LF- is -LCF-, and RL1A is H or C1-3 alkyl. In this reaction, compound (1) and compound (2) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in the presence of a condensing agent, in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 60°C, generally for 0.1 hours to 5 days, to obtain an amide compound. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Examples of the condensing agent include PyBOP, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a hydrochloride (EDC-HCl) thereof, N,N'-dicyclohexylcarbodiimide (DCC), CDI, diphenylphosphoryl azide (DPPA), and PyAOP. Use of an additive (for example, HOBt or dimethylaminopyridine) is sometimes preferred for the reaction. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, or an inorganic base, such as potassium carbonate, sodium carbonate and potassium hydroxide, is sometimes advantageous for smoothly promoting the reaction. Alternatively, a method of converting compound (1) into a reactive derivative, followed by an acylation reaction, can be used. Examples of the reactive derivative of a carboxylic acid include an acid halide obtained by a reaction with a halogenating agent, such as phosphorus oxychloride and thionyl chloride, a mixed acid anhydride obtained by a reaction with isobutyl chloroformate or the like, and an active ester obtained by condensation with 1-hydroxybenzotriazole or the like. The reaction of the reactive derivative and compound (2) can be performed in a solvent inactive for the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon and an ether, under a condition ranging from cooling to heating, preferably at -20°C to 120°C. [Reference] S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, Vol. 1, Academic Press Inc., 1991 The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry (5th edition)", Vol. 16 (2005) (Maruzen)

[0144] (Production Method 2) (PG71 represents a protecting group of NH contained in R1, and R11 represents divalent group formed by elimination of H from NH contained in R1. The same shall apply hereinafter.)

[0145] This production method is another method for producing the compound of formula (I). The compound of formula (I) can be obtained by subjecting compound (3) to a deprotection reaction. Examples of the protecting group shown here include a tertbutoxycarbonyl group, a triphenylmethyl group, a tetrahydro-2H-pyran-2-yl group, a methoxymethyl group, a dimethylmethanediyl group, and a tert-butylsulfinyl group and the like. This deprotection reaction is performed by stirring the compound under a condition ranging from cooling to reflux with heat, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, such as MeOH and EtOH, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an ether, such as diethyl ether, THF, DOX and dimethoxyethane, DMF, DMSO, MeCN or water, and a mixture thereof. Examples of the deprotection reagent include, but are not particularly limited to, an acid, such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid and the like. By selecting a protecting group, the deprotection can be performed by a catalytic hydrogenation reaction. Examples of the protecting group include a benzyl group, a p- methoxybenzyl group, and a benzyloxycarbonyl group and the like. Moreover, deprotection can also be performed with a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of the protecting group include a tert-butyl(dimethyl)silyl group and a (trimethylsilyl)ethoxymethyl group. Furthermore, examples of the protecting group which can be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, a benzoyl group and the like. For example, the following can be referred to as a reference. P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, 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] (Production Method 3) (5) This production method is a method for producing a compound of formula (I-2) included in the compound of formula (I), wherein A and E are N and CH, respectively, by a reaction of compound (4) and compound (5). In this reaction, compound (4) and compound (5) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in the presence of a condensing agent, in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 60°C, generally for 0.1 hours to 5 days. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Examples of the condensing agent include PyBOP, HATU, CDI, and PyAOP and the like. Performing 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, is sometimes advantageous for smoothly promoting the reaction. Alternatively, the compound of formula (I-2) can also be obtained by converting compound (4) into a reactive derivative in which a hydroxyl group at the 4-position of compound (4) is converted to chloro group using a chlorinating reagent, such as phosphorus oxychloride and thionyl chloride, followed by addition of compound (5) in the presence of an organic base, such as TEA, DIPEA and pyridine, or an inorganic base, such as potassium carbonate, cesium carbonate and potassium acetate. The reaction of the reactive derivative and compound (5) can be performed in a solvent inactive for the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon and an ether, under a condition ranging from cooling to heating, preferably at -20°C to 120°C. (Production Method 4) [Chemical Formula 246] This production method is the second method for producing a compound of formula (I-2) included in the compound of formula (I), wherein A and E are N and CH, respectively, by subjecting compound (115) to an oxidation reaction in the first step, followed by a reaction 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 later. In the second step, the compound of formula (I-2) can be produced by performing an ipso substitution reaction of compound (18) under the same conditions as in the third step of Raw Material Synthesis 1 described later.

[0147] (Raw Material Synthesis 1) [Chemical Formula 247] Eleventh Twelfth step Fourth step i G Fifth step Sixth step Eighth step (wherein LG2, LG4, LG6, LG7, LG8, and LG81, which are the same or different, each represent leaving group. PG4 represents protecting group of OH, PG7 and PG71 each represent protecting group of NH contained in R1, R11 represents divalent group formed by elimination of H from NH contained in R1, PG8 represents protecting group which can be deprotected under catalytic hydrogenation reaction conditions, and PG81 represents protecting group of COOH. Moreover, the deprotection can also be performed in stages by selecting protecting groups deprotectable under different deprotection conditions as PG4, PG7, PG71, PG8, and PG81. RLG2 represents C1-12 alkyl group, and BLG represents boronic acid group, boronic acid group protected with protecting group of boronic acid such as boronic acid pinacol ester group, or trifluoroborate group (hereinafter, sometimes described as boronic acid group or the like). Examples of the leaving group shown here include Cl, Br, I, methanesulfonyloxy group, and p-toluenesulfonyloxy group and the like. The same shall apply hereinafter)

[0148] This production method is the first method for producing compound (1)-1 included in compound (1), which is a raw material compound of Production Method 1, wherein A and E are N and CH, respectively.

[0149] (First Step) This step is a method for producing compound (7) from compound (6). This reaction is performed by stirring compound (6) under a condition ranging from cooling to reflux with heat, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, acetone, DMF and THF. In addition, a mixed solvent of the above solvent and water is sometimes suitable for the reaction. Examples of the reagent used in this reaction include, but are not particularly limited to, aqueous sodium hydroxide and aqueous potassium hydroxide. For example, the following can be referred to as a reference about this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th edition)", Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p. 1378-1382.

[0150] (Second Step) This step is a method for producing compound (8) by protection of a hydroxyl group of compound (7) with the protecting group. In the case of protection with a tert-butyl group, for example, this reaction is performed by stirring compound (7) in the presence of a tert-butyl protection reagent under a condition ranging from cooling to reflux with heat, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, tBuOH, and DMF. Examples of the tert-butyl protection reagent include, but are not particularly limited to, isobutene, 2-tert-butyl-1,3-diisopropylisourea and the like. Moreover, compound (8) can be produced by a dehydration condensation reaction of compound (7) and tBuOH. For example, the following can be referred to as a reference about this reaction. P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014 Org. Lett., 2012, 14, 17, p. 4678-4681

[0151] (Third Step) This step is a method for producing compound (10) by an ipso substitution reaction of compound (8) and compound (9), RLG2-SH. Examples of the RLG2-SH used here include C1-12 alkylthiols, for example, ethanethiol and dodecanethiol. In this reaction, compound (8) and compound (9) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction or with no solvent, under a condition ranging from cooling to reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN, NMP and a mixture thereof. Performing the reaction in the presence of an organic base, such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), tBuOK and KHMDS, or an inorganic base, such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate, is sometimes advantageous for smoothly promoting the reaction.

[0152] (Fourth Step) This step is a method for producing compound (12) by an ipso substitution reaction of compound (10) and compound (11), PG8-OH. Examples of the PG8-OH used here include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol. The reaction conditions are the same as in the third step of Raw Material Synthesis 1.

[0153] (Fifth Step) This step is a method for producing compound (14) by a Suzuki-Miyaura coupling reaction of compound (12) and compound (13), a boronic acid derivative composed of an R2-boronic acid group or the like. Examples of the boronic acid group or the like used here include, but are not particularly limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triol borate salt group, and a trifluoroborate group. In this reaction, compound (12) and the boronic acid derivative composed of the R2-boronic acid group or the like are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, under a condition ranging from room temperature to reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane or chloroform, an aromatic hydrocarbon, such as benzene, toluene or xylene, an ether, such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, an alcohol, such as MeOH, EtOH, isopropyl alcohol, butanol or amyl alcohol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water and a mixture thereof. Examples of the base include an inorganic base, such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, PdCl2(PPh3)2, PdCl2(dppf)-CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. Performing the reaction in the presence of a ligand, such as SPhos, RuPhos and 1,1'-bis(diphenylphosphino)ferrocene, is sometimes advantageous for smoothly promoting the reaction. In addition, heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction. [Reference] J. Am. Chem. Soc., 2005, 127, p.4685-4696 Org. Lett. 2011, 13, p. 3948-3951 Org. Lett. 2012, 14, p. 1278-1281 When LG6 is halogen, compound (14) (where R2 is hydrogen) can be produced by a dehalogenation reaction of compound (12) with Pd catalyst and a reducing agent. [Reference] 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 a Suzuki-Miyaura coupling reaction of compound (14) and compound (15). The reaction conditions are the same as in the fifth step of Raw Material Synthesis 1. When compound (16) has an axial chirality, compound (16) is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a common separation operation, for example, separation using ODS column chromatography or silica gel column chromatography.

[0155] (Seventh Step) This step is a method for producing compound (17) by an oxidation reaction of compound (16). In this reaction, compound (16) is treated with an oxidant in an equal amount or an excess amount in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 80°C, generally for 0.1 hours to 3 days. In this reaction, oxidation with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is suitably used. Examples of the solvent include a halogenated hydrocarbon, such as dichloromethane, DMF, ethyl acetate, MeCN, and a mixture thereof. Other examples of the oxidant include cumene hydroperoxide, Oxone, active manganese dioxide, chromic acid, potassium permanganate, sodium periodate and the like. [Reference] The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry)", 5th edition, Vol. 17, Maruzen, 2004 When compound (17) has an axial chirality, compound (17) may be obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a common separation operation, for example, separation using ODS column chromatography or silica gel column chromatography, and separation by SFC using a chiral column.

