Tertiary amide derivative substituted with four-membered ring structure

Abstract

The present disclosure provides: a tertiary amide derivative which is substituted with a four-membered ring structure and is useful as a medicine, and a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising the components or an agent for treating or preventing pathoses involving CBP / P300, the agent comprising the composition. More specifically, the present disclosure provides a compound represented by formula (1) [in the formula, A represents CHF or CH2, B represents formula (B-1), the ring Q represents a six- to ten-membered aromatic hydrocarbon ring which may be substituted or a five- to ten-membered aromatic heterocyclic ring which may be substituted, Z represents –O-, -N(R7a)-, a six- to ten-membered divalent aromatic ring group which may be substituted, a five- to ten-membered divalent aromatic heterocyclic group which may be substituted, or a four- to ten-membered divalent non-aryl heterocyclic group which may be substituted, and R1, R2a, R2b, R3, R4, and R5 are as described in the specification] or a pharmaceutically acceptable salt thereof.

Description

Tertiary amide derivatives substituted with a four-membered ring structure

[0001] The present disclosure relates to tertiary amide derivatives substituted with a quaternary carbon that are useful as pharmaceuticals, and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing them, or therapeutic or preventive agents for pathologies involving CBP / P300 that contain these compositions.

[0002] Chromosomes dynamically control gene replication and transcription by changing their higher-order structure through methylation of their constituent DNA and various modifications (acetylation, methylation, phosphorylation, ubiquitination, etc.) of their histones (histones H2A, H2B, H3, H4) (Non-patent Document 1).

[0003] Histone acetylation is a common post-translational modification in eukaryotes that promotes gene transcription. Histone acetyltransferases (HATs), which function during histone acetylation, are enzymes that transfer acetyl groups to the lysine side chains of histones. HATs are broadly classified into four types based on amino acid sequence homology, higher-order structure, and function. They are CBP / P300 (E1A binding protein p300 / CREB binding protein), GCN5 / PCAF (general control nonrepressed-protein 5 / P300 / CBP-associated factor), MYST (MOZ, Ybf2 / Sas3, Sas2, and Tip60), and Rtt109 (Regulator of Tyl Transposition gene production 109). P300 and its paralog CBP share over 90% amino acid sequence homology, and in addition to the HAT domain, they contain CH1 / CH2 / CH3 domains (cysteine-histidine rich domains), a KIX domain, and a bromodomain (Non-Patent Document 2).

[0004] CBP / P300 was discovered as a binding partner for E1A adenoviral protein and cAMP-regulated enhancer binding protein, respectively (Non-Patent Documents 3-5). Subsequently, it was discovered that CBP / P300 has HAT activity (Non-Patent Documents 6 and 7). Its substrate specificity was also investigated, and it was reported that it acetylates not only lysine residues on histones (H2A, H2B, H3, and H4), but also p53 (Non-Patent Document 8), MyoD (Non-Patent Document 9), STAT3 (Non-Patent Document 10), and androgen receptor (Non-Patent Document 11), among others. CBP / P300 is also involved in numerous biological reactions, such as division, proliferation, and differentiation (Non-Patent Document 12).

[0005] CBP / P300 has been reported to play an important role in the growth of various cancers, including prostate cancer (Non-Patent Documents 13 and 14), liver cancer (Non-Patent Documents 15 and 16), lung cancer (Non-Patent Documents 17 to 19), breast cancer (Non-Patent Document 20), colon cancer and gastric cancer (Non-Patent Document 21), blood cancer (Non-Patent Documents 22 and 23), pancreatic cancer (Non-Patent Document 24), bladder cancer (Non-Patent Document 25), gastrointestinal stromal tumor (Non-Patent Document 26), NUT midline carcinoma (Non-Patent Document 27), ovarian cancer (Non-Patent Document 28), malignant rhabdoid tumor, and epithelioid sarcoma (Patent Document 11).

[0006] For these reasons, drugs that inhibit the function of CBP / P300 are expected to be useful as antitumor agents. To date, patent documents 1 to 10 and non-patent document 29 have been disclosed as small molecule inhibitors that target the HAT domain of CBP / P300.

[0007] International Publication No. WO 2016 / 044770, International Publication No. WO 2018 / 235966, International Publication No. WO 2019 / 111980, International Publication No. WO 2019 / 049061, International Publication No. WO 2019 / 161157, International Publication No. WO 2019 / 161162, International Publication No. WO 2020 / 176558, International Publication No. WO 2019 / 201291, International Publication No. WO 2020 / 108500, International Publication No. WO 2020 / 198567, International Publication No. WO 2022 / 138944

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[0009] The present disclosure provides compounds that exert anticancer effects by inhibiting CBP / P300, which has been reported to be overexpressed, mutated, or hyperactive in various cancers. Preferably, the present disclosure provides compounds that have high CBP / P300 inhibitory activity, as well as "high water solubility that exerts anticancer effects upon intravenous administration" and "high oral absorbability that exerts anticancer effects upon oral administration." In other words, the present disclosure provides compounds that are extremely useful as anticancer agents that can be expected to be applied to the treatment of a wide range of cancer types.

[0010] As a result of extensive investigations, the present inventors have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "the compound of the present disclosure") exhibits excellent anticancer activity due to its strong inhibitory effect on the HAT domain of CBP / P300, and exhibits high oral absorbability and water solubility suitable for oral and intravenous administration, and have thus completed the present disclosure.

[0011] That is, the present disclosure is as follows.

[0012] [Section 1] [Wherein, A is CHF or CH ２ B represents the following formula (B-1): [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring], ring Q represents an optionally substituted 6- to 10-membered aromatic hydrocarbon ring or an optionally substituted 5- to 10-membered aromatic heterocycle, Z represents -O-, -N(R ７ａ )-, an optionally substituted 6- to 10-membered divalent aromatic ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, or an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group; R １ is an optionally substituted C １－６ Alkyl or optionally substituted C ３－１０ represents an alicyclic group, R ２ａ and R ２ｂ each independently represents an optionally substituted C １－６ represents alkyl, where R ２ａ and R ２ｂtogether with the carbon atom to which they are attached, may be substituted C ３－６ R may form a cycloalkylene or an optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group; ３ is an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３－１０ represents an alicyclic group or an optionally substituted 4- to 10-membered non-aryl heterocyclic group, ４ represents a single bond, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ represents a cycloalkylene or an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, ５ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C １－３ Alkoxy, —NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , optionally substituted C ３－１０ an alicyclic group, an optionally substituted 4- to 10-membered non-aryl heterocyclic group, an optionally substituted C ６－１０ R represents an aryl or an optionally substituted 5- to 10-membered heteroaryl; ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or an optionally substituted C １－６ [Item 2] A compound represented by the formula: wherein R represents an alkyl group, or a pharmaceutically acceptable salt thereof. １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ａ , R７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R ９ａ , R ９ｂ , an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C ３－１０ Alicyclic group, optionally substituted C ３－６ Cycloalkylene, optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ cycloalkylene, an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, or an optionally substituted C １－３ Each alkoxy is independently (1) a halogen atom, (2) a hydroxyl group, or (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio (10) C ３－１０ (11) an alicyclic group, (12) a carboxyl group, (13) -COR １０ , (14)-CO ２ R １０ , (15)-CONR １１ R １２ , (16)-NR １１ R１２ , (17)-NR １３ COR １０ , (18)-NR １３ CO ２ R １０ , (19)-NR １３ SO ２ R １０ , (20)-NR １３ CONR １１ R １２ , (21)-NR １３ SO ２ NR １１ R １２ , (22)-SO ２ R １０ , (23)-SO ２ NR １１ R １２ , (24)-OCOR １０ , (25)-OCO ２ R １０ , (26)-OCONR １１ R １２ (27) sulfo, (28) phosphate, (29) cyano, and (30) nitro, wherein the (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio, (10)C ３－１０ The alicyclic group and the group shown in (11) 3- to 10-membered non-aryl heterocyclic group are (a) a halogen atom, (b) a hydroxyl group, or (c) C ６－１０ (d) 5- to 12-membered heteroaryl; (e) C １－６ (f) alkyl, ２－６ alkenyl, (g) C ２－６ alkynyl, (h) C １－６ Alkoxy, (i) C ３－１０ (j) an alicyclic group, (k) a carboxyl group, (l) —COR１０ , (m)-CO ２ R １０ , (n)-CONR １１ R １２ , (o)-NR １１ R １２ , (p)-NR １３ COR １０ , (q)-NR １３ SO ２ R １０ , (r)-SO ２ R １０ , (s)-SO ２ NR １１ R １２ (t) sulfo, (u) phosphate, (v) cyano, and (w) nitro; R １０ However, if there are multiple, each independently, C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, and R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When R is an alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, １３ is a hydrogen atom or C １－６ Item 3: The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R９ａ , R ９ｂ , an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C ３－１０ Alicyclic group, optionally substituted C ３－６ Cycloalkylene, optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ cycloalkylene, an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, or an optionally substituted C １－３ Each alkoxy is independently (1) a halogen atom, (2) a hydroxyl group, or (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C optionally substituted with 1 to 3 halogen atoms; １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C ３－１０ (10) an alicyclic group, (11) a carboxyl group, (12) -COR １０ , (13)-CO ２ R １０ , (14)-CONR １１ R １２ , (15)-NR １１ R １２ , (16)-SO ２ R １０ , (17)-SO ２ NR １１ R １２(18) sulfo, (19) phosphate, (20) cyano, and (21) nitro; R １０ However, if there are multiple, each independently, C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, and R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When R is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R ９ａ , R ９ｂ , an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C ３－１０Alicyclic group, optionally substituted C ３－６ Cycloalkylene, optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ cycloalkylene, an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, or an optionally substituted C １－３ (1) a halogen atom; (2) a hydroxyl group; (3) a phenyl; (4) a 5- or 6-membered heteroaryl; or (5) a C group optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, (6) C １－６ Alkoxy, (7) C ３－７ (8) an alicyclic group, (9) a 3- to 7-membered non-aryl heterocyclic group, １０ , (10)-CO ２ R １０ , (11)-CONR １１ R １２ , (12)-NR １１ R １２ , (13)-SO ２ R １０ , (14)-SO ２ NR １１ R １２ (15) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of cyano, １０ However, if there are multiple, each independently, C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, and R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６When B is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. [Item 5] The compound according to any one of Items 1 to 3, wherein B is a group represented by the following formula (B-2), (B-3), or (B-4): [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring, a represents 0, 1 or 2, b represents 1 or 2, R ８ represents a hydrogen atom or an optionally substituted C １－６ represents alkyl, R ９ａ and R ９ｂ are each independently a hydrogen atom, a halogen atom, or an optionally substituted C １－６ [Item 6] The compound according to any one of Items 1 to 4, wherein R represents alkyl, or a pharmaceutically acceptable salt thereof. １ C optionally substituted with 1 to 3 fluorine atoms １－３ [Item 7] The compound according to any one of Items 1 to 5, wherein R is alkyl, or a pharmaceutically acceptable salt thereof. １ But CF ３ [Item 8] The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ３ But C ６－１０ Aryl (the aryl is a halogen atom and an optionally substituted C １－６ alkyl), or 5-10 membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms and C １－６ [Item 9] The compound according to any one of Items 1 to 7, wherein R is a substituted or unsubstituted alkyl group, and R is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof. ３ [Item 10] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein R is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl. ３[Item 11] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 9, wherein ring Q is 4-fluorophenyl or 4-fluoro-2-pyridyl. [Item 12] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 9, wherein ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring is free of halogen atoms and C １－６ [Item 12] The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 10, wherein ring Q is a benzene ring (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl). １－６ [Item 13] The compound according to any one of items 1 to 12, wherein a is 1 or 2, or a pharmaceutically acceptable salt thereof. [Item 14] The compound according to any one of items 1 to 13, wherein a is 1, or a pharmaceutically acceptable salt thereof. [Item 15] The compound according to any one of items 1 to 14, wherein b is 1, or a pharmaceutically acceptable salt thereof. [Item 16] The compound according to any one of items 1 to 15, wherein a is 1 and b is 1, or a pharmaceutically acceptable salt thereof. [Item 17] The compound according to any one of items 1 to 15, wherein a is 1 and b is 1. [Wherein, A is CHF or CH ２ represents R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents —O—, a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C１－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C１－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ represents a hydrogen atom or a halogen atom; ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２may be the same or different, and R １１ and R １２ Both are C １－６ [Item 18] The compound according to Item 17, wherein A is CHF, or a pharmaceutically acceptable salt thereof. [Item 19] R ６ [Item 20] The compound or pharmaceutically acceptable salt thereof according to any one of Items 17 or 18, wherein Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ [Item 21] The compound or pharmaceutically acceptable salt thereof according to any one of items 17 to 19, wherein Z is a 5-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ [Item 22] The compound according to any one of Items 17 to 20, wherein R is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R１２ [Item 23] The compound according to any one of Items 17 to 21, wherein R is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. ５ is a hydrogen atom, a halogen atom, a cyano, -NR ７ｂ R ７ｃ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ [Item 24] The compound or pharmaceutically acceptable salt thereof according to any one of items 17 to 22, wherein formula (1) is the following formula (3): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is C １－６ Alkyl (the alkyl is a halogen atom, C１－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ [Item 25] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl, and R is an alkyl group ... ３ [Item 26] The compound according to Item 24, wherein R is 4-fluorophenyl, or a pharmaceutically acceptable salt thereof. ３ [Item 27] ​​The compound according to any one of items 24 and 25, wherein R is 4-fluoro-2-pyridyl, or a pharmaceutically acceptable salt thereof. ４ [Item 28] The compound according to any one of Items 24 to 26, wherein R is a 4- to 10-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 29] The compound according to any one of Items 24 to 27, wherein R is a 4- to 6-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 30] The compound or pharmaceutically acceptable salt thereof according to any one of Items 24 to 28, wherein R is azetidinylene or piperidinylene. ５ But, C １－６alkyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ [Item 31] The compound according to any one of Items 24 to 29, wherein R is a substituted or unsubstituted alkyl group, and R is a substituted or unsubstituted alkyl group, and R is an ... ５ But, C １－３ alkyl, or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ [Item 32] The compound according to any one of Items 24 to 30, wherein R is a substituted or unsubstituted alkyl group, and ... ５ [Item 33] The compound according to any one of Items 24 to 31, wherein R is methyl, or a pharmaceutically acceptable salt thereof. ５ [Item 34] The compound according to any one of Items 24 to 31, wherein R is oxetanyl, or a pharmaceutically acceptable salt thereof. １１ and R １２ [Item 35] The compound or pharmaceutically acceptable salt thereof according to any one of Items 24 to 33, wherein: is a methyl group. [Item 35] The compound or pharmaceutically acceptable salt thereof according to any one of Items 24 to 33, wherein: [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR１１ R １２ and a 4- to 10-membered non-aryl heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ [Item 36] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl, and R is an alkyl group ... ４ [Item 37] The compound according to Item 35, wherein R is a 4- to 10-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 38] The compound according to any one of Items 35 and 36, wherein R is a 4- to 6-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 39] The compound according to any one of Items 35 to 37, wherein R is azetidinylene, or a pharmaceutically acceptable salt thereof. ５ But, C １－６ alkyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ [Item 40] The compound according to any one of Items 35 to 38, wherein R is a substituted or unsubstituted alkyl group, and R is a substituted or unsubstituted alkyl group, and R is an ... ５ But, C １－３alkyl, or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ [Item 41] The compound according to any one of Items 35 to 39, wherein R is a substituted or unsubstituted alkyl group, and R is a substituted or unsubstituted alkyl group, and R is an ... ５ [Item 42] The compound or pharmaceutically acceptable salt thereof according to any one of Items 35 to 40, wherein formula (1) is the following formula (5): [Wherein, A is CHF or CH ２ represents R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C１－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－３ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ represents a hydrogen atom or a halogen atom; ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, ８ is a hydrogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６[Item 43] The compound according to Item 42, wherein A is CHF, or a pharmaceutically acceptable salt thereof. [Item 44] R ６ [Item 45] The compound or pharmaceutically acceptable salt thereof according to any one of Items 42 or 43, wherein Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ [Item 46] The compound or pharmaceutically acceptable salt thereof according to any one of Items 42 to 44, wherein Z is a 5-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ [Item 47] The compound according to any one of Items 42 to 45, wherein R is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ [Item 48] The compound according to any one of Items 42 to 46, wherein R is a substituted or unsubstituted alkyl group, and R is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof. ５But, hydrogen atom, hydroxyl group, cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ７ｄ But C １－６ Alkyl (the alkyl is a halogen atom and C １－６ [Item 49] The compound according to any one of Items 42 to 47, wherein R is a substituted or unsubstituted alkyl group, and R is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof. ８ But, C １－６ [Item 50] The compound according to any one of Items 42 to 48, or a pharmaceutically acceptable salt thereof, wherein R is alkyl. ８ [Item 51] The compound or pharmaceutically acceptable salt thereof according to any one of Items 42 to 49, wherein: is a methyl group. [Item 52] The compound or pharmaceutically acceptable salt thereof according to any one of Items 42 to 49, wherein: [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR１１ R １２ and R ５ is a hydrogen atom, a hydroxyl group, a cyano, a C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ [Item 52] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl, and R is an alkyl group ... ３ [Item 53] The compound according to Item 51, wherein R is 4-fluorophenyl, or a pharmaceutically acceptable salt thereof. ３ [Item 54] The compound according to any one of Items 51 and 52, wherein R is 4-fluoro-2-pyridyl, or a pharmaceutically acceptable salt thereof. ４ is a single bond, or C１－６ Alkylene (the alkylene is a halogen atom and C １－６ [Item 55] The compound according to any one of Items 51 to 53, wherein R is a substituted or unsubstituted alkyl group, and R is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof. ４ [Item 56] The compound or pharmaceutically acceptable salt thereof according to any one of Items 51 to 54, wherein R is a single bond. ４ But C １－６ Alkylene (the alkylene is a halogen atom and C １－６ [Item 57] The compound according to any one of Items 51 to 54, wherein R is a substituted or unsubstituted alkyl group, and R is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof. ５ But, hydroxyl group, cyano C １－６ Alkyl, C ３－１０ [Item 58] The compound according to any one of Items 51 to 56, wherein R is an alicyclic group, or a 4- to 10-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ５ [Item 59] The compound or pharmaceutically acceptable salt thereof according to any one of Items 51 to 57, wherein R is a methyl group. ５ [Item 60] The compound or pharmaceutically acceptable salt thereof according to any one of Items 51 to 57, wherein formula (1) is the following formula (7): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R５ is a hydrogen atom, cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When R is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ is a single bond, or C １－６ Alkylene (the alkylene is a halogen atom and C １－６ Item 62. The compound according to any one of items 60 and 61, wherein R is a substituted or unsubstituted alkyl group, and R is an ... ４ [Item 63] The compound or pharmaceutically acceptable salt thereof according to any one of Items 60 and 61, wherein R is a single bond. ４ But C １－６ Alkylene (the alkylene is a halogen atom and C １－６[Item 64] The compound according to any one of Items 60 to 62, wherein R is a substituted or unsubstituted alkyl group, and R is optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof. ５ But, C １－６ [Item 65] The compound according to any one of Items 60 to 63, wherein R is alkyl, or cyano, or a pharmaceutically acceptable salt thereof. ５ [Item 66] The compound or pharmaceutically acceptable salt thereof according to any one of Items 60 to 64, wherein R is a methyl group. ５ [Item 67] The compound or pharmaceutically acceptable salt thereof according to any one of Items 60 to 64, wherein: is cyano. [Item 67] The compound or pharmaceutically acceptable salt thereof according to any one of Items 60 to 64, wherein: [Wherein, A is CHF or CH ２ represents R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－３ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ represents a hydrogen atom or a halogen atom; ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, ９ａ and R ９ｂ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２may be the same or different, and R １１ and R １２ Both are C １－６ [Item 68] The compound according to Item 1, wherein A is CHF, or a pharmaceutically acceptable salt thereof. [Item 69 ...70] The compound according to Item 1, wherein A is CHF, or a pharmaceutically acceptable salt thereof. [Item 71] The compound according to Item 1, wherein A is CHF, or a pharmaceutically acceptable salt thereof. [Item 72] The compound according to Item 1, wherein A is CHF, or a pharmaceutically acceptable salt thereof. [Item 73] The compound according to Item 1, wherein R is CHF, or a pharmaceutically acceptable salt thereof. ６ [Item 70] The compound or pharmaceutically acceptable salt thereof according to any one of Items 67 or 68, wherein Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ [Item 71] The compound or pharmaceutically acceptable salt thereof according to any one of Items 67 to 69, wherein Z is a 5-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ [Item 72] The compound according to any one of Items 67 to 70, wherein R is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R１２ [Item 73] The compound according to any one of Items 67 to 71, wherein R is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. ５ is a hydrogen atom, cyano, -NR ７ｂ R ７ｃ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ [Item 74] The compound according to any one of Items 67 to 72, wherein R is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. ９ａ and R ９ｂ [Item 75] The compound or pharmaceutically acceptable salt thereof according to any one of Items 67 to 73, wherein is a fluorine atom. [Item 76] The compound or pharmaceutically acceptable salt thereof according to any one of Items 67 to 73, wherein the compound represented by Formula (1) is represented by the following Formula (9): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２and R ５ is a hydrogen atom, cyano, C １－６ Alkyl, C １－６ Alkenyl, C １－６ Alkynyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ [Item 76] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl, and R is an alkyl group ... ３ [Item 77] The compound according to Item 75, wherein R is 4-fluorophenyl, or a pharmaceutically acceptable salt thereof. ３ [Item 78] The compound according to any one of Items 75 and 76, wherein R is 4-fluoro-2-pyridyl, or a pharmaceutically acceptable salt thereof. ４ [Item 79] The compound according to any one of Items 75 to 77, wherein R is a 4- to 10-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 80] The compound according to any one of Items 75 to 78, wherein R is a 4- to 6-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 81] The compound according to any one of Items 75 to 79, wherein R is azetidinylene, or a pharmaceutically acceptable salt thereof.５ [Item 82] The compound according to any one of Items 75 to 80, wherein R is a 4- to 10-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ５ [Item 83] The compound according to any one of Items 75 to 81, wherein R is a 4- to 6-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ５ [Item 84] The compound or pharmaceutically acceptable salt thereof according to any one of Items 75 to 82, wherein formula (1) is the following formula (10): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, cyano, C １－６ Alkyl, C １－６ Alkenyl, C １－６ Alkynyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１and R １２ Both are C １－６ [Item 85] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl, and R is an alkyl group ... ４ [Item 86] The compound according to Item 84, wherein R is a 4- to 10-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 87] The compound according to any one of Items 84 and 85, wherein R is a 4- to 6-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ４ [Item 88] The compound according to any one of Items 84 to 86, wherein R is azetidinylene, or a pharmaceutically acceptable salt thereof. ５ [Item 89] The compound according to any one of Items 84 to 87, wherein R is a 4- to 10-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ５ [Item 90] The compound according to any one of Items 84 to 88, wherein R is a 4- to 6-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof. ５[Item 91] The compound according to any one of Items 84 to 89, or a pharmaceutically acceptable salt thereof, wherein is oxetanyl. [Item 92] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 1), 2-[(1'S)-5'-{1-[(3-fluoro-1-methylazetidin-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 2), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 3), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]acetamide (Example 4), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]acetamide (Example 5),N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 6), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 7), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]acetamide (Example 8), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]acetamide (Example 9), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 10),2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 11), N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 12), 2-{(1'S)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 13), 2-[(1'S,3'R)-3'-fluoro-5'-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 14), 2-[(1'S,3'R)-3'-fluoro-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 15), 2-[(1'S)-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 16),2-[(1'S,3'R)-3'-fluoro-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 17), 2-[(1'S)-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 18), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxa-4-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 19), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 20), N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 21),2-[(1'S,3'R)-5'-(1-{[3-(dimethylamino)oxetan-3-yl]methyl}-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 22), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 23), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 24), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 25), 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 26),2-{(1'S,3'R)-3'-fluoro-5'-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 27), 2-[(1'R,3'S)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 28), 2-[(1'S,3'R)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 29), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 30), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 31),2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 32), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 33), 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 34), 2-[(1'S,3'R)-3'-Fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide (Example 35). [Item 92] The compound according to Item 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 7),2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 10), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 20), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 23), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 24), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 25),2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 30), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 31), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 32), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 33), 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 34). [Item 93] A medicament comprising the compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. [Item 94] A pharmaceutical composition comprising the compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof. [Item 95]A therapeutic and / or preventive agent for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease, comprising as an active ingredient the compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof. [Item 96] A therapeutic and / or preventive agent for cancer, comprising as an active ingredient the compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof. [Item 97] The therapeutic and / or preventive agent according to Item 95 or 96, wherein the cancer is at least one type of cancer selected from the group consisting of SMARC-deficient cancer, SS18-SSX fusion cancer, and ARID-deficient cancer. [Item 98] The cancer is selected from the group consisting of malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid / rhabdoid tumor, schwannoma, chordotomy meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma, chordoma, myoepithelial tumor, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basaloid carcinoma of the paranasal sinus, esophageal cancer, papillary thyroid cancer, follicular thyroid cancer, gastrointestinal stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary cancer, endometrial cancer, myoepithelioma-like tumor of the female vulva, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung carcinoma, lung neuroendocrine tumor, and gastrointestinal stromal tumor. The therapeutic and / or prophylactic agent according to any one of Items 95 to 97, wherein the cancer is at least one type selected from the group consisting of uterine junction cancer, gastric cancer, bladder cancer, lung squamous cell carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver cancer, lung pleomorphic carcinoma, breast sarcoma, ovarian small cell carcinoma, primary gallbladder tumor, uterine sarcoma, ovarian granulosa tumor, adrenocortical carcinoma, small cell lung cancer, ovarian cancer, endometrial cancer, neuroblastoma, ovarian mucinous tumor, nasal and paranasal cancer, thoracic sarcoma, biliary tract cancer, neuroblastoma, melanoma, breast cancer, unclassifiable round cell sarcoma, rhabdomyosarcoma, and Ewing's sarcoma. [Item 99] A method for treating or preventing cancer, non-alcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of the compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof. [Item 100] Use of the compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or preventive agent for cancer, nonalcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease. [Item 101][Item 102] The compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer, non-alcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease. [Item 103] The compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer, non-alcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease. [Item 104] The compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer, non-alcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease. [Item 105] The compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and drugs that inhibit the activity of cell growth factors and their receptors. [Item 106] The pharmaceutical composition according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and drugs that inhibit the activity of cell growth factors and their receptors.

