TW202532410A - Tertiary amide derivatives substituted with four-membered ring structures - Google Patents

Abstract

The present invention provides a tertiary amide derivative with a four-membered ring structure substitution useful as a medicine, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, or a therapeutic or preventive agent for CBP/P300-related diseases containing the composition. More specifically, the present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof: [In the formula, A represents CHF or CH ₂ , and B represents the following formula (B-1): Ring Q represents an optionally substituted 6- to 10-membered aromatic hydrocarbon ring or an optionally substituted 5- to 10-membered aromatic heterocyclic ring; Z represents -O-, -N( ^R7a )-, an optionally substituted 6- to 10-membered divalent aromatic cyclic group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, or an optionally substituted 4- to 10-membered divalent non-aryl heterocyclic group; ^R1 , ^R2a and ^R2b , ^R3 , ^R4 , and ^R5 are as described in the specification.

Description

Tertiary amide derivatives substituted with four-membered ring structures

The present invention relates to a tertiary amide derivative substituted with a quaternary carbon, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, or a therapeutic or preventive agent for CBP/P300-related diseases containing the same.

Chromosomes dynamically control gene replication or transcription through changes in their higher-order structure through methylation modifications of their constituent DNA or various modifications (acetylation, methylation, phosphorylation, ubiquitination, etc.) of histone proteins (histone H2A, H2B, H3, H4) (Non-patent Reference 1).

Acetylation of histones is a common post-translational modification in eukaryotes, contributing to gene transcription. Histone acetyltransferases (HATs), enzymes that transfer acetyl groups to the lysine side chains of histones, are broadly classified into four classes based on amino acid sequence homology, higher-order structure, and function. These include CBP/P300 (E1A binding protein p300/CREB binding protein), GCN5/PCAF (general control non-inhibitory protein 5/P300/CBP-associated factor), MYST (MOZ, Ybf2/Sas3, Sas2, and Tip60), and Rtt109 (protein product 109 of the Ty1 transposase gene). P300 shares over 90% amino acid sequence homology with its paralog, CBP. In addition to the HAT domain, it also possesses CH1/CH2/CH3 domains (cysteine-histidine rich domains), a KIX domain, and a bromodomain (Non-Patent Reference 2).

CBP/P300 was discovered to bind to adenovirus E1A protein and cAMP-regulated enhancer binding protein (Non-patent References 3-5). Subsequently, CBP/P300 was shown to possess HAT activity (Non-patent References 6 and 7), and its substrate specificity has been carefully studied. It has been reported that, in addition to lysine residues in histones (H2A, H2B, H3, and H4), it also acetylates p53 (Non-patent Reference 8), MyoD (Non-patent Reference 9), STAT3 (Non-patent Reference 10), and androgen receptors (Non-patent Reference 11). Furthermore, CBP/P300 is involved in numerous biological reactions, including division, proliferation, and differentiation (Non-patent Reference 12).

CBP/P300 has been reported to play an important role in the growth of various cancers. Examples include prostate cancer (non-patent references 13 and 14), liver cancer (non-patent references 15 and 16), lung cancer (non-patent references 17–19), breast cancer (non-patent reference 20), colorectal and gastric cancer (non-patent reference 21), hematological cancer (non-patent references 22 and 23), pancreatic cancer (non-patent reference 24), bladder cancer (non-patent reference 25), gastrointestinal stromal tumor (non-patent reference 26), midline NUT carcinoma (non-patent reference 27), ovarian cancer (non-patent reference 28), and malignant rhabdomyosarcoma and epithelioid sarcoma (patent reference 11).

Given the above situation, drugs that inhibit the function of CBP/P300 are expected to be useful as anti-tumor agents. Currently, patent documents 1-10 and non-patent documents 29 disclose low-molecular-weight inhibitors targeting the HAT domain of CBP/P300. Prior Art Patent Documents

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 Documents

Non-patent reference 1: Genes Dev. 2002, 16 (14): 1739-1742. Non-patent reference 2: Mol Genet Metab. 2016, 119 (1-2): 37-43. Non-patent reference 3: Virology. 1985, 147 (1): 142-153. Non-patent reference 4: Mol Cell Biol. 1986, 6 (5): 1579-1589. Non-patent reference 5: Nature. 1993, 365 (6449): 855-859. Non-patent reference 6: Cell. 1996, 87 (5): 953-959. Non-patent reference 7: Nature. 1996, 384 (6610): 641-643. Non-patent reference 8: Cell. 1997, 90 (4): 595-606. Non-patent reference 9: J Biol Chem. 2000, 275 (44): 34359-34364. Non-patent reference 10: Science. 2005, 307 (5707): 269-273. Non-patent reference 11: J Biol Chem. 2000, 275 (27), 20853-20860. Non-patent reference 12: J Cell Sci. 2001, 114 (Pt 13): 2363-2373. Non-patent reference 13: Adv Exp Med Biol. 2008; 617: 535-540. Non-patent reference 14: Prostate. 2008, 68 (10): 1097-1104. Non-patent reference 15: Cancer Lett. 2011, 310 (2): 140-147. Non-patent reference 16: J Transl Med. 2011, 9: 5. Non-patent reference 17: Int J Clin Exp Pathol. 2014, 7 (2): 760-767. Non-patent reference 18: Nat Genet. 2012, 44 (10): 1104-1110. Non-patent reference 19: Clin Cancer Res. 2005, 11 (2Pt 1): 512-519. Non-patent reference 20: Genes Cancer. 2016, 7 (3-4): 98-109. Non-patent reference 21: Oncogene. 1996, 12 (7): 1565-1569. Non-patent reference 22: Proc Natl Acad Sci USA. 1997, 94 (16): 8732-8737. Non-patent reference 23: Blood. 2012, 120 (15): 3058-3068. Non-patent reference 24: Nat Genet. 2000, 24 (3): 300-303. Non-patent reference 25: Nat Genet. 2011, 43 (9): 875-878. Non-patent reference 26: Oncol Rep. 2016, 36 (5): 2763-2770. Non-patent reference 27: J Biol Chem. 2015, 290 (5): 2744-2758. Non-patent reference 28: Oncotarget. 2016, 7 (14): 17790-17804. Non-patent reference 29: Bioorg Med Chem Lett. 2021, 39: 127854-127859.

[Technical means to solve the problem]

The present invention provides a compound that exerts anticancer effects in various cancers by inhibiting CBP/P300, which has been reported to be overexpressed, mutated, or hyperfunctional. Preferably, the compound has high CBP/P300 inhibitory activity and combines high water solubility for anticancer effects via intravenous administration with high oral absorption for anticancer effects via oral administration. This provides a compound that is highly useful as an anticancer agent with potential application in the treatment of a wide range of cancer types.

The present inventors conducted intensive research and discovered that the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as the "compound of the present invention") has a strong inhibitory effect on the HAT domain of CBP/P300, thereby exhibiting excellent anti-cancer effects. In addition, the compound exhibits high oral absorption and water solubility suitable for oral and intravenous administration, thereby completing the present invention.

That is, the present invention is as follows.