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

[0157] (Ninth Step) This step is a method for producing compound (20) by deprotection by a catalytic hydrogenation reaction of compound (19). This reaction can be performed by stirring compound (19) under hydrogen atmosphere, under a condition ranging from normal pressure to increased pressure, in a solvent inactive for the reaction, such as MeOH, EtOH, ethyl acetate and THF, in the presence of a metal catalyst, under a condition ranging from cooling to heating, preferably at room temperature, for 1 hour to 5 days. As the metal catalyst, a palladium catalyst, such as Pd / C or palladium black, a platinum catalyst, such as a platinum plate or platinum oxide, a nickel catalyst, such as reduced nickel or Raney nickel, or the like is used. The addition of an inorganic base, such as NaHCO3, is sometimes suitable for the reaction to prevent deprotection of the protecting groups of PG4 and PG7.

[0158] (Tenth Step) This step is a method for producing compound (22) by a reaction of compound (20) and compound (21). This reaction is performed using compound (20) and compound (21) in an equal amount or with one compound thereof in an excess amount by reacting a mixture of the compounds in the presence of a base, in a solvent inactive for the reaction, under a condition ranging from cooling to reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, an aromatic hydrocarbon, such as benzene, toluene and xylene, an alcohol, such as MeOH and EtOH, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Examples of the base include, but are not particularly limited to, an organic base, such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium and tBuOK, and an inorganic base, such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. Performing the reaction in the presence of a phase transfer catalyst, such as tetra-n-butylammonium chloride, is sometimes advantageous. For example, the following can be referred to as a reference about this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry)", 5th edition, Vol. 14, Maruzen, 2005 Moreover, compound (21) in which LG81 is halogen can be produced by halogenation of a compound in which the moiety corresponding to LG81 is a hydroxy group. Examples of the halogenating agent used here include, but are not particularly limited to, thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide and the like. For example, the following can be referred to as a reference about this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry)", 5th edition, Vol. 13, Maruzen, 2004 Furthermore, compound (21) in which LG81 is a sulfonyloxy group can be produced by sulfonylation of a compound in which the moiety corresponding to LG81 is a hydroxy group in the presence of a base. Examples of the sulfonylating reagent used here include, but are not particularly limited to, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride and the like. Examples of the base include, but are not particularly limited to, for example, TEA, DIPEA, pyridine, tetramethylethylenediamine and the like. For example, the following can be referred to as a reference about this reaction. Synthesis 1999, 9, p. 1633-1636

[0159] (Eleventh Step) This step is a method for producing compound (23) by performing deprotection of PG4 and PG7, which are the protecting groups of compound (22), and further protecting a deprotected NH group contained in R11 with another protecting group PG71. The reaction can be carried out under the same reaction conditions as in the step described in Production Method 2 by adding, in addition to compound (22) and the deprotection reagent, a protection reagent for protecting the NH group with a PG71 group.

[0160] (Twelfth Step) This step is a method for producing compound (24) by a reaction of compound (23) and compound (5). The reaction conditions are the same as in the Production Method 3.

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

[0162] (Raw Material Synthesis 2) [Chemical Formula 248] (wherein PG82 represents C1-3 alkyl. The same shall apply hereinafter)

[0163] This production method is the first method for producing compound (3-1) included in compound (3), which is a raw material compound of Production Method 2, wherein A is N, -LA- included in -L- is CO, -LB- is -N(RL1A)- or a saturated heterocyclic divalent group containing 1 or 2 nitrogen atoms optionally substituted, -LC-LD-LE-LF- is -LCF-, and RL1A is H or C1-3 alkyl.

[0164] (First Step) This step is a method for producing compound (26) by a reaction of compound (25) and compound (5). The reaction conditions are the same as in Production Method 3.

[0165] (Second Step) This step is a method for producing compound (27) by hydrolysis of compound (26) under basic conditions. This reaction is carried out by stirring compound (26) under a condition ranging from cooling to reflux with heat, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, acetone, DMF and THF. In addition, a mixed solvent of the above solvent and water is sometimes suitable for the reaction. Examples of the hydrolysis reagent include, but are not particularly limited to, aqueous sodium hydroxide, aqueous potassium hydroxide, and trimethyltin hydroxide. For example, the following can be referred to as a reference about this reaction. The Chemical Society of Japan, "Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th edition)", Vol. 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, 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 in the step described in Production Method 1.

[0167] (Raw Material Synthesis 3) [Chemical Formula 249]

[0168] This production method is the second method for producing compound (3-1) included in compound (3), which is a raw material compound of Production Method 2, wherein A is N, -LA- included in -L- is CO, -LB- is -N(R1A)- or a saturated heterocyclic divalent group containing 1 or 2 nitrogen atoms optionally substituted, -LC-LD-LE-LF- is -LCF-, and RL1A is H or C1-6 alkyl.

[0169] (First Step) This step is a method for producing compound (29) by a reaction of compound (20) and compound (28). The reaction conditions are the same as in the tenth step of Raw Material Synthesis 1.

[0170] (Second Step) This step is a method for producing compound (30) by subjecting compound (29) to a deprotection reaction. The reaction conditions are the same as 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 in the step described in Production Method 1.

[0172] (Fourth Step) This step is a method for producing compound (32) by performing deprotection of PG4 and PG7, which are the protecting groups of compound (31), and further protecting a deprotected NH group contained in R11 with another protecting group PG71. The reaction can be carried out under the same reaction conditions as in the step described in Production Method 2 by adding, in addition to compound (31) and the deprotection reagent, a protection reagent for protecting the NH group with the PG71 group.

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

[0174] (Raw Material Synthesis 4) [Chemical Formula 250] (wherein -L'- represents -LA-LB-LC-LD- contained in -L-, and PG83 represents a protecting group of NH bonded to L', wherein RL' is H or C1-3 alkyl, or RL' together with a nitrogen atom and L' adjacent thereto may form divalent group of saturated hetero ring containing 1 or 2 nitrogen atoms)

[0175] This production method is a method for producing compound (4-1) included in compound (4), which is a raw material compound of Production Method 3, wherein -LE- and -LF- contained in -L- are -N(RL')- and -CH2-, respectively.

[0176] (First Step) This step is a method for producing compound (34) by a reaction of compound (20) and compound (33). The reaction conditions are the same as in the tenth step of Raw Material Synthesis 1.

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

[0178] (Third Step) This step is a step of producing compound (4-1) from compound (35) and compound (36) by a reductive amination reaction when -RZ is -CHO or by an alkylation reaction when -Rz is -CH2-LG81. When -RZ is -CHO, the reaction is carried out by stirring compound (35) and compound (36) in an equivalent amount or with one compound thereof in an excess equivalent amount in the presence of a reducing agent and acetic acid, in a solvent inactive for the reaction, under a condition ranging from ice-bath cooling to room temperature, generally for 1 hour to 5 days. Examples of the reducing agent used here include, but are not particularly limited to, NaBH(OAc)3, 2-picoline borane, and NaBH3CN. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, dichloroethane and chloroform, an ether-based solvent, such as THF, diethyl ether and DOX, an alcohol-based solvent, such as MeOH and EtOH, and MeCN. When -RZ is -CH2-LG81, the reaction conditions are the same as in the tenth step of Raw Material Synthesis 1.

[0179] (Raw Material Synthesis 5) [Chemical Formula 251] (wherein PG41 represents a protecting group of NH, and R31 represents R3a-N(R3b)CO-, R3c- OCO- or R3d-CO-)

[0180] This production method is a method for producing compound (52) included in compound (1), which is a raw material compound of Production Method 1, wherein E is CH, R3 is formula (VIII), formula (IX) or formula (X), and X3 is O.

[0181] (First Step) This step is a method for producing compound (37) by an ipso substitution reaction of compound (6) and compound (9), RLG2-SH. The reaction conditions are the same as in the third step of Raw Material Synthesis 1.

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

[0183] (Third Step) This step is a method for producing compound (40) by an ipso substitution reaction of compound (38) and compound (39), which has an amino group protected with the protecting group PG41. In this reaction, compound (38) and compound (39) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 60°C, generally for 0.1 hours to 5 days. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, a halogenated hydrocarbon, such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Performing 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, is sometimes advantageous for smoothly promoting the reaction.

[0184] (Fourth Step) This step is a method for producing compound (41) by a Suzuki-Miyaura coupling reaction of compound (40) and compound (13), a boronic acid derivative composed of an R2-boronic acid group or the like. The reaction conditions are the same as in the fifth step of Raw Material Synthesis 1.

[0185] (Fifth Step) This step is a method for producing compound (42) by a Suzuki-Miyaura coupling reaction of compound (41) and compound (15). The reaction conditions are the same as in the fifth step of Raw Material Synthesis 1. When compound (42) has an axial chirality, compound (16) is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a common separation operation, for example, separation using ODS column chromatography or silica gel column chromatography.

[0186] (Sixth Step) This step is a method for producing compound (43) by an oxidation reaction of compound (42). The reaction conditions are the same as in the seventh step of Raw Material Synthesis 1. When compound (43) has an axial chirality, the compound may be obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a common separation operation, for example, separation using ODS column chromatography or silica gel column chromatography, and separation by SFC using a chiral column.

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

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

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

[0190] (Tenth 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 in the step described in Production Method 2.

[0191] (Eleventh Step) This step is a step of producing compound (51) by subjecting compound (47) to a urea formation reaction using compound (48), a carbamate formation 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) were performed by using an equal amount of compound (48) or compound (49) with respect to compound (47) or one of them in excess over the other, and stirring the mixture of the compounds in the presence of a condensing agent, in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 60°C, generally for 0.1 hours to 5 days. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN, and a mixture thereof. Examples of the condensing agent include CDI, triphosgene, bis(4-nitrophenyl) carbonate, and 4-nitrophenyl chloroformate. Use of an additive (for example, HOBt or dimethylaminopyridine) is sometimes preferred for the reaction. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, or an inorganic base, such as potassium carbonate, sodium carbonate and potassium hydroxide, is sometimes advantageous for smoothly promoting the reaction. The reaction conditions for the amidation reaction using compound (50) are the same as in the step described in Production Method 1. This step is a method for producing compound (52) by subjecting compound (51) to a deprotection reaction. The reaction conditions are the same as in the step described in Production Method 2.