[0013] The present disclosure provides CBP / P300 inhibitors, including tertiary amide derivatives substituted at quaternary carbons and pharmaceutically acceptable salts thereof. The present disclosure provides drugs that inhibit the function of CBP / P300, which are applicable to a wide range of diseases and administration methods. The present disclosure also provides compounds represented by formula (1), which are tertiary amide derivatives substituted at quaternary carbons, and drugs related to these, which can be used as these drugs.

[0014] The compounds of the present disclosure exhibit excellent CBP / P300 inhibitory activity and are useful as therapeutic agents for diseases in which CBP / P300 is involved, and specifically are applicable to patients with cancer, non-alcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, metabolic disease, etc.

[0015] The present disclosure will be described in more detail below. Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will prevail.

[0016] The terms used in this specification are explained below.

[0017] In this specification, the number of substituents in a group defined as "optionally substituted" is not particularly limited, as long as substitution is possible. When the number of substituents is specified and the description "substituted" with that number of substituents is made, it means that there is substitution with that number of substituents. For example, "substituted with 2 to 5 substituents" means that there is substitution with 2, 3, 4, or 5 substituents. Furthermore, unless otherwise specified, the description of each group also applies when that group is a part or substituent of another group.

[0018] Examples of "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom or a chlorine atom is preferred.

[0019] "C １－６ "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. ６ "Alkyl" means alkyl having 6 carbon atoms, and the same applies to other numbers. １－６ As the alkyl, preferably "C １－４ alkyl", and more preferably "C １－３ "C alkyl" is an example. １－３Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. １－４ Specific examples of "alkyl" include the above-mentioned "C １－３ In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. １－６ Specific examples of "alkyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like can be mentioned.

[0020] "C ２－６ "Alkenyl" means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. ２－６ Alkenyl is preferably "C ２－４ "C alkenyl" is an example. ２－４ Specific examples of "alkenyl" include vinyl, propenyl, methylpropenyl, butenyl, etc. ２－６ Specific examples of "alkenyl" include the above-mentioned "C ２－４ In addition to the specific examples of "alkenyl", pentenyl, hexenyl, etc. are also included.

[0021] "C ２－６ "Alkynyl" means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. ２－６ As the "alkynyl", preferably "C ２－４ "C alkynyl" is an example. ２－４ Specific examples of "alkynyl" include propynyl, methylpropynyl, butynyl, etc. ２－６ Specific examples of "alkynyl" include the above-mentioned "C ２－４ In addition to the specific examples of "alkynyl", methylbutynyl, pentynyl, hexynyl, etc. are included.

[0022] "C１－６ "Alkoxy" means "C １－６ "C alkyloxy" １－６ The "C alkyl" moiety is １－６ "C" is synonymous with "alkyl." １－６ The "alkoxy" is preferably "C １－４ Alkoxy" is preferred, and "C １－３ "Alkoxy" is an example. １－３ Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. １－４ Specific examples of "alkoxy" include the above-mentioned "C １－３ In addition to the specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. １－６ Specific examples of "alkoxy" include the above-mentioned "C １－４ In addition to the specific examples of "alkoxy", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like can be mentioned.

[0023] "C １－６ "C" in "Alkylthio" １－６ The "C alkyl" moiety is １－６ "C" is synonymous with "alkyl." １－６ As the alkylthio, preferably "C １－４ alkylthio", and more preferably "C １－３ "Alkylthio" is an example. １－３ Specific examples of "alkylthio" include methylthio, ethylthio, propylthio, 1-methylethylthio, etc. １－４ Specific examples of "alkylthio" include the above-mentioned "C １－３ In addition to the specific examples of "alkylthio", butylthio, 1,1-dimethylethylthio, 1-methylpropylthio, 2-methylpropylthio, etc. are also included. １－６Specific examples of "alkylthio" include the above-mentioned "C １－４ In addition to the specific examples of "alkylthio", pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylbutylthio, 2-methylbutylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, hexylthio, and the like are included.

[0024] "C １－６ "Alkylene" means a divalent saturated hydrocarbon group having 1 to 6 carbon atoms, which may be straight or branched. １－６ As the "alkylene", preferably "C １－４ alkylene", and more preferably "C １－３ "C alkylene" is an example. １－３ Specific examples of "alkylene" include a methylene group, an ethylene group, and a propylene group. １－４ Specific examples of "alkylene" include the above-mentioned "C １－３ In addition to the specific examples of "alkylene," examples include a butylene group, a 1,1-dimethylethylene group, a 1,2-dimethylethylene group, a 1-methyltrimethylene group, and a 2-methyltrimethylene group. １－６ Specific examples of "alkylene" include the above-mentioned "C １－４ In addition to the specific examples of "alkylene," examples include a pentylene group, a 1,1-dimethyltrimethylene group, a 1,2-dimethyltrimethylene group, a 1-methylbutylene group, a 2-methylbutylene group, a 1-methylpentylene group, a 2-methylpentylene group, a 3-methylpentylene group, a hexylene group, and the like.

[0025] "C ２－６ "Alkenylene" means a straight or branched chain divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. ２－６ As the alkenylene, preferably "C ２－４ "C alkenylene" is an example. ２－４ Specific examples of "alkenylene" include a vinylene group, a vinylidene group, a propenylene group, a methylpropenylene group, and a butenylene group.２－６ Specific examples of "alkenyl" include the above-mentioned "C ２－４ In addition to the specific examples of "alkenyl", pentenylene group, hexenylene group, etc. are also included.

