Tertiary amide derivatives substituted with a 4-membered ring structure

Abstract

The present invention provides tertiary amide derivatives substituted with a 4-membered ring structure useful as a pharmaceutical, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these, or therapeutic or prophylactic agents for CBP / P300-related pathological conditions containing these compositions. [Solution] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof. TIFF2026135569000073.tif3977 (A: CHF or CH2. B: Amide derivative of a secondary amine. Ring Q: Substituted / unsubstituted 6-10 member aromatic hydrocarbon ring, substituted / unsubstituted 5-10 member aromatic heterocycle. Z: O, substituted / unsubstituted 6-10 member divalent aromatic ring group, substituted / unsubstituted 5-10 member divalent aromatic heterocycle group, etc. R 4 : Single bond, substituted / unsubstituted C 1-6 Alkylene, etc. 5 :H, halogen, OH, cyano, substituted / unsubstituted C 1-6 (Alkyl compounds, etc.)

Description

[Technical Field]

[0001] This disclosure relates to tertiary amide derivatives substituted with quaternary carbons that are useful as pharmaceuticals, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing these, or therapeutic or prophylactic agents for CBP / P300-related conditions containing these compositions. [Background technology]

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

[0003] Histone acetylation is a common post-translational modification in eukaryotes that promotes gene transcription. Histone acetyltransferases (HATs), which function in histone acetylation, are enzymes that transfer acetyl groups to the lysine side chains of histones and are broadly classified into four types based on amino acid sequence homology, higher-order structure, and function. These 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 more than 90% amino acid sequence homology and, in addition to the HAT domain, also contain CH1 / CH2 / CH3 domains (cysteine-histidine rich domains), a KIX domain, and a bromodomain (Non-Patent Literature 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 found that CBP / P300 possesses HAT activity (Non-Patent Documents 6, 7), and its substrate specificity was investigated further. It was reported that, in addition to lysine residues of histones (H2A, H2B, H3, and H4), it also acetylates p53 (Non-Patent Document 8), MyoD (Non-Patent Document 9), STAT3 (Non-Patent Document 10), and androgen receptor (Non-Patent Document 11). Furthermore, CBP / P300 is involved in numerous biological reactions such as cell 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. Examples include prostate cancer (Non-Patent Documents 13, 14), liver cancer (Non-Patent Documents 15, 16), lung cancer (Non-Patent Documents 17-19), breast cancer (Non-Patent Document 20), colorectal and gastric cancer (Non-Patent Document 21), hematological cancers (Non-Patent Documents 22, 23), pancreatic cancer (Non-Patent Document 24), bladder cancer (Non-Patent Document 25), gastrointestinal stromal tumors (Non-Patent Document 26), NUT midline carcinoma (Non-Patent Document 27), ovarian cancer (Non-Patent Document 28), malignant rhabdoid tumors and epithelioid sarcomas (Patent Document 11).

[0006] Based on the above, drugs that inhibit the function of CBP / P300 are expected to be useful as antitumor agents. To date, small molecule inhibitors targeting the HAT domain of CBP / P300 have been disclosed in Patent Documents 1 to 10 and Non-Patent Document 29. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2016 / 044770 [Patent Document 2] International Publication No. 2018 / 235966 [Patent Document 3] International Publication No. 2019 / 111980 [Patent Document 4] International Publication No. 2019 / 049061 [Patent Document 5] International Publication No. 2019 / 161157 [Patent Document 6] International Publication No. 2019 / 161162 [Patent Document 7] International Publication No. 2020 / 176558 [Patent Document 8] International Publication No. 2019 / 201291 [Patent Document 9] International Publication No. 2020 / 108500 [Patent Document 10] International Publication No. 2020 / 198567 [Patent Document 11] International Publication No. 2022 / 138944 [Non-patent literature]

[0008] [Non-Patent Document 1] Genes Dev.2002,16(14):1739-1742. [Non-Patent Document 2] Mol Genet Metab.2016,119(1-2):37-43. [Non-Patent Document 3] Virology. 1985, 147(1): 142-153. [Non-Patent Document 4] Mol Cell Biol.1986,6(5):1579-1589. [Non-Patent Document 5] Nature.1993,365(6449):855-859. [Non-Patent Document 6] Cell. 1996, 87(5):953-959. [Non-Patent Document 7] Nature.1996,384(6610):641-643. [Non-Patent Document 8] Cell. 1997, 90(4): 595-606.

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[0009] This disclosure aims to provide compounds that exert anticancer effects by inhibiting CBP / P300, which has been reported to be highly expressed, mutated, or hyperfunctional in various cancers. Preferably, the disclosure provides compounds that have high CBP / P300 inhibitory activity and also possess both "high water solubility to exert anticancer effects by intravenous administration" and "high oral absorption to exert anticancer effects by oral administration." In other words, it provides compounds that are extremely useful as anticancer agents that can be applied to the treatment of a wide range of cancer types.

[0010] As a result of intensive studies, the inventors of the present invention have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "the compound of the present disclosure") has a strong inhibitory effect on the HAT domain of CBP / P300, exhibits an excellent anticancer effect, and shows high oral absorbability and water solubility suitable for oral administration and intravenous administration, thus completing the present disclosure.