[Item 1] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: [Chemical 1] [wherein, A represents CHF or CH ₂ , and B represents the following formula (B-1): [Chemical 2] [wherein, * represents the bonding position to the nitrogen atom of the hydantoin ring], Ring Q represents an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, or an optionally substituted 5- to 10-membered aromatic heterocyclic ring, Z represents -O-, -N(R ^7a )-, an optionally substituted 6- to 10-membered divalent aromatic cyclic group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, or an optionally substituted 4- to 10-membered divalent non-aromatic heterocyclic group, R ¹ represents an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-10 alicyclic group, R ^2a and R ^2b each independently represent an optionally substituted C _1-6 alkyl group, wherein R ^2a and R ^2b , together with the carbon atoms to which they are bonded, may form an optionally substituted C R represents a C _3-6 cycloalkylene group, or an optionally substituted 4-6 membered divalent non-aryl heterocyclic group; ^R represents a C _6-10 aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted C _3-10 alicyclic group, or an optionally substituted 4-10 membered non-aryl heterocyclic group; ^R represents a single bond, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, or an optionally substituted 4-10 membered divalent non-aryl heterocyclic group; ^R represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _1-3 alkoxy group, or -NR ^7b R ^7c , -SO ₂ R ^7d , -CONR ^7e R ^7f , an optionally substituted C _3-10 alicyclic group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _6-10 aryl group, or an optionally substituted 5-10 membered heteroaryl group, R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or an optionally substituted C _1-6 alkyl group]. [Item 2] The compound according to Item 1 or a pharmaceutically acceptable salt thereof, wherein 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 , ring Q, and Z are an optionally substituted 6- to 10-membered aromatic alkyl ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic alkyl ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic ring group, an optionally substituted C The _6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _3-10 alicyclic group, an optionally substituted C _3-6 cycloalkylene group, an optionally substituted 4-6 membered divalent non-aryl heterocyclic group, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, an optionally substituted 4-10 membered divalent non-aryl heterocyclic group, or an optionally substituted C _1-3 alkoxy group may be independently selected from (1) a halogen atom, (2) a hydroxyl group, (3) a C _6-10 aryl group, (4) 5-12 membered heteroaryl, (5) C _1-6 alkyl, (6) C _2-6 alkenyl, (7) C _2-6 alkynyl, (8) C _1-6 alkoxy, (9) C _1-6 alkylthio, (10) C _3-10 alicyclic group, (11) 3-10 membered non-aromatic heterocyclic group, (12) carboxyl, (13) -COR ¹⁰ , (14) -CO ₂ R ¹⁰ , (15) -CONR 11 R 12 , (16) -NR ¹¹ R ¹² , (17) -NR ¹³ COR ¹⁰ , (18) -NR ¹³ CO ² _R ¹⁰ , (19) -NR ¹³ SO ₂ R ¹⁰ , (20) -NR ¹³ CONR ¹¹ R ^{12 ,} (21) -NR ¹³ SO ₂ NR ¹¹ R ¹² , (22) -SO ₂ R ¹⁰ , (23) -SO ₂ NR ¹¹ R ¹² , (24) -OCOR ¹⁰ , (25) -OCO ₂ R ¹⁰ , (26) -OCONR ¹¹ R ¹² , (27) sulfo, (28) phosphate, (29) cyano, and (30) nitro, wherein the above-mentioned (3) C _6-10 aryl, (4) 5-12 membered heteroaryl, (5) C _1-6 alkyl, (6) C _2-6 alkenyl, (7) C _2-6 alkynyl, (8) C _1-6 alkoxy, (9) C _1-6 alkylthio, (10) C The group represented by the _3-10 membered alicyclic group and (11) the 3-10 membered non-aromatic heterocyclic group may be selected from (a) a halogen atom, (b) a hydroxyl group, (c) a C _6-10 aryl group, (d) a 5-12 membered heteroaryl group, (e) a C _1-6 alkyl group, (f) a C _2-6 alkenyl group, (g) a C _2-6 alkynyl group, (h) a C _1-6 alkoxy group, (i) a C _3-10 alicyclic group, (j) a 3-10 membered non-aromatic heterocyclic group, (k) a carboxyl group, (l) -COR ¹⁰ , (m) -CO ₂ R ¹⁰ , (n) -CONR ¹¹ R ¹² , (o) -NR ¹¹ R ¹² , (p) -NR ¹³ COR ¹⁰ , (q) -NR ¹³ SO ₂ R ¹⁰ , (r)-SO ₂ R ¹⁰ , (s)-SO ₂ NR ¹¹ R ¹² , 1 to 5 substituents selected from the group consisting of (t) sulfo, (u) phosphate, (v) cyano, and (w) nitro, R ¹⁰ when there are plural R 10s are each independently a C _1-6 alkyl group, R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group, and when there are plural R ¹¹ or R ¹² , R ^{11 or R 12 may be the same or different. Here, when R 11 and R 12 bonded to} the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and R ¹³ is a hydrogen atom or C _1-6 alkyl. [Item 3] The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein 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 , the optionally substituted 6- to 10-membered aromatic hydrocarbon ring, the optionally substituted 5- to 10-membered aromatic heterocyclic ring, the optionally substituted 6- to 10-membered divalent aromatic hydrocarbon ring group, the optionally substituted 5- to 10-membered divalent aromatic heterocyclic ring group, the optionally substituted C The _6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _3-10 alicyclic group, an optionally substituted C _3-6 cycloalkylene group, an optionally substituted 4-6 membered divalent non-aryl heterocyclic group, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, an optionally substituted 4-10 membered divalent non-aryl heterocyclic group, or an optionally substituted C _1-3 alkoxy group may be independently selected from (1) a halogen atom, (2) a hydroxyl group, (3) a C _6-10 aryl group, (4) 5-12 membered heteroaryl group, (5) C _1-6 alkyl group which may be substituted with 1-3 halogen atoms, (6) C _2-6 alkenyl group, (7) C _2-6 alkynyl group, (8) C _1-6 alkoxy group, (9) C _3-10 alicyclic group, (10) 3-10 membered non-aromatic heterocyclic group, (11) carboxyl group, (12) -COR ¹⁰ , (13) -CO ₂ R ¹⁰ , (14) -CONR ¹¹ R ¹² , (15) -NR ¹¹ R ¹² , (16) -SO ₂ R ¹⁰ , (17) -SO ₂ NR ¹¹ R ¹² , (18) sulfo group, (19) phosphate group, (20) cyano, and (21) nitro, substituted by 1 to 5 substituents, which may be the same or different, from the group consisting of: (20) cyano, and ( ²¹⁾ nitro; ^R10 , when present in plural, each independently represents a _C1-6 alkyl group; ^R11 and ^{R12 ,} when present in plural, each independently represents a hydrogen atom or a _C1-6 alkyl group; ^R11 or ^R12 , when present in plural, may be the same or different; herein, when ^R11 and ^R12 bonded to the same nitrogen atom are both _C1-6 alkyl, they may form together with the nitrogen atom to which they are bonded a 3-8 membered nitrogen-containing non-aromatic heterocyclic group. [Item 4] The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein 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 , ring Q, and Z are an optionally substituted 6- to 10-membered aromatic alkyl ring, an optionally substituted 5- to 10-membered aromatic heterocyclic ring, an optionally substituted 6- to 10-membered divalent aromatic alkyl ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic ring group, an optionally substituted C The _6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _3-10 alicyclic group, an optionally substituted C _3-6 cycloalkylene group, an optionally substituted 4-6 membered divalent non-aryl heterocyclic group, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, an optionally substituted 4-10 membered divalent non-aryl heterocyclic group, or an optionally substituted C _1-3 alkoxy group may be independently selected from (1) a halogen atom, (2) a hydroxyl group, (3) a phenyl group, (4) a 5-6 membered heteroaryl group, (5) C _1-6 alkyl which may be substituted with 1 to 3 halogen atoms, (6) C _1-6 alkoxy, (7) C _3-7 alicyclic group, (8) 3-7 membered non-aromatic heterocyclic group, (9) -COR ¹⁰ , (10) -CO ₂ R ¹⁰ , (11) -CONR ¹¹ R ¹² , (12) -NR ¹¹ R ¹² , (13) -SO ₂ R ¹⁰ , (14) -SO ₂ NR ¹¹ R ¹² , and (15) cyano, substituted with 1 to 5 substituents which are the same or different, wherein R ¹⁰ , when present in plural, is independently C _1-6 alkyl, R ¹¹ and R ¹² are independently hydrogen or C _1-6 alkyl, R ¹¹ or R When there are multiple ^R11 or R12, each ^R11 or ^R12 may be the same or different. Here, when ^R11 and ^R12 bonded to the same nitrogen atom are both _C1-6 alkyl, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. [Item 5] A compound as described in any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof, wherein B is the following formula (B-2), (B-3), or (B-4): [Chemical 3] [In the formula, * represents the bonding position to the nitrogen atom of the hydantoin ring, a represents 0, 1, or 2, b represents 1, or 2, R ⁸ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group, and R ^9a and R ^9b each independently represent a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group.] [Item 6] The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-3 alkyl group optionally substituted with 1 to 3 fluorine atoms. [Item 7] The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R ¹ is CF ₃ . [Item 8] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 7, wherein R ³ is a C _6-10 aryl group (the aryl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a substituted C _1-6 alkyl group), or a 5-10 membered heteroaryl group (the heteroaryl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 9] The compound or pharmaceutically acceptable salt thereof according to any one of Items 1 to 8, wherein R ³ is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl. [Item 10] The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl. [Item 11] The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring Q is a 6-10 membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 12] The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring Q is a benzene ring (the benzene ring may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 13] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 1 to 12, wherein a is 1 or 2. [Item 14] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 1 to 13, wherein a is 1. [Item 15] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 1 to 14, wherein b is 1. [Item 16] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 1 to 15, wherein a is 1 and b is 1. [Item 17] The compound or pharmaceutically acceptable salt thereof as described in Item 1, wherein Formula (1) is the following Formula (2): [Chemical 4] [In the formula, A represents CHF or CH ₂ , R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents -O-, a 6- to 10-membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 ^R4 represents a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to ³ substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents ^which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group ^{, -NR7bR7c} , -SO ₂ R ^7d , -CONR ^7e R ^7f , C _1-6 alkyl (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkenyl (the alkenyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkynyl (the alkynyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkoxy (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 1-6 alkyl and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by ^1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR 11 R 12), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NR 11 R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁶ represents a hydrogen atom or a halogen atom, R ^7b , R ^7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group, when there are plural R ¹¹ or R ¹² , R ^{R 11} or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded. [Item 18] The compound as described in Item 17 or a pharmaceutically acceptable salt thereof, wherein A is CHF. [Item 19] The compound as described in Item 17 or 18 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom. [Item 20] The compound or pharmaceutically acceptable salt thereof according to any one of Items 17 to 19, wherein Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). [Item 21] A compound according to any one of Items 17 to 20, or a pharmaceutically acceptable salt thereof, wherein Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). [Item 22] A compound as described in any one of Items 17 to 21, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ). [Item 23] The compound according to any one of Items 17 to 22, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a halogen atom, a cyano group, -NR ^7b R ^7c , a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a C _1-6 alkoxy group (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 ^1-3 substituents which may be the same or different from the group consisting of 1-2). [Item 24] The compound described in Item 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (3): [Chemical 5] [In the formula, R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R _1-6 alkyl group and -NR 11 R ¹² ), or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 same or different substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R 11 or R ¹² , each R ¹¹ or R ¹² may be the same or different. Herein, when R ¹¹ and R ¹² bonded to the _{same nitrogen atom are both C 1-6} ^alkyl groups, they may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded]. [Item 25] The compound according to Item 24, or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl. [Item 26] The compound according to Item 24 or 25, or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluoro-2-pyridyl. [Item 27] The compound according to any one of Items 24 to 26, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4- to 10-membered divalent non-aromatic heterocyclic group. [Item 28] The compound according to any one of Items 24 to 27, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4- to 6-membered divalent non-aromatic heterocyclic group. [Item 29] The compound according to any one of Items 24 to 28, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is an azetidinyl group or a piperidinyl group. [Item 30] A compound as described in any one of Items 24 to 29, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-6 alkyl group, or a 4-10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 31] A compound as described in any one of Items 24 to 30, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-3 alkyl group, or a 4-6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 32] The compound described in any one of Items 24 to 31, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a methyl group. [Item 33] The compound described in any one of Items 24 to 31, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is an oxacyclobutyl group. [Item 34] The compound described in any one of Items 24 to 33, or a pharmaceutically acceptable salt thereof, wherein R ¹¹ and R ¹² are methyl groups. [Item 35] The compound described in Item 1, or a pharmaceutically acceptable salt thereof, wherein Formula (1) is the following Formula (4): [Chemical 6] [In the formula, R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ); R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group; when there are plural R ¹¹ or R ¹² groups, each R ¹¹ or R ¹² may be the same or different; herein, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group. [Item 36] The compound according to Item 35, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a 4- to 10-membered, divalent, non-aryl heterocyclic group. [Item 37] The compound according to Item 35 or 36, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a 4- to 6-membered, divalent, non-aryl heterocyclic group. [Item 38] The compound according to any one of Items 35 to 37, or a pharmaceutically acceptable salt thereof, wherein ^R4 is an azetidinyl group. [Item 39] A compound as described in any one of Items 35 to 38, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-6 alkyl group, or a 4-10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 40] A compound as described in any one of Items 35 to 39, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-3 alkyl group, or a 4-6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). [Item 41] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 35 to 40, wherein R ⁵ is oxacyclobutyl. [Item 42] The compound or pharmaceutically acceptable salt thereof as described in Item 1, wherein Formula (1) is the following Formula (5): [Chemical 7] [In the formula, A represents CHF or CH ₂ , R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6-10 membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 ^R4 represents a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to ³ substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents ^which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group ^{, -NR7bR7c} , -SO ₂ R ^7d , -CONR ^7e R ^7f , C _1-6 alkyl (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkenyl (the alkenyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkynyl (the alkynyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-3 alkoxy (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 1-6 alkyl and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by ^1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR 11 R 12), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 1-6 alkyl group and -NR 11 ^{R 12} ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), R ⁶ represents a hydrogen atom or a halogen atom, R ^7a , R ^7b , R 7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group) ^, R ⁸ represents a hydrogen atom or a C _{1-6 alkyl group (the alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom and a C 1-6} alkyl group _[43 ] The compound according to Item ⁴² , or ^a pharmaceutically acceptable salt thereof, wherein A ^is _CHF . [ ^{44 ] The compound according to Item 42 or Item 43 , or} a ^{pharmaceutically acceptable salt thereof, wherein R 6 is} a _hydrogen atom. [Item 45] A compound as described in any one of Items 42 to 44, or a pharmaceutically acceptable salt thereof, wherein Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). [Item 46] A compound as described in any one of Items 42 to 45, or a pharmaceutically acceptable salt thereof, wherein Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ). [Item 47] A compound as described in any one of items 42 to 46, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group). [Item 48] The compound according to any one of items 42 to 47, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a hydroxyl group, a cyano group, a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12). _1-6 alkyl (the alkyl group may be substituted with ¹ to 3 substituents which are the same or different and are selected from the group consisting of halogen atoms and C _1-6 alkyl groups). [Item ⁴⁹ ] The compound as described in any one of Items 42 to 48, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a C _1-6 alkyl group. [Item 50] The compound as described in any one of Items 42 to 49, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a methyl group. [Item 51] The compound as described in Item 1, or a pharmaceutically acceptable salt thereof, wherein Formula (1) is the following Formula (6): [Chemical 8] [In the formula, R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a hydroxyl group, a cyano group, a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C a _3-10 membered alicyclic group (the alicyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R ¹¹ or R ¹² , each R ¹¹ or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² are bonded to the same nitrogen atom, they are both C [Item 52] The compound as described in Item ₅₁ or a pharmaceutically acceptable salt thereof, wherein R 3 is 4-fluorophenyl. [Item 53] The compound as described in Item 51 or 52 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluoro-2-pyridyl. [Item 54] The compound as described in any one of Items 51 to 53 or a pharmaceutically acceptable salt thereof, wherein R ^{4 is} a single bond, or a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkylene group). [Item 55] The compound according to any one of Items 51 to 54, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a single bond. [Item 56] The compound according to any one of Items 51 to 54, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a _C1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a _C1-6 alkyl group). [Item 57] The compound according to any one of Items 51 to 56, or a pharmaceutically acceptable salt thereof, wherein ^R5 is a hydroxyl group, a cyano _C1-6 alkyl group, a _C3-10 alicyclic group, or a 4-10 membered non-aromatic heterocyclic group. [Item 58] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 51 to 57, wherein R ⁵ is methyl. [Item 59] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 51 to 57, wherein R ⁵ is oxacyclobutyl. [Item 60] The compound or pharmaceutically acceptable salt thereof as described in Item 1, wherein Formula (1) is the following Formula (7): [Chemical 9] [In the formula, R ³ represents a 4-fluorophenyl group or a 4-fluoro-2-pyridyl group, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a cyano group, a C _{1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C 1-6 alkyl} group, a hydroxyl group, and -NR ¹¹ R _1-6 alkyl group and -NR 11 R ¹² ), or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 same or different substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R 11 or R ¹² , each R ¹¹ or R ¹² may be the same or different. Herein, when R ¹¹ and R ¹² bonded to the _{same nitrogen atom are both C 1-6} ^alkyl groups, they may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded]. [Item 61] The compound as described in Item 60, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond or a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkylene group). [Item 62] The compound as described in Item 60 or 61, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond. [Item 63] The compound as described in any one of Items 60 to 62, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkylene group). [Item 64] The compound according to any one of Items 60 to 63, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-6 alkyl group or a cyano group. [Item 65] The compound according to any one of Items 60 to 64, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a methyl group. [Item 66] The compound according to any one of Items 60 to 64, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a cyano group. [Item 67] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein Formula (1) is the following Formula (8): [Chemical 10] [In the formula, A represents CHF or CH ₂ , R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6-10 membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 ^R4 represents a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to ³ substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents ^which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group ^{, -NR7bR7c} , -SO ₂ R ^7d , -CONR ^7e R ^7f , C _1-6 alkyl (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkenyl (the alkenyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkynyl (the alkynyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-3 alkoxy (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 1-6 alkyl and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by ^1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR 11 R 12), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C 1-6 alkyl group, and -NR 11 R ¹² ), R ⁶ represents a hydrogen atom or a halogen atom, R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ^9a and R ^9b each independently represent a hydrogen atom, a halogen atom, or a C [Item ₆₈ ] The compound according to Item ⁶⁷ , or ^a pharmaceutically acceptable salt thereof, wherein A is _CHF . [Item ^{69 ]} The compound according to Item ⁶⁷ or Item ₆₈ , or a ^{pharmaceutically acceptable salt thereof, wherein R 6 is a hydrogen} _atom . [Item 70] A compound as described in any one of Items 67 to 69, or a pharmaceutically acceptable salt thereof, wherein Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). [Item 71] A compound as described in any one of Items 67 to 70, or a pharmaceutically acceptable salt thereof, wherein Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ). [Item 72] A compound as described in any one of items 67 to 71, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ). [Item 73] The compound according to any one of Items 67 to 72, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a cyano group, -NR ^7b R ^7c , a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 ). ¹² , which are substituted with 1 to 3 substituents which are the same or different from the group consisting of 1 and 2). [Item 74] The compound according to any one of Items 67 to 73, or a pharmaceutically acceptable salt thereof, wherein R ^9a and R ^9b are fluorine atoms. [Item 75] The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein Formula (1) is the following Formula (9): [Chemical 11] [In the formula, R ³ represents a 4-fluorophenyl group or a 4-fluoro-2-pyridyl group, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkenyl group, a C _1-6 alkynyl group, or a 4-10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 ^[ Item ⁷⁶ ] The compound according to Item ⁷⁵ or a pharmaceutically acceptable salt thereof, wherein R ³ is _4- fluorophenyl. [Item ₇₇ ] The compound according to Item ⁷⁵ or ⁷⁶ or a ^{pharmaceutically acceptable salt thereof, wherein R 3 is 4 -} fluoro-2 ^- pyridyl. [Item 78] The compound according to any one of Items 75 to 77, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a 4- to 10-membered divalent non-aryl heterocyclic group. [Item 79] The compound according to any one of Items 75 to 78, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a 4- to 6-membered divalent non-aryl heterocyclic group. [Item 80] The compound according to any one of Items 75 to 79, or a pharmaceutically acceptable salt thereof, wherein ^R4 is an azetidinyl group. [Item 81] The compound according to any one of Items 75 to 80, or a pharmaceutically acceptable salt thereof, wherein ^R5 is a 4- to 10-membered non-aryl heterocyclic group. [Item 82] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 75 to 81, wherein R ⁵ is a 4- to 6-membered non-aryl heterocyclic group. [Item 83] The compound or pharmaceutically acceptable salt thereof as described in any one of Items 75 to 82, wherein R ⁵ is an oxacyclobutyl group. [Item 84] The compound or pharmaceutically acceptable salt thereof as described in Item 1, wherein Formula (1) is the following Formula (10): [Chemical 12] [In the formula, R ³ represents a 4-fluorophenyl group or a 4-fluoro-2-pyridyl group, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkenyl group, a C _1-6 alkynyl group, or a 4-10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural ^{R 11 or R 12, R 11 or R 12 may be the same or different. Here, when R 11 and R 12 bonded to} the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded]. [Item 85] The compound according to Item 84 or a pharmaceutically acceptable salt ^thereof , wherein R ⁴ is a 4-10 membered divalent non-aryl heterocyclic group. [Item 86] The compound according to Item 84 or 85, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a 4- to 6-membered divalent non-aryl heterocyclic group. [Item 87] The compound according to any one of Items 84 to 86, or a pharmaceutically acceptable salt thereof, wherein ^R4 is an azetidinyl group. [Item 88] The compound according to any one of Items 84 to 87, or a pharmaceutically acceptable salt thereof, wherein ^R5 is a 4- to 10-membered non-aryl heterocyclic group. [Item 89] The compound according to any one of Items 84 to 88, or a pharmaceutically acceptable salt thereof, wherein ^R5 is a 4- to 6-membered non-aryl heterocyclic group. [Item 90] The compound as described in any one of items 84 to 89 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is an oxacyclobutyl group. [Item 91] The compound as described in item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxacyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxacyclobutane-3-yl]acetamide (Example 1), 2-[(1'S)-5'-{1-[(3-fluoro-1-methylazetidin-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxacyclobutane-3-yl]acetamide (Example 2), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide (Example 3), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-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-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]acetamide (Example 5), N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide (Example 6), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide (Example 7), N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-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-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]acetamide (Example 9), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 10), 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 11), N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 12), 2-{(1'S)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 13), 2-[(1'S,3'R)-3'-fluoro-5'-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrrolidone-3-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxacyclobutane-3-yl]acetamide (Example 14), 2-[(1'S,3'R)-3'-fluoro-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 15), 2-[(1'S)-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 16), 2-[(1'S,3'R)-3'-fluoro-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 17), 2-[(1'S)-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 18), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(trifluoromethyl)-4-pyrazol-1H-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 19), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 20), N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 21), 2-[(1'S,3'R)-5'-(1-{[3-(dimethylamino)oxacyclobutane-3-yl]methyl}-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxacyclobutane-3-yl]acetamide (Example 22), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide (Example 23), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxocyclobutane-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 24), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxocyclobutane-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 25), 2-{(1'S,3'R)-5'-[1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 26), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 27), 2-[(1'R,3'S)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 28), 2-[(1'S,3'R)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 29), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 30), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 31), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 32), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 33), 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 34), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide (Example 35). [Item 92] The compound as described in Item 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide (Example 7), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 10), 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 20), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide (Example 23), 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxocyclobutane-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 24), 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxocyclobutane-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 25), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 30), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 31), 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 32), 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propan-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 33), 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide (Example 34). [Item 93] A medicament comprising a compound as described in any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. [Item 94] A pharmaceutical composition comprising a compound as described in any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof. [Item 95] A therapeutic and/or preventive agent for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease, which contains a compound as described in any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. [Item 96] A therapeutic and/or preventive agent for cancer, which contains a compound as described in any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. [Item 97] The therapeutic and/or preventive agent as described in Item 95 or 96, wherein the above-mentioned cancer is at least one cancer selected from the group consisting of SMARC-deficient cancer, SS18-SSX fusion cancer, and ARID-deficient cancer. [Item 98] The therapeutic agent and/or preventive agent as recited in any one of items 95 to 97, wherein the cancer is selected from malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid/rhabdoid tumor, neurotheliomas, chordoid meningiomas, neuroepithelial tumors, neurogliomas, craniopharyngiomas, neuroglioblastomas, chordoma, Myoepithelioma, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basal cell carcinoma of the nasal sinuses, esophageal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumor, undifferentiated rhabdomyosarcoma of the pancreas, gastrointestinal rhabdomyosarcoma, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumor of the vulva Tumor, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung carcinoma, pulmonary neuroendocrine tumor, esophagogastric junction cancer, gastric cancer, bladder cancer, squamous cell lung carcinoma, pancreatic cancer, medulloblastoma, clear cell kidney carcinoma, liver cancer, pleomorphic lung carcinoma, thoracic sarcoma, small cell ovarian carcinoma, primary gallbladder tumor, uterine sarcoma, ovarian granuloma At least one cancer selected from the group consisting of: hematoma, adrenocortical carcinoma, small cell lung cancer, ovarian cancer, corpus uteri cancer, neuroblastoma, ovarian mucinous tumor, sinus cancer, thoracic sarcoma, gallbladder cancer, pediatric neuroblastoma, melanoma, breast cancer, unclassified round cell sarcoma, rhabdomyosarcoma, and Evan's sarcoma. [Item 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 a therapeutically or prophylactically effective amount of a compound as described in any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof. [Item 100] Use of a compound as described in any one of Items 1 to 92, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic or preventive drug for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease. [Item 101] Use of a compound as described in any one of Items 1 to 92, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease. [Item 102] A compound as described in any one of Items 1 to 92, or a pharmaceutically acceptable salt thereof, for use 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 hormonal therapy agents, chemotherapy agents, immunotherapy agents, and agents that inhibit the action of cell growth factors and their receptors. [Item 103] A pharmaceutical composition comprising a compound according to any one of Items 1 to 92 or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is at least one selected from the group consisting of hormonal therapy agents, chemotherapy agents, immunotherapy agents, and agents that inhibit the action of cell growth factors and their receptors. [Effects of the Invention]