[0026] "C ３－１０ The term "alicyclic group" means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure. ３－１０ As the "alicyclic group", preferably "C ３－７ "C" is an alicyclic group. ３－７ Specific examples of the "alicyclic group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. ３－１０ Specific examples of the "alicyclic group" include the above-mentioned "C ３－７ In addition to the specific examples of the "alicyclic group", cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. are also included.

[0027] Also, "C ３－１０ The "alicyclic group" includes the C ３－１０ Bicyclic compounds in which an alicyclic group and an aromatic hydrocarbon ring are fused together are also included. Specific examples of such fused ring compounds include those having the structures shown below.

[0028] Specific examples of the crosslinked structure include the structures shown below.

[0029] "C ３－１０ "Cycloalkylene" means a cyclic divalent saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. ３－１０ As the "cycloalkylene", preferably "C ３－７ "Cycloalkylene" is an example. ３－７ Specific examples of "cycloalkylene" include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, etc. ３－１０ Specific examples of "cycloalkylene" include the above-mentioned "C ３－７In addition to the specific examples of "cycloalkylene", cyclooctylene, cyclononylene, cyclodecylene, adamantylene, etc. are included.

[0030] Specific examples of the crosslinked structure include the structures shown below.

[0031] "C ３－１０ "Cycloalkenylene" means a cyclic divalent unsaturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a bridged structure. ３－１０ Specific examples of "cycloalkenylene" include cyclobutenylene, cyclopentenylene, cyclohexenylene, and the like.

[0032] The term "3- to 10-membered saturated carbocyclic ring" refers to a cyclic saturated hydrocarbon having 3 to 10 carbon atoms. A preferred example of the "3- to 10-membered saturated carbocyclic ring" is a "4- to 6-membered saturated carbocyclic ring." Specific examples of the "4- to 6-membered saturated carbocyclic ring" include a cyclobutane ring, a cyclopentane ring, and a cyclohexane ring. Specific examples of the "3- to 10-membered saturated carbocyclic ring" include, in addition to the specific examples of the "4- to 6-membered saturated carbocyclic ring" mentioned above, a cyclopropane ring, a cycloheptane ring, cyclooctane, cyclononane, and cyclodecane.

[0033] The term "4- to 10-membered non-aryl heterocyclic group" refers to a monovalent non-aryl heterocyclic group consisting of 1 to 2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and 2 to 9 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. The atoms constituting the ring are -C(O)-, -S(O)-, -SO ２-, and may include those oxidized such as -. As the "4- to 10-membered non-aryl heterocyclic group", preferably, "4- to 6-membered non-aryl heterocyclic group" is mentioned. Specific examples of the "4- or 5-membered non-aryl heterocyclic group" include, for example, oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, tetrahydropyranyl, etc. As the "4- to 10-membered non-aryl heterocyclic group", in addition to the specific examples of the "4- to 6-membered monocyclic non-aryl heterocyclic group", for example, azepanyl, etc. As used herein, "azetidinylene" and the like refer to divalent groups such as "azetidinyl".

[0034] The "4- to 10-membered non-aryl heterocyclic group" also includes a bicyclic group in which the above-mentioned 4- to 10-membered non-aryl heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring form a fused ring group. Examples of the 6-membered aromatic hydrocarbon ring forming a fused ring group include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming a fused ring group include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "4- to 10-membered non-aryl heterocyclic group" forming a fused ring group include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and tetrahydronaphthyridinyl.

[0035] The term "4- to 10-membered divalent non-aryl heterocyclic group" refers to a divalent non-aryl heterocyclic group consisting of 1 to 2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and 2 to 9 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. The atoms constituting the ring are -C(O)-, -S(O)-, -SO ２-, and may be oxidized. As the "4- to 10-membered divalent non-aryl heterocyclic group", preferably, "4- to 6-membered divalent non-aryl heterocyclic group" is mentioned. Specific examples of the "4- to 6-membered divalent non-aryl heterocyclic group" include, for example, oxetanylene, azetidinylene, tetrahydrofurylene, pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, hexamethyleneiminylene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxooxazolidinylene, dioxooxazolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, tetrahydropyranylene, and the like. Examples of the "4- to 10-membered divalent non-aryl heterocyclic group" include, in addition to the specific examples of the "4- to 6-membered divalent non-aryl heterocyclic group", azepanylene and the like.

[0036] Furthermore, the "4- to 10-membered divalent non-aryl heterocyclic group" also includes a bicyclic group in which the above-mentioned 4- to 10-membered divalent non-aryl heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring form a fused ring group. Examples of the 6-membered aromatic hydrocarbon ring forming a fused ring group include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming a fused ring group include pyridine, pyrimidine, and pyridazine. Specific examples of the bicyclic "4- to 10-membered divalent non-aryl heterocyclic group" forming a fused ring group include dihydroindolylene, dihydroisoindolylene, dihydropurinylene, dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindolylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.

[0037] "C ６－１０ "Aryl" means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. ６－１０ Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. Preferably, phenyl is used.

[0038] Also, "C ６－１０ "Aryl" includes the above C６－１０ Aryl and C ４－６ Bicyclic rings formed by condensing with an alicyclic group or a 5- or 6-membered non-aryl heterocycle are also included. ６－１０ Specific examples of "aryl" include groups shown below.

[0039] The "aromatic hydrocarbon ring" is defined as the ring ６－１０ The term "aryl" refers to the ring portion of an "aryl."

[0040] "5- to 10-membered heteroaryl" means a monocyclic 5- to 7-membered aromatic heterocyclic ring group or a bicyclic 8- to 10-membered aromatic heterocyclic ring group containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. A "5- to 7-membered monocyclic heteroaryl" is preferred. More preferred is pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. Even more preferred is pyridyl. Specific examples of a "5- to 7-membered monocyclic heteroaryl" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, oxadiazolyl, triazolyl, and tetrazolyl. Specific examples of the "5- to 12-membered heteroaryl" include, in addition to the specific examples of the "5- to 7-membered monocyclic heteroaryl", indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, etc.

[0041] The term "aromatic heterocycle" refers to the ring moiety of the above "5- to 12-membered heteroaryl".

[0042] "3- to 10-membered cycloalkane" means a cyclic saturated hydrocarbon having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure, and a part of the ring may be fused with another ring. Specific examples of "3- to 10-membered cycloalkane" include cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.

[0043] The term "6- to 10-membered aromatic hydrocarbon ring" refers to a cyclic aromatic hydrocarbon having 6 to 10 carbon atoms, and a part of the ring may be fused with another ring. Specific examples of the "6- to 10-membered aromatic hydrocarbon ring" include a benzene ring and naphthalene.

[0044] The term "5- to 10-membered aromatic heterocycle" refers to a monocyclic 4- to 7-membered aromatic heterocycle or a bicyclic 8- to 12-membered aromatic heterocycle containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and a portion of the ring may be fused with another ring. Preferred examples include "5- to 6-membered aromatic heterocycles," "5-membered aromatic heterocycles," and "6-membered aromatic heterocycles." Specific examples of "5- to 6-membered aromatic heterocycles" include furan, thiophene, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, etc. Specific examples of "5-membered aromatic heterocycles" include pyrazole, furan, thiophene, oxazole, etc. Specific examples of "6-membered aromatic heterocycles" include pyridine, pyrazine, pyrimidine, pyridazine, etc.

[0045] The term "6- to 10-membered divalent aromatic hydrocarbon ring group" refers to a monocyclic or bicyclic divalent aromatic hydrocarbon ring group having 6 to 10 carbon atoms. A preferred example of the "6- to 10-membered divalent aromatic hydrocarbon ring group" is a "6-membered divalent aromatic hydrocarbon ring group." Specific examples of the "6- to 10-membered divalent aromatic hydrocarbon ring group" and "6-membered divalent aromatic hydrocarbon ring group" include a divalent benzene ring.

[0046] The term "5- to 10-membered divalent aromatic heterocyclic group" refers to a monocyclic divalent 5- to 7-membered aromatic heterocyclic ring group or a bicyclic divalent 8- to 10-membered aromatic heterocyclic ring group containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. A "5- to 6-membered divalent aromatic heterocyclic group" is preferred, and a "5-membered divalent aromatic heterocyclic group" is more preferred. Specific examples of the "5-membered divalent aromatic heterocyclic group" include divalent pyrazole, divalent furan, divalent thiophene, and divalent oxazole. Examples of the "5- to 10-membered divalent aromatic heterocyclic group" and the "5- to 6-membered divalent aromatic heterocyclic group" include, in addition to the specific examples of the "5-membered divalent aromatic heterocyclic group," divalent pyridine, divalent pyrimidine, divalent pyrazine, and divalent pyridazine.

[0047] "Cancer" refers to a malignant tumor, and includes carcinoma, sarcoma, and hematological malignancies. Specific examples of "cancer" include acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic, and promyelocytic), acute T-cell leukemia, basal cell carcinoma, gallbladder / bile duct cancer, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, choriocarcinoma, chorioepithelial carcinoma, urothelial carcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, cystadenocarcinoma, diffuse large B-cell lymphoma, proliferative dysfunction (dysplasia and metaplasia), embryonic Carcinoma, endometrial cancer, epithelial sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangiosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignant tumors and overgrowth of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus Sexual disorders, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulin These include hematoma, testicular tumor, uterine cancer, Wilms' tumor, malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid / rhabdoid tumor, schwannoma, chordomatoid meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma, chordoma, myoepithelial tumor, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basaloid carcinoma of the paranasal sinus, esophageal adenocarcinoma, papillary thyroid cancer, follicular thyroid cancer, gastrointestinal stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary cancer, endometrial cancer, myoepithelioma-like tumor of the female vulva, colorectal cancer, and mesothelioma.

[0048] In the present disclosure, "CBP" and "P300" are both histone acetyltransferases involved in chromatin regulation, and are paralogs. "CBP / P300" refers to "CBP" and "P300." Histone acetyltransferases are enzymes that transfer acetyl groups primarily, but not exclusively, to lysine residues present on the amino-terminal tails of histone proteins. CBP and P300 primarily, but not exclusively, acetylate histones H2A, H2B, H3, and H4. In particular, for histone H3, they primarily, but not exclusively, acetylate lysine 18, lysine 27, lysine 56, and lysine 122 (H3K18, H3K27, H3K56, and H3K122, respectively). Among these, acetylation of histone H3K27 is known as a marker of open chromatin and plays an important role in regulating gene expression (J Hum Genet. 2013 Jul; 58(7): 439-45). Substrates other than histones have been reported, including p53 (Cell. 1997 Aug; 90(4): 595-606), MyoD (J Biol Chem. 2000 Nov; 275(44): 34359-34364), STAT3 (Science. 2005 Jan; 307(5707): 269-273), and androgen receptor (J Biol Chem. 2000 Jul; 275(27): 20853-20860). As used herein, the terms "CBP" and "P300" generally refer to proteins, but may refer to nucleic acids encoding them or to genes as a concept, depending on the context, and those skilled in the art will be able to appropriately understand this depending on the context.

[0049] Important functional domains of CBP and P300 include the HAT domain, bromodomain (BRD), CH1 / CH2 / CH3 domain (cysteine-histidine rich domains), and KIX domain (Mol Genet Metab. 2016. 119(1-2):37-43). The HAT domain is a domain that has the activity of transferring an acetyl group to lysine residues present primarily, but not exclusively, on the amino-terminal tails of histone proteins. The bromodomain is a protein domain that recognizes N-acetylated lysine residues found primarily, but not exclusively, on the amino-terminal tails of histone proteins.

[0050] The term "CBP," as used herein, unless otherwise specified, refers to any native CBP from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses unprocessed CBP and any form of CBP that results from processing in cells. The term also encompasses naturally occurring variants of CBP, such as splice variants or allelic variants. Human CBP has been registered as UniProt Accession Number: Q92793. Representative amino acid sequences of human CBP are set forth as UniProt Q92793-1 (SEQ ID NO: 1) or UniProt Q92793-2 (SEQ ID NO: 2).

[0051] The term "P300," as used herein, unless otherwise specified, refers to any native P300 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses unprocessed P300 and any form of P300 that results from processing in the cell. The term also encompasses naturally occurring variants of P300, such as splice variants or allelic variants. Human P300 has been registered as UniProt Accession Number: Q09472. A representative amino acid sequence of human P300 is set forth in UniProt Q09472-1 (SEQ ID NO: 3).

[0052] A "CBP / P300 inhibitor" is a substance that inactivates, reduces the activity, and / or reduces the expression of CBP and / or P300. The "reduction of CBP / P300 expression" may act at any stage, such as the pre-transcriptional level (e.g., genomic level), the transcriptional level, the post-transcriptional regulatory level, the translational level, or the post-translational modification level. Preferred "CBP / P300 inhibitors" are HAT inhibitors and BRD inhibitors, and more preferably HAT inhibitors.

[0053] A "HAT inhibitor" is a compound that inhibits the histone acetyltransferase (HAT) activity of CBP and / or P300. In detecting histone acetyltransferase activity, for example, a method of detecting CoA-SH, which is generated as a by-product during the histone acetyltransferase reaction, using fluorescence (e.g., Gao T. et al. Methods Mol Biol. 2013; 981: 229-38), a method of detecting using radioisotopes (e.g., Lau OD et al. J Biol Chem. 2000; 275(29): 21953-9), a method of detecting acetylated histone peptides using the TR-FRET method (e.g., PerkinElmer, LANCE Ultra products and AlphaLISA products), and a method of detecting using NADH (e.g., Berndsen et al. Methods. 2005; 36(4): 321-31) can be used. HAT inhibitors include compounds disclosed in WO2016 / 044770, WO2016 / 044771, WO2016 / 044777, WO2018 / 235966, WO2019 / 111980, WO2019 / 049061, WO2019 / 161162, WO2019 / 161157, WO2019 / 201291, WO2020 / 108500.

[0054] A "BRD inhibitor" is a compound that inhibits the function of the bromodomain (BRD) of CBP and / or P300. To detect the function of the bromodomain, for example, a method of detecting the binding between the bromodomain and an acetylated lysine residue using the TR-FRET method (e.g., Acta Pharmacol Sin. 2020; 41(2): 286-292) can be used. Examples of BRD inhibitors include compounds disclosed in WO2017 / 205538, WO2016 / 086200, WO2018 / 073586, WO2019 / 055877, WO2017 / 140728, WO2019 / 191667, and WO2019 / 195846.

[0055] Histone acetyltransferase (HAT) activity is an enzymatic activity that transfers an acetyl group to a lysine residue in a substrate protein, such as a histone protein or p53.

[0056] Bromodomains are protein domains that recognize N-acetylated lysine residues, which are found, for example, on the amino-terminal tails of histone proteins.

[0057] In the compounds of the present disclosure represented by formula (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10), A, B, R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ６ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R ９ａ , R ９ｂ Preferred examples of a, b, ring Q and Z are as follows, but the technical scope of the present disclosure is not limited to the range of compounds listed below.

[0058] A preferred embodiment of A is CHF or CH ２ Examples include:

[0059] A more preferred embodiment of A is CHF.

[0060] Another preferred embodiment of A is CH ２ Examples include:

[0061] A preferred embodiment of B is represented by the following formula (B-1). [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring] More preferred embodiments of B include the following formula (B-2), (B-3) or (B-4). [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring]

[0062] R １ A preferred embodiment of the formula is C １－６ Alkyl, or C ３－１０ Alicyclic groups (the alkyl or alicyclic groups may be substituted with 1 to 3 identical or different halogen atoms) are also included.

[0063] R １ A more preferred embodiment of the above is C １－６ Alkyl, or C ３－１０ Alicyclic groups (the alkyl or alicyclic groups may be substituted with 1 to 3 fluorine atoms) are also included.

[0064] R １ A more preferred embodiment of the formula (I) is a C group optionally substituted with 1 to 3 fluorines. １－３ alkyl. １ As an even more preferred embodiment, CF ３ Examples include:

[0065] R ２ａ and R ２ｂ A preferred embodiment of the formula (I) is a C group which may be substituted with 1 to 3 halogen atoms, each of which may be the same or different. １－６ alkyl. ２ａ and R ２ｂ Another preferred embodiment of R ２ａ and R ２ｂ together with the carbon atom to which it is attached, C ３－６ Examples include forming a cycloalkylene or a 4- to 6-membered divalent non-aryl heterocyclic group (the cycloalkylene or divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different halogen atoms).