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

[0012] [Item 1] The following formula (1): [Chemical formula] [In the formula, A represents CHF or CH2, B represents the following formula (B-1): <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​It may form a cycloalkylene or a substituted 4-6 membered divalent nonaryl heterocyclic group, R 3 C may be substituted. 6-10 Aryl, optionally substituted 5-10 member heteroaryl, optionally substituted C 3-10 Represents an alicyclic group or a substituted 4-10 member non-aryl heterocyclic group, R 4 C is a single bond, and may be substituted. 1-6 Alkylene, C may be substituted. 3-10 Represents a cycloalkylene or an optionally substituted 4-10 membered divalent nonaryl heterocyclic group, R 5 C is a hydrogen atom, halogen atom, hydroxyl group, cyano, or may be substituted. 1-6 Alkyl, possibly substituted C 1-6 Alkenyl, C may be substituted 1-6 Alkynyl, C may be substituted. 1-3 Alkoxy, -NR 7b R 7c , -SO2R 7d ,-CONR 7e R 7f , C which may be substituted 3-10 Alicyclic groups, optionally substituted 4-10 membered nonaryl heterocyclic groups, optionally substituted C 6-10 Represents an aryl or a 5- to 10-membered heteroaryl, which may be substituted. R 7a , R 7b , R 7c , R 7d , R 7e , and R 7f Each of these is independently a hydrogen atom or a substituted C 1-6 [Represents alkyl] A compound represented by or a pharmaceutically acceptable salt thereof. [Section 2] R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , R7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8 , R 9a , R 9b , optionally substituted 6-10 member aromatic hydrocarbon rings in rings Q and Z, optionally substituted 5-10 member aromatic heterocycles, optionally substituted 6-10 member divalent aromatic hydrocarbon ring groups, optionally substituted 5-10 member divalent aromatic heterocycle groups, optionally substituted C 6-10 Aryl, optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member non-aryl heterocyclic group, optionally substituted C 1-6 Alkyl, possibly substituted C 1-6 Alkenyl, C may be substituted 1-6 Alkynyl, C may be substituted. 3-10 Alicyclic group, may be substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered divalent nonaryl heterocyclic group, optionally substituted C 1-6 Alkylene, C may be substituted. 3-10 Cycloalkylene, a substituted 4-10 membered divalent nonaryl heterocyclic group, or a substituted C 1-3 Each alkoxy independently (1) Halogen atom, (2) Hydroxyl group, (3)C 6-10 Ariel, (4) 5-12 member heteroaryls, (5)C 1-6 Alkyl, (6)C 2-6 Alkenil, (7)C 2-6 Alkinil, (8)C 1-6 Alkoxy, (9)C 1-6 Alkylthio (10)C 3-10 alicyclic group, (11) 3-10 member non-aryl heterocyclic group, (12) carboxyl, (13) -COR 10 , (14) -CO2R 10 , (15) -CONR 11 R 12 , (16) -NR 11 R 12 , (17) -NR 13 COR 10 , (18) -NR 13 CO2R 10 , (19) -NR 13 SO2R 10 , (20) -NR 13 CONR 11 R 12 , (21) -NR 13 SO2NR 11 R 12 , (22) -SO2R 10 , (23) -SO2NR 11 R 12 , (24) -OCOR 10 , (25) -OCO2R 10 , (26) -OCONR 11 R 12 ,​​​​​​​​​​​​​​​​​​​​​​​Alkylthio, (10)C 3-10 The groups shown in the alicyclic group and the (11)3-10 membered nonaryl heterocyclic group are (a) halogen atom, (b) Hydroxyl group, (c)C 6-10 Ariel, (d) 5-12 member heteroaryls, (e)C 1-6 Alkyl, (f)C 2-6 Alkenil, (g)C 2-6 Alkinil, (h)C 1-6 Alkoxy, (I C 3-10 alicyclic group, (j) 3-10 member non-aryl heterocyclic group, (k)carboxyl, (l)-COR 10 , (m)-CO2R 10 , (n)-CONR 11 R 12 , (o)-NR 11 R 12 , (p)-NR 13 COR 10 , (q)-NR 13 SO2R 10 , (r)-SO2R 10 , (s)-SO2NR 11 R 12 , (t) sulfo, (u) Phosphate group, (v) cyano, and (w) Nitro They may be substituted with 1 to 5 identical or different substituents selected from the group consisting of the following: R 10 However, if there are multiple, each is independent, C 1-6 It is alkyl, R 11 and R 12However, each is independent of a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. R 13 However, hydrogen atoms or C 1-6 It is alkyl. The compounds listed in item 1, or their pharmaceutically acceptable salts. [Section 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 , optionally substituted 6-10 member aromatic hydrocarbon rings in rings Q and Z, optionally substituted 5-10 member aromatic heterocycles, optionally substituted 6-10 member divalent aromatic hydrocarbon ring groups, optionally substituted 5-10 member divalent aromatic heterocycle groups, optionally substituted C 6-10 Aryl, optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member non-aryl heterocyclic group, optionally substituted C 1-6 Alkyl, possibly substituted C 1-6 Alkenyl, C may be substituted 1-6 Alkynyl, C may be substituted. 3-10 Alicyclic group, may be substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered divalent nonaryl heterocyclic group, optionally substituted C 1-6Alkylene, C may be substituted. 3-10 Cycloalkylene, a substituted 4-10 membered divalent nonaryl heterocyclic group, or a substituted C 1-3 Each alkoxy independently (1) Halogen atom, (2) Hydroxyl group, (3)C 6-10 Ariel, (4) 5-12 member heteroaryls, (5) C which may be substituted with 1 to 3 halogen atoms 1-6 Alkyl, (6)C 2-6 Alkenil, (7)C 2-6 Alkinil, (8)C 1-6 Alkoxy, (9)C 3-10 alicyclic group, (10) 3-10 member non-aryl heterocyclic group, (11) Carboxyl, (12)-COR 10 , (13)-CO2R 10 , (14)-CONR 11 R 12 , (15)-NR 11 R 12 , (16)-SO2R 10 , (17)-SO2NR 11 R 12 , (18) sulfo, (19) Phosphate group, (20) Cyano, and (21) Nitro They may be substituted with 1 to 5 identical or different substituents selected from the group consisting of the following: R 10 However, if there are multiple, each is independent, C 1-6 It is alkyl, R 11 and R 12 However, each is independent of a hydrogen atom or C1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 When alkyl, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. A compound as described in item 1 or 2, or a pharmaceutically acceptable salt thereof. [Section 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 , optionally substituted 6-10 member aromatic hydrocarbon rings in rings Q and Z, optionally substituted 5-10 member aromatic heterocycles, optionally substituted 6-10 member divalent aromatic hydrocarbon ring groups, optionally substituted 5-10 member divalent aromatic heterocycle groups, optionally substituted C 6-10 Aryl, optionally substituted 5-10 member heteroaryl, optionally substituted 4-10 member non-aryl heterocyclic group, optionally substituted C 1-6 Alkyl, possibly substituted C 1-6 Alkenyl, C may be substituted 1-6 Alkynyl, C may be substituted. 3-10 Alicyclic group, may be substituted C 3-6 Cycloalkylene, optionally substituted 4-6 membered divalent nonaryl heterocyclic group, optionally substituted C 1-6 Alkylene, C may be substituted. 3-10Cycloalkylene, a substituted 4-10 membered divalent nonaryl heterocyclic group, or a substituted C 1-3 Each alkoxy independently (1) Halogen atom, (2) Hydroxyl group, (3) Phenyl, (4) 5-6 member heteroaryls, (5) C which may be substituted with 1 to 3 halogen atoms 1-6 Alkyl, (6)C 1-6 Alkoxy, (7)C 3-7 alicyclic group, (8) 3-7 member nonaryl heterocyclic group, (9)-COR 10 , (10)-CO2R 10 , (11)-CONR 11 R 12 , (12)-NR 11 R 12 , (13)-SO2R 10 , (14)-SO2NR 11 R 12 , and (15) Cyano They may be substituted with 1 to 5 identical or different substituents selected from the group consisting of the following: R 10 However, if there are multiple, each is independent, C 1-6 It is alkyl, R 11 and R 12 However, each is independent of a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6When alkyl, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. A compound described in any one of items 1 to 3, or a pharmaceutically acceptable salt thereof. [Section 5] B is given by the following equations (B-2), (B-3), or (B-4): [ka] [In the formula, * represents the bond position with the nitrogen atom of the hydantoin ring, a represents 0, 1, or 2. b represents 1 or 2, R 8 is a hydrogen atom, or a substituted C 1-6 Represents alkyl, R 9a and R 9b Each of these is independently a hydrogen atom, a halogen atom, or a substituted C 1-6 [represents alkyl] A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 4. [Section 6] R 1 However, C may be substituted with 1 to 3 fluorine atoms. 1-3 It is alkyl. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 5. [Section 7] R 1 However, it is CF3. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 6. [Section 8] R 3 However, C 6-10 Aryl (where the aryl is a halogen atom and may be substituted with C) 1-6 (The substituents may be the same or different, selected from the group consisting of alkyls), or a 5-10 member heteroaryl (the heteroaryl is composed of a halogen atom and C 1-6(May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 7. [Section 9] R 3 However, it is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 8. [Section 10] R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 9. [Section 11] Ring Q is a 6-10 member aromatic hydrocarbon ring (the aromatic hydrocarbon ring contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 10. [Section 12] Ring Q is a benzene ring (the benzene ring contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 11. [Section 13] a is 1 or 2. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 12. [Section 14] a is 1, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 13. [Section 15] b is 1. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 14. [Section 16] a is 1 and b is 1, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 15. [Section 17] Equation (1) becomes the following equation (2): [ka] [In the formula, A represents CHF or CH2, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. Z is -O-, A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6(May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, halogen atom, Hydroxyl group, Cyano, -NR 7b R 7c , -SO2R 7d , -CONR 7e R 7f , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-6 Alkoxy (The alkoxy is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 6-10 Aryl (The aryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), 5-10 member heteroaryl (the heteroaryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 6 This represents a hydrogen atom or a halogen atom. R 7b , R 7c , R 7d , R 7e , and R 7f Each of them operates independently. Hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 This represents a molecule that may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. That is, The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 18] A is CHF. The compounds listed in item 17 or their pharmaceutically acceptable salts. [Section 19] R 6 However, it is a hydrogen atom. The compounds described in item 17 or 18, or their pharmaceutically acceptable salts. [Section 20] Z A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 17 to 19. [Section 21] Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 17 to 20. [Section 22] R 4but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 17 to 21. [Section 23] R 5 but, hydrogen atom, halogen atom, Cyano, -NR 7b R 7c , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-6 Alkoxy (The alkoxy is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 17 to 22. [Section 24] Equation (1) becomes the following equation (3): [ka] [In the formula, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 25] R 3 but, It is 4-fluorophenyl. The compounds listed in item 24 or their pharmaceutically acceptable salts. [Section 26] R 3 but, It is 4-fluoro-2-pyridyl, The compounds described in item 24 or 25, or their pharmaceutically acceptable salts. [Section 27] R 4 but, It is a 4-10 membered divalent nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 26. [Section 28] R 4 but, It is a 4-6 membered divalent nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 27. [Section 29] R 4 but, It is azetidinylene or piperidylene. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 28. [Section 30] R 5 but, C 1-6 Alkyl, or A 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 29. [Section 31] R 5 but, C 1-3 Alkyl, or A 4-6 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 30. [Section 32] R 5 but, It is methyl, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 31. [Section 33] R 5 but, It is oxetanil. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 31. [Section 34] R 11 and R 12 but, It is a methyl group, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 24 to 33. [Section 35] Equation (1) becomes the following equation (4): [ka] [In the formula, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 36] R 4 but, It is a 4-10 membered divalent nonaryl heterocyclic group. The compounds described in item 35 or their pharmaceutically acceptable salts. [Section 37] R 4 but, It is a 4-6 membered divalent nonaryl heterocyclic group. The compounds described in item 35 or 36, or their pharmaceutically acceptable salts. [Section 38] R 4 but, It is azetidinylene. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 35 to 37. [Section 39] R 5 but, C 1-6 Alkyl, or A 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 35 to 38. [Section 40] R 5 but, C 1-3 Alkyl, or A 4-6 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 35 to 39. [Section 41] R 5 but, It is oxetanil. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 35 to 40. [Section 42] Equation (1) is given by the following equation (5): [ka] [In the formula, A represents CHF or CH2, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. Z is A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C 1-6Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, halogen atom, Hydroxyl group, Cyano, -NR 7b R 7c , -SO2R 7d , -CONR 7e R 7f , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 1-3 Alkoxy (The alkoxy is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 6-10 Aryl (The aryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), 5-10 member heteroaryl (the heteroaryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 6 This represents a hydrogen atom or a halogen atom. R 7b , R 7c , R 7d , R 7e , and R 7f Each of them operates independently. Hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 This represents a molecule that may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. R 8 teeth, Hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 This represents a molecule that may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups. R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. That is, The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 43] A is CHF. The compounds described in item 42 or their pharmaceutically acceptable salts. [Section 44] R 6 However, it is a hydrogen atom. The compounds described in item 42 or 43, or their pharmaceutically acceptable salts. [Section 45] Z A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 42 to 44. [Section 46] Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 42 to 45. [Section 47] R 4 but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 42 to 46. [Section 48] R 5 but, hydrogen atom, Hydroxyl group, Cyano, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 7d However, C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 42 to 47. [Section 49] R 8 but, C 1-6 It is alkyl. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 42 to 48. [Section 50] R 8 but, A compound or a pharmaceutically acceptable salt thereof, which is a methyl group, as described in any one of items 42 to 49. [Section 51] Equation (1) is given by the following equation (6): [ka] [In the formula, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, Hydroxyl group, Cyano, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 11and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 52] R 3 but, It is 4-fluorophenyl. The compounds described in item 51 or their pharmaceutically acceptable salts. [Section 53] R 3 but, It is 4-fluoro-2-pyridyl, The compounds described in item 51 or 52, or their pharmaceutically acceptable salts. [Section 54] R 4 but, Single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 51 to 53. [Section 55] R 4 However, it is a single bond. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 51 to 54. [Section 56] R 4 However, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6(May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 51 to 54. [Section 57] R 5 but, Hydroxyl group, Cyano, C 1-6 Alkyl, C 3-10 Alicyclic group, or It is a 4-10 member non-aryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 51 to 56. [Section 58] R 5 but, It is a methyl group, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 51 to 57. [Section 59] R 5 but, It is oxetanil. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 51 to 57. [Section 60] Equation (1) is given by the following equation (7): [ka] [In the formula, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, Cyano, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 61] R 4 but, Single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of item 60. [Section 62] R 4 However, it is a single bond. The compounds described in item 60 or 61, or their pharmaceutically acceptable salts. [Section 63] R 4 However, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 60 to 62. [Section 64] R 5 but, C 1-6 Alkyl, or Cyano A compound or a pharmaceutically acceptable salt thereof as described in any one of items 60 to 63. [Section 65] R 5 but, It is a methyl group, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 60 to 64. [Section 66] R 5 but, Cyano A compound or a pharmaceutically acceptable salt thereof as described in any one of items 60 to 64. [Section 67] Equation (1) is given by the following equation (8): [ka] [In the formula, A represents CHF or CH2, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. Z is A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12(May be substituted with one to three identical or different substituents selected from the group consisting of the following), A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, halogen atom, Hydroxyl group, Cyano, -NR 7b R 7c , -SO2R 7d , -CONR 7e R 7f , C 1-6Alkyl (the alkyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, C 1-6 alkyl, a hydroxyl group, and -NR 11 R 12 ), C 1-6 Alkenyl (the alkenyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, C 1-6 alkyl, a hydroxyl group, and -NR 11 R 12 ), C 1-6 Alkynyl (the alkynyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, C 1-6 alkyl, a hydroxyl group, and -NR 11 R 12 ), C 1-3 Alkoxy (the alkoxy may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 ), C 3-10 Alicyclic group (the alicyclic group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 ), C 6-10 Aryl (the aryl may be substituted with the same or different 1 to​​​​​​​​​​​​​​​​1-6 alkyl and -NR ? 11 。 R 12 which may be substituted with one to three identical or different substituents selected from the group consisting of) R 6 represents a hydrogen atom or a halogen atom, R 7b , R 7c , R 7d , R 7e , and R 7f are each independently a hydrogen atom or C 1-6 alkyl (the alkyl may be substituted with one to three identical or different substituents selected from the group consisting of halogen atoms and C 1-6 alkyl), R 9a and R 9b are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl (the alkyl may be substituted with one to three identical or different substituents selected from the group consisting of halogen atoms and 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 When there are a plurality of them, each of R 11 or R 12 may be the same or different. Here, R 11 and R 12 bonded to the same nitrogen atom, when both are C 1-6 alkyl, they may together with the nitrogen atom to which each is bonded form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group], The compound according to item 1 or a pharmaceutically acceptable salt thereof. [Item 68] A is CHF, The compound according to item 67 or a pharmaceutically acceptable salt thereof. [Section 69] R 6 However, it is a hydrogen atom. The compounds described in item 67 or 68, or their pharmaceutically acceptable salts. [Section 70] Z A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 67 to 69. [Section 71] Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 67 to 70. [Section 72] R 4 but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 67 to 71. [Section 73] R 5 but, hydrogen atom, Cyano, -NR 7b R 7c , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound or a pharmaceutically acceptable salt thereof as described in any one of items 67 to 72. [Section 74] R 9a and R 9b but, Fluorine atom, A compound or a pharmaceutically acceptable salt thereof as described in any one of items 67 to 73. [Section 75] Equation (1) is given by the following equation (9): [ka] [In the formula, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, Cyano, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 76] R 3 but, It is 4-fluorophenyl. The compounds described in item 75 or their pharmaceutically acceptable salts. [Section 77] R 3 but, It is 4-fluoro-2-pyridyl, The compounds described in item 75 or 76, or their pharmaceutically acceptable salts. [Section 78] R 4 but, It is a 4-10 membered divalent nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 75 to 77. [Section 79] R 4 but, It is a 4-6 membered divalent nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 75 to 78. [Section 80] R 4 but, It is azetidinylene. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 75 to 79. [Section 81] R 5 but, It is a 4-10 member non-aryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 75 to 80. [Section 82] R 5 but, It is a 4-6 member nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 75 to 81. [Section 83] R 5 but, It is oxetanil. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 75 to 82. [Section 84] Equation (1) is given by the following equation (10): [ka] [In the formula, R 3 This represents 4-fluorophenyl or 4-fluoro-2-pyridyl. R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 5 teeth, hydrogen atom, Cyano, C 1-6 Alkyl, C 1-6 Alkenil, C 1-6 Alkinyl, or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 This represents (which may be substituted with one to three identical or different substituents selected from the group consisting of), R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compounds listed in item 1 or their pharmaceutically acceptable salts. [Section 85] R 4 but, It is a 4-10 membered divalent nonaryl heterocyclic group. The compounds listed in item 84 or their pharmaceutically acceptable salts. [Section 86] R 4 but, It is a 4-6 membered divalent nonaryl heterocyclic group. The compounds described in item 84 or 85, or their pharmaceutically acceptable salts. [Section 87] R 4 but, It is azetidinylene. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 84 to 86. [Section 88] R 5 but, It is a 4-10 member non-aryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 84 to 87. [Section 89] R 5 but, It is a 4-6 member nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 84 to 88. [Section 90] R 5 but, It is oxetanil. A compound or a pharmaceutically acceptable salt thereof as described in any one of items 84 to 89. [Section 91] The compound is selected from the following compounds, the compound described in item 1 or a pharmaceutically acceptable salt thereof: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 1), 2-[(1'S)-5'-{1-[(3-fluoro-1-methylazetidine-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetane-3-yl]acetamide (Example 2), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-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)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-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)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]acetamide (Example 5), N-[(5-fluoropyridine-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 6), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 7), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(5-fluoropyridine-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-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)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]acetamide (Example 9), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 10), 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazole-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 11), N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 12), 2-{(1'S)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 13), 2-[(1'S,3'R)-3'-fluoro-5'-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetane-3-yl]acetamide (Example 14), 2-[(1'S,3'R)-3'-fluoro-5'-(5-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 15), 2-[(1'S)-5'-(5-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 16), 2-[(1'S,3'R)-3'-fluoro-5'-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 17), 2-[(1'S)-5'-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 18), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxa-4-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 19), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 20), N-[(5-fluoropyridine-2-yl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 21), 2-[(1'S,3'R)-5'-(1-{[3-(dimethylamino)oxetane-3-yl]methyl}-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetane-3-yl]acetamide (Example 22), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidine-4-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-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-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 24), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 25), 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazole-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 26), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 27), 2-[(1'R,3'S)-3',6'-difluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 28), 2-[(1'S,3'R)-3',6'-difluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 29), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 30), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 31), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 32), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 33), 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 34), and 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide (Example 35). [Section 92] The compound is selected from the following compounds, the compound described in item 1 or a pharmaceutically acceptable salt thereof: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 7), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 10), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 20), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidine-4-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-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-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 24), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 25), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-inden]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 30), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 31), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 32), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 33), and 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide (Example 34). [Section 93] A pharmaceutical product containing a compound described in any one of items 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. [Section 94] A pharmaceutical composition containing a compound described in any one of items 1 to 92 or a pharmaceutically acceptable salt thereof. [Section 95] A therapeutic and / or prophylactic agent for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease, comprising as an active ingredient any compound described in any one of paragraphs 1 to 92 or a pharmaceutically acceptable salt thereof. [Section 96] A therapeutic and / or prophylactic agent for cancer containing, as an active ingredient, a compound described in any one of paragraphs 1 to 92 or a pharmaceutically acceptable salt thereof. [Section 97] The therapeutic and / or prophylactic 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. [Section 98] The aforementioned cancers include malignant rhabdoid tumors, epithelioid sarcomas, atypical teratomatoid / rhabdoid tumors, schwannomas, chordoma-like meningiomas, neuroepithelial tumors, glial neuronal tumors, craniopharyngiomas, glioblastomas, chordomas, myoepithelial tumors, extraskeletal myxoid chondrosarcomas, synovial sarcomas, ossifying fibromyxoid tumors, paranasal sinus basal cell carcinomas, esophageal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumors, undifferentiated pancreatic rhabdoid tumors, gastrointestinal rhabdoid tumors, renal medullary carcinomas, endometrial cancer, myoepithelioma-like tumors of the female vulva, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung carcinoma, pulmonary neuroendocrine tumors, gastrointestinal stromal tumors, and gastrointestinal stromal tumors. A therapeutic and / or prophylactic agent according to any one of paragraphs 95 to 97, for at least one type of cancer selected from the group consisting of junctional cancer, gastric cancer, bladder cancer, squamous cell carcinoma of the lung, pancreatic cancer, medulloblastoma, clear cell carcinoma of the kidney, liver cancer, pleomorphic lung cancer, thoracic sarcoma, small cell carcinoma of the ovary, primary tumor of the gallbladder, uterine sarcoma, granulosa tumor of the ovary, adrenocortical carcinoma, small cell lung cancer, ovarian cancer, endometrial cancer, neuroblastoma, mucinous neoplasm of the ovary, nasal and paranasal sinus cancer, thoracic sarcoma, biliary tract cancer, neuroblastoma, melanoma, breast cancer, unclassifiable round cell sarcoma, rhabdomyosarcoma, and Ewing's sarcoma. [Section 99] A method for treating or preventing cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease, comprising administering to a patient in need of treatment or prevention an effective amount of any one of items 1 to 92 of the Act on the Treatment or Prevention of Treatment of or Prevention of Treatment of or Prevention of Treatment of or Prevention of Treatment of or Prevention of Treatment of or Prevention of Treatment of a patient in need of treatment or prevention of treatment [Section 100] Use of any compound described in any one of paragraphs 1 to 92 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disorder. [Section 101] A compound or a pharmaceutically acceptable salt thereof, as described in any one of items 1 to 92, for use in the treatment or prevention of cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disorders. [Section 102] A compound or a pharmaceutically acceptable salt thereof, used in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, for the treatment of cancer, wherein the concomitant drug is at least one selected from the group consisting of hormone therapy agents, chemotherapy agents, immunotherapy agents, and agents that inhibit the action of cell growth factors and their receptors. [Section 103] A pharmaceutical composition comprising a compound described in 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, chemotherapy agents, immunotherapy agents, and agents that inhibit the action of cell growth factors and their receptors. [Effects of the Invention]

[0013] This disclosure provides CBP / P300 inhibitors comprising tertiary amide derivatives substituted with quaternary carbons and pharmaceutically acceptable salts thereof. This disclosure provides agents that inhibit the function of CBP / P300, applicable to a wide range of diseases and administration methods. Furthermore, this disclosure provides compounds represented by formula (1), which are tertiary amide derivatives substituted with a quaternary carbon, and related agents that can be used as such agents.

[0014] The compounds disclosed herein exhibit excellent CBP / P300 inhibitory activity and are useful as therapeutic agents for diseases involving CBP / P300, specifically applicable to patients with cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disorders. [Modes for carrying out the invention]

[0015] The following provides further details about this disclosure. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (for example, "a," "an," and "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

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

[0017] In this specification, there is no particular limit to the number of substituents on a group defined as “may be substituted,” as long as they are substituted. When a number of substituents is specified and it is stated that the group is “substituted” with that number of substituents, it means that the group is substituted with that number of substituents. For example, “substituted with 2 to 5 substituents” means that the group is substituted with 2, 3, 4, or 5 substituents. Also, unless otherwise specified, the description of each group applies even if that group is a part of or a substituent of another group.

[0018] Examples of "halogen atoms" include fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms. Preferably, fluorine atoms or chlorine atoms are used.