[0193] (Raw Material Synthesis 6) [Chemical Formula 252]

[0194] This production method is the second method for producing compound (1)- 1 included in compound (1), which is a raw material compound of Production Method 1, wherein A and E are N and CH, respectively.

[0195] (First Step) This step is a method for producing compound (53) by deprotection by a catalytic hydrogenation reaction of compound (17). The reaction conditions are the same as in the ninth step of Raw Material Synthesis 1. This step is a method for producing compound (54) by a reaction of compound (53) and compound (21). The reaction conditions are the same as in the tenth step of Raw Material Synthesis 1.

[0197] (Third Step) This step is a method for producing compound (55) by an ipso substitution reaction of compound (54) and compound (18). The reaction conditions are the same as in the third step of Raw Material Synthesis 1. The reaction in the fourth step can also 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 can be carried out under the same reaction conditions as in the step described in Production Method 2 by adding, in addition to compound (55) and the deprotection reagent, a protection reagent such as dihydropyran for protecting the NH group with a PG71 group.

[0199] (Fifth Step) This step is a method for producing compound (57) by a reaction of compound (56) and compound (5). The reaction conditions are 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 in the step described in Production Method 2. [Chemical Formula 253]

[0202] This production method is a method for producing compound (61) included in compound (3), which is a raw material compound of Production Method 2, wherein A is N, -LA- contained in -L- is CO, -LB- is -N(RL1A)- or divalent group of optionally substituted saturated hetero ring containing 1 or 2 nitrogen atoms, -LC-LD-LE-LF- is -LCF-, and RL1A is H or C1-6 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 in the step described in Production Method 2.

[0204] (Second Step) This step is a method for producing compound (59) by a reaction of compound (58) and compound (5). The reaction conditions are the same as in Production Method 3. This step is a method for producing compound (60) by subjecting compound (59) to a deprotection reaction. The reaction conditions are the same as 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 in the step described in Production Method 1.

[0207] (Raw Material Synthesis 8) [Chemical Formula 254]

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

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

[0210] (Second Step) This step is a method for producing compound (63) by a Suzuki-Miyaura coupling reaction of compound (62) and compound (13), a boronic acid derivative composed of an R2-boronic acid group or the like. The reaction conditions are the same as in the fifth step of Raw Material Synthesis 1.

[0211] (Third Step) This step is a method for producing compound (64) by a Suzuki-Miyaura coupling reaction of compound (63) and compound (15). The reaction conditions are the same as in the fifth step of Raw Material Synthesis 1. When compound (64) has an axial chirality, compound (16) is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a common separation operation, for example, separation using ODS column chromatography or silica gel column chromatography.

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

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

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

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

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

[0217] (Raw Material Synthesis 9) [Chemical Formula 255]

[0218] This production method is the third method for producing compound (1)-1 included in compound (1), which is a raw material compound of Production Method 1, wherein A and E are N and CH, respectively.

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

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

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

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

[0223] (Fifth Step) This step is a method for producing compound (74) by a Suzuki-Miyaura coupling reaction of compound (73) and compound (15). The reaction conditions are the same as in the fifth step of Raw Material Synthesis 1. When compound (74) has an axial chirality, compound (16) is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by a common separation operation, for example, separation using ODS column chromatography or silica gel column chromatography.

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

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

[0226] (Eighth Step) 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 in the step described in Production Method 2.

[0227] (Raw Material Synthesis 10) [Chemical Formula 256] (wherein LGCB represents a leaving group, and PGCB represents a protecting group of NH contained in L2)

[0228] This production method is a method for producing compound (2-1) included in compound (2), which is a raw material compound of Production Method 1, wherein -L2- and -L35- are divalent group of optionally substituted saturated hetero ring containing 2 nitrogen atoms and -CH2-, respectively.

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

[0230] (Second Step) This step is a method for producing compound (80) which is an aldehyde from compound (79). In this reaction, compound (79) and osmium tetroxide are reacted in the presence of an organic base, in a solvent inactive for the reaction, under a condition ranging from cooling to room temperature, to obtain a corresponding 1,2-diol compound, and then the 1,2-diol is oxidized by adding periodic acids to the reaction mixture to thus obtain compound (80), which is an aldehyde. Examples of the solvent used here include an alcohol, such as tBuOH, an ether, such as THF, DOX and 1,2-dimethoxyethane, an aromatic hydrocarbon, such as benzene, toluene and xylene, acetone, and a mixed solvent of these compounds and water. Examples of the organic base used here include pyridine and 2,6-lutidine, and examples of the periodic acid used here include sodium periodate and periodic acid. In this reaction, compound (80) can also be produced by performing an oxidative cleavage reaction using ozone instead of osmium tetroxide and periodic acid. For example, the following can be referred to as a reference about this reaction: Chem. Rev., 1958, 58, 5, p. 925-1010.

[0231] (Third Step) This step is a method for producing compound (82) by a reductive amination reaction using compound (80) and an amine compound, compound (81). The reaction conditions are the same as when -RZ is -CHO in third step of Raw Material Synthesis 4.

[0232] (Fourth Step) This step is a reaction step of producing compound (2-1) by subjecting compound (82) to a deprotection reaction. The reaction conditions are the same as in the Production Method 2.

[0233] (Raw Material Synthesis 11) [Chemical Formula 257] (PGL1 represents a protecting group of an amino group contained in compound (2)-2, for example, a tert-butoxycarbonyl group. LGL1 represents a leaving group, for example, halogen, and is Br in one embodiment.)

[0234] This production method is a method for producing compound (2)-2 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is a group represented by the formula (XXX-LB), LCF is bond, Z is a group represented by the following formula (XXII), and G is N. [Chemical Formula 258] (XXX-LB)         (XXII)

[0235] (First Step) This step is a method for producing compound (85) by reacting compound (83) and compound (84). In this reaction, compound (83) and compound (84) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, under a condition ranging from room temperature to reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane or chloroform, an aromatic hydrocarbon, such as benzene, toluene or xylene, an ether, such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, an alcohol, such as MeOH, EtOH, isopropyl alcohol, butanol or amyl alcohol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water and a mixture thereof. Examples of the base include an inorganic base, such as tBuONa, tBuOK, cesium carbonate, tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide and the like. Examples of the palladium catalyst include Pd(t-Bu3P)2, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCb(dppf)-CH2Cb, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate. Performing the reaction in the presence of a ligand, such as SPhos, RuPhos, 1,1'-bis(diphenylphosphino)ferrocene and Xphos and the like, is sometimes advantageous for smoothly promoting the reaction. In addition, heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction. This step is a method for producing compound (2)-2 by a deprotection reaction of compound (85). The reaction conditions are the same as in the step described in Production Method 2.

[0237] (Raw Material Synthesis 12) [Chemical Formula 259] (LGL2 represents a leaving group, for example, halogen, and is F in one embodiment.)

[0238] This production method is a method for producing compound (2)-3 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is the following formula (XXX-LB), LCF is bond, Z is a group represented by formula (XXVI), and G is N. [Chemical Formula 260] (XXX-LB)

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

[0240] (Second Step) This step is a method for producing compound (88) by reducing compound (87). The reaction is carried out by stirring compound (87) and a reducing agent in an equivalent amount or with one in an excess equivalent amount in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 100°C, generally for 1 hours to 5 days. Examples of the reducing agent used here include, but are not particularly limited to, BH3-THF, LAH, and LiBH4 and the like. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane and dichloroethane, an ether-based solvent, such as THF, diethyl ether and DOX, and an aromatic hydrocarbon, such as toluene and benzene and the like. Compound (88) can also be produced by reducing compound (87) through a hydrogenation reaction in the presence of a metal catalyst. In this case, Raney nickel and MeOH, for example, can be used as the metal catalyst and the solvent, respectively. In addition, addition of aqueous ammonia is sometimes suitable for the reaction.

[0241] (Third Step) This step is a method for producing compound (89) by reacting compound (88) with acrylic acid ester. The reaction is carried out by stirring compound (88) and the acrylic acid ester in an equivalent amount or with one in an excess equivalent amount in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 150°C, generally for 1 hour to 5 days. Examples of the acrylic acid ester used here include methyl acrylate and ethyl acrylate. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, dichloroethane and chloroform, and an ether-based solvent, such as THF, diethyl ether and DOX and the like.

[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 stirring compound (89) and the urea-forming reagent in an equivalent amount or with one in an excess equivalent amount in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 150°C, generally for 1 hour to 5 days. Examples of the urea-forming reagent used here include trimethylsilyl isocyanate and chlorosulfonyl isocyanate and the like. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, dichloroethane and chloroform, and an ether-based solvent, such as THF, diethyl ether and DOX and the like. Compound (90) can also 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 stirring compound (90) and a weak base in an equivalent amount or with one in an excess equivalent amount in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 100°C, generally for 1 hour to 5 days. Examples of the weak base used here include benzyltrimethylammonium hydroxide, potassium carbonate, potassium trimethylsilanolate and the like. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, dichloroethane and chloroform, an ether-based solvent, such as THF, diethyl ether and DOX, and MeCN and the like.

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

[0245] (Raw Material Synthesis 13) [Chemical Formula 261] (LGL3 represents a leaving group, such as halogen, and is I in one embodiment. PGZ1 represents a protecting group of NH contained in compound (95), such as a p-methoxybenzyl group.)

[0246] This production method is the first method for producing compound (2)-4 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is a group represented by the following formula (XXXIII-LB2), A2 is CH or N, LCF is -LC1-O-, LC1 represents -LC-LD-LE-, Z is a group represented by the following formula (XXVII), and G is N. [Chemical Formula 262] (XXXIII-LB2)             (XXVII)

[0247] (First Step) This step is a method for producing compound (94) by a Mitsunobu reaction of compound (92) and compound (93). The reaction is carried out by stirring compound (92) and compound (93) in an equivalent amount or with one compound thereof in an excess equivalent amount using a phosphine reagent and an azodicarboxylic acid ester in a solvent inactive for the reaction, under a condition ranging from cooling to heating, preferably at -20°C to 100°C, generally for 1 hour to 5 days. Examples of the phosphine reagent used here include triphenylphosphine, tricyclohexylphosphine, and tri-n-butylphosphine and the like. Examples of the azodicarboxylic acid ester used here include dimethyl azodicarboxylate, diethyl azodicarboxylate, and diisopropyl azodicarboxylate and the like. Examples of the solvent used here include, but are not particularly limited to, an ether-based solvent, such as THF, diethyl ether and DOX, benzene, and toluene and the like. Note that an azodicarboxylic acid amide, such as N,N,N',N'-tetramethylazodicarboxamide and bis(piperidinocarbonyl)diimide, may also be used instead of the azodicarboxylic acid ester. Moreover, compound (94) can be produced by an ipso substitution reaction of compound (92), in the presence of a base, with a compound in which OH of compound (93) is halogen. In this case, sodium hydride or tBuOK can be used as the base, and the other conditions are the same as in the third step of Raw Material Synthesis 1.