[0066] R ２ａ and R ２ｂ The most preferred embodiment of R ２ａ and R ２ｂ together with the carbon atom to which it is attached, C ３－６ Examples include forming a cycloalkylene or a 4- to 6-membered divalent non-aryl heterocyclic group (the cycloalkylene or divalent non-aryl heterocyclic group may be substituted with 1 to 3 fluorine atoms).

[0067] R ３ A preferred embodiment of the formula is C ６－１０ Aryl, 5- to 10-membered heteroaryl, C ３－１０ an alicyclic group, or a 4- to 10-membered non-aryl heterocyclic group (the aryl, heteroaryl, alicyclic group, or non-aryl heterocyclic group may contain no halogen atoms and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0068] R ３ A more preferred embodiment of the above is C ６－１０ Aryl (the aryl is a halogen atom and C １－６ alkyl), or 5-10 membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0069] R ３ A more preferred embodiment of the formula is C ６－１０ aryl or 5-10 membered heteroaryl (the heteroaryl is fluorine atom and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0070] R ３ An even more preferred embodiment of is 4-fluorophenyl, 4-(trifluoromethyl)phenyl or 4-fluoro-2-pyridyl, and more preferred is 4-fluorophenyl or 4-fluoro-2-pyridyl.

[0071] R ３ The most preferred embodiment of is 4-fluorophenyl.

[0072] R ３ Another most preferred embodiment of is 4-fluoro-2-pyridyl.

[0073] R ４ Preferred embodiments of are a single bond, C１－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of:

[0074] R ４ More preferred embodiments of the group include a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of:

[0075] R ４ More preferred embodiments of the group include a single bond, C １－６ Examples include alkylene and 4- to 6-membered divalent non-aryl heterocyclic groups.

[0076] R ４ An even more preferred embodiment of is a single bond.

[0077] R ４ As an even more preferred embodiment of １－６ Examples include alkylene.

[0078] R ４ An even more preferred embodiment of is a 4- to 6-membered divalent non-aryl heterocyclic group.

[0079] R４ The most preferred embodiment of is azetidinylene.

[0080] R ４ Another most preferred embodiment of is methylene.

[0081] R ５ Preferred embodiments of the group include a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, and —NR ７ｂ R ７ｃ , -SO ２ R ７ｄ or -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of:

[0082] R ５ More preferred embodiments of the group include a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, and C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of:

[0083] R ５ More preferred embodiments of the group include cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of:

[0084] R ５As an even more preferred embodiment of １－６ Examples include alkyl and 4- to 6-membered non-aryl heterocyclic groups.

[0085] R ５ The most preferred embodiment of is a methyl group or oxetane.

[0086] R ６ Preferred embodiments of include a hydrogen atom or a fluorine atom.

[0087] R ６ A more preferred embodiment of is a hydrogen atom.

[0088] R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ and R ７ｆ In a preferred embodiment, each independently represents a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0089] R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ and R ７ｆ More preferred embodiments of the above are each independently a hydrogen atom or a methyl group.

[0090] R ８ A preferred embodiment of is a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0091] R ８ A more preferred embodiment of the above is C １－６ Alkyl (the alkyl is a halogen atom and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0092] R ８ A more preferred embodiment of is a methyl group.

[0093] R ９ａ and R ９ｂ In a preferred embodiment, each independently represents a hydrogen atom, a halogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0094] R ９ａ and R ９ｂ More preferred embodiments of the above are each independently a halogen atom.

[0095] R ９ａ and R ９ｂ A more preferred embodiment of is a fluorine atom.

[0096] R １０ A preferred embodiment of the formula is C １－６ Examples of alkyl include:

[0097] R １１ and R １２ In a preferred embodiment, each independently represents a hydrogen atom or C １－６ Examples of alkyl include:

[0098] R １１ and R １２ In another preferred embodiment, R １１ and R １２ Both are C １－６ When they are alkyl, they may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded.

[0099] R １１ and R １２ A more preferred embodiment of is a methyl group.

[0100] A preferred embodiment of ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring is not substituted by a halogen atom or a C １－６and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0101] A more preferred embodiment of ring Q is a benzene ring (the benzene ring is a ring containing no halogen atom and C １－６ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl.

[0102] A more preferred embodiment of ring Q is a benzene ring.

[0103] Preferred embodiments of Z include —O—, a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not particularly limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and Z is a 4- to 10-membered divalent non-aryl heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ A more preferred embodiment of Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C１－６ Alkyl and -NR １１ R １２ and the like. The alkyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of:

[0104] An even more preferred embodiment of Z is a divalent pyrazole group.

[0105] Preferred embodiments of a include 0, 1, and 2.

[0106] More preferred embodiments of a include 1 and 2.

[0107] A more preferred embodiment of a is 1.

[0108] Preferred embodiments of b include 1 and 2.

[0109] A more preferred embodiment of b is 1.

[0110] A more preferred embodiment of a and b is when both are 1.

[0111] One embodiment of the compound represented by formula (1) is (A) below: (A) A is CHF or CH ２ B is represented by the following formula (B-1): [wherein * represents the bonding position of the hydantoin ring to the nitrogen atom], and ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring is not substituted by a halogen atom or a C １－６ alkyl), Z is —O—, a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R １ C optionally substituted with 1 to 3 fluorines １－３ alkyl, R ２ａ and R ２ｂ together with the carbon atoms to which they are attached, C ３－６ form a cycloalkylene or a 4- to 6-membered divalent non-aryl heterocyclic group (the cycloalkylene or divalent non-aryl heterocyclic group may be substituted with 1 to 3 fluorine atoms), R ３ But C ６－１０ Aryl (the aryl is a halogen atom and an optionally substituted C １－６ alkyl), or 5-10 membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms and C １－６ alkyl), and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -NR７ｂ R ７ｃ , -SO ２ R ７ｄ or -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), and R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0112] One embodiment of the compound represented by formula (1) is the following (B): (B) A is CHF or CH ２ B is represented by the following formula (B-2), (B-3), or (B-4): [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring, a is 0, 1, or 2, b is 1 or 2, and R ８ is a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), and R９ａ and R ９ｂ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ and ring Q is a 6- to 10-membered aromatic hydrocarbon ring (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms and C １－６ alkyl), Z is —O—, a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R １ But CF ３ and R ３ is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ or -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), and R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0113] One embodiment of the compound represented by formula (2) is the following (C): (C) A is CHF or CH ２ and R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, Z is a 4- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ But, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ is a hydrogen atom or a halogen atom, R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When they are alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0114] One embodiment of the compound represented by formula (2) is (D) below: (D) A is CHF, and Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group does not contain a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ But, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ is a hydrogen atom, and R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple１１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When they are alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0115] One embodiment of the compound represented by formula (3) is the following (E): (E) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ But, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple １１ or R １２may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0116] One embodiment of the compound represented by formula (3) is the following (F): (F) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a 4- to 6-membered divalent non-aryl heterocyclic group, R ５ But, C １－３ alkyl, or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ and optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, or a pharmaceutically acceptable salt thereof.

[0117] One embodiment of the compound represented by formula (3) is (G) below. (G) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is azetidinylene or piperidinylene, R ５ is oxetanyl, or a pharmaceutically acceptable salt thereof.

[0118] One embodiment of the compound represented by formula (4) is the following (H): (H) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is azetidinylene, R ５ is oxetanyl, or a pharmaceutically acceptable salt thereof.

[0119] One embodiment of the compound represented by formula (5) is the following (I): (I) A is CHF or CH ２Z is a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), and R ５ But, hydrogen atom, hydroxyl group cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ is a hydrogen atom or a halogen atom, R８ But C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When they are alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0120] One embodiment of the compound represented by formula (5) is the following (J): (J) A is CHF, and Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group does not contain a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, or C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), and R ５ But, hydroxyl group, cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ is a hydrogen atom, and R ８ is a methyl group, and R １１ and R １２ are each independently a hydrogen atom or C １－６ alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When they are alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0121] One embodiment of the compound represented by formula (6) is (K) below. (K) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, or C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), and R ５ But, hydroxyl group, cyano C １－６ Alkyl, C ３－１０a cycloaliphatic group, or a 4- to 10-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0122] One embodiment of the compound represented by formula (6) is (L) below. (L) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, or C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), and R ５ is a methyl group, or oxetanyl, or a pharmaceutically acceptable salt thereof.

[0123] One embodiment of the compound represented by formula (6) is (M) below. (M) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, and R ５ is a methyl group, or a pharmaceutically acceptable salt thereof.

[0124] One embodiment of the compound represented by formula (7) is (N) below. (N) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a single bond, and R ５ is a methyl group, or a pharmaceutically acceptable salt thereof.

[0125] One embodiment of the compound represented by formula (8) is the following (O): (O) A is CHF or CH ２ Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is not particularly limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R４ is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is １－６ Alkyl and -NR １１ R １２ and R ５ is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not particularly limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ is a hydrogen atom or a halogen atom, R ９ａ and R ９ｂ is a fluorine atom, or a pharmaceutically acceptable salt thereof.

[0126] One embodiment of the compound represented by formula (9) is the following (P): (P) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a 4- to 6-membered divalent non-aryl heterocyclic group, R ５ is a 4- to 6-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0127] One embodiment of the compound represented by formula (9) is (Q) below. ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is azetidinylene, R ５ is oxetanyl, or a pharmaceutically acceptable salt thereof.

[0128] One embodiment of the compound represented by formula (10) is the following (R): (R) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is a 4- to 6-membered divalent non-aryl heterocyclic group, R ５is a 4- to 6-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

[0129] One embodiment of the compound represented by formula (10) is the following (S): (S) R ３ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ is azetidinylene, R ５ is oxetanyl, or a pharmaceutically acceptable salt thereof.

[0130] The compound of the present disclosure may be administered orally, parenterally, or rectally, with the daily dosage varying depending on the type of compound, the administration method, the patient's symptoms, age, and other factors. For example, oral administration typically involves administering approximately 0.01 to 1,000 mg, more preferably approximately 0.1 to 500 mg, per kg of body weight to a human or mammal, in one or several divided doses. Parenteral administration, such as intravenous injection, typically involves administering approximately 0.01 to 300 mg, more preferably approximately 1 to 100 mg, per kg of body weight to a human or mammal. Examples of administration schedules include a single dose, once daily for three consecutive days, or twice daily for one week. Furthermore, each of the above-described administration methods can be repeated at intervals of approximately 1 to approximately 60 days.

[0131] The compounds of the present disclosure can be administered parenterally or orally, either directly or after formulation using an appropriate dosage form. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and poultices. The formulations are prepared by known methods using pharmaceutically acceptable additives. Depending on the purpose, additives that can be used include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavors. Specific examples of additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.

[0132] Methods for producing the compounds of the present disclosure represented by formulas (1) to (10) are described below with examples, but the methods for producing the compounds of the present disclosure are not limited to these. The compounds used in the following production methods may form salts as long as they do not interfere with the reaction.

[0133] The compounds of the present disclosure can be produced using known compounds as starting materials by, for example, the following production methods A, B, C, and D, or methods similar thereto, or by appropriately combining synthesis methods known to those skilled in the art.

[0134] Production Method A Among the compounds represented by formula (1), compound (1-11) in which A is CHF and Q is a benzene ring can be produced, for example, by the following production method. [In the formula, R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ and Z are as defined in [Item 1] above, and R ６ has the same meaning as [Item 16] above.]

[0135] Step 1-1: Preparation of Compound (1-3) Compound (1-3) is prepared by reacting compound (1-1) with compound (1-2) in the presence of a reducing agent in an inert solvent.

[0136] Specific examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.

[0137] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, and N-methyl-2-pyrrolidinone.

[0138] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 150° C., preferably 0° C. to 25° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0139] Step 1-2: Preparation of Compound (1-5) Compound (1-5) is prepared by an amidation reaction using compound (1-3) and compound (1-4) in an inert solvent in the presence of a base.

[0140] Specific examples of the base include inorganic bases such as potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0141] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0142] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 150° C., preferably 25° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0143] Step 1-3: Preparation of Compound (1-6) Compound (1-6) can be prepared by deprotecting the benzyl group of compound (1-5). For example, catalytic reduction using a metal catalyst such as palladium / carbon or palladium hydroxide / carbon under a hydrogen atmosphere can be applied.

[0144] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 100° C., preferably 0° C. to 25° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0145] Step 1-4: Preparation of Compound (1-8) Compound (1-8) is prepared by reacting compound (1-7) with a reducing agent. Compound (1-7) can be synthesized by the method described in WO2016 / 044770.

[0146] Specific examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.

[0147] The reaction temperature is not particularly limited, but is usually selected within the range of −78° C. to 150° C., preferably −78° C. to 25° C. The reaction time is usually 30 minutes to 72 hours, preferably 30 minutes to 24 hours.

[0148] Step 1-5: Preparation of Compound (1-9) Compound (1-9) is prepared by reacting compound (1-8) with a fluorinating agent in an inert solvent.

[0149] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0150] Specific examples of fluorinating agents include (diethylamino)sulfur trifluoride, FLUOLEAD, ＴＭ etc.

[0151] The reaction temperature is not particularly limited, but is usually selected within the range of −78° C. to 150° C., preferably −78° C. to 25° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0152] Step 1-6: Preparation of Compound (1-10) Compound (1-10) is prepared by Mitsunobu reaction using compound (1-6) and compound (1-9) in the presence of a Mitsunobu reagent in an inert solvent.

[0153] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; and ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and the like.

[0154] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, and the like. Cyanomethylenetrimethylphosphorane (Tsunoda reagent) can also be used.

[0155] The reaction temperature is not particularly limited, but is usually selected in the range of 0° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0156] Step 1-7: Preparation of Compound (1-11) Compound (1-11) is prepared by subjecting compound (1-10) to a palladium-catalyzed cross-coupling reaction using various coupling reagents in an inert solvent.

[0157] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0158] Specific examples of the palladium reagent include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0159] Specific examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.

[0160] Specific examples of the coupling reagent include Z-bonded boronic acid, Z-bonded boronic acid pinacol ester, and the like.

[0161] The reaction temperature is not particularly limited, but is usually selected from the range of 0°C to 150°C, preferably 25°C to 100°C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours. Production Method B Among the compounds represented by formula (1), compound (1-14) in which Q is a benzene ring can also be produced by the following production method. [In the formula, A, R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ and Z have the same meanings as those in [Item 1] above. ６has the same meaning as in [Item 16] above. W represents a halogen atom.]

[0162] Step 2-1: Preparation of Compound (2-1) Compound (2-1) is prepared by reacting compound (1-3) with an amidating agent in an inert solvent.

[0163] Specific examples of the amidating agent include chloroacetyl chloride, bromoacetyl chloride, and chloroacetic anhydride.

[0164] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone and N,N-dimethylpropylene urea; and pyridine.

[0165] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 150° C., preferably 25° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0166] Step 2-2: Preparation of Compound (1-13) Compound (1-13) is prepared by alkylation reaction using compound (2-1) and compound (1-12) in an inert solvent in the presence of a base.

[0167] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0168] Specific examples of the base include inorganic bases such as potassium carbonate and cesium carbonate; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0169] The reaction temperature is not particularly limited, but is usually selected in the range of 0° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0170] Step 2-3: Preparation of Compound (1-14) Compound (1-14) is prepared by subjecting compound (1-13) to a palladium-catalyzed cross-coupling reaction using various coupling reagents in an inert solvent.

[0171] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0172] Specific examples of the palladium reagent include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0173] Specific examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.

[0174] Specific examples of the coupling reagent include Z-bonded boronic acid, Z-bonded boronic acid pinacol ester, and the like.

[0175] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 150° C., preferably 25° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0176] Production Method C Among the compounds represented by formula (1), the compound (1-14) in which Q is a benzene ring can also be produced by the following production method. [In the formula, A, R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ and Z have the same meanings as those in [Item 1] above. ６ has the same meaning as [Item 16] above.]