According to the present invention, a CBP/P300 inhibitor comprising a quaternary carbon-substituted tertiary amide derivative and a pharmaceutically acceptable salt thereof is provided. The present invention provides a drug that inhibits the function of CBP/P300 and is applicable to a wide range of diseases and administration methods. Furthermore, the present invention provides a quaternary carbon-substituted tertiary amide derivative, i.e., a compound represented by formula (1), which can be used as such a drug, and related drugs.

The compounds of the present invention exhibit excellent CBP/P300 inhibitory activity and can be used as therapeutic agents for CBP/P300-related diseases. Specifically, they can be applied to patients with cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic diseases.

The present invention is described in further detail below. Throughout this specification, unless otherwise specified, expressions in the singular form should be understood to include the concept of the plural form. Therefore, unless otherwise specified, articles in the singular form (for example, "a", "an", "the", etc. in English) should be understood to include the concept of the plural form. In addition, unless otherwise specified, the terms used in this specification should be understood to be used in the meaning commonly used in the field. Therefore, unless otherwise defined, all professional terms and scientific and technical terms used in this specification have the same meaning as commonly understood by practitioners in the field to which the present invention belongs. In the event of a conflict, this specification (including definitions) takes precedence.

The following is an explanation of the terms used in this manual.

In this specification, the number of substituents in a group defined as "substitutable" is not particularly limited, as long as the group is capable of substitution. When the number of substituents is specified and the term "substituted with" that number of substituents is used, substitution with that number is indicated. For example, "substituted with 2 to 5 substituents" means substitution with 2, 3, 4, or 5 substituents. Furthermore, unless otherwise specified, the description of each group also applies to cases where the group is part of another group or a substituent.

The "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom.

"C _1-6 alkyl" refers to a linear or branched saturated alkyl group having 1 to 6 carbon atoms, and "C ₆ alkyl" refers to an alkyl group having 6 carbon atoms. The same applies to other numbers. Preferred examples of the C _1-6 alkyl group include "C _1-4 alkyl" and more preferred examples include "C _1-3 alkyl." Specific examples of "C _1-3 alkyl" include methyl, ethyl, propyl, and 1-methylethyl. Specific examples of "C _1-4 alkyl" include, in addition to those listed above as specific examples of "C _1-3 alkyl," butyl, 1,1-dimethylethyl, 1-methylpropyl, and 2-methylpropyl. Specific examples of the "C _1-6 alkyl group" include, in addition to those listed as specific examples of the "C _1-4 alkyl group", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and hexyl.

" _C2-6 alkenyl" refers to a linear or branched unsaturated alkyl group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. Preferred examples of " _C2-6 alkenyl" include " _C2-4 alkenyl." Specific examples of " _C2-4 alkenyl" include ethenyl, propenyl, methpropenyl, and butenyl. Specific examples of " _C2-6 alkenyl" include, in addition to those listed above as specific examples of " _C2-4 alkenyl," pentenyl and hexenyl.

" _C2-6 alkynyl" refers to a straight or branched unsaturated alkyl group having 2 to 6 carbon atoms and containing one triple bond. Preferred examples of the " _C2-6 alkynyl" group include " _C2-4 alkynyl." Specific examples of the " _C2-4 alkynyl" group include propynyl, methylpropynyl, and butynyl. Specific examples of the " _C2-6 alkynyl" group include, in addition to those listed above as specific examples of the " _C2-4 alkynyl" group, methylbutynyl, pentynyl, and hexynyl.

"C _1-6 alkoxy" refers to a "C _1-6 alkyloxy group," and the "C _1-6 alkyl" portion has the same meaning as the "C _1-6 alkyl" group described above. Preferred examples of the "C _1-6 alkoxy" group include a "C _1-4 alkoxy group," and more preferred examples include a "C _1-3 alkoxy group." Specific examples of the "C _1-3 alkoxy" group include a methoxy group, an ethoxy group, a propoxy group, and a 1-methylethoxy group. Specific examples of the "C _1-4 alkoxy" group include, in addition to those listed above as specific examples of the "C _1-3 alkyl" group, a butoxy group, a 1,1-dimethylethoxy group, a 1-methylpropoxy group, and a 2-methylpropoxy group. Specific examples of the "C _1-6 alkoxy group" include, in addition to those listed as specific examples of the "C _1-4 alkyl group", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, and hexyloxy.

The "C _1-6 alkyl" portion of a "C _1-6 alkylthio" group has the same meaning as the "C _1-6 alkyl" group described above. Preferred examples of the "C _1-6 alkylthio" group include a "C _1-4 alkylthio" group, and more preferred examples include a "C _1-3 alkylthio" group. Specific examples of the "C _1-3 alkylthio" group include a methylthio group, an ethylthio group, a propylthio group, and a 1-methylethylthio group. Specific examples of the "C _1-4 alkylthio" group include, in addition to those listed above as specific examples of the "C _1-3 alkylthio" group, a butylthio group, a 1,1-dimethylethylthio group, a 1-methylpropylthio group, and a 2-methylpropylthio group. Specific examples of the "C _1-6 alkylthio group" include, in addition to those exemplified as specific examples of the "C _1-4 alkylthio group" above, pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylbutylthio, 2-methylbutylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, and hexylthio.