[0248] (Second Step) This step is a method for producing compound (96) by a reaction of compound (94) and compound (95). This reaction is carried out by stirring compound (94) and compound (95) in an equivalent amount or with one compound thereof in an excess equivalent amount in the presence of a copper halide, a ligand and a base, in a solvent inactive for the reaction, under a condition ranging from ice-bath cooling to reflux with heat, generally for 1 hour to 5 days. Examples of the copper halide and the ligand used here include copper(I) iodide, 1,10-phenanthroline, and N,N,N',N'-tetramethylethylenediamine and the like. Examples of the base used here include, but are not particularly limited to, tripotassium phosphate and potassium carbonate and the like. Examples of the solvent used here include, but are not particularly limited to, an ether-based solvent, such as THF and DOX, benzene, toluene, and DOX and the like. In addition, heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction. In this step, the reaction can also be carried out in the same manner using a palladium catalyst. The reaction conditions are the same as in the third step of Raw Material Synthesis 16 described later.

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

[0250] (Raw Material Synthesis 14) [Chemical Formula 263] Second step (2)-4 PGZ1 (RZ1)r. (RZ1)r. (RZ\ First step (95) Third step HN.

[0251] This production method is the second method for producing compound (2) 4 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is a group represented by formula (XXXIII-LB2), A2 is CH or N, LCF is -LC1-O-, LC1 represents -LC-LD-LE-, Z is a group represented by formula (XXVII), and G is N. [Chemical Formula 264] (XXXIII-LB2)            (XXVII)

[0252] (First Step) This step is a method for producing compound (97) by a reaction of compound (93) and compound (95). The reaction conditions are the same as in the second step of Raw Material Synthesis 13.

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

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

[0255] (Raw Material Synthesis 15)

[0256] This production method is a method for producing compound (2)-5 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is a group represented by the following formula (XXXIII-LB2), A2 is CH or N, LCF is -LC1-, LC1 represents -LC-LD-LE-LF-, Z is a group represented by the following formula (XXVII)-1, and G is N. [Chemical Formula 266] (XXXIII-LB2)       (XXVII)-1

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

[0258] (Second Step) This step is a method of reducing compound (99) by a catalytic hydrogenation reaction to produce compound (100). The reaction conditions are the same as 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 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 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 in the fifth step of Raw Material Synthesis 12.

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

[0263] (Raw Material Synthesis 16) (LGL5 represents a leaving group, such as halogen, and is Br in one embodiment. Similarly, LGL6 represents a leaving group, such as halogen, and is I in one embodiment.)

[0264] This production method is a method for producing compound (2)-6 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is a group represented by formula (XXXIII-LB2), A2 is CH or N, LCF is -LC1-C =C-, LC1 represents -LC-LD-LE-, Z is a group represented by formula (XXVII), and G is N. [Chemical Formula 268] (XXXIII-LB2) (XXVII)

[0265] (First Step) This step is a method of oxidizing a hydroxyl group of compound (104) to produce compound (105). This reaction is carried out by stirring compound (104) and an oxidant in an equivalent amount or with one in an excess equivalent amount in a solvent inactive for the reaction, under a condition ranging from ice-bath cooling to room temperature, generally for 1 hour to 5 days. Examples of the oxidant used here include Dess-Martin periodinane and the like. Examples of the solvent used here include, but are not particularly limited to, an aromatic hydrocarbon, such as benzene, and a halogenated hydrocarbon, such as dichloromethane.

[0266] (Second Step) 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 compound (105) and the ethynyl group-introducing reagent in an equivalent amount or with one in an excess equivalent amount, in a solvent inactive for the reaction, under a condition ranging from ice-bath cooling to room temperature, generally for 1 hour to 5 days. Examples of the ethynyl group-introducing reagent used here include dimethyl (1-diazo-2-oxopropyl)phosphonate and the like. Examples of the solvent include, but are not particularly limited to, an alcohol, such as MeOH and EtOH, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an ether, such as THF, DOX and dimethoxyethane, DMF, DMSO, MeCN or water, and a mixture thereof.

[0267] (Third Step) This step is a method for producing compound (108) by a reaction of compound (107) and compound (95). In this reaction, compound (107) and compound (95) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, under a condition ranging from at room temperature to reflux with heat, preferably at 20°C to 150°C, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane or chloroform, an aromatic hydrocarbon, such as benzene, toluene or xylene, an ether, such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, an alcohol, such as MeOH, EtOH, isopropyl alcohol, butanol or amyl alcohol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water and a mixture thereof. Examples of the base include an inorganic base, such as cesium carbonate, tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide and the like. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCh(dppf)-CH2Ch, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate and the like. Performing the reaction in the presence of a ligand, such as SPhos, RuPhos, 1,1'-bis(diphenylphosphino)ferrocene, and Xphos and the like is sometimes advantageous for smoothly promoting the reaction. In addition, heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction.

[0268] (Fourth Step) This step is a method for producing compound (109) by a reaction of compound (106) and compound (108). In this reaction, compound (106) and compound (108) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base, a palladium catalyst, and a copper catalyst, under a condition ranging from room temperature to reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to 5 days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane or chloroform, an aromatic hydrocarbon, such as benzene, toluene or xylene, an ether, such as diethyl ether, THF, DOX or 1,2-dimethoxyethane, an alcohol, such as MeOH, EtOH, isopropyl alcohol, butanol or amyl alcohol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water and a mixture thereof. Examples of the base include an inorganic base, such as cesium carbonate, tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide and the like. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, PdCh(PPh3)2, PdCh(dppf)-CH2Cl2, Pd2(dba)3, RuPhos Pd G3, and palladium(II) acetate and the like, and examples of the copper catalyst include copper(I) iodide and the like. Examples of the base include TEA and DIPEA and the like.

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

[0270] (Raw Material Synthesis 17) [Chemical Formula 269] (LGL4 represents a leaving group, for example, halogen, and is Cl in one embodiment.)

[0271] This production method is a method for producing compound (2)-7 included in compound (2), which is a raw material compound of Production Method 1, wherein LB is a group represented by formula (XXXIII-LB1), LCF is -C(RL2XRL3)-C=C-, Z is a group represented by formula (XXIV), and G is N. [Chemical Formula 270] ( / mO    Ft y     n            \X (XXXIII-LB1)        (XXIV)

[0272] (First Sep) This step is a method for producing compound (112) from compound (110) and compound (111). This reaction is carried out by stirring compound (110) and compound (111) in an equivalent amount or with one compound thereof in an excess equivalent amount in a solvent inactive for the reaction, in the presence of a base, under a condition ranging from ice-bath cooling to room temperature, generally for 1 hour to 5 days. Examples of the base used here include TEA and the like. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an ether, such as THF, DOX and dimethoxyethane, DMF, DMSO, and MeCN and the like. In addition, addition of a copper salt such as copper(I) chloride and the like is sometimes suitable for the reaction. When RL2 and RL3 both are H, however, compound (112) can also be produced by a nucleophilic substitution reaction of compound (110) and compound (111) in the presence of a base. The reaction conditions in this case are the same as in the tenth step of Raw Material Synthesis 1.

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

[0274] (Raw Material Synthesis 18) [Chemical Formula 271]

[0275] This production method is a method for producing compound (120) included in compound (115), which is a raw material compound of Production Method 4, wherein -LA-included in -L- is CO, -LB- is -N(RL1A)- or divalent group of optionally substituted saturated hetero ring containing 1 or 2 nitrogen atoms, and -LC-LD-LE-LF- is -LCF-.

[0276] (First Step) This step is a step of producing compound (116) by reacting compound (54) and compound (9). The reaction conditions are the same as in the third step of Raw Material Synthesis 1.

[0277] (Second Step) This step is a step of producing compound (117) by performing a deprotection reaction of compound (116). The reaction conditions are the same as in the eleventh step of Raw Material Synthesis 1.

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

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

[0280] (Fifth Step) This step is a step of producing compound (120) by reacting compound (119) and compound (2). The reaction conditions are the same as in the third step of Raw Material Synthesis 2.