[0177] Step 3-1: Preparation of Compound (3-1) Compound (3-1) is prepared by subjecting compound (1-12) to a palladium-catalyzed cross-coupling reaction using various coupling reagents in an inert solvent.

[0178] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0179] Specific examples of the palladium reagent include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0180] Specific examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.

[0181] Specific examples of the coupling reagent include Z-bonded boronic acid, Z-bonded boronic acid pinacol ester, and the like.

[0182] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 150° C., preferably 25° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0183] Step 3-2: Preparation of Compound (1-14) Compound (1-14) is prepared by Mitsunobu reaction using compound (3-1) and compound (1-6) in the presence of a Mitsunobu reagent in an inert solvent.

[0184] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; and ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and the like.

[0185] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, and the like. Cyanomethylenetrimethylphosphorane (Tsunoda reagent) can also be used.

[0186] The reaction temperature is not particularly limited, but is usually selected in the range of 0° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0187] Production Method D Among the compounds represented by formula (1), the compound (1-14) in which Q is a benzene ring can also be produced by the following production method. [In the formula, A, R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ and Z have the same meanings as those in [Item 1] above. ６ has the same meaning as in [Item 16] above. W represents a halogen atom.]

[0188] Step 4-1: Preparation of Compound (1-14) Compound (1-14) is prepared by alkylation reaction using compound (3-1) and compound (2-1) in an inert solvent in the presence of a base.

[0189] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0190] Specific examples of the base include inorganic bases such as potassium carbonate and cesium carbonate; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0191] The reaction temperature is not particularly limited, but is usually selected in the range of 0° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0192] Production Method E: In the compound represented by formula (1), A is CH ２ The compound (1-17) in which Q is a benzene ring can be produced, for example, by the following production method. [In the formula, R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ and Z are as defined in [Item 1] above, and R ６ has the same meaning as [Item 16] above.]

[0193] Step 5-1: Preparation of Compound (1-16) Compound (1-16) is prepared by Mitsunobu reaction using compound (1-6) and compound (1-15) in the presence of a Mitsunobu reagent in an inert solvent. Compound (1-15) can be synthesized by the method described in WO2016 / 044770.

[0194] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; and ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and the like.

[0195] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, and the like. Cyanomethylenetrimethylphosphorane (Tsunoda reagent) can also be used.

[0196] The reaction temperature is not particularly limited, but is usually selected in the range of 0° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0197] Step 5-2: Preparation of Compound (1-17) Compound (1-17) is prepared by subjecting compound (1-16) to a palladium-catalyzed cross-coupling reaction using various coupling reagents in an inert solvent.

[0198] Specific examples of the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.

[0199] Specific examples of the palladium reagent include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.

[0200] Specific examples of the base include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.

[0201] Specific examples of the coupling reagent include Z-bonded boronic acid, Z-bonded boronic acid pinacol ester, and the like.

[0202] The reaction temperature is not particularly limited, but is usually selected from the range of 0° C. to 150° C., preferably 25° C. to 100° C. The reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.

[0203] In the above-described production methods, starting materials or intermediates for which production methods are not described are either commercially available or can be synthesized from commercially available compounds by methods known to those skilled in the art or methods similar thereto.

[0204] In each reaction of the production method described above, even when the use of a protecting group is not specifically specified, a protecting group can be used as needed. For example, when any functional group other than the reactive site changes under the reaction conditions described, or when the method described is inappropriate to carry out without a protecting group, the target compound can be obtained by protecting the functional group other than the reactive site as needed and deprotecting it after the reaction or after a series of reactions.

[0205] Examples of the protecting group that can be used include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, etc.

[0206] Introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the aforementioned Protective Groups in Organic Synthesis) or a method analogous thereto.

[0207] In this specification, protecting groups, condensing agents, etc. may be represented by abbreviations according to IUPAC-IUB (International Board of Biochemical Nomenclature) commonly used in this technical field. Note that the names of compounds used in this specification do not necessarily conform to the IUPAC nomenclature.

[0208] The intermediates or target compounds in the above-described production methods can be converted into other compounds included in the present disclosure by appropriately converting their functional groups (for example, by protecting or deprotecting the functional groups as necessary, and then performing various conversions using amino, hydroxyl, carbonyl, halogen, etc. as a stepping stone). The conversion of functional groups can be performed by a commonly used method (see, for example, Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).

[0209] The intermediates and target compounds in the above-described production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). In addition, the intermediates can also be used in the next reaction without any particular purification.

[0210] Examples of the protecting group that can be used include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc. Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, benzyl, etc.

[0211] Introduction and removal of the protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the aforementioned Protective Groups in Organic Synthesis) or a method analogous thereto.

[0212] In this specification, protecting groups, condensing agents, etc. may be represented by abbreviations according to IUPAC-IUB (International Board of Biochemical Nomenclature) commonly used in this technical field. Note that the names of compounds used in this specification do not necessarily conform to the IUPAC nomenclature.

[0213] The intermediates or target compounds in the above-described production methods can be converted into other compounds included in the present disclosure by appropriately converting their functional groups (for example, by protecting or deprotecting the functional groups as necessary, and then performing various conversions using amino, hydroxyl, carbonyl, halogen, etc. as a stepping stone). The conversion of functional groups can be performed by a commonly used method (see, for example, Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).

[0214] The intermediates and target compounds in the above-described production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). In addition, the intermediates can also be used in the next reaction without any particular purification.

[0215] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate; and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzene ring sulfonate, para-toluenesulfonate, and camphorsulfonate. Furthermore, base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt; and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0216] Suitable salts of starting materials and intermediates, as well as salts acceptable as pharmaceutical raw materials, are conventional non-toxic salts, which can be appropriately selected by those skilled in the art, including, for example, acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzene ring sulfonate, formate, toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), salts with amino acids (e.g., arginine, aspartic acid, glutamic acid, etc.), metal salts such as alkali metal salts (e.g., sodium salt, potassium salt), alkaline earth metal salts (e.g., calcium salt, magnesium salt), ammonium salts, organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), and others.

[0217] The compounds of the present disclosure may be isotopically enriched, e.g.２ H (or D), ３ H (or T), １１ C. １３ C. １４ C. １３ N. １５ N. １５ O. ３５ S. １８ F. １２５ I, etc.), and these compounds are also included in the compounds of the present disclosure.

[0218] The present disclosure includes compounds represented by formulas (1) to (10) or pharmaceutically acceptable salts thereof. In addition, the compounds of the present disclosure may exist in the form of hydrates and / or solvates with various solvents (such as ethanol solvates), and these hydrates and / or solvates are also included in the compounds of the present disclosure.

[0219] Furthermore, the compounds of the present disclosure include all possible isomers such as optical isomers based on optically active centers, atropisomers based on axial or planar chirality resulting from restricted intramolecular rotation, other stereoisomers, tautomers, geometric isomers, and the like, as well as all types of crystalline forms, and mixtures thereof.

[0220] In particular, optical isomers and atropisomers can be obtained as racemates, or as optically active isomers when optically active starting materials or intermediates are used. Furthermore, if necessary, at an appropriate stage of the production method, the racemate of the corresponding starting material, intermediate, or final product can be physically or chemically resolved into its optical antipodes by known separation methods such as a method using an optically active column or fractional crystallization. Examples of such resolution methods include a diastereomeric method in which a racemate is reacted with an optically active resolving agent to synthesize two diastereomers, which are then separated by a method such as fractional crystallization, taking advantage of their different physical properties.

[0221] When it is desired to obtain a pharmaceutically acceptable salt of a compound of the present disclosure, if the compound represented by formulas (1) to (7) is obtained in the form of a pharmaceutically acceptable salt, it may be purified as is, or if it is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a conventional method.

[0222] The compound of the present disclosure can be used in combination with other drugs to enhance its effect.Specifically, the compound of the present disclosure can be used in combination with drugs such as hormone therapy agents, chemotherapy agents, immunotherapy agents, and drugs that inhibit cell growth factors and their receptor activity.Hereinafter, drugs that can be used in combination with the compound of the present disclosure will be abbreviated as "concomitant drugs."

[0223] The compounds of the present disclosure exhibit excellent anticancer effects even when used as a single agent, but by further using them in combination with one or several of the above-mentioned concomitant drugs (multidrug combination), the effects can be further enhanced or the patient's QOL can be improved.

[0224] Examples of "hormonal therapeutic agents" include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestol, tadenane, mepartricin, raloxifene, ormeloxifene, levormeloxifene, antiestrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), birth control pills, mepitiostane, testololactone, aminoglutethimide, LH-RH derivatives (LH-RH agonists (e.g., goserelin acetate, buserelin, levothyroxine), levothyroxine, ... prorelin, etc.), LH-RH antagonists), droloxifene, epitiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane, etc.), antiandrogens (e.g., flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.), adrenocortical hormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (e.g., abiraterone, etc.), retinoids, and agents that slow the metabolism of retinoids (e.g., liarozole, etc.).

[0225] Examples of "chemotherapeutic agents" that can be used include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. Representative examples are listed below.

[0226] Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozotocin, Examples of drugs include benzodiazepine, pipobroman, etoglucide, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trofosfamide, zinostatin stimalamer, adozelesin, systostin, bizelesin, trabectedin, and DDS formulations thereof.

[0227] Examples of "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galocitabine, emitefur, capecitabine, etc.), aminopterin, nelzarabine, leucoporin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS preparations thereof.

[0228] Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, eribulin, and DDS preparations thereof.

[0229] Examples of "plant-derived anticancer agents" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and DDS formulations thereof.

[0230] Examples of "molecular targeted therapeutic agents" include imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, nilotinib, lapatinib, pazopanib, ruxolitinib, crizotinib, vemurafenib, vandetanib, ponatinib, cabozantinib, tofacitinib, regorafenib, bosutinib, axitinib, dabrafenib, trametinib, nintedanib, idelalisib, ceritinib, lenvatinib, palbociclib, alectinib, afatinib, osimertinib, ribociclib, abemaciclib, and brigadimin. These include tinib, neratinib, copanlisib, cobimetinib, ibrutinib, acalabrutinib, encorafenib, binimetinib, baricitinib, fostamatinib, lorlatinib, erdafitinib, entrectinib, dacomitinib, sirolimus, everolimus, temsirolimus, olaparib, rucaparib, niraparib, venetoclax, azacitidine, decitabine, vorinostat, panobinostat, tazemetostat, romidepsin, bortezomib, carfilzomib, larotrectinib, and ixazomib.

[0231] "Immunomodulators" include, for example, lenalidomide and pomalidomide.

[0232] Examples of "other chemotherapeutic agents" include sobuzoxane.

[0233] Examples of "immunotherapeutic agents (BRM)" include picibanil, krestin, sizofiran, lentinan, ubenimex, interferon, interleukin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, and Toll-like receptor agonists (e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.).

[0234] The cell growth factor in the drug that inhibits the action of cell growth factors and their receptors may be any substance that promotes cell growth, and typically includes a peptide with a molecular weight of 20,000 or less that exerts its effect at low concentrations by binding to a receptor. Specifically, EGF (epidermal growth factor) or a substance having substantially the same activity as EGF (e.g., TGFalpha, etc.), insulin or a substance having substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, etc.), FGF (fibroblast growth factor) or a substance having substantially the same assay as FGF (e.g., acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10, etc.), and other cell growth factors (e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), etc.). growth factor), PDGF (platelet-derived growth factor), TGF-beta (transforming growth factor beta), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), heregulin, angiopoietin, etc.

[0235] "SMARC-deficient cancer" refers to cancer in which the SMARC gene is defective and / or expression of the SMARC protein is deleted or attenuated. Preferably, it is cancer in which the SMARC gene is deleted and / or expression of the SMARC protein is deleted. More preferably, it is cancer in which the SMARCB1 gene, SMARCA2 gene, SMARCA4 gene, or SMARCA2 / A4 gene is deleted. Specifically, these include malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid / rhabdoid tumor, schwannoma, chordotomy meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma, chordoma, myoepithelial tumor, unclassifiable round cell sarcoma, rhabdomyosarcoma, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basaloid carcinoma of the paranasal sinus, esophageal adenocarcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumor, pancreatic undifferentiated rhabdoid tumor, and gastrointestinal rhabdoid tumor. tumors, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumors of the female vulva, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung carcinoma, lung neuroendocrine tumor, esophageal cancer, gastroesophageal junction cancer, stomach cancer, bladder cancer, squamous cell lung carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver cancer, ovarian small cell carcinoma, ovarian mucinous tumor, endometrial cancer, uterine sarcoma, nasal and paranasal cancer, thoracic sarcoma, pulmonary pleomorphic carcinoma, thoracic sarcoma, ovarian small cell carcinoma, primary gallbladder tumor, and uterine sarcoma are preferred.

[0236] "SMARCB1-deficient cancer" refers to cancer in which the SMARCB1 gene is defective and / or expression of the SMARCB1 protein is deleted or attenuated. Preferably, it is cancer in which the SMARCB1 gene is deleted and / or expression of the SMARCB1 protein is deleted. More preferably, it is cancer in which the SMARCB1 gene is deleted. Specific examples include malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid / rhabdoid tumor, schwannoma, chordotomy meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma, chordoma, myoepithelial tumor, unclassifiable round cell sarcoma, rhabdomyosarcoma, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, paranasal sinus basaloid cell carcinoma, esophageal adenocarcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumor of the female vulva, colorectal cancer, and mesothelioma. Preferably, the tumor is malignant rhabdoid tumor.

[0237] "SMARCA2-deficient cancer" refers to cancer in which the SMARCA2 gene is defective and / or expression of the SMARCA2 protein is deleted or attenuated. Preferably, it is cancer in which the SMARCA2 gene is deleted and / or expression of the SMARCA2 protein is deleted. More preferably, it is cancer in which the SMARCA2 gene is deleted. Specific examples include lung adenocarcinoma, lung large cell carcinoma, lung neuroendocrine tumor, esophageal cancer, gastroesophageal junction cancer, and malignant rhabdoid tumor. Preferably, it is lung adenocarcinoma.

[0238] "SMARCA4-deficient cancer" refers to cancer in which the SMARCA4 gene is defective and / or expression of the SMARCA4 protein is deleted or attenuated. Preferably, it is cancer in which the SMARCA4 gene is deleted and / or expression of the SMARCA4 protein is deleted. More preferably, it is cancer in which the SMARCA4 gene is deleted. Specific examples include lung adenocarcinoma, esophageal cancer, gastroesophageal junction cancer, gastric cancer, bladder cancer, lung squamous cell carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver cancer, ovarian small cell carcinoma, ovarian mucinous tumor, endometrial cancer, mesothelioma, uterine sarcoma, nasal and paranasal cancer, rhabdoid tumor, and thoracic sarcoma. Preferably, it is lung adenocarcinoma.

[0239] "SMARCA2 / A4-deficient cancer" refers to cancer in which the SMARCA2 gene and the SMARCA4 gene are deleted, and / or the expression of the SMARCA2 protein and the SMARCA4 protein is deleted or attenuated. Preferably, it is cancer in which the SMARCA2 gene and the SMARCA4 gene are deleted, and / or the expression of the SMARCA2 protein and the SMARCA4 protein is deleted. More preferably, it is cancer in which the SMARCA2 gene and the SMARCA4 gene are deleted. Specific examples include lung adenocarcinoma, lung pleomorphic carcinoma, lung large cell carcinoma, esophageal cancer, gastroesophageal junction cancer, breast sarcoma, ovarian small cell carcinoma, primary gallbladder tumor, uterine sarcoma, malignant rhabdoid tumor, ovarian granulosa tumor, adrenocortical carcinoma, and small cell lung cancer. Preferably, it is lung adenocarcinoma.

[0240] "ARID-deficient cancer" refers to cancer in which the ARID gene is defective and / or expression of the ARID protein is deleted or attenuated. Preferably, it is cancer in which the ARID gene is deleted and / or expression of the ARID protein is deleted. More preferably, it is cancer in which the ARID1A gene, the ARID1B gene, or the ARID1A / 1B gene is deleted. Specific examples include ovarian cancer, gastric cancer, biliary tract cancer, pancreatic cancer, endometrial cancer, neuroblastoma, colorectal cancer, bladder cancer, liver cancer, melanoma, breast cancer, medulloblastoma, and neuroblastoma. Preferably, it is ovarian cancer.