"C _1-6 alkylene" refers to a linear or branched divalent saturated alkyl group having 1 to 6 carbon atoms. Preferred examples of "C _1-6 alkylene" include "C _1-4 alkylene," and more preferred examples include "C _1-3 alkylene." Specific examples of "C _1-3 alkylene" include methylene, ethylene, propylene, and trimethylene. Specific examples of "C _1-4 alkylene," in addition to those listed above as specific examples of "C _1-3 alkylene," include butylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1-methyltrimethylene, and 2-methyltrimethylene. Specific examples of the "C _1-6 alkylene group" include, in addition to those listed as specific examples of the "C _1-4 alkylene group", pentylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 1-methylbutylene, 2-methylbutylene, 1-methylpentylene, 2-methylpentylene, 3-methylpentylene, and hexylene.

" _C2-6 alkenylene" refers to a straight or branched divalent unsaturated alkyl group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. A preferred example of a " _C2-6 alkenylene" is a " _C2-4 alkenylene." Specific examples of " _C2-4 alkenylene" include vinylene, vinylene, propenylene, methylpropenylene, and butenylene. Specific examples of " _C2-6 alkenyl" include, in addition to those listed above as specific examples of " _C2-4 alkenyl," pentenylene and hexenylene.

A "C _3-10 alicyclic group" refers to a cyclic saturated alkyl group having 3 to 10 carbon atoms, including those having some unsaturated bonds and cross-linked structures. Preferred examples of the "C _3-10 alicyclic group" include a "C _3-7 alicyclic group." Specific examples of the "C _3-7 alicyclic group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Specific examples of the "C _3-10 alicyclic group" include, in addition to those listed above as specific examples of the "C _3-7 alicyclic group," cyclooctyl, cyclononyl, cyclodecyl, and adamantyl.

Furthermore, "C _3-10 alicyclic group" also includes a bicyclic group formed by condensing the aforementioned C _3-10 alicyclic group with an aromatic hydrocarbon ring. Specific examples of such condensed compounds include the structures shown below. [Chemistry 13]

As specific examples of the cross-linked structure, for example, the following structures can be cited. [Chemistry 14]

" _C3-10 cyclolene alkyl" refers to a cyclic, divalent, saturated alkyl group having 3 to 10 carbon atoms, including those having some unsaturated bonds and cross-linked structures. Preferred examples of " _C3-10 cyclolene alkyl" include " _C3-7 cyclolene alkyl." Specific examples of " _C3-7 cyclolene alkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Specific examples of the "C _3-10 cyclolene alkyl group" include, in addition to those exemplified as the specific examples of the "C _3-7 cyclolene alkyl group", a cyclolene octyl group, a cyclolene nonyl group, a cyclohexyl group, an adamantyl group and the like.

As specific examples of the cross-linked structure, for example, the following structures can be cited. [Chemistry 15]

"C _3-10 cycloalkenylene" refers to a cyclic, divalent unsaturated alkyl group having 3 to 10 carbon atoms, including cross-linked structures. Specific examples of "C _3-10 cycloalkenylene" include cyclobutenylene, cyclopentenylene, and cyclohexenylene.

"3- to 10-membered saturated carbon ring" refers to a cyclic saturated hydrocarbon having 3 to 10 carbon atoms. Preferred examples of the "3- to 10-membered saturated carbon ring" include "4- to 6-membered saturated carbon ring." Specific examples of the "4- to 6-membered saturated carbon ring" include cyclobutane, cyclopentane, and cyclohexane. Specific examples of the "3- to 10-membered saturated carbon ring" include, in addition to those listed above as specific examples of the "4- to 6-membered saturated carbon ring," cyclopropane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.

A "4- to 10-membered non-aryl heterocyclic group" refers to a monovalent non-aryl heterocyclic group comprising 1-2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and 2-9 carbon atoms. These groups also include those partially containing unsaturated bonds and cross-linked structures. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO ₂ -. Preferred examples of the "4- to 10-membered non-aryl heterocyclic group" include "4- to 6-membered non-aryl heterocyclic groups." Specific examples of the "4- or 5-membered non-aromatic heterocyclic group" include oxacyclobutyl, azacyclobutyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, piperidinyl, oxolinyl, thiooxolinyl, dioxothiooxolinyl, tetrahydropyranyl, and the like. Examples of the "4- to 10-membered non-aryl heterocyclic group" include, in addition to the specific examples of the "4- to 6-membered monocyclic non-aryl heterocyclic group," azacycloheptanyl and the like. In this specification, "azetidinyl" and the like refer to divalent groups such as "oxacyclobutyl."

Furthermore, the term "4- to 10-membered non-aromatic heterocyclic group" also includes bicyclic groups formed by forming a condensed ring group with a 4- to 10-membered non-aromatic heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. Examples of the 6-membered aromatic hydrocarbon ring forming the condensed ring group include a benzene ring. Examples of the 6-membered aromatic heterocyclic ring forming the condensed ring include pyridine, pyrimidine, and pyridine. Specific examples of the bicyclic "4- to 10-membered non-aromatic heterocyclic group" forming a condensed cyclic group include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxetyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and tetrahydrooxidinyl.

A "4- to 10-membered divalent non-aryl heterocyclic group" refers to a divalent non-aryl heterocyclic group comprising 1-2 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, and 2-9 carbon atoms. These groups also include those partially containing unsaturated bonds and cross-linked structures. The atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO ₂ -. Preferred examples of the "4- to 10-membered divalent non-aryl heterocyclic group" include "4- to 6-membered divalent non-aryl heterocyclic groups." Specific examples of the "4- to 6-membered divalent non-aromatic heterocyclic group" include azetidinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, piperidinyl, oxalinyl, thiooxalinyl, dioxaloxalinyl, hexamethyleneimino, oxazolidinyl, thiazolidinyl, oxalicylidinyl, dioxalicylidinyl, oxalicylidinyl, dioxalicylidinyl, dioxalicylidinyl, tetrahydrofuranyl, and tetrahydropyranyl. Examples of the "4- to 10-membered divalent non-aryl heterocyclic group" include, in addition to the specific examples of the "4- to 6-membered divalent non-aryl heterocyclic group", an azoheterocycloheptyl group and the like.

Furthermore, the term "4- to 10-membered divalent non-aromatic heterocyclic group" also includes bicyclic groups formed by forming a condensed ring group with a 4- to 10-membered divalent non-aromatic heterocyclic group or a 6-membered aromatic heterocyclic group. Examples of the 6-membered aromatic heterocyclic group forming the condensed ring group include a benzene ring. Examples of the 6-membered aromatic heterocyclic group forming the condensed ring group include pyridine, pyrimidine, and pyrimidine. Specific examples of the bicyclic "4- to 10-membered divalent non-aromatic heterocyclic group" forming a condensed cyclic group include a dihydroindolinyl group, a dihydroisindolinyl group, a dihydropurinyl group, a dihydrothiazolopyrimidinyl group, a dihydrobenzodioxane group, an isoindolinyl group, an indazolyl group, a tetrahydroquinolinyl group, a tetrahydroisquinolinyl group, and a tetrahydrooxidinyl group.

"C _6-10 aryl" refers to an aromatic alkyl group having 6 to 10 carbon atoms. Specific examples of "C _6-10 aryl" include phenyl, 1-naphthyl, and 2-naphthyl. Phenyl is preferred.

Furthermore, "C _6-10 aryl" also includes a bicyclic group formed by forming a condensed ring group with the above-mentioned C _6-10 aryl group and a C _4-6 alicyclic group or a 5-6-membered non-aryl heterocyclic ring. Specific examples of the bicyclic "C _6-10 aryl" forming a condensed ring group include the following groups. [Chemistry 16]

The "aromatic hydrocarbon ring" means the ring portion of the above-mentioned "C _6-10 aryl group".

"5- to 10-membered heteroaryl" refers to a monocyclic 5- to 7-membered aromatic heterocyclic group or a bicyclic 8- to 10-membered aromatic heterocyclic group containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. A "5- to 7-membered monocyclic heteroaryl" is preferred. A pyridyl, pyrimidinyl, quinolyl, or isoquinolyl group is more preferred. A pyridyl group is even more preferred. Specific examples of the "5- to 7-membered monocyclic heteroaryl group" include pyridyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, triazolyl, triazolyl, oxadiazolyl, triazolyl, and tetrazolyl. Specific examples of the "5- to 12-membered heteroaryl group" include, in addition to those listed as specific examples of the "5- to 7-membered monocyclic heteroaryl group", indolyl, indazolyl, benzopyranyl, quinolyl, isoquinolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, and benzimidazolyl.

The "aromatic heterocyclic ring" refers to the ring portion of the above-mentioned "5- to 12-membered heteroaryl group".

"3-10-membered cycloalkanes" refer to saturated cyclic hydrocarbons with 3-10 carbon atoms, including those with unsaturated bonds and cross-linked structures. A portion of the ring may be condensed to form another ring. Specific examples of "3-10-membered cycloalkanes" include cyclobutane, cyclopentane, cyclohexane, and cycloheptane.

"A 6- to 10-membered aromatic hydrocarbon ring" refers to a cyclic aromatic hydrocarbon with 6 to 10 carbon atoms, wherein a portion of the ring may be condensed to form another ring. Specific examples of "a 6- to 10-membered aromatic hydrocarbon ring" include benzene and naphthalene.

"5- to 10-membered aromatic heterocycle" refers to a monocyclic 4- to 7-membered aromatic heterocycle or a bicyclic 8- to 12-membered aromatic heterocycle containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. A portion of the ring may be condensed to form another ring. Preferred examples include "5- to 6-membered aromatic heterocycle," "5-membered aromatic heterocycle," and "6-membered aromatic heterocycle." Specific examples of "5- to 6-membered aromatic heterocycle" include furan, thiophene, oxazole, pyrazole, pyridine, pyrilium, pyrimidine, and pyrimidine. Specific examples of the "five-membered aromatic heterocyclic ring" include pyrazole, furan, thiophene, and oxazole. Specific examples of the "six-membered aromatic heterocyclic ring" include pyridine, pyrilamide, pyrimidine, and pyrimidine.