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

[0282] Test Example 1: Evaluation of KRAS degradation activity on human G12V mutant KRAS-positive pancreatic cancer line PA-TU-8902 The KRAS degradation activity of test compounds was evaluated by measuring the KRAS expression levels according to Cell ELISA. PA-TU-8902 cells (DSMZ, ACC 179) were seeded at 36 liL each on 384-well plates (from Greiner bio-one) to give 1.5 x 104 cells per well. As for the cell culture conditions, DMEM medium (from Sigma-Aldrich) containing 10% fetal bovine serum (from Cytiva) was used in the presence of 5% CO2 at 37°C. The next day, the test compounds (10 points having final concentrations in the range of 1 liM to 0.03 nM) and dimethyl sulfide (DMSO), which was the solvent for the test compounds, as a negative control were diluted 100-fold with a fresh medium and were added at 4 l L per well, followed by culturing for 24 hours. The next day, the culture supernatant was removed, and 4% paraformaldehyde phosphate buffer (from FUJIFILM Wako Pure Chemical Corporation) was added at 20 lL per well. The plates were allowed to stand for 30 minutes at room temperature to thus immobilize the cells. Thereafter, the supernatant was removed, and 0.1% Polyoxyethylene(10) Octylphenyl Ether (from FUJIFILM Wako Pure Chemical Corporation)-containing phosphate buffered saline (PBS) was added at 20 lL per well. After the culture was allowed to stand for 10 minutes at room temperature, the supernatant was removed. PBS was added at 25 lL per well, and the supernatant was removed to thus wash each well. The washing was performed twice in total. Subsequent washing operations were performed in the same manner. Next, 0.5% sodium dodecyl sulfate (SDS; from ThermoFisher Scientific)-containing PBS was added at 20 lL per well. After the culture was allowed to stand for 10 minutes at room temperature, the supernatant was removed by centrifugation of the plates. After washing with PBS, the supernatant was removed by centrifugation, and Intercept Blocking Buffer (from LI-COR Biosciences) was added at 20 lL per well. After the culture was allowed to stand for 30 minutes at room temperature, the supernatant was removed by centrifugation, and a solution obtained by diluting, as primary antibodies, anti-KRAS antibody (EPR23474-76; Rabbit mAb; from Abcam; 1,000fold diluted) and anti-p-actin antibody (Anti-beta Actin antibody; Mouse mAb; from Abcam; 1000-fold diluted) with Intercept Blocking Buffer was added as a mixed solution at 15 lL per well and allowed to stand overnight at 4°C. The next day, the supernatant was removed by centrifugation and washed with PBS. The supernatant was removed by centrifugation, and a solution obtained by diluting, as secondary antibodies, anti-rabbit IgG antibody (IRDye 800CW Goat anti-Rabbit IgG; from LI-COR Biosciences) and anti-mouse IgG antibody (IRDye 680RD Donkey anti-Mouse IgG; from LI-COR Biosciences) 1,000-fold with Intercept Blocking Buffer was added as a mixed solution at 15 uL per well. After the culture was allowed to stand for 1 hour at room temperature, the supernatant was removed by centrifugation and washed with PBS. After removing the supernatant, the plates were dried with air at room temperature for 2 hours or more, and the fluorescent signals at 721 to 740 nm and 816 to 840 nm were measured with Odyssey M Imaging System (from Li-COR Biosciences). The degradation rate of KRAS was calculated based on the KRAS signaling value of 0% at the time of addition of DMSO, which was corrected with the signaling value of Pactin, and the KRAS signaling value of 100% when stained only with the anti-P-actin antibody. The 50% degradation concentration (DC50) of KRAS was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) and formula (I-I) are shown in tables below.

[0283] [Table 1-1] Ex DC50(nM) Ex DC50(nM) Ex DC50(nM) 1 1.5 13 2.4 25 2.1 2 1.4 14 0.92 26 0.87 3 1.8 15 4.0 27 2.9 4 1.3 16 5.0 28 0.64 5 2.5 17 2.3 29 0.35 6 5.2 18 0.93 30 0.89 7 1.1 19 0.91 31 6.0 8 5.6 20 0.96 32 1.2 9 1.6 21 1.8 33 4.9 10 8.3 22 2.7 34 1.7 11 0.90 23 1.5 12 1.3 24 1.2 Ex DC50(nM) 35 1.8 36 0.24 37 0.45 38 0.31 39 0.93 40 0.25 41 0.68

[0285] Test Example 2: Evaluation of non-anchorage-dependent cell growth inhibitory effect on human G12V mutant KRAS-positive pancreatic cancer line PA-TU-8902, human G12D mutant KRAS-positive pancreatic cancer line PK-59, human G12C mutant KRASpositive pancreatic cancer line MIA PaCa-2, human G12C mutant KRAS-positive lung cancer line NCI-H358, human G12D mutant KRAS-positive colorectal cancer line GP2d, human G13D mutant KRAS-positive colorectal cancer line LoVo, or human wild-type KRAS gene amplification-positive gastric cancer line MKN1 The non-anchorage-dependent cell growth inhibitory effect of test compounds was evaluated by spheroid 3D cell 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 seeded on low-cell-adhesive round bottom 384-well plates (Prime Surface: from Sumitomo Bakelite) at 36 pL / well to give 5 x 102 cells per well, and the PA-TU-8902 cells were cultured under the same conditions as in Test Example 1. The GP2d cells were cultured using DMEM medium containing 10% fetal bovine serum in the presence of 5% CO2 at 37°C. The PK-59 cells, MIA PaCa-2 cells, LoVo cells, NCI-H358 cells, or MKN1 cells were cultured using RPMI-1640 medium (from Sigma-Aldrich) containing 10% fetal bovine serum in the presence of 5% CO2 at 37°C. The next day, the test compounds (10 points having final concentrations in the range of 10 pM to 0.03 nM) and DMSO, which was the solvent for the test compounds, as a negative control were diluted 100-fold with a fresh medium and were added at 4 pL to each well containing the PA-TU-8902 cells, PK-59 cells, MIA PaCa-2 cells, LoVo cells, NCI-H358 cells, or MKN1 cells. After culturing in the presence of 5% CO2 at 37°C for 6 days, CellTiter Glo 2.0 (from Promega) was added at 20 u.L per well. After stirring with a plate mixer at room temperature for 1 hour, the luminescent signals were measured with ARVO X3 (from PerkinElmer). With the signaling value in treatment with DMSO taken as a survival rate of 100% and with the signaling value in the medium alone without cells taken as a survival rate of 0%, the 50% inhibitory concentration (IC50) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results for some test compounds of formula (I) and formula (I-I) are shown in tables below. Ex G12V (PA-TU-8902) IC5o(nM) G12D (PK-59) IC50(nM) G12C (MIA PaCa-2) IC50(nM) G13D (LoVo) IC50(nM) 1 16 7.3 4.6 30 2 11 11 2.8 130 3 20 49 8.0 140 4 9.1 16 2.9 70 5 18 66 7.3 160 6 36 25 7.2 300 7 10 4.6 3.2 40 8 32 18 24 47 9 12 67 8.8 140 10 59 79 19 610 11 5.7 4.8 2.8 40 12 16 15 4.2 91 13 21 30 6.7 120 14 8.9 5.1 1.8 33 15 20 9.6 4.6 75 16 41 41 11 170 17 29 30 6.9 230 18 7.3 5.6 2.2 35 19 11 5.7 3.9 51 20 8.5 4.1 3.1 46 21 13 11 9.7 39 22 33 22 12 270 23 12 7.3 4.9 47 24 11 6.2 4.6 73 25 20 17 9.3 230 26 6.7 12 3.0 42 27 25 39 11 190 28 5.9 7.4 2.1 32 29 2.0 7.7 1.6 28 30 9.6 14 3.8 42 31 36 76 18 670 32 12 6.0 2.9 31 33 30 17 9.6 200 34 20 13 5.1 55 Ex G12C (NCI-H358) IC50 (nM) Wild-type amplification (MKN1) IC50(nM) 1 2.9 3.1 7 1.9 2.9 14 1.5 2.1 20 2.8 2.8 24 1.7 1.9

[0288] Test Example 3: Evaluation of anti-tumor activity in human G12D mutant KRASpositive colorectal cancer line GP2d tumor-bearing mice GP2d cells were cultured under the same conditions as in Test Example 2. The GP2d cells were collected and suspended in PBS, and a cell suspension prepared at 4.0 x 107 cells / mL with two equal volumes of VitroGel Hydrogel Matrix (from TheWell Bioscience) was subcutaneously inoculated into 4- to 5-week-old male nude mice (BALB / c-nu (nu / nu), from The Jackson Laboratory Japan, Inc.) in a volume of 100 liL. About two weeks after the inoculation, the mice were divided into groups so that all the groups had approximately the same tumor volume and body weight, and administration of a test compound was started on the next day. The study was conducted for 5 mice each of a vehicle control group and test compound administration groups. The test compounds were dissolved in a solvent containing ethanol (from FUJIFILM Wako Pure Chemical Corporation), a 5% glucose solution (from Otsuka Pharmaceutical), 1 M hydrochloric acid, a 50% solution of (2-hydroxypropyl)-p-cyclodextrin (HP—pCD) (from ROQUETTE), HCO-40 (from Nikko Chemicals Co., Ltd.), and 1 M sodium hydroxide solution at a liquid amount ratio of 4:84.4:1.1:1:9:0.5. The test compound or vehicle control was administered into the tail vein. The administration was performed once a week and twice in total. The tumor sizes and the body weights were measured twice a week. The tumor volumes were calculated using the following equation. [Tumor volume (mm3)] = [Long diameter of tumor (mm)] x [Short diameter of tumor (mm)]2 x 0.5 The tumor growth inhibition rate (%) by the test compound was calculated with the tumor volume of the test compound administration group on the previous day of the start of the administration taken as 100% inhibition and the tumor volumes of the vehicle groups two weeks after the day of grouping taken as 0% inhibition. In addition, when the tumor volume of a test compound administration group was smaller than the tumor volume on the previous day of the start of the administration, the tumor regression rate (%) by the test compound was calculated with the tumor volume on the previous day of the start of the administration taken as 0% regression and with the tumor volume 0 taken as 100% regression. The results for some test compounds of formula (I) and formula (I-I) are shown in a table below.

[0289] [Table 3] Ex Dose (mg / kg) Anti-tumor activity 1 3 85% inhibition 7 3 24% regression 14 3 97% inhibition 20 3 18% regression 24 3 29% regression

[0290] Test Example 4: Evaluation of anti-tumor activity in human G12V mutant KRASpositive pancreatic cancer line PA-TU-8988S tumor-bearing mice PA-TU-8988S cells are cultured using DMEM medium containing 10% fetal bovine serum in the presence of 5% CO2 at 37°C. The PA-TU-8988S cells are collected and suspended in PBS, and a cell suspension prepared at 5.0 x 107 cells / mL with Cultrex Basement Membrane Extract (from R&D systems) to have a final concentration of 5.0 mg / mL is subcutaneously inoculated into 4- to 5-week-old male nude mice (BALB / c-nu (nu / nu), from The Jackson Laboratory Japan, Inc.) in a volume of 100 pL. About two weeks after the inoculation, the mice are divided into groups so that all the groups have approximately the same tumor volume and body weight, and administration of a test compound is started on the next day. The study is conducted for 5 mice each of a vehicle control group and test compound administration groups. The test compound is dissolved in the same solvent as in Test Example 3. The test compound or vehicle control is administered into the tail vein. The administration is performed two or three times at an interval of once a week. The tumor sizes and the body weights were measured twice a week. The tumor volumes, the tumor growth inhibition rate (%) by the test compound, and the tumor regression rate (%) by the test compound are calculated in the same manner as in Test Example 3.