[0241] "ARID1A-deficient cancer" refers to cancer in which the ARID1A gene is defective and / or expression of the ARID1A protein is deleted or attenuated. Preferably, it is cancer in which the ARID1A gene is deleted and / or expression of the ARID1A protein is deleted. More preferably, it is cancer in which the ARID1A gene is deleted. Specific examples include ovarian cancer, gastric cancer, biliary tract cancer, pancreatic cancer, uterine cancer, neuroblastoma, colorectal cancer, and bladder cancer. Preferably, it is ovarian cancer.

[0242] "ARID1B-deficient cancer" refers to cancer in which the ARID1B gene is defective and / or expression of the ARID1B protein is deleted or attenuated. Preferably, it is cancer in which the ARID1B gene is deleted and / or expression of the ARID1B protein is deleted. More preferably, it is cancer in which the ARID1B gene is deleted. Specific examples include ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, melanoma, breast cancer, medulloblastoma, uterine cancer, bladder cancer, and gastric cancer. Preferably, it is ovarian cancer.

[0243] "ARID1A / 1B-deficient cancer" refers to cancer in which the ARID1A gene and the ARID1B gene are deficient and / or the expression of the ARID1A protein and the ARID1B protein is deleted or attenuated. Preferably, it is cancer in which the ARID1A gene and the ARID1B gene are deleted and / or the expression of the ARID1A protein and the ARID1B protein is deleted. More preferably, it is cancer in which the ARID1A gene and the ARID1B gene are deleted. Specific examples include ovarian cancer, colorectal cancer, endometrial cancer, neuroblastoma, bladder cancer, and gastric cancer. Preferably, it is ovarian cancer.

[0244] "SS18-SSX fusion cancer" refers to cancer in which the SS18 gene and the SSX gene are fused. Specific examples include synovial sarcoma and Ewing's sarcoma. Synovial sarcoma is preferred.

[0245] "Heart disease" refers to a condition caused by some kind of damage to the heart, resulting in poor blood circulation. Specifically, it includes cardiomyopathy, heart failure, and myocardial infarction.

[0246] "Metabolic diseases" are diseases caused by impaired metabolic function, specifically dyslipidemia and diabetes.

[0247] The administration period of the compound of the present disclosure and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. The compound of the present disclosure and the concomitant drug may also be used as a combination drug. The dose of the concomitant drug can be appropriately selected based on clinically used doses. The compounding ratio of the compound of the present disclosure to the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present disclosure. Furthermore, for the purpose of suppressing side effects, the compound of the present disclosure may be used in combination with drugs (concomitant drugs) such as antiemetics, hypnotics, and anticonvulsants.

[0248] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." When specified in this specification as "within a range of two values," the range includes the two values ​​themselves.

[0249] All references cited herein, including scientific literature, patents, patent applications, and the like, are incorporated by reference in their entirety to the same extent as if each were specifically set forth.

[0250] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the scope of the claims.

[0251]

[0252]

[0253]

[0254] The present disclosure will be explained in more detail below with reference to Reference Examples, Examples and Test Examples, but the present disclosure is not limited thereto.

[0255] The following abbreviations may be used in the present specification: Me: methyl Et: ethyl Ph: phenyl Bn: benzyl Boc: tert-butoxycarbonyl DMPU: N,N'-dimethylpropyleneurea n-: normal- tert-: tertiary- p-: para- Ac: acetyl dppf: 1,1'-bis(diphenylphosphino)ferrocene X-PHOS: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0256] The NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained using a JNM-ECS400 nuclear magnetic resonance spectrometer (400 MHz) manufactured by JEOL Ltd.

[0257] Symbols used in NMR include s for singlet, d for doublet, dd for doublet of doublets, t for triplet, td for doublet of triplets, q for quartet, m for multiplet, br for broad, brs for broad singlet, brm for broad multiplet, and J for coupling constant.

[0258] The LC / MS (Liquid Chromatography-Mass Spectrometry) analysis conditions used for compound identification are as follows: Among the observed mass spectrometry values ​​[MS (m / z)], the value corresponding to the monoisotopic mass (accurate mass consisting of only the main isotope) was defined as [M+H] ＋ , [M-H] － or [M+2H] ２＋ etc., and retention time is indicated as Rt (min).

[0259] LC / MS measurement method: Detector: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solvent: Solution A: 0.06% formic acid / H ２ O, B solution: 0.06% formic acid / MeCN Gradient condition: 0.0-1.3min Linear gradient from B 2% to 96% Flow rate: 0.8mL / min UV: 220nm and 254nm Column temperature: 40℃

[0260] Reference Example 1 N-(4-fluorobenzyl)-2-hydroxy-N-(3-(trifluoromethyl)oxetan-3-yl)acetamide

[0261] a) Preparation of N-(4-fluorobenzyl)-3-(trifluoromethyl)oxetan-3-amine (Compound Y1) 3-(trifluoromethyl)oxetan-3-amine hydrochloride (10.0 g) was dissolved in chloroform (188 mL), and 4-fluorobenzaldehyde (7.25 mL) and sodium triacetoxyborohydride (22.4 g) were added at 0°C, followed by stirring at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (10.6 g). LC-MS ([M+H] ＋ / Rt(min)): 250.1 / 0.936

[0262] b) Preparation of 2-(benzyloxy)-N-(4-fluorobenzyl)-N-(3-(trifluoromethyl)oxetan-3-yl)acetamide (Compound Y2) Compound Y1 (7.6 g) was dissolved in DMPU (102 mL), and sodium hydride (2.0 g) was added at 0° C., followed by stirring at room temperature for 30 minutes. Benzyloxyacetyl chloride (12.0 mL) was added at 0° C., followed by stirring at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (10.8 g). LC-MS ([M+H] ＋ / Rt(min)): 398.2 / 1.034

[0263] c) Preparation of N-(4-fluorobenzyl)-2-hydroxy-N-(3-(trifluoromethyl)oxetan-3-yl)acetamide Compound Y2 (15.1 g) was dissolved in methanol (127 mL), and palladium hydroxide-activated carbon (2.1 g) was added, followed by stirring at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered through Celite, the residue was washed with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (11.0 g). LC-MS ([M+H] ＋ / Rt(min)): 308.1 / 0.745

[0264] Reference Examples 2 to 5 According to the method described in Reference Example 1, the compounds of Reference Examples 2 to 6 were obtained using the corresponding starting compounds.

[0265]

[0266] Reference Example 8 (3'R,4S)-5'-bromo-3'-fluoro-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione

[0267] a) Preparation of (3'S,4S)-5'-bromo-3'-hydroxy-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione (Compound Y3) (4S)-5'-Bromospiro(imidazolidine-4,1'-indene)-2,3',5(2'H)-trione (20.0 g) was dissolved in methanol (339 mL), and sodium borohydride (2.8 g) was added at -78°C, followed by stirring at 0°C for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at 0°C. The reaction mixture was extracted twice with an ethyl acetate / methanol mixture. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure to give the title compound (19.0 g). LC-MS ([M+H]+ / Rt (min)): 297.0 / 0.529 b) Preparation of (3'R,4S)-5'-bromo-3'-fluoro-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione Compound Y3 (18.6 g) was dissolved in dichloromethane (313 mL), and (diethylamino)sulfur trifluoride (28.9 mL) was added at -78°C, followed by stirring at 0°C for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0°C. The reaction mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (15.6 g). LC-MS ([M+H]+ / Rt (min)): 299.0 / 0.681

[0268] Reference Example 9 (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl)-N-(4-fluorobenzyl)-N-(3-(trifluoromethyl)oxetan-3-yl)acetamide

[0269] The compound of Reference Example 1 (264 mg) was dissolved in tetrahydrofuran (3 mL), and (S)-5'-bromo-2',3'-dihydrospiro(imidazolidine-4,1'-indene)-2,5-dione (230 mg), diisopropyl azodicarboxylate (0.56 mL), and triphenylphosphine (279 mg) were added at 0°C, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (460 mg). LC-MS ([M+H]+ / Rt (min)): 572.3 / 1.038

[0270] Reference Examples 10 to 16 According to the method described in Reference Example 9, the compounds of Reference Examples 10 to 16 were obtained using the corresponding starting compounds.

[0271]

[0272] Reference Example 17 (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl)-N-(1-methyl-3-(trifluoromethyl)azetidin-3-yl)acetamide

[0273] a) The compound of Reference Example 3 (1.83 g) was dissolved in tetrahydrofuran (29 mL), and (S)-5'-bromo-2',3'-dihydrospiro(imidazolidine-4,1'-indene)-2,5-dione (1.21 g), bis(2-methoxyethyl) azodicarboxylate (1.3 g), and triphenylphosphine (1.5 g) were added at 0°C, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over magnesium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound. LC-MS ([M+H]+ / Rt (min)): 615.2 / 1.178 b) Preparation of (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl)-N-(1-methyl-3-(trifluoromethyl)azetidin-3-yl)acetamide Compound Y4 obtained above was dissolved in chloroform (17 mL), and trifluoroacetic acid (13.2 mL) was added at room temperature, followed by stirring for 5 hours. The reaction mixture was evaporated under reduced pressure, followed by triene azeotropy. The obtained crude product was dissolved in chloroform (21 mL), and 37% aqueous formalin solution (1.4 mL) and sodium triacetoxyborohydride (2.7 g) were added at 0°C, followed by stirring at room temperature for 15 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C. The reaction mixture was extracted twice with chloroform. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, and then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.16 g). LC-MS ([M+H]+ / Rt (min)): 583.3 / 0.778

[0274] Reference Examples 18 to 22 According to the method described in Reference Example 17, the compounds of Reference Examples 18 to 22 were obtained using the corresponding starting compounds.

[0275]

[0276] Example 1 N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide

[0277] The compound of Reference Example 9 (100 mg) was dissolved in 1,4-dioxane (0.7 mL) and water (0.2 mL), and potassium carbonate (52 mg), 1-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazole-4-boronic acid pinacol ester (68 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (14 mg) were added at room temperature, followed by stirring at 90°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The resulting organic layer was washed with saturated brine and dried over sodium sulfate, then filtered off, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to give the title compound (29 mg). LC-MS ([M+H]+ / Rt (min)): 669.5 / 1.005

[0278] Examples 2 to 35 According to the method described in Example 1, the compounds of Examples 2 to 35 were obtained using the corresponding compounds of Reference Examples and commercially available compounds as starting materials.

[0279]

[0280] Comparative Example 1 The compound of Comparative Example 1 was obtained using the method described in WO2016 / 044770. LC-MS ([M+H]+ / Rt (min)): 619.4 / 0.938

[0281] Comparative Example 2 The compound of Comparative Example 2 was obtained using the method described in WO2020 / 108500. LC-MS ([M+H]+ / Rt (min)): 531.3 / 0.965

[0282] Test Examples Test results for representative compounds of the present disclosure are shown below, and the pharmacological characteristics, chemical characteristics, and pharmacokinetics of the compounds are explained, but the present disclosure is not limited to these test examples.

[0283] Test Example 1: HAT Activity Inhibition Experiment Using SensoLyte HAT (p300) Assay Kit (ANASPEC, AS-72172), the HAT activity inhibitory ability of HAT inhibitors was evaluated. Specifically, 7.5 μL of recombinant p300 solution diluted 10-fold with assay buffer was added to 7.5 μL of the compounds of Examples 1 to 35 diluted with assay buffer, and the mixture was incubated at room temperature for 10 minutes. 7.5 μL of acetyl-CoA solution diluted 10-fold with assay buffer and 15 μL of histone H3 peptide diluted 10-fold with assay buffer were added thereto, and the mixture was incubated at 37°C for 30 minutes. 37.5 μL of Stop Solution was added to terminate the reaction. 75 μL of p300 Developer solution diluted 50-fold with assay buffer was added, and the mixture was incubated at room temperature for 30 minutes under light-shielded conditions. Using a multiplate reader, fluorescence at 513 nm was measured when irradiated with excitation light at 389 nm. Based on the measured fluorescence intensity, the IC ５０ The values ​​were calculated, and the results are shown in Table 5.

[0284]

[0285] As shown in Table 5, a series of the compounds of the present invention were confirmed to inhibit the function of the HAT domain of P300 / CBP. Among them, Examples 3 to 5, 7, 9 to 13, 15, 17, 18 to 20, 23 to 27, and 29 to 35 particularly showed strong inhibition of HAT activity.

[0286] Test Example 2: Cell proliferation inhibition experiment using G-401 cells G-401 cells (derived from malignant rhabdoid tumor) were obtained from the American Type Culture Collection (ATCC). G-401 cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C and 5% CO ２ The cells were cultured under the conditions.

[0287] 500 cells were seeded per well in a 384-well plate. One day after seeding, Examples 1 to 35 were added so that the final concentration of DMSO was 0.1%, and the cells were cultured for 3 days. After the culture was completed, cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). From the viability curve, the IC corresponding to the concentration of the evaluation compound showing 50% inhibition of cell proliferation was determined. ５０ The values ​​were calculated, and the results are shown in Table 6.

[0288]

[0289] As shown in Table 6, a series of the compounds of the present invention exhibited a strong cell growth inhibitory effect on G-401 cells, which are cells derived from malignant rhabdoid tumor. Among them, Examples 2 to 5, 7, 9 to 13, 15, 17, 19, 20, 22 to 27, and 29 to 35 particularly exhibited a strong cell growth inhibitory effect.

[0290] Test Example 3: Cell proliferation inhibition experiment using Kuramochi cells Kuramochi cells (derived from ovarian cancer) were obtained from the JCRB (Japanese Collection of Research Bioresources) cell bank. Kuramochi cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C and 5% CO. ２ The cells were cultured under the conditions.

[0291] 500 cells were seeded per well in a 384-well plate. One day after seeding, Examples 3, 7, 9, 10, 11, 20, 23-25, and 30-34 were added to the wells to a final DMSO concentration of 0.1%, and the wells were cultured for 6 days. After the culture was completed, cell viability was measured using a CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). From the viability curve, the IC value, which corresponds to the concentration of the compound under evaluation that exhibits 50% inhibition of cell proliferation, was determined. ５０ The values ​​were calculated. The results are shown in Table 7.

[0292] .

[0293] Test Example 4: Cell proliferation inhibition experiment using RMGI cells RMGI cells (derived from ovarian cancer) were obtained from the JCRB Cell Bank. RMGI cells were cultured in Ham's F12 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C and 5% CO ２ The cells were cultured under the conditions.

[0294] 200 cells were seeded per well in a 384-well plate. One day after seeding, Examples 3, 7, 9, 10, 11, 20, and 23-25 ​​were added so that the final concentration of DMSO was 0.1%, and the cells were cultured for 6 days. After the culture was completed, cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). From the viability curve, the IC value, which corresponds to the concentration of the evaluation compound that shows 50% inhibition of cell proliferation, was determined. ５０ The values ​​were calculated, and the results are shown in Table 8.