"6- to 10-membered divalent aromatic alkyl cyclic group" refers to a monocyclic or bicyclic divalent aromatic alkyl cyclic group having 6 to 10 carbon atoms. A preferred example of the "6- to 10-membered divalent aromatic alkyl cyclic group" is a "6-membered divalent aromatic alkyl cyclic group." Specific examples of the "6- to 10-membered divalent aromatic alkyl cyclic group" and the "6-membered divalent aromatic alkyl cyclic group" include a divalent benzene ring.

A "5- to 10-membered divalent aromatic heterocyclic group" refers to a monocyclic divalent 5- to 7-membered aromatic heterocyclic group, or a bicyclic divalent 8- to 10-membered aromatic heterocyclic group, containing 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Preferred examples include "5- to 6-membered divalent aromatic heterocyclic groups," and more preferred examples include "5-membered divalent aromatic heterocyclic groups." Specific examples of "5-membered divalent aromatic heterocyclic groups" include divalent pyrazole, divalent furan, divalent thiophene, and divalent oxazole. Examples of the "5- to 10-membered divalent aromatic heterocyclic group" and the "5- to 6-membered divalent aromatic heterocyclic group" include, in addition to the specific examples of the "5-membered divalent aromatic heterocyclic group" mentioned above, divalent pyridine, divalent pyrimidine, divalent pyrilium, and divalent indole.

"Cancer" means a malignant tumor, including carcinoma, sarcoma and hematological malignancy. Specific examples of "cancer" include: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, gallbladder cholangiocarcinoma, bladder cancer, Brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, choriocarcinoma, villous epithelial carcinoma, urothelial carcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia, colorectal cancer, cystic adenocarcinoma, diffuse large B-cell lymphoma, abnormal proliferation function (proliferation malformations and developmental abnormalities), embryonal carcinoma, uterine carcinoma, epithelial sarcoma, ependymoma, epithelial carcinoma, erythroblastic leukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, neuroglioma, neuroglioblastoma, neurogliosarcoma, Heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphangioendothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, lymphocytic 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, oligodendroglial carcinoma Neurocytoma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary cancer, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, spermatoma, skin cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial sarcoma, Sweat gland carcinoma, thyroid carcinoma, Waldenstrom's macroglobulinemia, testicular tumor, uterine cancer, Wilms' tumor, malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid/rhabdoid tumor, neurotheliomas, chordoid meningiomas, neuroepithelial tumors, neurogliomas, craniopharyngiomas, neuroglioblastomas, chordomas, myoepithelioma, extraosseous myxoma Fluid-like chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basal cell carcinoma of the nasal sinuses, esophageal adenocarcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumor, undifferentiated rhabdomyosarcoma of the pancreas, gastrointestinal rhabdomyosarcoma, renal medullary carcinoma, endometrial carcinoma, myoepithelioma-like tumor of the female vulva, colorectal cancer, and mesothelioma, etc.

In this invention, "CBP" and "P300" are both histone acetyltransferases involved in chromatin control and are paralogs. "CBP/P300" refers to both CBP and P300. Histone acetyltransferases are enzymes that primarily, but not exclusively, transfer acetyl groups to lysine residues present in the amino-terminal tails of histones. CBP and P300 primarily, but not exclusively, acetylate histones H2A, H2B, H3, and H4. In particular, regarding histone H3, acetylation is primarily, but not limited to, lysine 18, lysine 27, lysine 56, and lysine 122 (H3K18, H3K27, H3K56, and H3K122, respectively). Among them, acetylation of histone H3K27 is known to be a mark of open chromatin and plays an important role in regulating gene expression (J Hum Genet. 2013 Jul; 58 (7): 439-45). As substrates other than tissue proteins, 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) have been reported. In this specification, when "CBP" and "P300" are used, they generally refer to proteins, but depending on the circumstances, they may also refer to nucleic acids encoding them or genes as a concept. The industry can understand the meaning appropriately according to the context.

Key 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). HAT domains are primarily, but not exclusively, domains that have the activity of transferring acetyl groups to lysine residues present in the amino-terminal tails of tissue proteins. Bromodomains are protein domains that primarily, but not exclusively, recognize N-acetylated lysine residues observed in the amino-terminal tails of tissue proteins.

The term "CBP" as used herein, unless otherwise specified, refers to any naturally occurring CBP from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). This term encompasses unprocessed CBP and any form of CBP produced by processing in cells. The term also encompasses naturally occurring variants of CBP, such as splice variants or allelic variants. Human CBP is accessioned as UniProt Accession Number: Q92793. Representative amino acid sequences of human CBP are represented by UniProt Q92793-1 (SEQ ID NO: 1) or UniProt Q92793-2 (SEQ ID NO: 2).

The term "P300" used in this specification, unless otherwise specified, refers to any naturally occurring P300 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). This term encompasses unprocessed P300 and any form of P300 produced by processing in cells. The term also encompasses naturally occurring variants of P300, such as splice variants and allelic variants. Human P300 is accessioned as UniProt Accession Number: Q09472. The representative amino acid sequence of human P300 is represented by UniProt Q09472-1 (SEQ ID NO: 3).

"CBP/P300 inhibitors" are substances that inactivate, reduce the activity, and/or decrease the expression of CBP and/or P300. "Reduction of CBP/P300 expression" can also mean that the inhibitory effect occurs at any level, including the pre-transcriptional level (e.g., genomic level), the transcriptional level, the post-transcriptional regulatory level, the translational level, or the post-translational modification level. Preferred "CBP/P300 inhibitors" are HAT inhibitors and BRD inhibitors, with HAT inhibitors being more preferred.

"HAT inhibitors" are compounds that inhibit the histone acetyltransferase (HAT) activity of CBP and/or P300. When detecting the activity of histone acetyltransferase, for example, the following methods can be used: a method of detecting CoA-SH produced as a by-product during the histone acetyltransferase reaction using fluorescence (e.g., Gao T. et al. Methods Mol Biol. 2013; 981: 229-38); a method of detecting using radioisotopes (e.g., Lau OD et al. J Biol Chem. 2000; 275 (29): 21953-9); a method of detecting acetylated histone peptides by the TR-FRET method (e.g., PerkinElmer, LANCE Ultra products or AlphaLISA products); and a method of detecting using NADH (e.g., Berndsen et al. Methods. 2005; 36 (4): 321-31). 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.

"BRD inhibitors" are compounds that inhibit the function of the bromodomain (BRD) of CBP and/or P300. To detect the function of the bromodomain, for example, a method for detecting the binding of the bromodomain to an acetyl lysine residue by TR-FRET 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.

Histone acetyltransferase (HAT) activity is an enzymatic activity that transfers an acetyl group to a lysine residue in a substrate protein. Examples of such substrates include histones and p53.

Bromodomains are protein domains that recognize N-acetylated lysine residues. N-acetylated lysine residues are observed, for example, on the amino-terminal tails of histone proteins.

In the compounds of the present invention represented by formula (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10), preferred examples of A, B, ^R1 , ^R2a , ^R2b , ^R3 , ^R4 , ^R5 , ^R6 , ^R7a , ^R7b , ^R7c , ^R7d , ^R7e , ^R7f , R8, ^R9a , ^R9b , ^a , b, ring Q and Z are described below. However, the technical scope of the present invention is not limited to the compounds exemplified below.

Preferred examples of A include CHF and CH ₂ .

As a better example of A, CHF can be cited.

Another more preferred embodiment of A includes CH ₂ .

As a preferred embodiment of B, the following formula (B-1) can be cited. [Chemical 17] [Wherein, * represents the bonding position with the nitrogen atom of the hydantoin ring] More preferred embodiments of B include the following formulas (B-2), (B-3), or (B-4). [Chemical 18] [Where * represents the bonding position with the nitrogen atom of the hydantoin ring]

Preferred embodiments of R ¹ include C _1-6 alkyl groups or C _3-10 alicyclic groups (the alkyl group or alicyclic group may be substituted with 1 to 3 halogen atoms which may be the same or different).

More preferred aspects of R ¹ include: C _1-6 alkyl groups, or C _3-10 alicyclic groups (the alkyl groups or alicyclic groups may be substituted with 1 to 3 fluorine atoms).

A further preferred embodiment of R ¹ includes C _1-3 alkyl which may be substituted with 1 to 3 fluorine groups. A further preferred embodiment of R ¹ includes CF ₃ .

Preferred embodiments of R ^2a and R ^2b include, independently, a C _1-6 alkyl group which may be substituted with 1 to 3 halogen atoms which may be the same or different. Another preferred embodiment of R ^2a and R ^2b includes a case where R ^2a and R ^2b, together with the carbon atom to which they are bound, form a C _3-6 cycloalkylene group or a 4-6 membered divalent non-aryl heterocyclic group (the cycloalkylene group or divalent non-aryl heterocyclic group may be substituted with 1 to 3 halogen atoms which may be the same or different).

As the most preferred embodiment of R ^2a and R ^2b , the following can be cited: R ^2a and R ^2b together with the carbon atom to which they are bound form a C _3-6 cycloalkylene group or a 4-6 membered divalent non-aryl heterocyclic group (the cycloalkylene group or divalent non-aryl heterocyclic group may be substituted with 1-3 fluorine atoms).

Preferred embodiments of R ³ include: a C _6-10 aryl group, a 5-10 membered heteroaryl group, a C _3-10 alicyclic group, or a 4-10 membered non-aryl heterocyclic group (the aryl group, heteroaryl group, alicyclic group, or non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

More preferred aspects of R ³ include: a C _6-10 aryl group (the aryl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 5-10 membered heteroaryl group (the heteroaryl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

Further preferred aspects of R ³ include: a C _6-10 aryl group or a 5-10 membered heteroaryl group (the heteroaryl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a fluorine atom and a C _1-6 alkyl group).

As a further preferred embodiment of R ³ , 4-fluorophenyl, 4-(trifluoromethyl)phenyl or 4-fluoro-2-pyridyl can be exemplified, and 4-fluorophenyl or 4-fluoro-2-pyridyl is more preferred.