[0019] "C 1-6 "Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms, and "C6 alkyl" refers to an alkyl group with 6 carbon atoms. The same applies to other numbers. 1-6 Preferably, "C" is used as the alkyl group. 1-4 Examples include "alkyl", and more preferably "C 1-3 "Alkyl" is one example. 1-3Specific examples of "alkyl" include, for example, methyl, ethyl, propyl, and 1-methylethyl. 1-4 A specific example of "alkyl" is, for example, the aforementioned "C 1-3 In addition to the examples listed for "alkyl," other examples include butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2-methylpropyl. 1-6 A specific example of "alkyl" is, for example, the aforementioned "C 1-4 In addition to the examples listed for "alkyl," other examples include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and hexyl.

[0020] "C 2-6 "Alkenyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. 2-6 "C" is preferred as "Alkenyl" 2-4 "Alkenil" is one example. 2-4 Examples of "alkenyls" include vinyl, propenyl, methylpropenyl, and butenyl. 2-6 For example, the aforementioned "C 2-4 In addition to the examples given for "alkenyl," other examples include pentenyl and hexenyl.

[0021] "C 2-6 "Alkynyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond. 2-6 "Alkinyl" is preferably "C 2-4 "Alkinyl" is one example. 2-4 Specific examples of "alkynyl" include, for example, propynyl, methylpropynyl, and butynyl. 2-6 For example, the aforementioned "C 2-4 In addition to the examples given for "alkynyl," other examples include methylbutynyl, pentynyl, and hexynyl.

[0022] "C 1-6 "Alkoxy" is "C 1-6 This refers to "alkyloxy," and "C 1-6 The "alkyl" portion is the aforementioned "C 1-6 It is synonymous with "alkyl". 1-6 Preferably, "C" is used as the "alkoxy" 1-4 "Alkoxy" is one example, and more preferably "C 1-3 "alkoxy" is one example. 1-3 Specific examples of "alkoxy" include, for example, methoxy, ethoxy, propoxy, and 1-methylethoxy. 1-4 A specific example of "alkoxy" is, for example, the aforementioned "C 1-3 In addition to the examples given for "alkoxy," other examples include butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, and 2-methylpropoxy. 1-6 A specific example of "alkoxy" is, for example, the aforementioned "C 1-4 In addition to the examples given for "alkoxy," other examples include pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, and hexyloxy.

[0023] "C 1-6 "C" of "alkylthio" 1-6 The "alkyl" portion is the aforementioned "C 1-6 It is synonymous with "alkyl". 1-6 Preferably, "C" is used as the alkylthio. 1-4 Examples include "alkylthio", and more preferably "C 1-3 "Alkylthio" is one example. 1-3 Specific examples of "alkylthio" include, for example, methylthio, ethylthio, propylthio, 1-methylethylthio, etc. 1-4 A specific example of "alkylthio" is, for example, the aforementioned "C 1-3In addition to the examples listed as "alkylthio", other examples include butylthio, 1,1-dimethylethylthio, 1-methylpropylthio, 2-methylpropylthio, etc. 1-6 A specific example of "alkylthio" is, for example, the aforementioned "C 1-4 In addition to the examples listed for "alkylthio," other examples include pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylbutylthio, 2-methylbutylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, and hexylthio.

[0024] "C 1-6 "Alkylene" refers to a divalent saturated hydrocarbon group having 1 to 6 carbon atoms, in a linear or branched chain configuration. 1-6 "alkylene" is preferably "C 1-4 "Alkylene" is one example, and more preferably "C 1-3 "Alkylene" is one example. 1-3 Specific examples of "alkylene" include, for example, methylene groups, ethylene groups, and propylene groups. 1-4 A specific example of "alkylene" is, for example, the aforementioned "C 1-3 In addition to the examples listed as "alkylenes," other examples include the butylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, 1-methyltrimethylene group, and 2-methyltrimethylene group. 1-6 A specific example of "alkylene" is, for example, the aforementioned "C 1-4 In addition to the examples listed as "alkylenes," other examples include pentylene groups, 1,1-dimethyltrimethylene groups, 1,2-dimethyltrimethylene groups, 1-methylbutylene groups, 2-methylbutylene groups, 1-methylpentylene groups, 2-methylpentylene groups, 3-methylpentylene groups, and hexylene groups.

[0025] "C 2-6 "Alkenylene" refers to a linear or branched divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. 2-6 "C" is preferred as "Alkenylene"2-4 "Alkenylene" is one example. 2-4 Specific examples of "alkenylene" include vinylene group, vinylidene group, propenylene group, methylpropenylene group, butenylene group, etc. 2-6 For example, the aforementioned "C 2-4 In addition to the examples given for "alkenyl," other examples include the pentenylene group and the hexenylene group.

[0026] "C 3-10 "Alicyclic group" refers to a cyclic saturated hydrocarbon group with 3 to 10 carbon atoms, and includes those with some unsaturated bonds and those with a bridged structure. 3-10 Preferably, "C" is used as the "alicyclic group". 3-7 "Alicyclic group" is one example. 3-7 Specific examples of "alicyclic groups" include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3-10 A specific example of an "alicyclic group" is, for example, the aforementioned "C 3-7 In addition to the examples given for "alicyclic groups," other examples include cyclooctyl, cyclononyl, cyclodecyl, and adamantyl.

[0027] Also, "C 3-10 The "alicyclic group" is the C 3-10 This also includes bicyclic compounds in which an alicyclic group and an aromatic hydrocarbon ring are fused. Specific examples of such fused compounds include, for example, the structure shown below. [ka]

[0028] Specific examples of the above-mentioned cross-linked structure include, for example, the structure shown below. [ka]

[0029] "C 3-10"Cycloalkylene" refers to a cyclic, divalent saturated hydrocarbon group with 3 to 10 carbon atoms, and includes those with some unsaturated bonds and those with a cross-linked structure. 3-10 "Cycloalkylene" is preferably "C 3-7 "Cycloalkylene" is one example. 3-7 Specific examples of "cycloalkylenes" include, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene. 3-10 A specific example of "cycloalkylene" is, for example, the aforementioned "C 3-7 In addition to the examples given for "cycloalkylene," other examples include cyclooctylene, cyclononylene, cyclodecylene, and adamantylene.

[0030] Specific examples of the above-mentioned cross-linked structure include, for example, the structure shown below. [ka]

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

[0032] A "3- to 10-membered saturated carbon ring" refers to a cyclic saturated hydrocarbon having 3 to 10 carbon atoms. Preferably, a "4- to 6-membered saturated carbon ring" is included as a "3- to 10-membered saturated carbon ring." Specific examples of a "4- to 6-membered saturated carbon ring" include, for example, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, etc. Specific examples of a "3- to 10-membered saturated carbon ring," in addition to those listed above as examples of a "4- to 6-membered saturated carbon ring," include, for example, a cyclopropane ring, a cycloheptane ring, a cyclooctane, a cyclononane, a cyclodecane, etc.

[0033] A "4- to 10-membered nonaryl heterocyclic group" refers to a monovalent nonaryl heterocyclic group composed 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 with some unsaturated bonds and bridged structures. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO2-. A preferred example of a "4- to 10-membered nonaryl heterocyclic group" is a "4- to 6-membered nonaryl heterocyclic group." Specific examples of "4-6 member non-aryl heterocyclic groups" include, for example, oxetanil, azetidinil, pyrrolidinil, imidazolidinil, oxazolidinil, thiazolidinil, oxoimidazolidinil, dioxoimidazolidinil, oxoxazolidinil, dioxoxazolidinil, dioxothiazolidinil, tetrahydrofuranil, piperidinil, morpholinil, thiomorpholinil, dioxothiomorpholinil, and tetrahydropyranil. Specific examples of "4-10 member non-aryl heterocyclic groups" include, in addition to those listed above as specific examples of "4-6 member non-aryl heterocyclic groups," azepanil.

[0034] Furthermore, the term "4-10 membered non-aryl heterocyclic group" also includes bicyclic groups in which a 4-10 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 6-membered aromatic hydrocarbon rings forming a fused ring group include benzene rings. Examples of 6-membered aromatic heterocyclic rings forming a fused ring group include pyridine, pyrimidine, and pyridazine. Specific examples of bicyclic "4-10 membered non-aryl heterocyclic groups" forming a fused ring group include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and tetrahydronaphthilidinyl.

[0035] A "4- to 10-membered divalent nonaryl heterocyclic group" refers to a divalent nonaryl heterocyclic group composed 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 with some unsaturated bonds and bridged structures. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO2-. A preferred example of a "4- to 10-membered divalent nonaryl heterocyclic group" is a "4- to 6-membered divalent nonaryl heterocyclic group." Specific examples of "4-6 membered divalent nonaryl heterocyclic groups" include, for example, oxetanylene, azetidinylene, tetrahydrofrylene, pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, hexamethyleneimylene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxoxozolidinylene, dioxoxozolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, and tetrahydropyranylene. Specific examples of "4-10 membered divalent nonaryl heterocyclic groups" include, in addition to those listed above as specific examples of "4-6 membered divalent nonaryl heterocyclic groups," azepanylene, etc. In this specification, "azetidinylene," etc., refers to divalent groups such as "azetidinyl."

[0036] Furthermore, the term "4-10 membered divalent nonaryl heterocyclic group" also includes bicyclic groups in which a 4-10 membered divalent nonaryl heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring form a fused ring group. Examples of 6-membered aromatic hydrocarbon rings forming a fused ring group include benzene rings. Examples of 6-membered aromatic heterocyclic rings forming a fused ring group include pyridine, pyrimidine, and pyridazine. Specific examples of bicyclic "4-10 membered divalent nonaryl heterocyclic groups" forming a fused ring group include, for example, dihydroindrylene, dihydroisoindrylene, dihydroprinylene, dihydrothiazolopyrimidinylene, dihydrobenzodioxanylene, isoindrylene, indazoylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.

[0037] "C 6-10 "Aryl" refers to an aromatic hydrocarbon ring group with 6 to 10 carbon atoms. 6-10 Specific examples of "aryl" include, for example, phenyl, 1-naphthyl, and 2-naphthyl. Phenyle is preferred.

[0038] Also, "C 6-10 "Aryl" is the aforementioned C 6-10 Aryl and C 4-6 This also includes bicyclic compounds in which an alicyclic group or a 5-6 membered non-aryl heterocycle forms a fused ring group. 6-10 Specific examples of "aryl" include the groups shown below. [ka]

[0039] "Aromatic hydrocarbon ring" refers to the above "C 6-10 It refers to the ring portion of "aryl".

[0040] "5-10 membered heteroaryl" means a monocyclic 5-7 membered aromatic heterocyclic cyclic group or a bicyclic 8-10 membered aromatic heterocyclic cyclic group containing 1-4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Preferably, it is a "5-7 membered monocyclic heteroaryl." More preferably, it is pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. Even more preferably, it is pyridyl. Specific examples of "5-7 membered monocyclic heteroaryl" include, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, oxadiazolyl, triazolyl, tetrazolyl, etc. Specific examples of "5-12 member heteroaryls" include, in addition to those listed above as specific examples of "5-7 member monocyclic heteroaryls," indolyl, indazolyl, clomenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, and benzimidazolyl.

[0041] "Aromatic heterocycle" refers to the ring portion of the "5-12 member heteroaryl" mentioned above.

[0042] "3- to 10-membered cycloalkanes" refer to cyclic saturated hydrocarbons with 3 to 10 carbon atoms, including those with some unsaturated bonds and bridged structures, and some rings may be fused with other rings. Specific examples of "3- to 10-membered cycloalkanes" include cyclobutane, cyclopentane, cyclohexane, and cycloheptane.

[0043] A "6-10 member aromatic hydrocarbon ring" refers to a cyclic aromatic hydrocarbon having 6 to 10 carbon atoms, and may have a portion of the ring fused with another ring. Specific examples of a "6-10 member aromatic hydrocarbon ring" include, for example, a benzene ring and naphthalene.

[0044] A "5-10 member aromatic heterocycle" refers to a monocyclic 5-7 member aromatic heterocycle or a bicyclic 8-10 member aromatic heterocycle containing 1-4 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. Preferably, a "5-6 member aromatic heterocycle," a "5 member aromatic heterocycle," or a "6 member aromatic heterocycle" is mentioned. Specific examples of a "5-6 member aromatic heterocycle" include, for example, furan, thiophene, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, and pyridazine. Specific examples of a "5 member aromatic heterocycle" include, for example, pyrazole, furan, thiophene, and oxazole. Specific examples of a "6 member aromatic heterocycle" include, for example, pyridine, pyrazine, pyrimidine, and pyridazine.

[0045] "6-10 membered divalent aromatic hydrocarbon ring group" refers to a monocyclic or bicyclic divalent aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Preferably, "6 membered divalent aromatic hydrocarbon ring group" is included as "6-10 membered divalent aromatic hydrocarbon ring group". Specific examples of "6-10 membered divalent aromatic hydrocarbon ring group" and "6 membered divalent aromatic hydrocarbon ring group" include, for example, a divalent benzene ring.

[0046] "5-10 membered divalent aromatic heterocyclic group" means a monocyclic divalent 5-7 membered aromatic heterocyclic cyclic group or a bicyclic divalent 8-10 membered aromatic heterocyclic cyclic group containing 1-4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Preferably, "5-6 membered divalent aromatic heterocyclic groups" are mentioned, and more preferably, "5 membered divalent aromatic heterocyclic groups" are mentioned. Specific examples of "5 membered divalent aromatic heterocyclic groups" include, for example, divalent pyrazole, divalent furan, divalent thiophene, and divalent oxazole. Examples of "5-10 membered divalent aromatic heterocyclic groups" and "5-6 membered divalent aromatic heterocyclic groups" include, in addition to the examples given for "5 membered divalent aromatic heterocyclic groups," divalent pyridine, divalent pyrimidine, divalent pyrazine, and divalent pyridazine.

[0047] "Cancer" refers to malignant tumors and includes carcinoma, sarcoma, and hematological malignancies. Specific examples of "cancer" include, for example, acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, gallbladder and 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 disorders (dysplasia and metaplasia), and embryonic tumors. Endometrial carcinoma, endometrial cancer, epithelial sarcoma, ependymal cell carcinoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, gliablastoma, gliosarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, intralymphatic sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant tumors and hypergrowth 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, oligodendroma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary carcinoma, papillary carcinoma, pineal glandoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminomastoma, skin cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma, thyroid cancer, Valdenström macroglobulin Examples include rhabdoid tumors, testicular tumors, uterine cancer, Wilms' tumor, malignant rhabdoid tumors, epithelioid sarcomas, atypical teratomatous / rhabdoid tumors, schwannomas, chordoid meningiomas, neuroepithelial tumors, glial neuronal tumors, craniopharyngiomas, glioblastomas, chordomas, myoepithelial tumors, extraskeletal myxoid chondrosarcomas, synovial sarcomas, ossifying fibromyxoid tumors, paranasal sinus basal cell carcinoma, esophageal adenocarcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumors, undifferentiated pancreatic rhabdoid tumors, gastrointestinal rhabdoid tumors, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumors of the female vulva, colorectal cancer, and mesothelioma.

[0048] In this disclosure, "CBP" and "P300" are both histone acetyltransferases involved in chromatin regulation, and they are paralogs. "CBP / P300" means "CBP" and "P300". Histone acetyltransferases are enzymes that primarily, but not exclusively, transfer acetyl groups to lysine residues located on the amino-terminal tails of histone proteins. CBP and P300 primarily, but not exclusively, acetylate histone 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) residues. In particular, histone H3K27 acetylation 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). Other substrates that have been reported include 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). In this specification, when "CBP" and "P300" are used, they usually mean proteins, but depending on the context, they may also refer to nucleic acids that encode them or genes as a concept, which will be appropriately understood by those skilled in the art depending on the context.