[0295]

[0296] Test Example 5: Solubility Test The solubility was measured for Examples 7, 10, 20, 23, 24, 30 to 34, Comparative Example 1, and Comparative Example 2. The test compound was added to 10 mmol / L glycine buffer (pH 2.0) and 10 mmol / L citrate buffer (pH 3.0) and stored in a thermostatic chamber at 5°C. After standing overnight, the solution was filtered through a membrane filter, and the concentration of the filtrate was measured by HPLC. The HPLC measurement conditions were as follows: HPLC conditions Column: Acquity UPLC BEH C18, 1.7 μm, 50 × 2.1 mm Column temperature: 40 °C Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A / B (min): 95 / 5 (0) → 0 / 100 (3.5) → 0 / 100 (4) → 95 / 5 (4.01) → 95 / 5 (5) Flow rate: 0.8 mL / min Detection: UV-visible detector Measurement wavelength: 254 nm Injection volume: 5 μL or Column: Acquity UPLC BEH C18, 1.7 μm, 50 × 2.1 mm Column temperature: 40 °C Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A / B (min): 80 / 20 (0) → 40 / 60 (3.0) → 0 / 100 (3.5) → 0 / 100 (4) → 80 / 20 (4.01) → 80 / 20 (5) Flow rate: 0.8 mL / min Detection: UV-visible detector Measurement wavelength: 254 nm Injection volume: 2 μL or Column: Acquity UPLC BEH C18, 1.7 μm, 50 × 2.1 mm Column temperature: 40 ° C Mobile phase: A: Water containing 0.1% trifluoroacetic acid B: Acetonitrile A / B (min): 80 / 20 (0) → 40 / 60 (3.0) → 0 / 100 (3.5) → 0 / 100 (4) → 100 / 0 (4.01) → 100 / 0 (5) Flow rate: 0.8 mL / min Detection: UV-visible detector Measurement wavelength: 254 nm Injection volume: 3 μL

[0297] The test results are shown in Table 9. Examples 7, 10, 20, 23, 24, and 30 to 34 exhibited high solubility. On the other hand, Comparative Examples 1 and 2 exhibited extremely low solubilities of 0.002 mg / mL, 0.004 mg / mL, and 0.005 mg / mL at pH 2.0 and pH 3.0, respectively. These test results demonstrated that Examples 7, 10, 20, 23, 24, and 30 to 34 are compounds that exhibit exceptional effects on solubility.

[0298]

[0299] Test Example 6: Membrane permeability test

[0300] The membrane permeability of the test compound was tested by artificial membrane permeability assay (PAMPA) as follows. 200 μL of System solution (pION Inc.) containing the test compound and 4 μL of GIT Lipid-0 (pION Inc.) were added to the donor plate. 200 μL of Acceptor Sink Buffer (pION Inc.) was added to the acceptor plate. Both plates were overlaid and incubated at 37°C for 4 hours, after which the UV of the acceptor and donor solutions was measured using a UV plate reader (190-500 nm). Compounds with poor UV absorption were measured using LC-MS. The permeability coefficient Pe (10 －６ cm / sec) was calculated using the following formula:

[0301] The test results are shown in Table 10.

[0302]

[0303] Test Example 7: Pharmacokinetic study in mice A test compound was administered to 7-week-old female BALB / c (BALB / cAnN CrlCrlj) mice intravenously in a 50% PEG solution (0.01 mol / L HCl) (administration dose: 1 mg / kg) or orally in a 0.5% methylcellulose aqueous solution (administration dose: 10 mg / kg), and blood was collected at the following times: Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration The collected blood was centrifuged at 3000 rpm for 10 minutes using a refrigerated centrifuge set at 4°C, and the obtained plasma was measured by LC-MS. A calibration curve was prepared from the peak area of ​​the test substance divided by the peak area of ​​the internal standard (peak ratio) in MS and the concentration of the plasma calibration curve sample. The concentration in each sample was calculated from the peak ratio and the calibration curve.

[0304] The test results for Examples 1, 3 to 5, 7, 9 to 12, 20, and 23 to 25 are shown in Table 11. From the test results, it was confirmed that the compounds of the present invention are excellent in pharmacokinetics and are also useful in vivo.

[0305]

[0306] Test Example 8: Evaluation of efficacy by oral administration using G-401 xenograft model mice 4-7 week-old BALB / cAnNCrj-nu / nu mice (CANN.Cg-Foxn1<nu> / CrlCrlj, Jackson Laboratory Japan) were intradermally inoculated with 5x10 G-401 cells (ATCC). ５ The tumors were transplanted under the condition of 10 to 40 days after the transplantation, and then the engraftment of G-401 cells was confirmed. After that, the test compound suspended in a solvent such as 0.5% methylcellulose solution was orally administered twice a day at a dose of 1 to 100 mg / kg. The tumor volume was measured over time from the start of administration, and the effect of the test compound on reducing tumor volume was evaluated. The tumor volume can be calculated using the following formula using the minor and major diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm ３ ] = 0.5 × minor axis [mm] × (major axis [mm]) ２

[0307] The control group administered with only a solvent such as 0.5% methylcellulose solution was compared with the test compound administered group, and the T / C was calculated using the following formula to evaluate the antitumor effect: T / C (%) = (tumor volume at the end of administration in the test compound administered group - tumor volume at the start of administration in the test compound administered group) / (tumor volume at the end of administration in the control administered group - tumor volume at the start of administration in the control administered group) x 100

[0308] The test results for Examples 7, 10, 20, and 23 are shown in Table 12. The test results show that Examples 7, 10, 20, and 23 exhibited potent antitumor effects in the G-401 xenograft model, which is a cell line derived from malignant rhabdoid tumor.

[0309]

[0310] Test Example 9: Efficacy evaluation test by intravenous administration using G-401 xenograft model mice 4-7 week-old BALB / cAnNCrj-nu / nu mice (CANN.Cg-Foxn1<nu> / CrlCrlj, Jackson Laboratory Japan) were intradermally injected with 5 x 10 G-401 cells (ATCC). ５ The tumors were transplanted under the condition of 10 to 40 days after the transplantation, and then the engraftment of G-401 cells was confirmed. After that, the test compound suspended in a solvent such as 10 mmol / L glycine buffer (pH 2.0) was administered via the tail vein at a dose of 0.015 to 20 mg / kg at least once a week. The tumor volume was measured over time from the start of administration, and the effect of the test compound on reducing tumor volume was evaluated. The tumor volume can be calculated using the following formula using the minor and major diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm ３ ] = 0.5 × minor axis [mm] × (major axis [mm]) ２ A control group administered with only a solvent such as 10 mmol / L glycine buffer (pH 2.0) was compared with the test compound administered group, and the T / C was calculated using the following formula to evaluate the antitumor effect: T / C (%) = (tumor volume at the end of administration in the test compound administered group - tumor volume at the start of administration in the test compound administered group) / (tumor volume at the end of administration in the control administered group - tumor volume at the start of administration in the control administered group) x 100

[0311] The test results for Examples 7, 10, 20, 23, and 24 and Comparative Example 1 are shown in Table 13. These test results show that Examples 7, 10, 20, 23, and 24 exhibited potent antitumor effects even when administered intravenously in a G-401 xenograft model, which uses cells derived from malignant rhabdoid tumors. On the other hand, Comparative Example 1 did not exhibit any antitumor effect, even when administered at the maximum concentration.

[0312]

[0313] Test Example 10: Evaluation of Dopamine Receptor Inhibitory Activity The binding evaluation assay was outsourced to Eurofins and performed. Specifically, CHO-S / hDAT cells were homogenized using an incubation buffer consisting of 50 mmol / L Tris-HCl, pH 7.4, 100 mmol / L NaCl, 1 μmol / L Leupeptin, and 10 μmol / L PMSF. The membrane pellet obtained by centrifugation was resuspended in the incubation buffer to prepare a membrane preparation. The test compound (1-10 μmol / L DMSO solution), membrane preparation, and 0.15 nmol / L [3H]kParoxetine were mixed and incubated for 180 minutes at 4°C. The cell membrane and [125I]RTI-55 complex was bound to a GF / B filter mat by vacuum filtration and washed with 50 mmol / L Tris-HCl, pH 7.4. The effect on the receptor was evaluated by measuring radioactivity using a scintillation counter.

[0314] The test results are shown in Table 14.

[0315]

[0316] Test Example 11: Evaluation of Serotonin Receptor Inhibitory Activity The binding assay was outsourced to Eurofins and performed. Specifically, HEK293 / hSERT cells were homogenized using a buffer consisting of 100 mmol / L NaCl, 1 μmol / L Leupeptin, 10 μmol / L PMSF, and 50 mmol / L Tris-HCl, pH 7.4. The membrane pellet obtained by centrifugation was resuspended in an incubation buffer consisting of 50 mmol / L Tris-HCl, pH 7.4, 120 mmol / L NaCl, and 5 mmol / L KCl to prepare a membrane preparation. The test compound (1-10 μmol / L DMSO solution), membrane preparation, and 0.4 nmol / L [3H]Paroxetin were mixed and incubated at 25°C for 60 minutes. The complex of cell membranes and [H]Paroxetin was bound to a GF / B filter mat by vacuum filtration and washed with 50 mmol / L Tris-HCl, pH 7.4. The effect on the receptor was assessed by measuring radioactivity using a scintillation counter.

[0317] The test results are shown in Table 15.

[0318]

[0319] The results of Test Examples 10 and 11 confirmed that the compounds of the present disclosure do not act on off-targets that pose safety concerns. On the other hand, it was revealed that Comparative Example 2 has a strong inhibitory effect on dopamine receptors and serotonin receptors.

[0320] The results of Test Examples 1 to 11 show that the compounds disclosed herein exhibited potent HAT inhibitory activity (Test Example 1) and potent cancer cell proliferation inhibitory effects (Test Examples 2 to 4). Furthermore, the compounds disclosed herein exhibited excellent solubility (Test Example 5), high membrane permeability (Test Example 6), and favorable pharmacokinetics (Test Example 7), as well as exceptional antitumor effects (Test Example 8). Furthermore, the compounds disclosed herein exhibited exceptional antitumor effects in xenograft model mice even when administered intravenously (Test Example 9), and also exhibited exceptionally significant and exceptional safety profiles because they did not exhibit strong inhibitory activity against off-target dopamine receptors and serotonin receptors (Test Examples 10 and 11).

[0321] The present inventors have newly discovered a problem that the compounds of Comparative Example 1 and Comparative Example 2 have low solubility, making intravenous administration difficult. Generally, structural transformation to increase solubility weakens lipid solubility and impairs membrane permeability. However, among the compounds of the present invention, the compounds represented by formulas (2) to (7) in particular have a unique effect of combining excellent solubility (Test Example 5) and high membrane permeability (Test Example 6), and are excellent CBP / P300 inhibitors that can be administered orally and intravenously.

[0322] Among the compounds of the present invention, Examples 7, 10, 20, 23, 24, 25, and 30 to 34, which are represented by formula (2), formula (3), formula (5), or formula (6), exhibited potent HAT inhibitory activity (Test Example 1) and potent cancer cell proliferation inhibitory effects (Test Examples 2 to 4). In addition, while structural transformation to increase solubility generally reduces lipophilicity and impairs membrane permeability, Examples 7, 10, 20, 23, 24, and 30 to 34 exhibited better solubility than Comparative Examples 1 and 2 (Test Example 5) and membrane permeability equivalent to Comparative Examples 1 and 2 (Test Example 6), demonstrating distinct effects. Furthermore, Examples 7, 10, 20, 23, and 24 exhibited excellent pharmacokinetics (Test Example 7). Examples 7, 10, 20, and 23 exhibited exceptional antitumor effects upon oral administration (Test Example 8), and also exhibited exceptionally significant intratumor effects upon intravenous administration that Comparative Example 1 could not achieve (Test Example 9). These CBP / P300 inhibitors have profiles suitable for oral and intravenous administration. Furthermore, Comparative Example 2 exhibited strong inhibitory activity against off-target dopamine receptors and serotonin receptors, while Examples 7, 10, 20, 23, 24, and 25 did not exhibit strong inhibitory activity, demonstrating exceptionally significant and distinct safety profiles (Test Examples 10 and 11). (Note) While the present disclosure has been illustrated using preferred embodiments thereof, it should be understood that the scope of the present disclosure should be interpreted solely by the scope of the claims. It should be understood that the patents, applications, and other literature cited herein are incorporated by reference in their entirety as if the contents themselves were specifically set forth herein.

[0323] The compounds of the present disclosure and pharmaceutically acceptable salts thereof are useful as therapeutic or preventive agents for pathologies involving CBP / P300 by potently inhibiting CBP / P300.

Claims

1. [Wherein, A is CHF or CH ２ B represents the following formula (B-1): [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring], ring Q represents an optionally substituted 6- to 10-membered aromatic hydrocarbon ring or an optionally substituted 5- to 10-membered aromatic heterocycle, Z represents -O-, -N(R ７ａ )-, an optionally substituted 6- to 10-membered divalent aromatic ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, or an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group; R １ is an optionally substituted C １－６ Alkyl or optionally substituted C ３－１０ represents an alicyclic group, R ２ａ and R ２ｂ each independently represents an optionally substituted C １－６ represents alkyl, where R ２ａ and R ２ｂ together with the carbon atom to which they are attached, may be substituted C ３－６ R may form a cycloalkylene or an optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group; ３ is an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３－１０ represents an alicyclic group or an optionally substituted 4- to 10-membered non-aryl heterocyclic group, ４ represents a single bond, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ represents a cycloalkylene or an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, ５ represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C １－３ Alkoxy, —NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , optionally substituted C ３－１０ an alicyclic group, an optionally substituted 4- to 10-membered non-aryl heterocyclic group, an optionally substituted C ６－１０ R represents an aryl or an optionally substituted 5- to 10-membered heteroaryl; ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or an optionally substituted C １－６ or a pharmaceutically acceptable salt thereof.

2. R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R ９ａ , R ９ｂ , an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C ３－１０ Alicyclic group, optionally substituted C ３－６ Cycloalkylene, optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ cycloalkylene, an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, or an optionally substituted C １－３ Each alkoxy is independently (1) a halogen atom, (2) a hydroxyl group, or (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio (10) C ３－１０ (11) an alicyclic group, (12) a carboxyl group, (13) -COR １０ , (14)-CO ２ R １０ , (15)-CONR １１ R １２ , (16)-NR １１ R １２ , (17)-NR １３ COR １０ , (18)-NR １３ CO ２ R １０ , (19)-NR １３ SO ２ R １０ , (20)-NR １３ CONR １１ R １２ , (21)-NR １３ SO ２ NR １１ R １２ , (22)-SO ２ R １０ , (23)-SO ２ NR １１ R １２ , (24)-OCOR １０ , (25)-OCO ２ R １０ , (26)-OCONR １１ R １２ (27) sulfo, (28) phosphate, (29) cyano, and (30) nitro, wherein the (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio, (10)C ３－１０ The alicyclic group and the group shown in (11) 3- to 10-membered non-aryl heterocyclic group are (a) a halogen atom, (b) a hydroxyl group, or (c) C ６－１０ (d) 5- to 12-membered heteroaryl; (e) C １－６ (f) alkyl, ２－６ alkenyl, (g) C ２－６ alkynyl, (h) C １－６ Alkoxy, (i) C ３－１０ (j) an alicyclic group, (k) a carboxyl group, (l) —COR １０ , (m)-CO ２ R １０ , (n)-CONR １１ R １２ , (o)-NR １１ R １２ , (p)-NR １３ COR １０ , (q)-NR １３ SO ２ R １０ , (r)-SO ２ R １０ , (s)-SO ２ NR １１ R １２ (t) sulfo, (u) phosphate, (v) cyano, and (w) nitro; R １０ However, if there are multiple, each independently, C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, and R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ When R is an alkyl, they may be joined together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, １３ is a hydrogen atom or C １－６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is an alkyl group; 3. R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R ９ａ , R ９ｂ , an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C ３－１０ Alicyclic group, optionally substituted C ３－６ Cycloalkylene, optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ cycloalkylene, an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, or an optionally substituted C １－３ Each alkoxy is independently (1) a halogen atom, (2) a hydroxyl group, or (3) C ６－１０ (4) 5- to 12-membered heteroaryl; (5) C optionally substituted with 1 to 3 halogen atoms; １－６ alkyl, (6) C ２－６ alkenyl, (7) C ２－６ alkynyl, (8) C １－６ Alkoxy, (9) C ３－１０ (10) an alicyclic group, (11) a carboxyl group, (12) -COR １０ , (13)-CO ２ R １０ , (14)-CONR １１ R １２ , (15)-NR １１ R １２ , (16)-SO ２ R １０ , (17)-SO ２ NR １１ R １２ (18) sulfo, (19) phosphate, (20) cyano, and (21) nitro; R １０ However, if there are multiple, each independently, C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, and R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein when each is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group.