[0291] Test Example 5: Evaluation of anti-tumor activity on human G12C mutant KRASpositive lung cancer line NCI-H358 tumor-bearing mice NCI-H358 cells are cultured in the same manner as in Test Example 2. The NCI-H358 cells are collected and suspended in PBS, and a cell suspension prepared at 5.0 x 107 cells / mL with two equal volumes of VitroGel Hydrogel Matrix (from TheWell Bioscience) is subcutaneously inoculated into 4- to 5-week-old male nude mice (BALB / c-nu (nu / nu), from The Jackson Laboratory Japan, Inc.) in a volume of 100 liL. About three weeks after the inoculation, the mice are divided into groups so that all the groups have approximately the same tumor volume and body weight, and administration of test compounds is started on the next day. The study is conducted for 5 mice each of a vehicle control group and test compound administration groups. The test compound is dissolved in the same solvent as in Test Example 3. The test compound or vehicle control is administered into the tail vein. The administration is performed two or three times at an interval of once a week. The tumor sizes and the body weights are measured twice or three times a week. The tumor volumes, the tumor growth inhibition rate (%) by the test compound, and the tumor regression rate (%) by the test compound are calculated in the same manner as in Test Example 3.

[0292] As a result of the above tests, a degradation-inducing action of G12V mutant KRAS was observed for some compounds of formula (I) and formula (I-I). Moreover, cell growth 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 were observed for some compound of formula (I) and formula (I-I). Further, anti-tumor activity in human G12D mutant KRAS-positive colorectal cancer line tumor-bearing mice was observed for some compounds of formula (I) and formula (I-I). Therefore, the compounds of formula (I) and formula (I-I) can be used for the treatment of cancer, in particular, G12C mutant, G12D mutant, G12V mutant and G13D mutant KRASpositive cancer, and the like.

[0293] A pharmaceutical composition containing one or more compounds of formula (I) and formula (I-I) or a salt thereof as active ingredients can be prepared using an excipient usually used in the art, i.e., a pharmaceutical excipient, a pharmaceutical carrier or the like through a method usually used. The administration may be either oral administration with a tablet, pill, capsule, granule, powder, liquid or other agent or parenteral administration with an intraarticular, intravenous, intramuscular or other injection, a transmucosal agent, an inhalant or the like.

[0294] As a solid composition for oral administration, a tablet, powder, granular or other agent is used. In such a solid composition, one or more active ingredients are mixed with at least one inert excipient. The composition may contain an inert additive, such as a lubricant, a disintegrant, a stabilizer and a dissolution aid according to a conventional method. A tablet or pill may be coated with a sugar coating or a film soluble in the stomach or intestine, as needed. A liquid composition for oral administration includes a pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir agent and contains a generally used inactive diluent, for example, purified water or EtOH. The liquid composition may contain, in addition to the inactive diluent, an adjuvant, such as a solubilizer, a wetting agent and a suspending agent, a sweetening agent, a flavor, an aromatic, or a preservative.

[0295] The injection agent for parenteral administration contains a sterile aqueous or nonaqueous solution, a suspension, or an emulsion. Examples of the aqueous solvent include distilled water for injection or physiological saline. An example of the nonaqueous solvent is an alcohol, such as EtOH. Such a composition may further contain an isotonizing agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer or a dissolution aid. These compositions are sterilized, for example, by filtration through a bacteria-retaining filter, incorporation of a microbicide or irradiation. In addition, such a composition can be produced as a sterile solid composition, which is dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0296] The transmucosal agent, such as an inhalant and a transnasal agent, is used in a solid, liquid or semi-solid form and can be produced according to a conventionally known method. For example, a known excipient and in addition, a pH modifier, a preservative, a surfactant, a lubricant, a stabilizer, a thickener or the like may be appropriately added. The administration can be performed using a device for appropriate inhalation or insufflation. For example, the agent can be administered using a known device, such as a metering and administering inhalation device, or an atomizer, as a compound alone or a powder of a mixture formulated, or as a solution or a suspension in combination with a medically acceptable carrier. A dry powder inhaler or the like may be for a single administration or multiple administrations, and dry powder or powder-containing capsule can be used. Alternatively, the agent may be used in a form of a pressurized aerosol spray or the like using an appropriate ejection agent, for example, a suitable gas, such as a chlorofluoroalkane or carbon dioxide.

[0297] In the case of a common oral administration, the daily dose is appropriately about 0.001 to 100 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, further preferably 0.1 to 10 mg / kg body weight, and the dose is given once or is divided into two to four times in a day. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg / kg body weight and is given once or is divided into multiple times in a day. In addition, the daily dose of a transmucosal agent is about 0.001 to 100 mg / kg body weight and is given once or is divided into multiple times in a day. The dose is appropriately decided depending on the individual case taking the symptom, age, sex and the like into account.

[0298] Depending on the route of administration, dosage form, site of administration and types of excipient and additive, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, in one embodiment, 0.01 to 50% by weight, of one or more compounds of formula (I) and formula (I-I) or salts thereof which are active ingredients.

[0299] The compounds of formula (I) and formula (I-I) can be used in combination with various therapeutic or prophylactic agents for diseases in which the compounds of formula (I) and formula (I-I) are considered to exhibit efficacy. The combination use may be simultaneous administration or separate administration in succession, or administered at a desired interval. A simultaneous administration preparation may be a formulated agent or may be separately formulated. EXAMPLES

[0300] Hereinafter, the production methods of the compounds of formula (I) and compound (I-I) will be described in more detail based on Examples. Note that the present invention is not limited to compounds described in Examples below. The production methods of raw material compounds are also shown in the Production Examples. Although the production methods of the compounds of formula (I) and formula (I-I) are not limited only to the production methods of specific Examples described below, the compounds of formula (I) and formula (I-I) can also be produced by a combination of these production methods or methods obvious to a person skilled in the art.

[0301] Note that, in the present specification, a compound is sometimes named by using a naming soft, such as ACD / Name(R) (Advanced Chemistry Development, Inc.).

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

[0303] Production Example 1 Under an argon atmosphere, to a mixed solution in MeOH (70 mL) and THF (70 mL) 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) were added sodium hydrogen carbonate (1,551 mg) and 10% Pd / C (about 50% water content, 994 mg) at room temperature, and under a hydrogen atmosphere, the mixture was stirred overnight at ambient temperature and pressure. After argon replacement, the reaction mixture was filtered through celite(R) pad using CHCl3 / IPA (4 / 1, 100 mL) and EtOH / water (10 / 1, 100 mL), and the filtrate was concentrated under reduced pressure. After EtOAc and water were added, the separated organic layer was washed with saturated saline, was dried over anhydrous magnesium sulfate, and was filtered and concentrated under reduced pressure, thus obtaining (7M)-4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (2,705 mg) as a foam-like solid.

[0304] Production Example 2 To a DMF (150 mL) solution of (7M)-4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazoline-8-ol (10.3 g) were added tert-butyl 4-(chloromethyl)benzoate (5.5 g) and cesium carbonate (18 g) under ice-bath cooling, and under an argon atmosphere, the mixture was stirred at 40°C overnight. The reaction was quenched with saturated aqueous ammonium chloride solution under ice-bath cooling. EtOAc and water were added to separate the organic layer from the aqueous layer, and the organic layer was washed once with saturated saline, was dried over anhydrous sodium sulfate, was filtered and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc), thus obtaining 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 foamlike solid.

[0305] Production Example 3 To a THF (10 mL) 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) was added tBuOK (160 mg) under ice-bath cooling, and the mixture was stirred for 30 minutes under ice-bath cooling. The reaction was quenched with saturated aqueous ammonium chloride solution under ice-bath cooling. EtOAc and water were added to separate the organic layer from the aqueous layer, and the aqueous layer was extracted twice with EtOAc. The collected organic layer was dried over anhydrous sodium sulfate, was filtered and was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc), thus obtaining 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 foam-like solid.

[0306] Production Example 4 To a THF (10 mL) 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) were added 3,4-dihydro-2H-pyrane (0.5 mL) and p-toluenesulfonic acid monohydrate (270 mg) under ice-bath cooling, and under an argon atmosphere, the mixture was stirred at room temperature overnight. After Et3N (1.3 mL) was added under ice-bath cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH), thus obtaining 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 foam-like solid.

[0307] Production Example 5 To a MeCN (10 mL) 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) were added DIPEA (0.9 mL) and PyAOP (720 mg) under ice-bath cooling, and under an argon atmosphere, the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl3 / MeOH / 28% aqueous ammonia), thus obtaining 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 foam-like solid.

[0308] Production Example 6 To a CH2Cl2 (10 mL) 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) was added TFA (2.4 mL) under ice-bath cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, THF (3 mL) and saturated aqueous sodium hydrogen carbonate were added under ice-bath cooling, and the mixture was stirred under ice-bath cooling for 1 minute. CHCl3 / IPA (4 / 1) and water were added, the pH was adjusted to 8 to 9 by the addition of hydrochloric acid (1M), and the aqueous layer was extracted four times with CHCl3 / IPA (4 / 1). The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, thus obtaining 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] Production Example 7 At room temperature, 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-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 liL) and stirred under microwave irradiation at 150°C for 1 hour. At room temperature, CuI (400 mg), tripotassium phosphate (450 mg) and TMEDA (0.31 mL) were added thereto, and the mixture was stirred under microwave irradiation at 150°C for 1.5 hours. Water and EtOAc were added to the reaction mixture at room temperature. The mixture was filtered, and the filtrate was extracted three times with EtOAc. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl3 / MeOH), thus obtaining 1-(2-hydroxypyridin-4-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (204 mg) as a foam-like solid. At room temperature, 1-(2-hydroxypyridin-4-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-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). Under ice-bath cooling, N,N,N',N'-tetramethylazodicarboxamide (1,253 mg) and tri-n-butylphosphine (1.97 mL) were added, and the mixture was stirred under an argon atmosphere at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture at room temperature, and the mixture was extracted three times with EtOAc. The collected organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, then filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / EtOAc), thus obtaining 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] Production Example 9 At room temperature, 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 (1,750 mg) was dissolved in TFA (28 mL). TfOH (1.51 mL) was added at room temperature, and the mixture was stirred under an argon atmosphere at 60°C for 4 hours. The reaction mixture was concentrated under reduced pressure, Et3N (4 mL) was added to the resulting residue under ice-bath cooling, and the mixture was purified by basic silica gel column chromatography (CHCl3 / MeOH / 28% aqueous ammonium), thus obtaining 1-{2-[2-(3-azaspiro[5.5]undecan-9-yl)ethoxy]pyridin-4-yl}-1,3-diazinane-2,4-dione (1,451 mg) as a solid.