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

[0050] As used herein, the term "CBP" refers to any naturally occurring CBP from any vertebrate source, including primates (e.g., humans) and mammals such as rodents (e.g., mice and rats), unless otherwise specified. The term encompasses unprocessed CBP and any form of CBP resulting from cellular processing. The term also encompasses naturally occurring variants of CBP, such as splice variants or allele variants. Human CBP is registered under UniProt Accession Number: Q92793. Representative amino acid sequences of human CBP are shown in UniProt Q92793-1 (SEQ ID NO: 1) or UniProt Q92793-2 (SEQ ID NO: 2).

[0051] As used herein, the term "P300" refers, unless otherwise specified, to any natural P300 from any vertebrate source, including primates (e.g., humans) and mammals such as rodents (e.g., mice and rats). This term encompasses unprocessed P300 and any form of P300 resulting from cellular processing. It also encompasses naturally occurring variants of P300, such as splice variants or allele variants. Human P300 is registered under UniProt Accession Number: Q09472. A representative amino acid sequence of human P300 is shown in UniProt Q09472-1 (SEQ ID NO: 3).

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

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

[0054] A "BRD inhibitor" is a compound that inhibits the function of the bromodomain (BRD) of CBP and / or P300. For detecting the function of the bromodomain, for example, a method that detects the binding of the bromodomain to an acetylated lysine residue by the TR-FRET method can be used (e.g., Acta Pharmacol Sin. 2020;41(2):286-292). 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 the enzymatic activity that transfers an acetyl group to a lysine residue of a substrate protein. Examples of substrates include histone proteins and p53.

[0056] A bromodomain is a protein domain that recognizes N-acetylated lysine residues. N-acetylated lysine residues are found, for example, at the amino-terminal tail of histone proteins.

[0057] In the compounds of this 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 components of a, b, ring Q, and Z are as follows, but the technical scope of this disclosure is not limited to the compounds listed below.

[0058] Preferred embodiments of A include CHF or CH2.

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

[0060] Another more preferred embodiment of A is CH2.

[0061] A preferred embodiment of B is given by the following formula (B-1). [ka] [In the formula, * represents the bond position with the nitrogen atom of the hydantoin ring.] A more preferred embodiment of B is the following formula (B-2), (B-3), or (B-4). [ka] [In the formula, * represents the bond position with the nitrogen atom of the hydantoin ring.]

[0062] R 1 A preferred embodiment is C 1-6 Alkyl, or C 3-10 Examples include alicyclic groups (the alkyl or alicyclic group may be substituted with the same or different 1 to 3 halogen atoms).

[0063] R 1 A more preferred embodiment is C 1-6 Alkyl, or C 3-10 Examples include alicyclic groups (the alkyl or alicyclic group may be substituted with 1 to 3 fluorine atoms).

[0064] R 1 A more preferred embodiment is C which may be substituted with 1 to 3 fluorine atoms. 1-3 Alkyl compounds are examples. R 1 A more preferred embodiment is CF3.

[0065] R 2a and R 2b A preferred embodiment is C, which may be independently substituted with the same or different 1 to 3 halogen atoms. 1-6 Alkyl compounds are examples. R 2a and R 2b Another preferred embodiment is R 2a and R 2b Together with the carbon atom to which it is bonded, C 3-6 Examples include the formation of a cycloalkylene or a 4-6 membered divalent nonaryl heterocyclic group (the cycloalkylene or divalent nonaryl heterocyclic group may be substituted with the same or different 1-3 halogen atoms).

[0066] R 2a and R 2b In the most preferred embodiment of R 2a and R 2b together with the carbon atom to which they are attached form a C 3-6 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 In a preferred embodiment of R 6-10 aryl, 5- to 1- membered heteroaryl, C 3-10 alicyclic group, or a 4- to 10-membered non-aryl heterocyclic group (the aryl, heteroaryl, alicyclic group or non-aryl heterocyclic group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl).

[0068] R 3 In a more preferred embodiment of R 6-10 aryl (the aryl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl), or 5- to 10-membered heteroaryl (the heteroaryl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl). [[ID=�9]]

[0069] R 3 In an even more preferred embodiment of R 6-10 aryl or 5- to 10-membered heteroaryl (the heteroaryl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of fluorine atoms and C 1-6 alkyl).

[0070] R 3More preferred embodiments include 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl, and more preferably 4-fluorophenyl or 4-fluoro-2-pyridyl.

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

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

[0073] R 4 A preferred embodiment is a single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyls), or a 4 to 10-membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group is composed of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of )

[0074] R 4 A more preferred embodiment is a single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyls), or a 4 to 10-membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group is composed of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of )

[0075] R 4 A more preferred embodiment is a single bond, C 1-6 Examples include alkylenes or 4-6 membered divalent nonaryl heterocyclic groups.

[0076] R 4 A more preferred embodiment is a single bond.

[0077] R 4 A more preferred embodiment is C 1-6 Alkylene is one example.

[0078] R 4 A more preferred embodiment is a 4-6 membered divalent nonaryl heterocyclic group.

[0079] R 4 The most preferred embodiment is azetidinylene.

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

[0081] R 5 Preferred embodiments include hydrogen atoms, halogen atoms, hydroxyl groups, cyano, -NR 7b R 7c , -SO2R 7d or -CONR 7e R 7f , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkynyl (the alkynyl is a halogen atom, C1-6 Alkyl, hydroxyl group and -NR 11 R 12 (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), C 1-6 Alkoxy (the alkoxy is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), C 3-10 A cycloaliphatic group (the cycloaliphatic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), C 6-10 Aryl (the aryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), a 5- to 10-membered heteroaryl (the heteroaryl is a halogen atom, C 1-6 Alkyl and -NR<968>R 12 (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of)).

[0082] ​​​​​​​​​​​​​​11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of )

[0083] R 5 A more preferred embodiment is cyano, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (The substituents may be the same or different, selected from the group consisting of , or 1-6 Alkyl and -NR 11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of )

[0084] R 5 A more preferred embodiment is C 1-6 Examples include alkyl groups or 4-6 membered non-aryl heterocyclic groups.

[0085] R 5 The most preferred embodiments include a methyl group or an oxetanyl group.

[0086] R 6 Preferred embodiments include hydrogen atoms or fluorine atoms.

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

[0088] R 7a , R 7b , R 7c , R 7d , R 7e and R 7f A preferred embodiment is one in which each is independently a hydrogen atom or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups).

[0089] R 7a , R 7b , R 7c , R 7d , R 7e and R 7f More preferred embodiments include, independently, a hydrogen atom or a methyl group.

[0090] R 8 A preferred embodiment includes a hydrogen atom or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups).

[0091] R 8 A more preferred embodiment is C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups).

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

[0093] R 9a and R 9b A preferred embodiment includes, independently, a hydrogen atom, a halogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups).

[0094] R 9a and R 9b A more preferred embodiment includes, independently, halogen atoms.

[0095] R 9a and R9b A more preferred embodiment is a fluorine atom.

[0096] R 10 A preferred embodiment is C 1-6 Alkyl compounds are examples.

[0097] R 11 and R 12 A preferred embodiment is one in which each is independently a hydrogen atom or C 1-6 Alkyl compounds are examples.

[0098] R 11 and R 12 Another preferred embodiment is R bonded to the same nitrogen atom. 11 and R 12 Both are C 1-6 In the case of alkyl groups, these groups can combine with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group.

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

[0100] A preferred embodiment of ring Q is a 6-10 member aromatic hydrocarbon ring (the aromatic hydrocarbon ring contains a halogen atom and C 1-6 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups).

[0101] A more preferred embodiment of ring Q is a benzene ring (the benzene ring having a halogen atom and C 1-6 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups).

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

[0103] A preferred embodiment of Z is a -O-, 6-10 membered divalent aromatic ring group (the divalent aromatic ring group is a halogen atom, C1-6 Alkyl and -NR 11 R 12 (The group consisting of may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), a 5 to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may consist of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The group consisting of may be substituted with the same or different 1 to 3 substituents selected from the group consisting of ), or a 4 to 10-membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group may consist of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of ) A more preferred embodiment of Z is a 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group comprises a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The group consisting of may be substituted with the same or different 1 to 3 substituents selected from the group consisting of ), or a 5 to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may consist of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of ) A more preferred embodiment of Z is a five-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group comprises a halogen atom, C 1-6 Alkyl and -NR 11 R 12 Examples include (which may be substituted with one to three identical or different substituents selected from the group consisting of )

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

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

[0106] A more preferred embodiment of a is 1 or 2.

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

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

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

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

[0111] One embodiment of the compound represented by formula (1) is (A) below. (A) A is CHF or CH2, B is given by the following equation (B-1): [ka] [In the formula, * represents the bond position with the nitrogen atom of the hydantoin ring], Ring Q is a 6-10 member aromatic hydrocarbon ring (the aromatic hydrocarbon ring contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) Z is a -O-, 6-10 membered divalent aromatic ring group (the divalent aromatic ring group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The group consisting of may be substituted with the same or different 1 to 3 substituents selected from the group consisting of), a 5 to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may consist of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The group consisting of may be substituted with the same or different 1 to 3 substituents selected from the group consisting of ), or a 4 to 10-membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group may consist of a halogen atom, C 1-6 Alkyl and -NR11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 1 However, C may be substituted with 1 to 3 fluorine atoms. 1-3 It is alkyl, R 2a and R 2b However, together with the carbon atoms to which they are bonded, C 3-6 A cycloalkylene or a 4-6 membered divalent nonaryl heterocyclic group (the cycloalkylene or divalent nonaryl heterocyclic group may be substituted with 1-3 fluorine atoms) is formed. R 3 However, C 6-10 Aryl (where the aryl is a halogen atom and may be substituted with C) 1-6 (The substituents may be the same or different, selected from the group consisting of alkyls), or a 5-10 member heteroaryl (the heteroaryl is composed of a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 4 However, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyls), or a 4 to 10-membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group is composed of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 5 However, hydrogen atoms, halogen atoms, hydroxyl groups, cyano, -NR 7b R 7c , -SO2R 7d or -CONR7e R 7f , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkoxy (The alkoxy is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 6-10 Aryl (The aryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The heteroaryl may be substituted with one or three identical or different substituents selected from the group consisting of the following), 5-10 member heteroaryls (the heteroaryl may be a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The substituents may be the same or different, selected from the group consisting of , or 1-6 Alkyl and -NR 11 R 12(May be substituted with one to three identical or different substituents selected from the group consisting of) R 7b , R 7c , R 7d , R 7e and R 7f However, each is independent of a hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 11 and R 12 However, each is independent of a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0112] One embodiment of the compound represented by formula (1) is (B) below. (B) A is CHF or CH2, B is given by the following equations (B-2), (B-3), or (B-4): [ka] [In the formula, * represents the bond position with the nitrogen atom of the hydantoin ring, a is 0, 1, or 2, b is 1 or 2, R 8 However, a hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6(May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 9a and R 9b Each of these is independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) Ring Q is a 6-10 member aromatic hydrocarbon ring (the aromatic hydrocarbon ring contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) Z is a -O-, 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The group consisting of may be substituted with the same or different 1 to 3 substituents selected from the group consisting of ), or a 4 to 10-membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group may consist of a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 1 However, it is CF3, R 3 However, these are 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl. R 4 However, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (The substituents may be the same or different, selected from the group consisting of alkyls, or a 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group may consist of a halogen atom, C1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 5 However, hydrogen atoms, halogen atoms, hydroxyl groups, cyano, -NR 7b R 7c , -SO2R 7d or -CONR 7e R 7f , C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 1-6 Alkoxy (The alkoxy is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of ), C 6-10 Aryl (The aryl is a halogen atom, C 1-6 Alkyl and -NR 11 R 12(The heteroaryl may be substituted with one or three identical or different substituents selected from the group consisting of the following), 5-10 member heteroaryls (the heteroaryl may be a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (The substituents may be the same or different, selected from the group consisting of , or 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 7b , R 7c , R 7d , R 7e and R 7f However, each is independent of a hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C) 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 11 and R 12 However, each is independent of a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0113] One embodiment of the compound represented by formula (2) is (C) below. (C) A is CHF or CH2, R 3However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, Z A 4-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 4 but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 5 but, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 6 However, it is a hydrogen atom or a halogen atom, R11 and R 12 However, each is independent of a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0114] One embodiment of the compound represented by formula (2) is (D) below. (D) A is CHF, Z A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 4 but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 5 but, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 6 However, it is a hydrogen atom, R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0115] One embodiment of the compound represented by formula (3) is (E) below. (E) R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 5 but, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 11 and R 12 However, each is independent of a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0116] One embodiment of the compound represented by formula (3) is (F) below. (F) R 3However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 However, it is a 4-6 membered divalent nonaryl heterocyclic group, R 5 but, C 1-3 Alkyl, or A 4-6 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound or a pharmaceutically acceptable salt thereof.

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

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

[0119] One embodiment of the compound represented by formula (5) is (I) below. (I) A is CHF or CH2, Z A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 but, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or C 3-10 Cycloalkylene (the cycloalkylene contains a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 5 but, hydrogen atom, Hydroxyl group Cyano, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 6 However, it is a hydrogen atom or a halogen atom, R 8 However, C 1-6 It is alkyl, R 11 and R 12 However, each is independent of a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6 In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0120] One embodiment of the compound represented by formula (5) is (J) below. (J) A is CHF, Z A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R4 but, Single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 5 but, Hydroxyl group, Cyano, C 1-6 Alkyl (The alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl, and -NR groups 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the following), C 3-10 Alicyclic group (The alicyclic group is a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of the above), or 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 6 However, it is a hydrogen atom, R 8 However, it is a methyl group, R 11 and R 12 Each of these is independently a hydrogen atom or C 1-6 It is alkyl, R 11 or R 12 If there are multiple, R 11 or R 12 Each of these may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 Both are C 1-6In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0121] One embodiment of the compound represented by formula (6) is (K) below. (K) R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 but, Single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 5 but, Hydroxyl group, Cyano, C 1-6 Alkyl, C 3-10 Alicyclic group, or It is a 4-10 member non-aryl heterocyclic group. A compound or a pharmaceutically acceptable salt thereof.

[0122] One embodiment of the compound represented by formula (6) is (L) below. (L) R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 but, Single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and C 1-6 (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) R 5 but, Methyl group, or It is oxetanil. A compound or a pharmaceutically acceptable salt thereof.

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

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

[0125] One embodiment of the compound represented by formula (8) is (O) below. (O) A is CHF or CH2, Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 3 However, it is 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 However, a 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12(May be substituted with one to three identical or different substituents selected from the group consisting of) R 5 However, a 4-10 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C 1-6 Alkyl and -NR 11 R 12 (May be substituted with one to three identical or different substituents selected from the group consisting of) R 6 However, it is a hydrogen atom or a halogen atom, R 9a and R 9b However, the fluorine atom A compound or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0130] The compounds disclosed herein may be administered orally, parenterally, or rectally, and the daily dose will vary depending on the type of compound, the method of administration, and the patient's symptoms and age. For example, in the case of oral administration, typically about 0.01 to 1000 mg per kg of human or mammalian body weight, more preferably about 0.1 to 500 mg, can be administered in one to several divided doses. In the case of parenteral administration, such as intravenous injection, typically about 0.01 mg to 300 mg per kg of human or mammalian body weight, more preferably about 1 mg to 100 mg, can be administered. Examples of administration schedules include single doses, once daily for three consecutive days, or twice daily for one consecutive week. Furthermore, each of the above-described administration methods can be repeated at intervals of approximately 1 day to 60 days.

[0131] The compounds of this disclosure can be administered directly or in a suitable dosage form by parenteral or oral administration. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices. The formulations are manufactured by known methods using pharmaceutically acceptable excipients. Depending on the purpose, excipients may include excipients, disintegrants, binders, fluidizers, lubricants, coatings, solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavorings. Specifically, examples 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, stearyl fumarate sodium, polyethylene glycol, propylene glycol, titanium dioxide, and talc.