As a most preferred embodiment of R ³ , 4-fluorophenyl can be exemplified.

Another preferred embodiment of R ³ includes 4-fluoro-2-pyridyl.

Preferred embodiments of R ⁴ include: a single bond, a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), a C _3-10 cycloalkylene group (the cycloalkylene group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ).

More preferred aspects of R ⁴ include: a single bond, a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ).

Further preferred aspects of R ⁴ include a single bond, a C _1-6 alkylene group, or a 4-6 membered divalent non-aromatic heterocyclic group.

As an example of an improvement over R ⁴ , we can cite the single key.

As a further preferred embodiment of R ⁴ , there can be mentioned C _1-6 alkylene.

As a further preferred embodiment of R ⁴ , there can be mentioned: a 4- to 6-membered divalent non-aromatic heterocyclic group.

As a most preferred embodiment of R ⁴ , azetidinyl can be exemplified.

Another preferred embodiment of R ⁴ includes methylene.

Preferred embodiments of R ⁵ include: a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -NR ^7b R ^7c , -SO ₂ R ^7d or -CONR ^7e R ^7f , a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), a C _1-6 alkenyl group (the alkenyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), a C _{1-6 alkynyl group (the alkynyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C 1-6} alkyl group, a hydroxyl group and -NR ¹¹ R 12 ), a C _1-6 alkyl ... 1-6 alkyl and -NR ¹¹ R ¹² ), a C _1-6 alkoxy group (the alkoxy group may be substituted by ^1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR 11 R 12), a C _3-10 alicyclic group (the alicyclic group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 _1-6 alkyl and -NR 11 R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1-3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C 1-6 alkyl group, and -NR ¹¹ R ¹² ).

More preferred aspects of R ⁵ include: a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ).

Further preferred aspects of R ⁵ include: cyano, C _1-6 alkyl (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), or a 4-6 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ).

As a further preferred embodiment of R ⁵ , there can be mentioned: a C _1-6 alkyl group, or a 4-6 membered non-aromatic heterocyclic group.

As the most preferred embodiment of R ⁵ , there can be mentioned methyl or oxacyclobutyl.

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

As a more preferred embodiment of R ⁶ , a hydrogen atom can be exemplified.

Preferred embodiments of ^R7a , ^R7b , ^R7c , ^R7d , ^R7e , and ^R7f include, independently, a hydrogen atom, or a _C1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a _C1-6 alkyl group).

More preferred embodiments of R ^7a , R ^7b , R ^7c , R ^7d , R ^7e and R ^7f can each independently be exemplified by a hydrogen atom or a methyl group.

Preferred embodiments of R ⁸ include a hydrogen atom, or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

As a more preferred embodiment of R ⁸ , there can be exemplified a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

A further preferred embodiment of R ⁸ includes a methyl group.

Preferred embodiments of R ^9a and R ^9b include, independently, a hydrogen atom, a halogen atom, or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

As more preferred aspects of R ^9a and R ^9b , each independently can be exemplified by a halogen atom.

As a further preferred embodiment of R ^9a and R ^9b , a fluorine atom can be exemplified.

As a preferred embodiment of R ¹⁰ , a C _1-6 alkyl group can be exemplified.

Preferred embodiments of R ¹¹ and R ¹² include, independently, a hydrogen atom or a C _1-6 alkyl group.

Another preferred embodiment of R ¹¹ and R ¹² includes the following: when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they can form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.

As a further preferred embodiment of R ¹¹ and R ¹² , a methyl group can be exemplified.

Preferred embodiments of ring Q include 6- to 10-membered aromatic hydrocarbon rings (the aromatic hydrocarbon rings may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

As a more preferred embodiment of ring Q, a benzene ring (the benzene ring may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group) can be exemplified.

As an example of a more preferred embodiment of ring Q, a benzene ring can be cited.

Preferred embodiments of Z include -O-, a 6- to 10-membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). More preferred aspects of Z include: a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ); or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). A further preferred embodiment of Z includes a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ).

A further preferred embodiment of Z includes a divalent pyrazolyl group.

Preferable examples of a include 0, 1, or 2.

As a better form of a, we can cite: 1, or 2.

As a better example of a, we can cite the following: 1.

As a better example of b, we can cite: 1 or 2.

As a better example of b, we can cite the following: 1.

As a more preferred embodiment of a and b, an embodiment in which both are 1 can be cited.

As one embodiment of the compound represented by formula (1), the following (A) can be cited. (A) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF or CH ₂ , and B is the following formula (B-1): [Chemical 19] [wherein * represents the bonding position to the nitrogen atom of the hydantoin ring], ring Q is a 6-10 membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), Z is -O-, a 6-10 membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 1-6 alkyl and -NR 11 ^{R 12} ), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ¹ is a C _1-3 alkyl group which may be substituted by 1-3 fluorine atoms, R ^2a and R ^2b , together with the carbon atom to which they are bound, form a C _3-6 cycloalkylene group, or a 4-6 membered divalent non-aryl heterocyclic group (the cycloalkylene group or divalent non-aryl heterocyclic group may be substituted by 1-3 fluorine atoms), R ³ is a C _6-10 aryl group (the aryl group may be substituted by a halogen atom and a substituted C ^-NR _{11 R} ^​ _{​ ​ ​ ​ ​} ^1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of -NR 11 R 12), R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -NR ^7b R ^7c , -SO ₂ R ^7d or -CONR ^7e R ^7f , a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), a C _{1-6 alkenyl group (the alkenyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C 1-6} alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), a C _1-6 alkynyl group (the alkynyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, _{a C 1-6 alkyl} group, a hydroxyl group and -NR ¹¹ R 12 1-6 alkyl and -NR ¹¹ R ¹² ), a C _1-6 alkoxy group (the alkoxy group may be substituted by ^1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR 11 R 12), a C _3-10 alicyclic group (the alicyclic group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 1-6 alkyl group and -NR 11 ^{R 12} ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), R ^7b , R ^7c , R ^7d , R ^7e and R ^7f are each independently a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ¹¹ and R ¹² are each independently a hydrogen atom or a C _1-6 alkyl group, when there are plural R 11 or R 12, ^{R 11} or R ¹² are each independently a hydrogen atom or a C 1-6 alkyl group. ¹² may be the same or different. Here, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.

As one embodiment of the compound represented by formula (1), the following (B) can be cited. (B) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF or CH ₂ , and B is the following formula (B-2), (B-3), or (B-4): [Chemical 20] [wherein, * represents the bonding position to the nitrogen atom of the hydantoin ring, a is 0, 1, or 2, b is 1, or 2, R ⁸ is a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ^9a and R ^9b are each independently a hydrogen atom, a halogen atom, or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group)], Ring Q is a 6-10 membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), Z is -O-, a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ¹ is CF ₃ , R ³ is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl, R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and C _{R 5} is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -NR 7b R _7c , -SO 2 R 7d or -CONR 7e R 7f , a C 1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group, which may be the same or different), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), R ⁵ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, -NR ^7b R ^7c , -SO ₂ R ^7d or -CONR ^7e R ^7f , a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR 11 R 12 ^1-6 alkyl, hydroxyl and -NR ^{11 R 12), C 1-6 alkenyl (the alkenyl group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a hydroxyl group and -NR 11 R} _{12 )} ^, C _1-6 alkynyl (the alkynyl group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkoxy (the alkoxy group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), C _3-10 alicyclic group (the alicyclic group may be substituted by 1-3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 R ¹² ), C _6-10 aryl (the aryl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), R ^7b , R ^7c , R ^7d , R ^7e and R ^7f are each independently a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group); R ¹¹ and R ¹² are each independently a hydrogen atom or a C _1-6 alkyl group; when there are plural R ¹¹ or R ¹² groups, each R ¹¹ or R ¹² may be the same or different; herein, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may, together with the nitrogen atom to which they are bonded, form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group.

As one embodiment of the compound represented by formula (2), the following (C) can be exemplified. (C) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF or CH ₂ , R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, Z is a 4- to 10-membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and C R5 is _C1-6 alkyl (the alkyl group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a _C1-6 alkyl group, a hydroxyl group, and ^{-NR11R12 )} , or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and -NR11R12), ^R5 is _C1-6 alkyl (the alkyl group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a _C1-6 alkyl group, a hydroxyl group, and ^-NR11R12 ), or a ^4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of ^a halogen atom, a C1-6 alkyl group, and ^-NR11R12 ), R R ¹¹ and R ^{12 each} independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R ¹¹ or R ¹² groups, each R ¹¹ or R ¹² group may be the same or different. Here, when both R ¹¹ and R ¹² groups bonded to the same nitrogen atom are C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.

As one embodiment of the compound represented by formula (2), the following (D) can be cited. (D) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF, Z is a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and C R5 is _C1-6 alkyl (the alkyl group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a _C1-6 alkyl group, a hydroxyl group, and ^{-NR11R12 )} , or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and -NR11R12), ^R5 is _C1-6 alkyl (the alkyl group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a _C1-6 alkyl group, a hydroxyl group, and ^-NR11R12 ), or a ^4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and are selected from the group consisting of ^a halogen atom, a C1-6 alkyl group, and ^-NR11R12 ), R ^wherein R ¹¹ and R ¹² are each independently a hydrogen atom or a C _1-6 alkyl group. When there are multiple R ¹¹ or R ¹² , each R ¹¹ or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.

As one embodiment of the compound represented by formula (3), the following (E) can be cited. (E) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ is a C 1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a _{C 1-6 alkyl} group, a hydroxyl group, and -NR ¹¹ R 1-6 alkyl groups, and -NR 11 R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1-3 same or different substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² are each independently a hydrogen atom or a C _1-6 alkyl group. When there are plural R 11 or R 12 groups, each R ¹¹ or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² bonded to the _{same nitrogen atom are both C 1-6} ^{alkyl groups} , they may form a 3-8 membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded.