[0312] Production Example 10 To a DMSO (3 mL) solution of 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2, 4-dione (300 mg), tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (340 mg) and Pd(tBu3P)2 (46 mg) was added tBuONa (170 mg) at room temperature, and the mixture was stirred under microwave irradiation at 100°C for 1 hour under an argon atmosphere. Water was added at room temperature, the mixture was extracted three times with EtOAc. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (hexane / CHCl3 / MeOH), thus obtaining tert-butyl 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methyl-1H-indazol-6-tl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (205 mg) as a solid.

[0313] Production 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 CH2Cl2 (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 / CHCl3 / MeOH), thus obtaining 1-[5-fluoro-1-methyl-6-(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-1H-indazol-3-yl]-1,3-diazinane-2,4-dione (130 mg) as a solid.

[0314] Production 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), DIPEA (720 uL) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. Subsequently, ethylhydrazine dihydrochloride (835 mg) and DIPEA (3.5 mL) were added to the reaction mixture. 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. Then, the resulting powder was collected by filtration and was dried under reduced pressure, thus obtaining 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] Production 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 uL) and DL-lactic acid (100 uL) was stirred under microwave irradiation at 120°C for 4 hours and at 130°C for 2 hours. The reaction mixture was poured into EtOAc / water and extracted three times with EtOAc. The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, then 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 multiple portions under ice-bath cooling, and the mixture was stirred for 10 minutes under ice-bath cooling and for 1 hour at room temperature. Sodium cyanate (90 mg) was added under ice-bath 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 aqueous sodium hydroxide (1M), once with saturated aqueous sodium hydrogen carbonate and once with saturated saline, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The resulting residue was dissolved in MeCN (10 mL), benzyltrimethylammonium hydroxide (40% MeOH solution, 250 pL) 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 the residue was purified by silica gel column chromatography (CHCl3 / MeOH), thus obtaining 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 foam-like solid.

[0316] Production 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 CH2Cl2 (3 mL), TFA (500 pL) 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, followed by HCl / EtOAc (4 M, 500 pL) at room temperature. The mixture was stirred for 20 minutes at room temperature and then concentrated under reduced pressure. The residue was suspended in EtOAc, collected by filtration, 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-diazinane-2,4-dionen hydrochloride (204 mg) as a solid.

[0317] Production Example 15 7-Bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-phenylethoxy]quinazoline (4.7 g) and CH2Cl2 (90 mL) were added, followed by mCPBA (about 30% water content, 4.8 g) with stirring in an ice bath. Then, the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with CH2Cl2, washed with saturated aqueous sodium thiosulfate and saturated aqueous sodium hydrogen carbonate, and separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed under reduced pressure. To the residue were added 3-dimethylamino-2,2-dimethyl-1-propanol (1.6 mL) and THF (50 mL), and tBuOK (2 g) was added in a MeOH / ice bath with stirring. Then, the mixture was stirred in the same bath under an argon atmosphere for 0.5 hours. Ice and saturated aqueous ammonium chloride were poured into the reaction mixture which was returned to room temperature, followed by extraction with EtOAc twice. The organic layer was washed with saturated saline, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / EtOAc), thus obtaining 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] Production 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. Then, the mixture was stirred under an argon atmosphere at room temperature for 3 hours. After Et3N (3 mL) was added to the reaction mixture, the solvent was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (CHCl3 / MeOH), thus obtaining 7-bromo-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-ol (2.97 g) as a foam-like solid.

[0319] Production 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, and the mixture was subjected to an operation of degassing under reduced pressure / filling with argon several times and was then stirred under an argon atmosphere at 80°C for 2 hours. To the cooled reaction mixture was poured ice water and extracted twice with EtOAc. The collected organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane / EtOAc), thus obtaining (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 (diastereomeric mixture derived from axial chirality, 189 mg) as a foam-like solid.

[0320] Production Example 19 To (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) were added MeOH (5 mL) and 20% Pd(OH)2 / C (about 50% water content, 60 mg), and the mixture was stirred under a hydrogen atmosphere at ambient temperature and pressure for 1 hour. To the reaction mixture was added celite(R) and was filtered through celite(R) pad while washing with EtOAc and CHCl3. Toluene (about 5 mL) was added to the filtrate, and the solvent was removed under reduced pressure, thus obtaining (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 foam-like solid. Triisopropylsilane (0.12 mL) and CH2Cl2 (3 mL) were poured into 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]...

Claims

1. A compound represented by formula (I) or a salt thereof:[Chemical Formula 1](I)whereinA is CRA or N,RA is H, C1-3 alkyl, -CN, or -O-(C1-3 alkyl),E is CH or N,X1 is -CH2-, -O-, or -NRX1-,RX1 is H or optionally substituted C1-3 alkyl,provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom,together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11-membered saturated hetero ring group,R1 is represented by the following formula (II), (III), (IV), (V), (VI), or (VII):[Chemical Formula 2](II)               (III)              (IV)                   (V)                 (VI)              (VII)R1a and R1b are the same or different, and are each H, methyl, F, or Cl,R1c is F, Cl, methyl, ethyl, trifluoromethyl, or cyclopropyl,R1d is H, methyl, ethyl, F, Cl, or -C-C-H,R2 is H, halogen, optionally substituted C1-3 alkyl, cyclopropyl, or vinyl,R3 is a group selected from the group consisting of the following formulas (VIII),(XI), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII):[Chemical Formula 3]R3a n-r i3b(VIII)r-NX n ''R'(IX)(X)X (XI)(X")X^3gR yX (XV)(XIII)(XVI)X (XIV)(XVII)R3a is -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2,R3b is H or C1-3 alkyl,R3c and R3d are -(CH2)pCHR3e-NRN1RN2; -(CH2)pCHR3e-OR3f; 4- to 6-membered saturated hetero ring group optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, and -NRN1RN2; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, -C1-3 alkylene-OR3f, -C1-3 alkylene-NRN1RN2, -OR3f, and -NRN1RN2,R3e is H, F, or C1-3 alkyl,R3f is the same or different, and is H or C1-3 alkyl,R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-memberedheteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6-membered saturated hetero ring group,R3h is H, F, or C1-3 alkyl,R3i is the same or different, and is a group selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN, and oxo, ortwo R3is present on the same carbon atom together with the carbon atom adjacent thereto may form spiro ring having a ring selected from the group consisting of C3-6 cycloalkane and 4- to 6-membered saturated hetero ring, wherein the spiro ring is optionally substituted with 1 to 2 groups selected from the group of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two adjacent carbon atoms together with the two carbon atoms may form fused ring having ring selected from the group consisting of C3-6 cycloalkane and 4- to 6-membered saturated hetero ring, wherein the fused ring is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo, orR3i present on two non-adjacent carbon atoms together with the two carbon atoms may form bridged structure composed of 1 to 2 carbon atoms, and ring having the bridged structure is optionally substituted with 1 to 2 groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen, and oxo,RN1 and RN2 are the same or different, and are each H or C1-3 alkyl, orRN1 and RN2 together with the nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group, orR3e and RN1 together with the carbon atom and the nitrogen atom bonded thereto may form optionally substituted 4- to 6-membered saturated hetero ring group,R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,X3 is O or S,X4 is -CH2-, -CH2-CH2-, -O-CH2-, -O-, or -O-NH-,n1 is 1 or 2,p is 1 or 2,q is 1 to 8,R4 is optionally substituted C1-6 alkyl, optionally substituted piperidinyl, or optionally substituted tetrahydropyranyl,Y is phenylene or pyridinediyl, wherein the phenylene is optionally substituted with F,L is -(LA-LB-LC-LD-LE-LF)-,LA, LB, LC, LD, LE, and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O,RL1A is H or C1-3 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):[Chemical Formula 4]R 2 (XVIII)(XIX)(XX)(XXI)                    (XXII)                 (XXIII)(XXIV)               (XXV)              (XXVI)           (XXVII)(XXVIII)(XXIX)ring B is benzene ring or 6-membered hetero ring,ring Hy is 5- or 6-membered hetero ring,RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5,RZ2 is H or C1-3 alkyl,RZ3 is H or C1-3 alkyl,RZ4 is the same or different, and is H or C1-3 alkyl,RZ5 is C1-3 alkyl,L is bonded to ring B in the above formulas (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXVI), (XXVIII), and (XXIX), to the benzene ring in formulas (XXIV) and (XXV), and to ring Hy in formula (XXVII),r is 1 or 2, andG is N or CH,provided that when G is N, Z is the above formula (XVIII), (XXII), (XXIII),(XXIV), (XXVI), (XXVII), or (XXIX).

2. The compound or a salt thereof according to claim 1,wherein E is CH,R3 is a group represented by the following formula (XII), (XIII), (XIV), or (XVII):[Chemical Formula 5]„3gR 92J\„3fX R(xii)XR3jH2N(XIII).......\ /        oO N       X2(xiv) XH N )=O(XVII)R3f is the same or different, and is H or C1-3 alkyl,R3g is optionally substituted C3-6 cycloalkyl, optionally substituted 5-memberedheteroaryl, optionally substituted 6-membered heteroaryl, or optionally substituted 4- to 6membered saturated hetero ring group,R3j is a group selected from the group consisting of H, OH, halogen, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 5-membered heteroaryl, optionally substituted 6membered heteroaryl, and -CN,X2 is -O-, -NH-, or -N(C1-3 alkyl)-,L is -(LA-LB-LC-LD-LE-LF)-,LA, LB, LC, LD, LE and LF are the same or different, and are each a group selected from the group consisting of bond, -O-, -NRL1A-, divalent group of optionally substituted saturated hetero ring, optionally substituted C1-3 alkylene, optionally substituted C3-6 cycloalkylene, C2-3 alkynediyl optionally substituted with C1-3 alkyl, and C=O,RL1A is H or C1-3 alkyl,Z is a group selected from the group consisting of formulas (XXII), (XXIV), (XXVI), and (XXVII):(XXII)(XXIV)           (XXVI)            (XXVII)ring B is benzene ring or 6-membered hetero ring,ring Hy is 5- or 6-membered hetero ring,RZ1 is H, C1-3 alkyl, halogen, -O-(C1-3 alkyl), -NRZ42, -CN, -CONRZ42, or -NRZ4CORZ5,RZ2 is H or C1-3 alkyl,RZ4 is the same or different, and is H or C1-3 alkyl,RZ5 is C1-3 alkyl,r is 1 or 2,L is bonded to ring B in the above formulas (XXII) and (XXVI), to the benzene ring in formulas (XXIV), and to ring Hy in formula (XXVII), andG is N.