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

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

[0134] Manufacturing method A Compounds represented by formula (1), specifically those in which A is CHF and Q is a benzene ring (1-11), can be produced, for example, by the following method. [ka] [In the formula, R 1 , R 2a , R 2b , R 3 , R4 , R 5 And Z is the same as in [Item 1] above, and R 6 This is synonymous with [paragraph 16] above.

[0135] Process 1-1: Manufacturing process for compound (1-3) Compound (1-3) is produced by reacting compound (1-1) and compound (1-2) in an inert solvent in the presence of a reducing agent.

[0136] Specific examples of reducing agents include sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

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

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

[0139] Process 1-2: Manufacturing process for compounds (1-5) Compounds (1-5) are produced by an amidation reaction using compounds (1-3) and (1-4) in an inert solvent in the presence of a base.

[0140] Specific examples of bases 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 inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether-based 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 a range of 0°C to 150°C, preferably from 25°C to 100°C. The reaction time is usually from 1 hour to 72 hours, preferably from 1 hour to 24 hours.

[0143] Steps 1-3: Manufacturing process for compounds (1-6) Compounds (1-6) are produced by removing the benzyl group from compound (1-5). For example, catalytic reduction using metal catalysts 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 a range of 0°C to 100°C, preferably from 0°C to 25°C. The reaction time is usually from 1 hour to 72 hours, preferably from 1 hour to 24 hours.

[0145] Steps 1-4: Manufacturing process for compounds (1-8) Compound (1-8) is produced by reacting compound (1-7) with a reducing agent. Compound (1-7) can be synthesized using the method described in WO2016 / 044770.

[0146] Specific examples of reducing agents include sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride.

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

[0148] Steps 1-5: Manufacturing process for compounds (1-9) Compounds (1-9) are produced by reacting compound (1-8) with a fluorinating agent in an inert solvent.

[0149] Specific examples of inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether-based 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, for example, (diethylamino) sulfur trifluoride and FLUOLEAD. TM These are some examples.

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

[0152] Process 1-6: Manufacturing process for compounds (1-10) Compounds (1-10) are produced by the Mitsunobu reaction using compounds (1-6) and (1-9) in an inert solvent in the presence of Mitsunobu's reagent.

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

[0154] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, etc. Cyanomethylenetrimethylphosphoran (Kakuda Reagent) can also be used.

[0155] The reaction temperature is not particularly limited, but is usually selected from 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] Steps 1-7: Manufacturing process for compounds (1-11) Compounds (1-11) are produced by carrying out a palladium-catalyzed cross-coupling reaction with compound (1-10) using various coupling reagents in an inert solvent.

[0157] Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether-based 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 palladium reagents include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1'-bis(diphenylphosphineno)ferrocene]palladium(II) dichloride.

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

[0160] Specific examples of coupling reagents include, for example, boronic acids with a Z bond and pinacol ester of boronic acid with a Z bond.

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

[0162] Process 2-1: Manufacturing process for compound (2-1) Compound (2-1) is produced by reacting compound (1-3) with an amidating agent in an inert solvent.

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

[0164] Specific examples of inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether-based 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 a range of 0°C to 150°C, preferably from 25°C to 100°C. The reaction time is usually from 1 hour to 72 hours, preferably from 1 hour to 24 hours.

[0166] Step 2-2: Manufacturing process for compounds (1-13) Compounds (1-13) are produced by an alkylation reaction using compounds (2-1) and (1-12) in an inert solvent in the presence of a base.

[0167] Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether-based 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 bases 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 from 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: Manufacturing process for compounds (1-14) Compounds (1-14) are produced by carrying out a palladium-catalyzed cross-coupling reaction with compound (1-13) using various coupling reagents in an inert solvent.

[0171] Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether-based 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 palladium reagents include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1'-bis(diphenylphosphineno)ferrocene]palladium(II) dichloride.

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

[0174] Specific examples of coupling reagents include, for example, boronic acids with a Z bond and pinacol ester of boronic acid with a Z bond.

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

[0176] Manufacturing method C Among the compounds represented by formula (1), compounds (1-14) in which Q is a benzene ring can also be produced by the following method. [ka] [In the formula, A, R 1 , R 2a , R 2b , R 3 , R 4 , R5 , and Z are equivalent to those in [Section 1] above. R 6 This is synonymous with [paragraph 16] above.

[0177] Process 3-1: Manufacturing process for compound (3-1) Compound (3-1) is produced by carrying out a palladium-catalyzed cross-coupling reaction with compound (1-12) using various coupling reagents in an inert solvent.

[0178] Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether-based 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 palladium reagents include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1'-bis(diphenylphosphineno)ferrocene]palladium(II) dichloride.

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

[0181] Specific examples of coupling reagents include, for example, boronic acids with a Z bond and pinacol ester of boronic acid with a Z bond.

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

[0183] Step 3-2: Manufacturing process for compounds (1-14) Compounds (1-14) are produced by the Mitsunobu reaction using compounds (3-1) and (1-6) in an inert solvent in the presence of Mitsunobu's reagent.

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

[0185] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, etc. Cyanomethylenetrimethylphosphoran (Kakuda Reagent) can also be used.

[0186] The reaction temperature is not particularly limited, but is usually selected from 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] Manufacturing method D Among the compounds represented by formula (1), compounds (1-14) in which Q is a benzene ring can also be produced by the following method. [ka] [In the formula, A, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and Z are equivalent to those in [Section 1] above. R 6 This is equivalent to [item 16] above. W represents a halogen atom.

[0188] Process 4-1: Manufacturing process for compounds (1-14) Compounds (1-14) are produced by an alkylation reaction using compounds (3-1) and (2-1) in an inert solvent in the presence of a base.

[0189] Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether-based 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 bases 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 from 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] Manufacturing method E Compounds represented by formula (1), in which A is CH2 and Q is a benzene ring (1-17), can be produced, for example, by the following method. [ka] [In the formula, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 And Z is the same as in [Item 1] above, and R 6 This is synonymous with [paragraph 16] above.

[0193] Step 5-1: Manufacturing process for compounds (1-16) Compound (1-16) is produced by the Mitsunobu reaction using compound (1-6) and compound (1-15) in an inert solvent in the presence of Mitsunobu's reagent. Compound (1-15) can be synthesized using the method described in WO2016 / 044770.

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

[0195] Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, etc. Cyanomethylenetrimethylphosphoran (Kakuda Reagent) can also be used.

[0196] The reaction temperature is not particularly limited, but is usually selected from 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: Manufacturing process for compounds (1-17) Compounds (1-17) are produced by carrying out a palladium-catalyzed cross-coupling reaction with compound (1-16) in an inert solvent using various coupling reagents.

[0198] Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether-based 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 palladium reagents include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butylphosphine)palladium(0), and [1,1'-bis(diphenylphosphineno)ferrocene]palladium(II) dichloride.

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

[0201] Specific examples of coupling reagents include, for example, boronic acids with a Z bond and pinacol ester of boronic acid with a Z bond.

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

[0203] In the manufacturing methods described above, if the manufacturing method for the starting materials or intermediates is not described, they can be obtained commercially or synthesized from commercially available compounds by methods known to those skilled in the art or by similar methods.

[0204] In each reaction of the manufacturing method described above, protecting groups may be used as needed, even if their use is not explicitly stated. For example, if any functional group other than the reaction site changes under the described reaction conditions, or if it is inappropriate to carry out the described method without a protecting group, the target compound can be obtained by protecting the non-reaction site as needed and then deprotecting it after the reaction is complete or after the series of reactions have been carried out.

[0205] As protecting groups, for example, those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be used. Specific examples of amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl. Specific examples of hydroxyl protecting groups include trialkylsilyls such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, and benzyl.

[0206] The introduction and elimination of protecting groups can be carried out by methods commonly used in organic synthesis (see, for example, Protective Groups in Organic Synthesis above) or by methods similar thereto.

[0207] In this specification, protecting groups, coupling agents, etc., may be represented by abbreviations commonly used in this art by IUPAC-IUB (Biochemical Nomenclature Committee). However, the compound names used in this specification do not necessarily follow IUPAC nomenclature.

[0208] The intermediates or target compounds in the manufacturing methods described above can be converted to other compounds included in this disclosure by appropriately transforming their functional groups (for example, by protecting or deprotecting functional groups as needed, and by performing various transformations using amino, hydroxyl, carbonyl, halogen, etc. as starting points). Functional group transformations can be carried out by commonly used methods (see, for example, Comprehensive Organic Transformations, RCLarock, John Wiley & Sons Inc. (1999), etc.).

[0209] The intermediates and target compounds in the manufacturing method described above can be isolated and purified by purification methods commonly used in organic synthesis chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). Furthermore, the intermediates can be used in subsequent reactions without any special purification.

[0210] As protecting groups, for example, those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999) can be used. Specific examples of amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl. Specific examples of hydroxyl protecting groups include trialkylsilyls such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, and benzyl.

[0211] The introduction and elimination of protecting groups can be carried out by methods commonly used in organic synthesis (see, for example, Protective Groups in Organic Synthesis above) or by methods similar thereto.

[0212] In this specification, protecting groups, coupling agents, etc., may be represented by abbreviations commonly used in this art by IUPAC-IUB (Biochemical Nomenclature Committee). However, the compound names used in this specification do not necessarily follow IUPAC nomenclature.

[0213] The intermediates or target compounds in the manufacturing methods described above can be converted to other compounds included in this disclosure by appropriately transforming their functional groups (for example, by protecting or deprotecting functional groups as needed, and by performing various transformations using amino, hydroxyl, carbonyl, halogen, etc. as starting points). Functional group transformations can be carried out by commonly used methods (see, for example, Comprehensive Organic Transformations, RCLarock, John Wiley & Sons Inc. (1999), etc.).

[0214] The intermediates and target compounds in the manufacturing method described above can be isolated and purified by purification methods commonly used in organic synthesis chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc.). Furthermore, the intermediates can be used in subsequent reactions without any special purification.

[0215] Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, or organic salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, and camphorsulfonate. Examples of base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, or 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-dibenzylatelamine. 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. These include, for example, acid addition salts such as organic acid salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, 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, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), and others that can be appropriately selected by those skilled in the art.

[0217] The compounds disclosed herein are isotopic elements (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 The compounds may be substituted with (I, etc.), and these compounds are also included in the compounds of this disclosure.

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

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

[0220] In particular, optical isomers and atrop isomers can be obtained as racemates, or as optically active compounds if optically active starting materials or intermediates are used. Furthermore, if necessary, the corresponding racemates of the starting materials, intermediates, or final products can be physically or chemically separated into their optical isomers by known separation methods such as optically active column methods or fractional crystallization methods at an appropriate stage of the manufacturing process. Examples of these separation methods include the diastereomer method, in which a racemate is reacted with an optically active resolving agent to synthesize two diastereomers, and these are separated by fractional crystallization or other methods, taking advantage of their differing physical properties.

[0221] When it is desired to obtain a pharmaceutically acceptable salt of the compounds of this disclosure, if the compounds represented by formulas (1) to (10) are obtained in the form of a pharmaceutically acceptable salt, they can be purified as is. If they are obtained in the form of a free salt, they can be dissolved or suspended in a suitable organic solvent, and an acid or base can be added to form a salt by conventional methods.

[0222] The compounds disclosed herein can be used in combination with other drugs for the purpose of enhancing their effects. Specifically, the compounds disclosed herein can be used in combination with drugs such as hormone therapy agents, chemotherapy agents, immunotherapy agents, and drugs that inhibit the action of cell growth factors and their receptors. Hereinafter, drugs that can be used in combination with the compounds disclosed herein will be abbreviated as "combination drugs."

[0223] The compounds disclosed herein exhibit excellent anticancer activity even when used as monotherapy, but their effects can be further enhanced or the patient's quality of life improved by combining them with one or more of the aforementioned combination drugs (multi-drug combination therapy).

[0224] Examples of "hormone therapy agents" include phosphestrol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestol, tadenan, mepaltricin, raloxifene, olmeroxifene, levolmeroxifene, anti-estrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), birth control pills, mepitiostane, testolactone, aminoglutetiimide, LH-RH derivatives (LH-RH agonists (e.g., goserelin acetate, buserelin, leucosurin acetate)). Examples include prorelin, LH-RH antagonists, droloxifen, epithiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozol hydrochloride, anastrozole, letrozole, exemestane, borozol, formestane, etc.), antiandrogens (e.g., flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.), corticosteroids (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (e.g., abiraterone, etc.), retinoids, and drugs that slow the metabolism of retinoids (e.g., rialozol, etc.).

[0225] Examples of "chemotherapeutic agents" include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecularly targeted therapies, immunomodulators, and other chemotherapeutic agents. Representative examples are listed below.

[0226] Examples of alkylating agents include nitrogen mustard, nitrogen mustard N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozodyne. Examples include rhinoplatin, rhinoplatin, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altoretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trophosphamide, dinostatin stimulamer, adzelesin, systemustine, bizelesin, trabectedin, and their DDS preparations.

[0227] Examples of "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine ocphosphat, ancitabine hydrochloride, 5-FU derivatives (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine, etc.), aminopterin, nerzarabine, leucoporin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxyuridine, mitogwazone, thiazophrine, ambamustine, bendamustine, and their DDS preparations.

[0228] Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, acralubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocartinostatin, mithramycin, zalcomycin, cartinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, eribulin, and their DDS preparations.

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

[0230] Examples of "molecularly targeted therapies" 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 Brigadone. Examples include tinib, neratinib, copanlisib, cobimetinib, ibrutinib, acalabrutinib, encorafenib, binimetinib, baricitinib, fostamatinib, lorlatinib, erdafitinib, entrectinib, dacomitinib, sirolimus, everolimus, temsirolimus, olaparib, lucaparib, niraparib, venetoclax, azacitidine, decitabine, vorinostat, panobinostat, tazemetostat, romidepsin, bortezomib, carfilzomib, larotrectinib, and ixazomib.

[0231] Examples of "immunomodulators" include lenalidomide and pomalidomide.

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

[0233] Examples of "immunotherapy agents (BRMs)" include picibanil, krestin, schizophyllan, 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 agonists, TLR8 agonists, TLR9 agonists, etc.).

[0234] In drugs that inhibit the action of cell growth factors and their receptors, any substance that promotes cell proliferation can be used as a cell growth factor. Typically, this refers to peptides with a molecular weight of 20,000 or less that exert their effects at low concentrations upon binding to their receptors. Specifically, these include EGF (epidermal growth factor) or substances with substantially the same activity (e.g., TGFalpha), insulin or substances with substantially the same activity (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, etc.), FGF (fibroblast growth factor) or substances with substantially the same assay (e.g., acidic FGF, basic FGF, KGK (keratinocyte growth factor), FGF-10, etc.), and other cell growth factors (e.g., CSF (colony stimukating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve 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 deficient and / or the expression of the SMARC protein is deficient or attenuated. Preferably, it is cancer in which the SMARC gene is deficient and / or the expression of the SMARC protein is deficient. More preferably, it is cancer in which the SMARCB1 gene, SMARCA2 gene, SMARCA4 gene, or SMARCA2 / A4 gene is deficient. Specifically, this includes malignant rhabdoid tumors, epithelioid sarcomas, atypical teratomatoid / rhabdoid tumors, schwannomas, chordoma-like meningiomas, neuroepithelial tumors, glial neuronal tumors, craniopharyngiomas, glioblastomas, chordomas, myoepithelial tumors, unclassifiable round cell sarcomas, rhabdomyosarcomas, extraskeletal myxoid chondrosarcomas, synovial sarcomas, ossifying fibromyxoid tumors, paranasal sinus basal cell carcinomas, esophageal adenocarcinomas, papillary thyroid carcinomas, follicular thyroid carcinomas, gastrointestinal stromal tumors, undifferentiated pancreatic rhabdoid tumors, and gastrointestinal rhabdoid tumors. Examples include tumors, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumors of the female vulva, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung cancer, pulmonary neuroendocrine tumors, 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, uterine sarcoma, nasal and paranasal sinus cancer, thoracic sarcoma, lung pleomorphic carcinoma, thoracic sarcoma, ovarian small cell carcinoma, primary gallbladder tumors, and uterine sarcoma. Preferably, malignant rhabdoid tumors and lung adenocarcinomas.