4. R １ , R ２ａ , R ２ｂ , R ３ , R ４ , R ５ , R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , R ７ｆ , R ８ , R ９ａ , R ９ｂ , an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted C ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, optionally substituted C １－６ Alkynyl, optionally substituted C ３－１０ Alicyclic group, optionally substituted C ３－６ Cycloalkylene, optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, optionally substituted C １－６ Alkylene, optionally substituted C ３－１０ cycloalkylene, an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group, or an optionally substituted C １－３ (1) a halogen atom; (2) a hydroxyl group; (3) a phenyl; (4) a 5- or 6-membered heteroaryl; or (5) a C group optionally substituted with 1 to 3 halogen atoms. １－６ alkyl, (6) C １－６ Alkoxy, (7) C ３－７ (8) an alicyclic group, (9) a 3- to 7-membered non-aryl heterocyclic group, １０ , (10)-CO ２ R １０ , (11)-CONR １１ R １２ , (12)-NR １１ R １２ , (13)-SO ２ R １０ , (14)-SO ２ NR １１ R １２ (15) optionally substituted with 1 to 5 identical or different substituents selected from the group consisting of cyano, １０ However, if there are multiple, each independently, C １－６ alkyl, R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, and R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein when each is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group.

5. B is the following formula (B-2), (B-3), or (B-4): [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring, a represents 0, 1 or 2, b represents 1 or 2, R ８ represents a hydrogen atom or an optionally substituted C １－６ represents alkyl, R ９ａ and R ９ｂ are each independently a hydrogen atom, a halogen atom, or an optionally substituted C １－６ 5. The compound according to claim 1, wherein R represents an alkyl group, or a pharmaceutically acceptable salt thereof.

6. R １ C optionally substituted with 1 to 3 fluorine atoms １－３ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group.

7. R １ But CF ３ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ３ But C ６－１０ Aryl (the aryl is a halogen atom and an optionally substituted C １－６ alkyl), or 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms and C １－６ 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9. R ３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl.

10. R ３ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is 4-fluorophenyl or 4-fluoro-2-pyridyl.

11. Ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring is free of halogen atoms and C １－６ 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:

12. Ring Q is a benzene ring (the benzene ring is substituted with a halogen atom and a C １－６ 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

13. The compound according to any one of claims 1 to 12, wherein a is 1 or 2, or a pharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein a is 1.

15. The compound according to any one of claims 1 to 14, wherein b is 1, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 15, wherein a is 1 and b is 1, or a pharmaceutically acceptable salt thereof.

17. Equation (1) is converted to the following equation (2): [Wherein, A is CHF or CH ２ represents R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents —O—, a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ represents a hydrogen atom or a halogen atom; ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein A is CHF.

19. R ６ The compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof, wherein: is a hydrogen atom.

20. Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is not substituted by a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ The compound according to any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof, wherein:

21. Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is not a halogen atom, C １－６ Alkyl and -NR １１ R １２ The compound according to any one of claims 17 to 20, or a pharmaceutically acceptable salt thereof, wherein:

22. R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ 22. The compound according to any one of claims 17 to 21, or a pharmaceutically acceptable salt thereof, wherein:

23. R ５ is a hydrogen atom, a halogen atom, a cyano, -NR ７ｂ R ７ｃ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ The compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, wherein:

24. Equation (1) is converted to the following equation (3): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

25. R ３ The compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein is 4-fluorophenyl.

26. R ３ The compound according to any one of claims 24 or 25, or a pharmaceutically acceptable salt thereof, wherein is 4-fluoro-2-pyridyl.

27. R ４ The compound according to any one of claims 24 to 26, wherein is a 4- to 10-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

28. R ４ The compound according to any one of claims 24 to 27, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 6-membered divalent non-aryl heterocyclic group.

29. R ４ The compound according to any one of claims 24 to 28, or a pharmaceutically acceptable salt thereof, wherein is azetidinylene or piperidinylene.

30. R ５ But, C １－６ alkyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ 30. The compound according to any one of claims 24 to 29, or a pharmaceutically acceptable salt thereof, wherein:

31. R ５ But, C １－３ alkyl, or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ 31. The compound according to any one of claims 24 to 30, or a pharmaceutically acceptable salt thereof, wherein:

32. R ５ The compound according to any one of claims 24 to 31, or a pharmaceutically acceptable salt thereof, wherein is methyl.

33. R ５ The compound according to any one of claims 24 to 31, or a pharmaceutically acceptable salt thereof, wherein is oxetanyl.

34. R １１ and R １２ The compound according to any one of claims 24 to 33, or a pharmaceutically acceptable salt thereof, wherein is a methyl group.

35. Equation (1) is converted into the following equation (4): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and a 4- to 10-membered non-aryl heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

36. R ４ The compound according to claim 35, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 10-membered divalent non-aryl heterocyclic group.

37. R ４ The compound according to any one of claims 35 and 36, wherein is a 4- to 6-membered divalent non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

38. R ４ The compound according to any one of claims 35 to 37, or a pharmaceutically acceptable salt thereof, wherein is azetidinylene.

39. R ５ But, C １－６ alkyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ 39. The compound according to any one of claims 35 to 38, or a pharmaceutically acceptable salt thereof, wherein:

40. R ５ But, C １－３ alkyl, or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is substituted with a halogen atom and a C １－６ 40. The compound according to any one of claims 35 to 39, or a pharmaceutically acceptable salt thereof, wherein:

41. R ５ The compound according to any one of claims 35 to 40, or a pharmaceutically acceptable salt thereof, wherein is oxetanyl.

42. Equation (1) is converted into the following equation (5): [Wherein, A is CHF or CH ２ represents R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－３ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ represents a hydrogen atom or a halogen atom; ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, ８ is a hydrogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein A is CHF.

44. R ６ 44. The compound according to claim 42 or 43, or a pharmaceutically acceptable salt thereof, wherein: is a hydrogen atom.

45. Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not substituted by a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ 45. The compound according to any one of claims 42 to 44, or a pharmaceutically acceptable salt thereof, wherein:

46. Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is not a halogen atom, C １－６ Alkyl and -NR １１ R １２ 46. The compound according to any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof, wherein:

47. R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ 47. The compound according to any one of claims 42 to 46, or a pharmaceutically acceptable salt thereof, wherein:

48. R ５ But, hydrogen atom, hydroxyl group, cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ７ｄ But C １－６ Alkyl (the alkyl is a halogen atom and C １－６ 48. The compound according to any one of claims 42 to 47, or a pharmaceutically acceptable salt thereof, wherein:

49. R ８ But, C １－６ The compound according to any one of claims 42 to 48, or a pharmaceutically acceptable salt thereof, wherein:

50. R ８ The compound according to any one of claims 42 to 49, or a pharmaceutically acceptable salt thereof, wherein is a methyl group.

51. Equation (1) is converted into the following equation (6): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a hydroxyl group, a cyano, a C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

52. R ３ 52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein: is 4-fluorophenyl.

53. R ３ 53. The compound according to claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein: is 4-fluoro-2-pyridyl.

54. R ４ is a single bond, or C １－６ Alkylene (the alkylene is a halogen atom and C １－６ 54. The compound according to any one of claims 51 to 53, or a pharmaceutically acceptable salt thereof, wherein:

55. R ４ The compound according to any one of claims 51 to 54, or a pharmaceutically acceptable salt thereof, wherein is a single bond.

56. R ４ But C １－６ Alkylene (the alkylene is a halogen atom and C １－６ 55. The compound according to any one of claims 51 to 54, or a pharmaceutically acceptable salt thereof, wherein:

57. R ５ But, hydroxyl group, cyano C １－６ Alkyl, C ３－１０ 57. The compound according to any one of claims 51 to 56, which is an alicyclic group, or a 4- to 10-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

58. R ５ The compound according to any one of claims 51 to 57, or a pharmaceutically acceptable salt thereof, wherein is a methyl group.

59. R ５ 58. The compound according to any one of claims 51 to 57, or a pharmaceutically acceptable salt thereof, wherein: is oxetanyl.

60. Equation (1) is converted into the following equation (7): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, cyano, C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

61. R ４ is a single bond, or C １－６ Alkylene (the alkylene is a halogen atom and C １－６ 61. The compound according to any one of claims 60 to 61, wherein R is 1 to 3, and R is 2 to 3, and R is 3 ...

62. R ４ 62. The compound of claim 60 or 61, or a pharmaceutically acceptable salt thereof, wherein: is a single bond.

63. R ４ But C １－６ Alkylene (the alkylene is a halogen atom and C １－６ 63. The compound according to any one of claims 60 to 62, or a pharmaceutically acceptable salt thereof, wherein:

64. R ５ But, C １－６ 64. The compound according to any one of claims 60 to 63, wherein R is alkyl, or cyano, or a pharmaceutically acceptable salt thereof.

65. R ５ The compound according to any one of claims 60 to 64, or a pharmaceutically acceptable salt thereof, wherein is a methyl group.

66. R ５ The compound according to any one of claims 60 to 64, or a pharmaceutically acceptable salt thereof, wherein is cyano.

67. Equation (1) is converted into the following equation (8): [Wherein, A is CHF or CH ２ represents R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), C ３－１０ Cycloalkylene (the cycloalkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C １－３ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and C ６－１０ Aryl (the aryl is a halogen atom, C １－６ Alkyl and -NR １１ R １２ and 5- to 10-membered heteroaryl (the heteroaryl may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R ６ represents a hydrogen atom or a halogen atom; ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ are each independently a hydrogen atom or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, ９ａ and R ９ｂ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C １－６ alkyl), which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of alkyl, １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

68. The compound of claim 67, or a pharmaceutically acceptable salt thereof, wherein A is CHF.

69. R ６ 69. The compound according to any one of claims 67 or 68, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

70. Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is not substituted by a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 5- to 10-membered divalent aromatic heterocyclic group (which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ 70. The compound according to any one of claims 67 to 69, or a pharmaceutically acceptable salt thereof, wherein:

71. Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is not a halogen atom, C １－６ Alkyl and -NR １１ R １２ 71. The compound according to any one of claims 67 to 70, or a pharmaceutically acceptable salt thereof, wherein:

72. R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ 72. The compound according to any one of claims 67 to 71, or a pharmaceutically acceptable salt thereof, wherein:

73. R ５ is a hydrogen atom, cyano, -NR ７ｂ R ７ｃ , C １－６ Alkyl (the alkyl is a halogen atom, C １－６ Alkyl, hydroxyl group and -NR １１ R １２ and C ３－１０ an alicyclic group (the alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom, C １－６ Alkyl and -NR １１ R １２ 73. The compound according to any one of claims 67 to 72, or a pharmaceutically acceptable salt thereof, wherein:

74. R ９ａ and R ９ｂ The compound according to any one of claims 67 to 73, or a pharmaceutically acceptable salt thereof, wherein is a fluorine atom.

75. Equation (1) is converted into the following equation (9): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, cyano, C １－６ Alkyl, C １－６ Alkenyl, C １－６ Alkynyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

76. R ３ 76. The compound of claim 75, or a pharmaceutically acceptable salt thereof, wherein is 4-fluorophenyl.

77. R ３ 77. The compound according to claim 75 or 76, or a pharmaceutically acceptable salt thereof, wherein: is 4-fluoro-2-pyridyl.

78. R ４ 78. The compound according to any one of claims 75 to 77, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 10-membered divalent non-aryl heterocyclic group.

79. R ４ 79. The compound according to any one of claims 75 to 78, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 6-membered divalent non-aryl heterocyclic group.

80. R ４ 80. The compound according to any one of claims 75 to 79, or a pharmaceutically acceptable salt thereof, wherein is azetidinylene.

81. R ５ The compound according to any one of claims 75 to 80, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 10-membered non-aryl heterocyclic group.

82. R ５ The compound according to any one of claims 75 to 81, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 6-membered non-aryl heterocyclic group.

83. R ５ The compound according to any one of claims 75 to 82, or a pharmaceutically acceptable salt thereof, wherein is oxetanyl.

84. Equation (1) is converted to the following equation (10): [In the formula, R ３ represents 4-fluorophenyl or 4-fluoro-2-pyridyl; R ４ is a single bond, C １－６ Alkylene (the alkylene is a halogen atom and C １－６ alkyl), or a 4- to 10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen atoms, C １－６ Alkyl and -NR １１ R １２ and R ５ is a hydrogen atom, cyano, C １－６ Alkyl, C １－６ Alkenyl, C １－６ Alkynyl, or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is not limited to a halogen atom, C １－６ Alkyl and -NR １１ R １２ and R １１ and R １２ are each independently a hydrogen atom or C １－６ represents alkyl, R １１ or R １２ If there are multiple １１ or R １２ may be the same or different, and R １１ and R １２ Both are C １－６ and when each is alkyl, they may be taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

85. R ４ 85. The compound of claim 84, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 10-membered divalent non-aryl heterocyclic group.

86. R ４ 86. The compound according to claim 84 or 85, or a pharmaceutically acceptable salt thereof, wherein: is a 4- to 6-membered divalent non-aryl heterocyclic group.

87. R ４ 87. The compound according to any one of claims 84 to 86, or a pharmaceutically acceptable salt thereof, wherein is azetidinylene.

88. R ５ The compound according to any one of claims 84 to 87, or a pharmaceutically acceptable salt thereof, wherein is a 4- to 10-membered non-aryl heterocyclic group.

89. R ５ The compound according to any one of claims 84 to 88, wherein is a 4- to 6-membered non-aryl heterocyclic group, or a pharmaceutically acceptable salt thereof.

90. R ５ 90. The compound according to any one of claims 84 to 89, or a pharmaceutically acceptable salt thereof, wherein: is oxetanyl.

91. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide; 2-[(1'S)-5'-{1-[(3-fluoro-1-methylazetidin-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]acetamide, N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S)-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S)-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxa-4-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-{[3-(dimethylamino)oxetan-3-yl]methyl}-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'R,3'S)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide.

92. The compound of claim 1 or a pharmaceutically acceptable salt thereof, selected from the following compounds: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-inden]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide.

93. A medicine containing, as an active ingredient, a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof.

94. A pharmaceutical composition comprising a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof.

95. A therapeutic and / or preventive agent for cancer, nonalcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease, comprising as an active ingredient the compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof.

96. A cancer treatment and / or prevention agent comprising, as an active ingredient, the compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof.

97. The therapeutic and / or preventive agent according to claim 95 or 96, wherein the cancer is at least one type of cancer selected from the group consisting of SMARC-deficient cancer, SS18-SSX fusion cancer, and ARID-deficient cancer.

98. The cancer is selected from the group consisting of malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid / rhabdoid tumor, schwannoma, chordomatoid meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma, chordoma, myoepithelial tumor, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basaloid carcinoma of the paranasal sinus, esophageal cancer, papillary thyroid cancer, follicular thyroid cancer, gastrointestinal stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumor of the female vulva, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell carcinoma of the lung, lung neuroendocrine tumor, and gastroesophageal The therapeutic and / or prophylactic agent according to any one of claims 95 to 97, wherein the cancer is at least one type selected from the group consisting of junctional carcinoma, gastric cancer, bladder cancer, lung squamous cell carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver cancer, lung pleomorphic carcinoma, breast sarcoma, ovarian small cell carcinoma, primary gallbladder tumor, uterine sarcoma, ovarian granulosa tumor, adrenocortical carcinoma, small cell lung cancer, ovarian cancer, endometrial cancer, neuroblastoma, ovarian mucinous tumor, nasal and paranasal cancer, thoracic sarcoma, biliary tract cancer, neuroblastoma, melanoma, breast cancer, unclassifiable round cell sarcoma, rhabdomyosarcoma, and Ewing's sarcoma.

99. A method for treating or preventing cancer, nonalcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease, comprising administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof.

100. Use of a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of cancer, nonalcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease.

101. A compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of cancer, nonalcoholic fatty liver disease (NAFLD), acute liver damage, heart disease, or metabolic disease.

102. A compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, for use in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more selected from the group consisting of hormone therapy agents, chemotherapeutic agents, immunotherapy agents, and drugs that inhibit the action of cell growth factors and their receptors, or a pharmaceutically acceptable salt thereof.

103. A pharmaceutical composition comprising a compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is at least one selected from the group consisting of hormone therapy agents, chemotherapeutic agents, immunotherapy agents, and drugs that inhibit the action of cell growth factors and their receptors.

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