3. The compound or a salt thereof according to claim 2,wherein X1 is -O- or -NRX1-,provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group,R1 is represented by the following formula (II), (III), or (IV):[Chemical Formula 7]R1a is the same or different, and is H or F,R1b is H,R1c is methyl or cyclopropyl,R1d is H,R2 is cyclopropyl,R3 is a group represented by formula (XIV):[Chemical Formula 8]X (xiv)R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b,R4a is C1-3 alkyl,R4b is C1-3 alkyl optionally substituted with -O-(C1-3 alkyl) or -N(C1-3 alkyl)2, or halogen,Y is phenylene,L is a group selected from the group consisting of the following formulas (XXX-L), (XXXI-L), (XXXII-L), (XXXIII-L), and (XXXIV-L):[Chemical Formula 9]NN. J(XXXII-L)L1rL4\ rL5(XXXIV-L)L1 is bond, C1-3 alkylene, -CH2-C=C-, -C1-3 alkylene-O-, or tetrahydropyridinediyl,L2 is -CH2-C-C- or -CH2CH2-O-,RL1 is H or methyl,A1 is CH or N,RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time,m and n are both 1 or both 2,RL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bondedthereto may form cyclopropane,Z is a group selected from the group consisting of formulas (XXX-Z), (XXXI-Z),and (XXXII-Z):[Chemical Formula 10](XXX-Z)(XXXI-Z)       (XXXII-Z)ZA is a group represented by the following formula (XXII-1) or (XXVI-2):[Chemical Formula 11](XXVI -2)(XXII -1)RZ11 is halogen, Z1 is CH or N,RZ2 is C1-3 alkyl,4.ring Hy is 5- or 6-membered hetero ring, andRZ1 is H, C1-3 alkyl, or halogen.The compound or a salt thereof according to claim 1, wherein E is CH,X1 is -O- or -NRX1-,RX1 is H or C1-3 alkyl,provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, may form optionally substituted 4- to 11membered saturated hetero ring group,R1 is represented by the following formula (II), (III), or (IV):[Chemical Formula 12](II)                 (III)               (IV)R1a is the same or different, and is H or F,R1b is H,R1c is methyl or cyclopropyl,R1d is H,R3 is a group represented by the following formula (XIV):[Chemical Formula 13]h2n   ......... >0   N___(XIV)R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of F; OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b, and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b,R4a is optionally substituted C1-3 alkyl,R4b is optionally substituted C1-3 alkyl, or halogen,Y is phenylene,L together with Z forms a group selected from the group consisting of the following formulas (XXX), (XXXI-X), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A):[Chemical Formula 14]ZA is a group represented by the following formula (XXII-1) or (XXVI-1):[Chemical Formula 15](XXII-1)          (XXVI-1)RZ11 is H or halogen,Z1, Z2, and Z3 are the same or different, and are each CH or N,RZ2 is C1-3 alkyl,L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, -C1-3 alkylene-C2-3 alkynediyl, or -C=C-,RLX is H or OH,ring Hy is a 5- or 6-membered hetero ring,L2is -C1-3 alkylene-C2-3 alkynediyl or -C1-3 alkylene-O-,RZ1 is H, halogen, C1-3 alkyl, -O-(C1-3 alkyl), or -CN,RL1 is H or C1-3 alkyl,A1 is CH or N,RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are the same or different, and are each 1 or 2,RL4 and RL5 are the same or different, and are each H or C1-3 alkyl, or the RL4 and RL5 together with the carbon atom bonded thereto may form C3-6 cycloalkane, or the RL4 and RL5 together with the carbon atom bonded thereto may form carbonyl, andG is N.

5. The compound or a salt thereof according to claim 4,wherein A is N,X1 is -O- or -NRX1-,provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group,R1 is represented by the following formula (II), (III), or (IV):[Chemical Formula 16](II)                (III)              (IV)R1a is the same or different, and is H or F,R1b is H,R1c is methyl or cyclopropyl,R1d is H,R2 is cyclopropyl,R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b,R4a is C1-3 alkyl,R4b is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH, -O-(C1-3 alkyl) and -N(C1-3 alkyl)2, or halogen,L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-X), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A):ZA is a group represented by the following formula (XXII-1) or (XXVI-2):[Chemical Formula 18](XXVI -2),N-N(XXII -1)RZ11 is halogen,Z1 is CH or N,RZ2 is C1-3 alkyl,L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C=C-,RLX is H or OH,ring Hy is a 5- or 6-membered hetero ring,L2 is -CIM' C- or -CH2CH2-O-,RZ1 is H, C1-3 alkyl, or halogen,RL1 is H or methyl,A1 is CH or N,RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, andRL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

6. The compound or a salt thereof according to claim 5,wherein X1 is -O- or -NRX1-,provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group,L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI-1X), (XXXII-1), (XXXIII-A1), (XXXIII-B1), (XXXIV-1), and (XXXI-A):[Chemical Formula 19]ZA is a group represented by the following formula (XXII-1) or (XXVI-2):[Chemical Formula 20]£. / ' ’(XXII-1)        (XXVI -2)RZ11 is halogen,Z1 is CH or N,RZ2 is C1-3 alkyl,L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-,RLX 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):Hy1a          Hy1a           Hy1arx                    rx                    lx(XXXV)         (XXXVI)        (XXXVII)(XXXVII-2)      (XXXVIII)       (XXXIX)RHy1a is H, C1-3 alkyl, or halogen,RHy1b is H or C1-3alkyl,L2 is -CIM' C- or -CH2CH2-O-,RZ1 is H, C1-3 alkyl, or halogen,RL1 is H or methyl,A1 is CH or N,RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, ring Hy3 is a ring selected from the group consisting of the following formulas (XL) and (XLI):[Chemical Formula 22]RHy3         RHy3(XL)              (XLI)RHy3 is H, C1-3 alkyl, or halogen, m and n are both 1 or both 2, and ring Hy2 is of the following formula (XLIII):RHy2(XLIII)RHy2 is H, C1-3 alkyl, or halogen, andRL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

7. The compound or a salt thereof according to claim 6,wherein L and Z together are a group represented by the formula (XXXI-1X): [Chemical Formula 24]L1 is -CH2CH2-O- or -CH2-C=C-,RLX is H,ring Hy1 is ring selected from the group consisting of the following formulas(XXXV) and (XXXVI):[Chemical Formula 25]Hy1a        RHy1a(XXXV)         (XXXVI)RHy1a is H, C1-3 alkyl, or halogen.

8. The compound or a salt thereof according to claim 1,wherein A is N,X1 is -O- or -NRX1-,provided that when X1 is -NRX1-, RX1 and R4 present on the same nitrogen atom, together with the nitrogen atom adjacent thereto, form optionally substituted 4- to 11membered saturated hetero ring group,R1 is represented by the following formula (II), (III), or (IV):[Chemical Formula 26]R1b is H,R1c is methyl or cyclopropyl,R1d is H,R2 is cyclopropyl,R4 is C1-6 alkyl or piperidinyl, and the C1-6 alkyl is optionally substituted with a group selected from the group consisting of OH; OCH3; N(R4a)2; C3-6 cycloalkyl optionally substituted with R4b; pyrrolidinyl optionally substituted with R4b; and morpholinyl optionally substituted with R4b, and the piperidinyl is optionally substituted with R4b,R4a is C1-3 alkyl,R4b is C1-3 alkyl optionally substituted with -O-(C1-3 alkyl) or -N(C1-3 alkyl)2, or halogen,L and Z together are a group selected from the group consisting of the following formulas (XXX), (XXXI), (XXXII), (XXXIII-A), (XXXIII-B), (XXXIV), and (XXXI-A): [Chemical Formula 27]ZA is a group represented by the following formula (XXII-1) or (XXVI-2):[Chemical Formula 28],N—N(XXVI -2)(XXII -1)RZ11 is halogen,Z1 is CH or N,RZ2 is C1-3 alkyl,L1 is bond, C1-3 alkylene, -C1-3 alkylene-O-, or -CH2-C-C-.ring Hy is 5- or 6-membered hetero ring,L2 is -CH;-C-C- or -CH2CH2-O-,RZ1 is H, C1-3 alkyl, or halogen,RL1 is H or methyl,A1 is CH or N,RL2 and RL3 are the same or different, and are each H, OH, or C1-3 alkyl, provided that RL2 and RL3 are never OH at the same time, and RL2 and RL3 are never H at the same time, m and n are both 1 or both 2, andRL4 and RL5 are both H, or the RL4 and RL5 together with the carbon atom bonded thereto may form cyclopropane.

9. The compound or a salt thereof according to claim 1,wherein the compound represented by formula (I) is selected from the group consisting of:(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.

10. A pharmaceutical composition comprising the compound or a salt thereof accordingto claim 1, and one or more pharmaceutically acceptable excipients.

11. The pharmaceutical composition according to claim 10, which is a pharmaceuticalcomposition for treating cancer.

12. Use of the compound or a salt thereof according to claim 1 for the manufacture of apharmaceutical composition for treating cancer.

13. The compound or a salt thereof according to claim 1 for use in treatment of cancer.

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

15. A method for treating cancer, comprising administrating an effective amount of thecompound or a salt thereof according to claim 1 to a subject.