[0236] "SMARCB1-deficient cancer" refers to cancer in which the SMARCB1 gene is deficient and / or the expression of the SMARCB1 protein is deficient or attenuated. Preferably, it is cancer in which the SMARCB1 gene is deficient and / or the expression of the SMARCB1 protein is deficient. More preferably, it is cancer in which the SMARCB1 gene is deficient. Specifically, these include malignant rhabdoid tumors, epithelioid sarcomas, atypical teratomatoid / rhabdoid tumors, schwannomas, chordoma-like meningiomas, neuroepithelial tumors, glial neuronal tumors, craniopharyngiomas, glioblastomas, chordomas, myoepithelial tumors, unclassifiable round cell sarcomas, rhabdomyosarcomas, extraskeletal myxoid chondrosarcomas, synovial sarcomas, ossifying fibromyxoid tumors, paranasal sinus basal cell carcinomas, esophageal adenocarcinomas, papillary thyroid carcinomas, follicular thyroid carcinomas, gastrointestinal stromal tumors, undifferentiated pancreatic rhabdoid tumors, gastrointestinal rhabdoid tumors, renal medullary carcinomas, endometrial cancers, myoepithelioma-like tumors of the female vulva, colorectal cancer, and mesothelioma. Preferably, these are malignant rhabdoid tumors.

[0237] "SMARCA2-deficient cancer" refers to cancer in which the SMARCA2 gene is deficient and / or the expression of the SMARCA2 protein is deficient or attenuated. Preferably, it is cancer in which the SMARCA2 gene is deficient and / or the expression of the SMARCA2 protein is deficient. More preferably, it is cancer in which the SMARCA2 gene is deficient. Specifically, examples include lung adenocarcinoma, large cell lung cancer, pulmonary 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 deficient and / or the expression of the SMARCA4 protein is deficient or attenuated. Preferably, it is cancer in which the SMARCA4 gene is deficient and / or the expression of the SMARCA4 protein is deficient. More preferably, it is cancer in which the SMARCA4 gene is deficient. Specifically, 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 neoplasm, endometrial cancer, mesothelioma, uterine sarcoma, nasal and paranasal sinus cancer, rhabdoid tumor, and thoracic sarcoma. Preferably, it is lung adenocarcinoma.

[0239] "SMARCA2 / A4 deficiency cancer" refers to cancer in which the SMARCA2 gene and the SMARCA4 gene are deficient, 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 deficient, 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 deficient. Specifically, examples include lung adenocarcinoma, lung pleomorphic carcinoma, large cell lung carcinoma, esophageal cancer, gastroesophageal junction cancer, thoracic 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 deficient and / or the expression of the ARID protein is deficient or attenuated. Preferably, it is cancer in which the ARID gene is deficient and / or the expression of the ARID protein is deficient. More preferably, it is cancer in which the ARID1A gene, ARID1B gene, or ARID1A / 1B gene is deficient. Specifically, examples include ovarian cancer, gastric cancer, biliary tract cancer, pancreatic cancer, uterine 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 deficient and / or the expression of the ARID1A protein is deficient or attenuated. Preferably, it is cancer in which the ARID1A gene is deficient and / or the expression of the ARID1A protein is deficient. More preferably, it is cancer in which the ARID1A gene is deficient. Specifically, 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 deficient and / or the expression of the ARID1B protein is deficient or attenuated. Preferably, it is cancer in which the ARID1B gene is deficient and / or the expression of the ARID1B protein is deficient. More preferably, it is cancer in which the ARID1B gene is deficient. Specifically, examples include ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, melanoma, breast cancer, medulloblastoma, endometrial cancer, bladder cancer, and gastric cancer. Preferably, it is ovarian cancer.

[0243] "ARID1A / 1B deficiency 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 deficient or attenuated. Preferably, it is 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 deficient. More preferably, it is cancer in which the ARID1A gene and the ARID1B gene are deficient. Specifically, 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. Specifically, this includes synovial sarcoma and Ewing's sarcoma. Synovial sarcoma is preferred.

[0245] "Heart disease" refers to illnesses caused by some kind of damage to the heart, which leads to impaired blood circulation. Specifically, these include cardiomyopathy, heart failure, and myocardial infarction.

[0246] "Metabolic diseases" are illnesses that result from impaired metabolic function. Specifically, these include dyslipidemia and diabetes.

[0247] The duration of administration of the compounds and concomitant drugs disclosed herein is not limited, and they may be administered simultaneously to the target patient or with a time difference. Alternatively, the compounds and concomitant drugs may be used as a combination preparation. The dosage of the concomitant drugs can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compounds and concomitant drugs can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, and combination. For example, if the target patient is a human, 0.01 to 100 parts by weight of the concomitant drug may be used for every 1 part by weight of the compound disclosed herein. Additionally, for the purpose of suppressing side effects, they can be used in combination with drugs such as antiemetics, hypnotics, and anticonvulsants (concomitant drugs).

[0248] In this specification, "or" is used when "at least one" of the items listed in the text can be adopted. The same applies to "or else". In this specification, when it is specified as "within the range of two values", that range includes the two values ​​themselves.

[0249] References such as scientific literature, patents, and patent applications cited herein are incorporated herein by reference to the same extent as they are specifically described herein.

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

[0251] Sequence ID 1

[0252] Sequence ID 2

[0253] Sequence ID 3 [Examples]

[0254] The present disclosure will be further described below with reference examples, examples, and test examples, but will not be limited thereto.

[0255] In this specification, the following abbreviations may be used. Me: Methyl Et: Ethyl Ph: Phenyl Bn: Benzyl Boc:tert-butoxycarbonyl DMPU:N,N'-dimethylpropyleneurea n-: normal- tert-: tert- p-:para- Ac: Acetyl dppf:1,1'-bis(diphenylphosphin)ferrocene X-PHOS:2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl

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

[0257] In NMR, the symbols used are as follows: s for single line, d for double line, dd for double double line, t for triple line, td for double triple line, q for quadruple line, m for multiline line, br for broad line, brs for broad single line, brm for broad multiline line, 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 (precise mass consisting only of the principal isotope) is [M+H]. + [MH] -Alternatively, [M+2H] 2+ These are indicated by, for example, and the retention time is indicated by Rt (minutes).

[0259] LC / MS measurement method: Detection equipment: ACQUITY® SQ detector (Waters Corporation) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7μm, 2.1mm x 30mm) Solvent: Solution A: 0.06% formic acid / H2O, Solution B: 0.06% formic acid / MeCN Gradient condition:0.0-1.3min Linear gradient from B 2% to 96% Flow rate: 0.8 mL / min UV: 220nm and 254nm Column temperature: 40℃

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

[0261] a) Preparation of N-(4-fluorobenzyl)-3-(trifluoromethyl)oxetane-3-amine (compound Y1) 10.0 g of 3-(trifluoromethyl)oxetane-3-amine hydrochloride was dissolved in 188 mL of chloroform, and 7.25 mL of 4-fluorobenzaldehyde and 22.4 g of sodium triacetoxyborohydride were added at 0°C. The mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and it was extracted twice with chloroform. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 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), sodium hydride (2.0 g) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. Benzyloxyacetyl chloride (12.0 mL) was added at 0°C, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and it was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 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), palladium hydroxide-activated carbon (2.1 g) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered by Celite, the residue was washed with methanol, and the solvent was removed by distillation 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 2~5 Compounds of Reference Examples 2 to 6 were obtained using the corresponding starting compounds, following the method described in Reference Example 1.

[0265] [Table 1-1] [Table 1-2]

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

[0267] a) Preparation of (3'S,4S)-5'-bromo-3'-hydroxy-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-2,5-dione (compound Y3) (4S)-5'-bromospiro(imidazolidin-4,1'-indene)-2,3',5(2'H)-trione (20.0 g) was dissolved in methanol (339 mL), sodium borohydride (2.8 g) was added at -78°C, and the mixture was stirred 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, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 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[imidazolidin-4,1'-indene]-2,5-dione Compound Y3 (18.6 g) was dissolved in dichloromethane (313 mL), and (diethylamino)sulfate trifluoride (28.9 mL) was added at -78°C. The mixture was stirred at 0°C for 2 hours. A saturated aqueous sodium bicarbonate solution 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, dried over magnesium sulfate, filtered off, and the solvent was removed by vacuum distillation. 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[imidazolidined-4,1'-inden]-1-yl)-N-(4-fluorobenzyl)-N-(3-(trifluoromethyl)oxetan-3-yl)acetamide [ka]

[0269] The compound from 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 and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (460 mg). LC-MS ([M+H]+ / Rt (min)): 572.3 / 1.038

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

[0271] [Table 2-1] [Table 2-2]

[0272] Reference example 17 (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-inden]-1-yl)-N-(1-methyl-3-(trifluoromethyl)azetidine-3-yl)acetamide [ka]

[0273] a) The compound from 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 and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, filtered off, and the solvent was removed by vacuum distillation. 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[imidazolidin-4,1'-inden]-1-yl)-N-(1-methyl-3-(trifluoromethyl)azetidine-3-yl)acetamide Compound Y4 obtained above was dissolved in chloroform (17 mL), trifluoroacetic acid (13.2 mL) was added at room temperature, and the mixture was stirred for 5 hours. The reaction mixture was removed by distillation under reduced pressure, and azeotropic distillation was performed using toluene. The resulting crude product was dissolved in chloroform (21 mL), 37% formalin aqueous solution (1.4 mL) and sodium triacetoxyborohydride (2.7 g) were added at 0°C, and the mixture was stirred at room temperature for 15 hours. Saturated sodium bicarbonate aqueous 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, filtered off, and the solvent was removed by distillation under reduced pressure. The residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.16 g). LC-MS ([M+H]+ / Rt (min)): 583.3 / 0.778

[0274] Reference examples 18~22 Compounds of Reference Examples 18-22 were obtained using the corresponding starting compounds, following the method described in Reference Example 17.

[0275] [Table 3]

[0276] Example 1 N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidinedine-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide [ka]

[0277] The compound from Reference Example 9 (100 mg) was dissolved in 1,4-dioxane (0.7 mL) and water (0.2 mL). Potassium carbonate (52 mg), 1-(1-(oxetan-3-yl)azetidine-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, and the mixture was stirred at 90°C for 2 hours. Water was added to the reaction mixture, and it was extracted twice with chloroform. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, filtered off, and the solvent was removed by vacuum distillation. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (29 mg). LC-MS ([M+H]+ / Rt (min)): 669.5 / 1.005

[0278] Examples 2-35 Compounds of Examples 2 to 35 were obtained using the corresponding reference compound and a commercially available compound as raw materials, in accordance with the method described in Example 1.

[0279] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11]

[0280] Comparative Example 1 [ka] 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 [ka] 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 example The following describes the test results for representative compounds of this disclosure, along with their pharmacological, chemical, and pharmacokinetic characteristics; however, this disclosure is not limited to these test examples.

[0283] Test Example 1: HAT Activity Inhibition Experiment The HAT inhibitory activity of HAT inhibitors was evaluated using the SensoLyte HAT(p300) Assay Kit (ANASPEC, AS-72172). Specifically, 7.5 μL of recombinant p300 solution diluted 10-fold with assay buffer was added to 7.5 μL of compounds from Examples 1-35 diluted with assay buffer, and incubated at room temperature for 10 minutes. Then, 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, and incubated at 37°C for 30 minutes. 37.5 μL of Stop Solution was added to stop the reaction. 75 μL of p300 Developer solution diluted 50-fold with assay buffer was added, and incubated at room temperature for 30 minutes under light-shielding conditions. Fluorescence at 513 nm was measured using a multi-plate reader when irradiated with 389 nm excitation light. Based on the measured fluorescence intensity, the IC2 concentration corresponding to the compound showing a 50% enzyme reaction inhibition rate is calculated. 50 The values ​​were calculated. The results are shown in Table 5.

[0284] [Table 5]

[0285] As shown in Table 5, the series of compounds of this disclosure were confirmed to inhibit the function of the HAT domain of P300 / CBP. In particular, Examples 3-5, 7, 9-13, 15, 17, 18-20, 23-27, and 29-35 showed potent inhibition of HAT activity.

[0286] Experiment Example 2: Cell proliferation inhibition experiment using G-401 cells G-401 cells (derived from malignant rhabdoid tumors) were obtained from the American Cell Culture and Cell Lineage Preservation Center (ATCC). The G-401 cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum and 1% penicillin / streptomycin under conditions of 37°C and 5% CO2.

[0287] 500 cells were seeded per well in a 384-well plate. One day after seeding, Examples 1-35 were added to achieve a final DMSO concentration of 0.1%, and the cells were cultured for 3 days. After culturing, cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). From the viability curve, the IC20 concentration corresponding to the evaluation compound showing a 50% inhibition of cell proliferation was determined. 50 The values ​​were calculated. The results are shown in Table 6.

[0288] [Table 6]

[0289] As shown in Table 6, the series of compounds disclosed herein showed potent cell proliferation inhibitory effects against G-401 cells, which are cells derived from malignant rhabdoid tumors. In particular, Examples 2-5, 7, 9-13, 15, 17, 19, 20, 22-27, and 29-35 showed potent cell proliferation inhibitory effects.

[0290] Experiment 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. The Kuramochi cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin under conditions of 37°C and 5% CO2.

[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 achieve a final DMSO concentration of 0.1%, and the cells were cultured for 6 days. After the culture period, cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). From the viability curve, the IC20 concentration corresponding to the evaluation compound that showed a 50% inhibition of cell proliferation was determined. 50 The values ​​were calculated. The results are shown in Table 7.

[0292] [Table 7]

[0293] Experiment Example 4: Cell proliferation inhibition experiment using RMGI cells RMGI cells (derived from ovarian cancer) were obtained from the JCRB cell bank. The RMGI cells were cultured in Ham's F12 medium containing 10% fetal bovine serum and 1% penicillin / streptomycin at 37°C under 5% CO2 conditions.

[0294] Cell viability was measured using a CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). Cells were seeded at a concentration of 200% per well in a 384-well plate. One day after seeding, Examples 3, 7, 9, 10, 11, 20, and 23-25 ​​were added to achieve a final DMSO concentration of 0.1%, and the cells were cultured for 6 days. After culturing, cell viability was measured using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). The IC2000 iontophoresis (IC2000) concentration, which corresponds to a 50% inhibition of cell proliferation, was determined from the viability curve. 50 The values ​​were calculated. The results are shown in Table 8.

[0295] [Table 8]

[0296] Test Example 5: Solubility Test Solubility was measured for Examples 7, 10, 20, 23, 24, 30-34, Comparative Example 1, and Comparative Example 2. The test compounds were added to 10 mmol / L glycine buffer (pH 2.0) and 10 mmol / L citrate buffer (pH 3.0) and stored in a constant temperature chamber at 5°C. After standing overnight, the solutions were filtered through a membrane filter, and the filtrate concentration was measured by HPLC. The measurement conditions for HPLC are as follows: HPLC conditions Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm Column temperature: 40℃ Mobile phase: A: 0.1% water containing 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: 0.8mL / min Detection: UV-Vis detector, measurement wavelength 254nm Injection volume: 5μL or Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm Column temperature: 40℃ Mobile phase: A: 0.1% water containing 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: 0.8mL / min Detection: UV-Vis detector, measurement wavelength 254nm Injection volume: 2μL or Column: Acquity UPLC BEH C18, 1.7μm, 50x2.1mm Column temperature: 40℃ Mobile phase: A: 0.1% water containing 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: 0.8mL / min Detection: UV-Vis detector, measurement wavelength 254nm Injection volume: 3μL

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

[0298] [Table 9]

[0299] Test Example 6: Membrane Permeability Test

[0300] The membrane permeability of the test compounds was tested using the Artificial Membrane Permeability Test (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. The two plates were stacked and incubated at 37°C for 4 hours. The UV of the acceptor and donor solutions was then measured using a UV plate reader (190-500 nm). Compounds with poor UV absorption were measured by LC-MS. The permeability coefficient of the drug Pe(10) was calculated. -6 The cm / sec value was calculated using the following formula.

number

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

[0302] [Table 10]

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

[0304] The test results for Examples 1, 3-5, 7, 9-12, 20, and 23-25 ​​are shown in Table 11. The results of this study confirmed that the compound disclosed herein exhibits superior pharmacokinetic properties and is useful in vivo.

[0305] [Table 11]

[0306] Test Example 8: Drug efficacy evaluation test by oral administration using G-401 xenograft model mice BALB / cAnNCrj-nu / nu mice (CAnN.Cg-Foxn1) 4-7 weeks old <nu>G-401 cells (ATCC) were introduced intradermally in 5x10 cells by / CrlCrlj, Jackson Laboratory Japan. 5 Transplantation was performed under cell / mouse conditions. After confirming the engraftment of G-401 cells 10 to 40 days after transplantation, the test compound, suspended in a solvent such as 0.5% methylcellulose solution, was orally administered twice daily at doses of 1 to 100 mg / kg. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the test compound. Tumor volume can be calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) using the following formula. Tumor volume [mm] 3 ] = 0.5 × minor axis [mm] × (major axis [mm]) 2

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

[0308] The test results for Examples 7, 10, 20, and 23 are shown in Table 12. Based on the results of this study, Examples 7, 10, 20, and 23 showed potent antitumor effects in a G-401 xenograft model using cells derived from malignant rhabdoid tumors.

[0309] [Table 12]

[0310] Test Example 9: Drug efficacy evaluation test by intravenous administration using G-401 xenograft model mice BALB / cAnNCrj-nu / nu mice (CAnN.Cg-Foxn1) 4-7 weeks old <nu>G-401 cells (ATCC) were introduced into the skin of 5x10 cells (Jackson Laboratory Japan) / CrlCrlj. 5 Transplantation was performed under cell / mouse conditions. After confirming the engraftment of G-401 cells 10 to 40 days after transplantation, the test compound, suspended in a solvent such as 10 mmol / L glycine buffer (pH 2.0), was administered via tail vein at a dose of 0.015 to 20 mg / kg at a frequency of at least once a week. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the test compound administration. Tumor volume can be calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) using the following formula. Tumor volume [mm] 3 ] = 0.5 × minor axis [mm] × (major axis [mm]) 2 The control group, administered only a solvent such as 10 mmol / L glycine buffer (pH 2.0), was compared with the test compound administration group, and the T / C ratio was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (Tumor volume at the end of administration in the test compound group - Tumor volume at the start of administration in the test compound group) / (Tumor volume at the end of administration in the control group - Tumor volume at the start of administration in the control group) × 100

[0311] The test results for Examples 7, 10, 20, 23, 24 and Comparative Example 1 are shown in Table 13. The results of this study showed that Examples 7, 10, 20, 23, and 24 demonstrated potent antitumor effects even with intravenous administration in a G-401 xenograft model derived from malignant rhabdoid tumor cells. On the other hand, Comparative Example 1 did not show any antitumor effect despite being administered at the maximum concentration.

[0312] [Table 13]

[0313] Test Example 10: Evaluation of Dopamine Receptor Inhibitory Activity The binding evaluation assay was commissioned to Eurofins. 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 the membrane formulation. The test compound (1-10 μmol / L DMSO solution), the membrane formulation, and 0.15 nmol / L [ 3 Mixed with [H]kParoxetine and incubated at 4°C for 180 minutes. Cell membranes and [ 125 The [I]RTI-55 complex was bound and washed with 50 mmol / L Tris-HCl, pH 7.4. The effect on the receptor was evaluated by measuring the radioactivity using a scintillation counter.

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

[0315] [Table 14]

[0316] Test Example 11: Evaluation of serotonin receptor inhibitory activity The binding evaluation assay was commissioned to Eurofins. Specifically, HEK293 / hSERT cells were homogenized using a buffer consisting of 100 mmol / L NaCl, 1 μmol / L Leupeptin, 10 μmol / L PMSF, 50 mmol / L Tris-HCl, and 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 the membrane formulation. The test compound (1-10 μmol / L DMSO solution), the membrane formulation, and 0.4 nmol / L [ 3 Mixed with [H]Paroxetin and incubated at 25°C for 60 minutes. Cell membranes and [ 3 The complex of [H]Paroxetin was bound and washed with 50 mmol / L Tris-HCl, pH 7.4. The effect on the receptor was evaluated by measuring the radioactivity using a scintillation counter.

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

[0318] [Table 15]

[0319] The results from Test Examples 10 and 11 confirmed that the compounds of this disclosure do not act on off-target substances of concern regarding safety. On the other hand, Comparative Example 2 was found to have a strong inhibitory effect on dopamine receptors and serotonin receptors.

[0320] The results from Test Examples 1-11 show that the compounds disclosed in this application exhibit potent HAT inhibitory activity (Test Example 1) and potent cancer cell proliferation inhibitory effects (Test Examples 2-4). Furthermore, the compounds disclosed in this application exhibit excellent solubility (Test Example 5), high membrane permeability (Test Example 6), and good pharmacokinetics (Test Example 7), as well as exceptional antitumor effects (Test Example 8). In addition, even when administered intravenously, the compounds disclosed in this application exhibit exceptional antitumor effects in xenograft model mice (Test Example 9) and showed exceptionally remarkable and unique safety by not exhibiting strong inhibitory activity against off-target dopamine receptors and serotonin receptors (Test Examples 10 and 11).

[0321] The inventors have newly identified a problem with Comparative Examples 1 and 2: their low solubility makes intravenous administration difficult. Generally, structural modifications to increase solubility reduce lipophilicity and impair membrane permeability. However, among the compounds disclosed herein, the compounds represented by formulas (2) to (7) in particular possess a unique effect of combining excellent solubility (Test Example 5) and high membrane permeability (Test Example 6), making them excellent CBP / P300 inhibitors that can be administered orally and intravenously.

[0322] Among the compounds disclosed herein, Examples 7, 10, 20, 23, 24, 25, and 30-34, which are included in formulas (2), (3), (5), or (6), showed potent HAT inhibitory activity (Test Example 1) and potent cancer cell proliferation inhibitory effect (Test Examples 2-4). In addition, while structural modifications to increase solubility generally reduce lipophilicity and impair membrane permeability, Examples 7, 10, 20, 23, 24, and 30-34 exhibited superior solubility (Test Example 5) compared to Comparative Examples 1 and 2, while also possessing membrane permeability equivalent to Comparative Examples 1 and 2 (Test Example 6), thus exhibiting a unique effect. Furthermore, Examples 7, 10, 20, 23, and 24 showed excellent pharmacokinetics (Test Example 7). Examples 7, 10, 20, and 23 exhibited exceptional antitumor effects when administered orally (Test Example 8), and also showed remarkably significant antitumor effects within tumors that Comparative Example 1 could not achieve when administered intravenously (Test Example 9), indicating that they are CBP / P300 inhibitors with profiles suitable for both oral and intravenous administration. Furthermore, while Comparative Example 2 showed strong inhibitory activity against off-target dopamine and serotonin receptors, Examples 7, 10, 20, 23, 24, and 25 did not show strong inhibitory activity, demonstrating exceptionally remarkable and heterogeneous safety (Test Examples 10 and 11). (Note) As described above, while the disclosure has been illustrated using preferred embodiments thereof, it is understood that the scope of the disclosure should be interpreted solely by the claims. Patents, applications and other documents cited herein should be incorporated herein by reference as if their contents were specifically described herein. This application claims priority to PCT / JP2024 / 004222 (filed with the Japan Patent Office on 7 February 2024), which is used as reference herein in its entirety. [Industrial applicability]

[0323] The compounds disclosed herein and their pharmaceutically acceptable salts are useful as therapeutic or prophylactic agents for conditions involving CBP / P300 by potently inhibiting CBP / P300.< / nu> < / nu>

Claims

1. The following formula (1): 【Chemistry 1】 [In the formula, A is CHF or CH ２ This represents, B is given by the following formula (B-1): 【Chemistry 2】 [In the formula, * represents the bonding position with the nitrogen atom of the hydantoin ring] Ring Q represents a substituted 6- to 10-membered aromatic hydrocarbon ring or a substituted 5- to 10-membered aromatic heterocycle. Z is -O-, -N(R ７ａ ) - Represents a substituted 6-10 member divalent aromatic ring group, a substituted 5-10 member divalent aromatic heterocyclic group, or a substituted 4-10 member divalent nonaryl heterocyclic group, R １ C may be substituted. 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 alkyl, wherein R ２ａ and R ２ｂ together with the carbon atom to which they are attached may form an optionally substituted C ３－６ cycloalkylene, or an optionally substituted 4- to 6-membered divalent non-aryl heterocyclic group, R ３ C may be substituted. ６－１０ Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted C ３－１０ Represents an alicyclic group or a 4- to 10-membered non-aryl heterocyclic group which may be substituted. R ４ C may be a single bond or substituted. １－６ Alkylene, C may be substituted. ３－１０ Represents a cycloalkylene or a 4- to 10-membered divalent nonaryl heterocyclic group, R ５ This includes a hydrogen atom, a halogen atom, a hydroxyl group, a cyano, and an optionally substituted C. １－６ Alkyl, optionally substituted C １－６ Alkenyl, C may be substituted. １－６ Alkynyl, C may be substituted. １－３ Alkoxy, -NR ７ｂ R ７ｃ , -SO ２ R ７ｄ , -CONR ７ｅ R ７ｆ , C may be substituted ３－１０ Alicyclic group, optionally substituted 4-10 member nonaryl heterocyclic group, optionally substituted C ６－１０ Represents an aryl group, or a 5- to 10-membered heteroaryl group which may be substituted. R ７ａ , R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ Each of these is independently a hydrogen atom or a substituted C atom. １－６ [Represents alkyl] A compound represented by 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 , optionally substituted 6-10 member aromatic hydrocarbon rings in rings Q and Z, optionally substituted 5-10 member aromatic heterocycles, optionally substituted 6-10 member divalent aromatic hydrocarbon ring groups, optionally substituted 5-10 member divalent aromatic heterocycle groups, optionally substituted C ６－１０ Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered nonaryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, C may be substituted. １－６ Alkynyl, C may be substituted. ３－１０ Alicyclic group, may be substituted C ３－６ Cycloalkylene, optionally substituted 4-6 membered divalent nonaryl heterocyclic group, optionally substituted C １－６ Alkylene, C may be substituted. ３－１０ Cycloalkylene, a substituted 4-10 membered divalent nonaryl heterocyclic group, or a substituted C １－３ Each alkoxy independently (1) Halogen atom, (2) Hydroxyl group, (3) C ６－１０ Ariel, (4) 5-12 member heteroaryls, (5) C １－６ Alkyl, (6) C ２－６ Alkenil, (7) C ２－６ Alkinil, (8) C １－６ Alkoxy, (9) C １－６ Alkylthio (10)C ３－１０ Alicyclic group, (11) 3- to 10-membered nonaryl heterocyclic group, (12) Carboxyl, (13)-COR １０ 、 (14)-CO ２ R １０ 、 (15) - COCOA 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 45 ２ NR １１ - １２ 、 (22)-SO ２ R １０ 、 (23)-SO ２ NR １１ R １２ 、 (24) - OCCURRENCE １０ 、 (25)-OCO ２ R １０ 、 (26)-OCONR １１ R １２ 、 (27) Sulfo, (28) Phosphate group, (29) Cyano, and (30) Nitro They may be substituted with one to five identical or different substituents selected from the group consisting of the following: Herein, (3)C ６－１０ (4) 5- to 12-membered heteroaryls, (5) C １－６ Alkyl, (6)C ２－６ Alkenil, (7) C ２－６ Alkinyl, (8) C １－６ Alkoxy, (9)C １－６ Alkylthio, (10)C ３－１０ The groups shown in (11) alicyclic groups and 3- to 10-membered nonaryl heterocyclic groups are (a) Halogen atom, (b) Hydroxyl group, (c) C ６－１０ Ariel, (d) 5-12 member heteroaryls, (e) C １－６ Alkyl, (f) C ２－６ Alkenil, (g) C ２－６ Alkinil, (h) C １－６ Alkoxy, (i)C ３－１０ Alicyclic group, (j) 3-10 member non-aryl heterocyclic group, (k) carboxyl, (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 group, (v) Cyano, and (w) Nitro They may be substituted with one to five identical or different substituents selected from the group consisting of the following: R １０ However, if there are multiple, each is independent, C １－６ It is alkyl, R １１ and R １２ However, each is independent of a hydrogen atom or C １－６ R represents alkyl. １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. R １３ However, hydrogen atoms or C １－６ It is alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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 , optionally substituted 6-10 member aromatic hydrocarbon rings in rings Q and Z, optionally substituted 5-10 member aromatic heterocycles, optionally substituted 6-10 member divalent aromatic hydrocarbon ring groups, optionally substituted 5-10 member divalent aromatic heterocycle groups, optionally substituted C ６－１０ Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered nonaryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, C may be substituted. １－６ Alkynyl, C may be substituted. ３－１０ Alicyclic group, may be substituted C ３－６ Cycloalkylene, optionally substituted 4-6 membered divalent nonaryl heterocyclic group, optionally substituted C １－６ Alkylene, C may be substituted. ３－１０ Cycloalkylene, a substituted 4-10 membered divalent nonaryl heterocyclic group, or a substituted C １－３ Each alkoxy independently (1) Halogen atom, (2) Hydroxyl group, (3) C ６－１０ Ariel, (4) 5-12 member heteroaryls, (5) C which may be substituted with 1 to 3 halogen atoms １－６ Alkyl, (6) C ２－６ Alkenil, (7) C ２－６ Alkinil, (8) C １－６ Alkoxy, (9) C ３－１０ Alicyclic group, (10) 3- to 10-membered nonaryl heterocyclic group, (11) Carboxyl, (12)-COR １０ 、 (13)-CO ２ R １０ 、 (14) - -CNR １１ R １２ 、 (15)-NR １１ R １２ 、 (16)-SO ２ R １０ 、 (17)-SO ２ NR １１ R １２ 、 (18) sulfo, (19) Phosphate group, (20) Cyano, and (21) Nitro They may be substituted with one to five identical or different substituents selected from the group consisting of the following: R １０ However, if there are multiple, each is independent, C １－６ It is alkyl, R １１ and R １２ However, each is independent of a hydrogen atom or C １－６ R represents alkyl. １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ When alkyl, these may combine with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

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 , optionally substituted 6-10 member aromatic hydrocarbon rings in rings Q and Z, optionally substituted 5-10 member aromatic heterocycles, optionally substituted 6-10 member divalent aromatic hydrocarbon ring groups, optionally substituted 5-10 member divalent aromatic heterocycle groups, optionally substituted C ６－１０ Aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered nonaryl heterocyclic group, optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkenyl, C may be substituted. １－６ Alkynyl, C may be substituted. ３－１０ Alicyclic group, may be substituted C ３－６ Cycloalkylene, optionally substituted 4-6 membered divalent nonaryl heterocyclic group, optionally substituted C １－６ Alkylene, C may be substituted. ３－１０ Cycloalkylene, a substituted 4-10 membered divalent nonaryl heterocyclic group, or a substituted C １－３ Each alkoxy independently (1) Halogen atom, (2) Hydroxyl group, (3) Phenyl, (4) 5-6 member heteroaryls, (5) C which may be substituted with 1 to 3 halogen atoms １－６ Alkyl, (6) C １－６ Alkoxy, (7) C ３－７ Alicyclic group, (8) 3- to 7-membered nonaryl heterocyclic groups, (9)-COR １０ 、 (10)-CO ２ R １０ 、 (11) - COCOA １１ R １２ 、 (12)-NR １１ R １２ 、 (13)-SO ２ R １０ 、 (14) - SO ２ NR １１ R １２ , and (15) Cyano They may be substituted with one to five identical or different substituents selected from the group consisting of the following: R １０ However, if there are multiple, each is independent, C １－６ It is alkyl, R １１ and R １２ However, each is independent of a hydrogen atom or C １－６ R represents alkyl. １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ When alkyl, these may combine with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. B is given by the following formulas (B-2), (B-3), or (B-4): 【Transformation 3】 [In the formula, * represents the bond position with the nitrogen atom of the hydantoin ring.] a represents 0, 1, or 2, b represents 1 or 2, R ８ is a hydrogen atom, or a substituted C １－６ Represents alkyl, R ９ａ and R ９ｂ Each of these is independently a hydrogen atom, a halogen atom, or an optionally substituted C １－６ [Represents alkyl] A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R １ However, C may be substituted with 1 to 3 fluorine atoms. １－３ It is alkyl. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R １ However, CF ３ That is, A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

8. R ３ However, C ６－１０ Aryl (the aryl is a halogen atom and may be substituted with C) １－６ (These may be substituted with one to three identical or different substituents selected from the group consisting of alkyls), or a 5 to 10-membered heteroaryl (the heteroaryl is composed of a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

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

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

11. Ring Q is a 6-10 member aromatic hydrocarbon ring (the aromatic hydrocarbon ring contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. Ring Q is a benzene ring (the benzene ring contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

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

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

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

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

17. Equation (1) becomes the following equation (2): 【Chemistry 4】 [In the formula, A is CHF or CH ２ This represents, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z is, -O-, A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.) C ３－１０ Cycloalkylene (the cycloalkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, halogen atom, Hydroxyl group, Cyano, -NR ７ｂ R ７ｃ 、 -SO ２ R ７ｄ 、 - -CNR ７ｅ R ７ｆ 、 C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ３－１０ Alicyclic group (The alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ６－１０ Aryl (the aryl is a halogen atom, C) １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) 5-10 member heteroaryl (the heteroaryl is a halogen atom, C) １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ６ This represents a hydrogen atom or a halogen atom. R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ Each of them operates independently. Hydrogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C) １－６ This represents a compound (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may combine with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

18. A is CHF. The compound according to claim 17 or a pharmaceutically acceptable salt thereof.

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

20. Z is A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 17 to 19 or a pharmaceutically acceptable salt thereof.

21. Z is a five-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 17 to 20 or a pharmaceutically acceptable salt thereof.

22. R ４ but, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 17 to 21 or a pharmaceutically acceptable salt thereof.

23. R ５ but, hydrogen atom, halogen atom, Cyano, -NR ７ｂ R ７ｃ 、 C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 17 to 22 or a pharmaceutically acceptable salt thereof.

24. Equation (1) becomes the following equation (3): 【Transformation 5】 [In the formula, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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

26. R ３ but, It is 4-fluoro-2-pyridyl. The compound according to claim 24 or 25, or a pharmaceutically acceptable salt thereof.

27. R ４ but, It is a 4- to 10-membered divalent nonaryl heterocyclic group. A compound according to any one of claims 24 to 26 or a pharmaceutically acceptable salt thereof.

28. R ４ but, It is a 4-6 membered divalent nonaryl heterocyclic group. A compound according to any one of claims 24 to 27 or a pharmaceutically acceptable salt thereof.

29. R ４ but, It is azetidinylene or piperidylene. A compound according to any one of claims 24 to 28 or a pharmaceutically acceptable salt thereof.

30. R ５ but, C １－６ Alkyl, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group comprises a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 24 to 29 or a pharmaceutically acceptable salt thereof.

31. R ５ but, C １－３ Alkyl, or A 4-6 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 24 to 30 or a pharmaceutically acceptable salt thereof.

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

33. R ５ but, It is oxetanil. A compound according to any one of claims 24 to 31 or a pharmaceutically acceptable salt thereof.

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

35. Equation (1) becomes the following equation (4): 【Transformation 6】 [In the formula, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

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

37. R ４ but, It is a 4-6 membered divalent nonaryl heterocyclic group. The compound according to claim 35 or 36, or a pharmaceutically acceptable salt thereof.

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

39. R ５ but, C １－６ Alkyl, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group comprises a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 35 to 38 or a pharmaceutically acceptable salt thereof.

40. R ５ but, C １－３ Alkyl, or A 4-6 member nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 35 to 39 or a pharmaceutically acceptable salt thereof.

41. R ５ but, It is oxetanil. A compound according to any one of claims 35 to 40 or a pharmaceutically acceptable salt thereof.

42. Equation (1) is given by the following equation (5): 【Transformation 7】 [In the formula, A is CHF or CH ２ This represents, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z is, A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.) C ３－１０ Cycloalkylene (the cycloalkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, halogen atom, Hydroxyl group, Cyano, -NR ７ｂ R ７ｃ 、 -SO ２ R ７ｄ 、 - -CNR ７ｅ R ７ｆ 、 C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－３ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ３－１０ Alicyclic group (The alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ６－１０ Aryl (the aryl is a halogen atom, C) １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) 5-10 member heteroaryl (the heteroaryl is a halogen atom, C) １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ６ This represents a hydrogen atom or a halogen atom. R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ Each of them operates independently. Hydrogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C) １－６ This represents a compound (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), R ８ teeth, Hydrogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C) １－６ This represents a compound (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may combine with the nitrogen atom to which they are bonded to form a 3- to 8-membered nitrogen-containing nonaryl heterocyclic group. That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

43. A is CHF. The compound according to claim 42 or a pharmaceutically acceptable salt thereof.

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

45. Z is A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 42 to 44 or a pharmaceutically acceptable salt thereof.

46. Z is a five-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 42 to 45 or a pharmaceutically acceptable salt thereof.

47. R ４ but, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or C ３－１０ Cycloalkylene (the cycloalkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 42 to 46 or a pharmaceutically acceptable salt thereof.

48. R ５ but, hydrogen atom, Hydroxyl group, Cyano, C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ３－１０ Alicyclic group (The alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ７ｄ However, C １－６ Alkyl (the alkyl is a halogen atom and C) １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 42 to 47 or a pharmaceutically acceptable salt thereof.

49. R ８ but, C １－６ It is alkyl. A compound according to any one of claims 42 to 48 or a pharmaceutically acceptable salt thereof.

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

51. Equation (1) becomes the following equation (6): 【Transformation 8】 [In the formula, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, Hydroxyl group, Cyano, C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ３－１０ Alicyclic group (The alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

52. R ３ but, It is 4-fluorophenyl. The compound according to claim 51 or a pharmaceutically acceptable salt thereof.

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

54. R ４ but, Single bond, or C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 51 to 53 or a pharmaceutically acceptable salt thereof.

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

56. R ４ However, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 51 to 54 or a pharmaceutically acceptable salt thereof.

57. R ５ but, Hydroxyl group, Cyano, C １－６ Alkyl, C ３－１０ Alicyclic group, or It is a 4- to 10-membered nonaryl heterocyclic group. A compound according to any one of claims 51 to 56 or a pharmaceutically acceptable salt thereof.

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

59. R ５ but, It is oxetanil. A compound according to any one of claims 51 to 57 or a pharmaceutically acceptable salt thereof.

60. Equation (1) becomes the following equation (7): 【Chemistry 9】 [In the formula, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, Cyano, C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

61. R ４ but, Single bond, or C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 60 or a pharmaceutically acceptable salt thereof.

62. R ４ However, it is a single bond. The compound according to claim 60 or 61, or a pharmaceutically acceptable salt thereof.

63. R ４ However, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups) A compound according to any one of claims 60 to 62 or a pharmaceutically acceptable salt thereof.

64. R ５ but, C １－６ Alkyl, or Cyano A compound according to any one of claims 60 to 63 or a pharmaceutically acceptable salt thereof.

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

66. R ５ but, Cyano A compound according to any one of claims 60 to 64 or a pharmaceutically acceptable salt thereof.

67. Equation (1) becomes the following equation (8): 【Chemistry 10】 [In the formula, A is CHF or CH ２ This represents, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z is, A 6-10 membered divalent aromatic ring group (the divalent aromatic ring group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups.) C ３－１０ Cycloalkylene (the cycloalkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, halogen atom, Hydroxyl group, Cyano, -NR ７ｂ R ７ｃ 、 -SO ２ R ７ｄ 、 - -CNR ７ｅ R ７ｆ 、 C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkenyl (the alkenyl is a halogen atom, C １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－６ Alkynyl (the alkynyl is a halogen atom, C １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C １－３ Alkoxy (the alkoxy is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ３－１０ Alicyclic group (The alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ６－１０ Aryl (the aryl is a halogen atom, C) １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) 5-10 member heteroaryl (the heteroaryl is a halogen atom, C) １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ６ This represents a hydrogen atom or a halogen atom. R ７ｂ , R ７ｃ , R ７ｄ , R ７ｅ , and R ７ｆ Each of them operates independently. Hydrogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C) １－６ This represents a compound (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), R ９ａ and R ９ｂ Each of them operates independently. hydrogen atom, halogen atom, or C １－６ Alkyl (the alkyl is a halogen atom and C) １－６ This represents a compound (which may be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

68. A is CHF. The compound according to claim 67 or a pharmaceutically acceptable salt thereof.

69. R ６ However, it is a hydrogen atom. The compound according to claim 67 or 68, or a pharmaceutically acceptable salt thereof.

70. Z is A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 67 to 69 or a pharmaceutically acceptable salt thereof.

71. Z is a five-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 67 to 70 or a pharmaceutically acceptable salt thereof.

72. R ４ but, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4-10 membered divalent nonaryl heterocyclic group (the divalent nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 67 to 71 or a pharmaceutically acceptable salt thereof.

73. R ５ but, hydrogen atom, Cyano, -NR ７ｂ R ７ｃ 、 C １－６ Alkyl (the alkyl is a halogen atom, C) １－６ Alkyl, hydroxyl, and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) C ３－１０ Alicyclic group (The alicyclic group is a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) A compound according to any one of claims 67 to 72 or a pharmaceutically acceptable salt thereof.

74. R ９ａ and R ９ｂ but, Fluorine atom, A compound according to any one of claims 67 to 73 or a pharmaceutically acceptable salt thereof.

75. Equation (1) is given by the following equation (9): 【Chemistry 11】 [In the formula, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4- to 10-membered divalent nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, Cyano, C １－６ Alkyl, C １－６ Alkenil, C １－６ Alkinyl, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

76. R ３ but, It is 4-fluorophenyl. The compound according to claim 75 or a pharmaceutically acceptable salt thereof.

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

78. R ４ but, It is a 4- to 10-membered divalent nonaryl heterocyclic group. A compound according to any one of claims 75 to 77 or a pharmaceutically acceptable salt thereof.

79. R ４ but, It is a 4-6 membered divalent nonaryl heterocyclic group. A compound according to any one of claims 75 to 78 or a pharmaceutically acceptable salt thereof.

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

81. R ５ but, It is a 4- to 10-membered nonaryl heterocyclic group. A compound according to any one of claims 75 to 80 or a pharmaceutically acceptable salt thereof.

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

83. R ５ but, It is oxetanil. A compound according to any one of claims 75 to 82 or a pharmaceutically acceptable salt thereof.

84. Equation (1) becomes the following equation (10): 【Chemistry 12】 [In the formula, R ３ This represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ４ teeth, single bond, C １－６ Alkylene (the alkylene contains a halogen atom and C １－６ (May be substituted with one to three identical or different substituents selected from the group consisting of alkyl groups), or A 4- to 10-membered divalent nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R ５ teeth, hydrogen atom, Cyano, C １－６ Alkyl, C １－６ Alkenil, C １－６ Alkinyl, or A 4- to 10-membered nonaryl heterocyclic group (the nonaryl heterocyclic group contains a halogen atom, C １－６ Alkyl and -NR １１ R １２ (May be substituted with one to three identical or different substituents selected from the group consisting of) R １１ and R １２ Each of these is independently a hydrogen atom or C １－６ Represents alkyl, R １１ or R １２ If there are multiple, R １１ or R １２ Each of these may be the same or different, and here, R bonded to the same nitrogen atom １１ and R １２ Both are C １－６ In the case of alkyl groups, these may, together with the nitrogen atom to which they are bonded, form a 3-8 member nitrogen-containing nonaryl heterocyclic group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

85. R ４ but, It is a 4- to 10-membered divalent nonaryl heterocyclic group. The compound according to claim 84 or a pharmaceutically acceptable salt thereof.

86. R ４ but, It is a 4-6 membered divalent nonaryl heterocyclic group. The compound according to claim 84 or 85, or a pharmaceutically acceptable salt thereof.

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

88. R ５ but, It is a 4- to 10-membered nonaryl heterocyclic group. A compound according to any one of claims 84 to 87 or a pharmaceutically acceptable salt thereof.

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

90. R ５ but, It is oxetanil. A compound according to any one of claims 84 to 89 or a pharmaceutically acceptable salt thereof.

91. The compound is selected from the following compounds, the compound according to claim 1 or a pharmaceutically acceptable salt thereof: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S)-5'-{1-[(3-fluoro-1-methylazetidine-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-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)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-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)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]acetamide, N-[(5-fluoropyridine-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(5-fluoropyridine-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazole-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(5-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S)-5'-(5-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S)-5'-(3-fluoro-1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxa-4-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, N-[(5-fluoropyridine-2-yl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-{[3-(dimethylamino)oxetan-3-yl]methyl}-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-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)piperidine-4-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazole-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'R,3'S)-3',6'-difluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3',6'-difluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, and 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide.

92. The compound is selected from the following compounds, the compound according to claim 1 or a pharmaceutically acceptable salt thereof: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)piperidine-4-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidine-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazole-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide, and 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide.

93. The following compounds described in claim 1 or pharmaceutically acceptable salts thereof: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxetan-3-yl)azetidine-3-yl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide.

94. The following compounds described in claim 1 or pharmaceutically acceptable salts thereof: 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide.

95. The following compounds described in claim 1 or pharmaceutically acceptable salts thereof: 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazole-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide.

96. The following compounds described in claim 1 or pharmaceutically acceptable salts thereof: 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxetan-3-yl)-1H-pyrazole-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide.

97. The following compounds described in claim 1 or pharmaceutically acceptable salts thereof: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxetan-3-yl)methyl]-1H-pyrazole-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridine-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide.

98. The following compounds described in claim 1 or pharmaceutically acceptable salts thereof: 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazole-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidine-3-yl]acetamide.

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