As one embodiment of the compound represented by formula (3), the following (F) can be exemplified. (F) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a 4- to 6-membered divalent non-aryl heterocyclic group, and R ⁵ is a C _1-3 alkyl group or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group).

As one embodiment of the compound represented by formula (3), the following (G) can be exemplified: (G) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is azetidinyl or piperidinyl, and R ⁵ is oxacyclobutyl.

As one embodiment of the compound represented by formula (4), the following (H) can be exemplified: (H) The compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is azetidinyl, and R ⁵ is oxacyclobutyl.

As one embodiment of the compound represented by formula (5), the following (I) can be exemplified. (I) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF or CH ₂ , Z is a 6-10 membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and C _1-6 alkyl), or a C _3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1-3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ⁵ is a hydrogen atom, a hydroxycyano group, a C _1-6 alkyl group (the alkyl group may be substituted by 1-3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by 1-3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 1-6 alkyl, R 11 and R 12 are each independently a hydrogen atom or a C _1-6 alkyl group. When there are plural R ¹¹ or R ¹² , each R 11 or R ¹² may be the same or different. Here, when R 11 and R ¹² are bonded to the same nitrogen atom, ^{both R 11} and R ¹² are ^C _1-6 alkyl, ^{and R 11 and R 12 are each} independently a hydrogen atom or a C _1-6 alkyl group. When the alkyl groups are _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.

As one embodiment of the compound represented by formula (5), the following (J) can be cited. (J) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF, Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond, or a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and C ^R5 is a _hydroxyl group, a cyano group, a _C1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, a hydroxyl group, and ^-NR11R12 ), a _C3-10 alicyclic group (the alicyclic group may be substituted by 1 to ³ substituents which may be the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl ^group , and ^-NR11R12 ), or a ^4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R6 is a hydrogen atom, R ⁸ is a methyl group, R ¹¹ and R ¹² are each independently a hydrogen atom or a C _1-6 alkyl group. When there are multiple R ¹¹ or R ¹² groups, each R ¹¹ or R ¹² group may be the same or different. Here, when R ¹¹ and R ¹² groups bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded.

As one embodiment of the compound represented by formula (6), the following (K) can be exemplified. (K) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond or a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), and R ⁵ is a hydroxyl group, a cyano C _1-6 alkyl group, a C _3-10 alicyclic group, or a 4-10 membered non-aromatic heterocyclic group.

As one embodiment of the compound represented by formula (6), the following (L) can be exemplified. (L) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond or a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), and R ⁵ is a methyl group or an oxacyclobutyl group.

As one embodiment of the compound represented by formula (6), the following (M) can be exemplified: (M) The compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond, and R ⁵ is methyl.

As one embodiment of the compound represented by formula (7), the following (N) can be exemplified: (N) The compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a single bond, and R ⁵ is methyl.

As one embodiment of the compound represented by formula (8), the following (O) can be cited. (O) The following compound or a pharmaceutically acceptable salt thereof, wherein A is CHF or CH ₂ , Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ^R5 is a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1-3 substituents which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R6 is a hydrogen atom or a ^halogen atom, and ^R9a and ^R9b are fluorine atoms.

As one embodiment of the compound represented by formula (9), the following (P) can be exemplified. (P) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a 4- to 6-membered divalent non-aromatic heterocyclic group, and R ⁵ is a 4- to 6-membered non-aromatic heterocyclic group.

As one embodiment of the compound represented by formula (9), the following (Q) can be exemplified: (Q) The compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is azetidinyl, and R ⁵ is oxacyclobutyl.

As one embodiment of the compound represented by formula (10), the following (R) can be exemplified. (R) The following compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is a 4- to 6-membered divalent non-aromatic heterocyclic group, and R ⁵ is a 4- to 6-membered non-aromatic heterocyclic group.

As one embodiment of the compound represented by formula (10), the following (S) can be exemplified: (S) The compound or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ is azetidinyl, and R ⁵ is oxacyclobutyl.

The compounds of the present invention may be administered orally, parenterally, or intrarectally. The daily dosage of the compounds of the present invention varies depending on the type of compound, the method of administration, the patient's symptoms and age, and other factors. For example, for oral administration, approximately 0.01 to 1000 mg, preferably approximately 0.1 to 500 mg, per kg of body weight of a human or mammal can be administered in one or more divided doses. For parenteral administration, such as by intravenous injection, approximately 0.01 to 300 mg, preferably approximately 1 to 100 mg, per kg of body weight of a human or mammal can be administered. Examples of the administration schedule include a single administration, a single administration for three consecutive days, or a double administration for one week. Furthermore, each of the above-described administration methods may be repeated at intervals of approximately 1 to 60 days.

The compounds of the present invention can be administered parenterally or orally, either directly or in a suitable dosage form. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, and dressings. Formulations are prepared using pharmaceutically acceptable additives and known methods. Depending on the intended use, additives may include excipients, disintegrants, binders, plasticizers, lubricants, coating agents, dissolving agents, solubilizers, thickening agents, dispersants, stabilizers, sweeteners, and flavorings. Specifically, for example, lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially alpha-starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc. can be mentioned.

The following describes the production methods of the compounds of the present invention represented by formulas (1) to (10), but the production methods of the compounds of the present invention are not limited thereto. The compounds used in the following production methods may also form salts as long as they do not hinder the reaction.

The compounds of the present invention can be produced using known compounds as starting materials, for example, by the following methods A, B, C, and D, or by suitable combinations thereof or other synthetic methods known to those skilled in the art.

Preparation Method A Compound (1-11) represented by formula (1) wherein A is CHF and Q is a benzene ring can be prepared, for example, by the following preparation method. [Chemical 21] [wherein, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ and Z have the same meanings as in the above-mentioned [Item 1], and R ⁶ has the same meaning as in the above-mentioned [Item 16]].

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

Specific examples of the reducing agent include sodium borohydride, sodium triacetyloxyborohydride, and sodium cyanoborohydride.

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

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

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

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

Specific examples of inert solvents include halides such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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

Step 1-3: Preparation of Compound (1-6) Compound (1-6) is prepared by deprotecting the benzyl group of Compound (1-5). For example, contact reduction using a metal catalyst such as palladium/carbon or palladium hydroxide/carbon in a hydrogen atmosphere can be used.

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

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

Specific examples of the reducing agent include sodium borohydride, sodium triacetyloxyborohydride, and sodium cyanoborohydride.

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

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

Specific examples of inert solvents include halides such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

Specific examples of fluorinating agents include diethylaminosulfur trifluoride and FLUOLEAD ^™ .

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

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

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

Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarbonamide, triphenylphosphine, and tributylphosphine. Cyanomethylenetrimethylphosphane (Takata's reagent) can also be used.

The reaction temperature is not particularly limited and 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.

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

Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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(diphenylphosphino)ferrocene]dichloridepalladium(II).

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

Specific examples of coupling reagents include Z-bound boronic acid and Z-bound boronic acid pinacol.

The reaction temperature is not particularly limited and is generally selected from the range of 0°C to 150°C, preferably 25°C to 100°C. The reaction time is generally 1 hour to 72 hours, preferably 1 hour to 24 hours. Preparation Method B Compound (1-14) represented by formula (1) wherein Q is a benzene ring can also be prepared by the following preparation method. [Chemical 22] [In the formula, A, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , and Z have the same meanings as in the above-mentioned [Item 1]. R ⁶ has the same meaning as in the above-mentioned [Item 16]. W represents a halogen atom]

Step 2-1: Preparation of Compound (2-1) Compound (2-1) is prepared by reacting Compound (1-3) with an amide reagent in an inert solvent.

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

Specific examples of inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea; and pyridine.

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

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

Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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

The reaction temperature is not particularly limited and 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.

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

Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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(diphenylphosphino)ferrocene]dichloridepalladium(II).

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

Specific examples of coupling reagents include Z-bound boronic acid and Z-bound boronic acid pinacol.

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

Preparation Method C Compound (1-14) wherein Q is a benzene ring in the compound represented by formula (1) can also be prepared by the following preparation method. [Chemical 23] [In the formula, A, ^R1 , ^R2a , ^R2b , ^R3 , ^R4 , ^R5 , and Z have the same meanings as in [Item 1] above. ^R6 has the same meaning as in [Item 16] above.]

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

Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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(diphenylphosphino)ferrocene]dichloridepalladium(II).

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

Specific examples of coupling reagents include Z-bound boronic acid and Z-bound boronic acid pinacol.

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

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

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

Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarbonamide, triphenylphosphine, and tributylphosphine. Cyanomethylenetrimethylphosphane (Takata's reagent) can also be used.

The reaction temperature is not particularly limited and 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.

Preparation Method D Compound (1-14) wherein Q is a benzene ring in the compound represented by formula (1) can also be prepared by the following preparation method. [Chemical 24] [In the formula, A, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ , and Z have the same meanings as in the above-mentioned [Item 1]. R ⁶ has the same meaning as in the above-mentioned [Item 16]. W represents a halogen atom]

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

Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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

The reaction temperature is not particularly limited and 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.

Preparation Method E : Compound (1-17) represented by formula (1) wherein A is CH ₂ and Q is a benzene ring can be prepared, for example, by the following preparation method. [Chemical 25] [wherein, R ¹ , R ^2a , R ^2b , R ³ , R ⁴ , R ⁵ and Z have the same meanings as in [Item 1] above, and R ⁶ has the same meaning as in [Item 16] above]

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

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

Examples of Mitsunobu reagents include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), bis(2-methoxyethyl) azodicarboxylate, N,N,N',N'-tetramethylazodicarbonamide, triphenylphosphine, and tributylphosphine. Cyanomethylenetrimethylphosphane (Takata's reagent) can also be used.

The reaction temperature is not particularly limited and 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.

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

Specific examples of inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidone, and N,N-dimethylpropylurea.

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(diphenylphosphino)ferrocene]dichloridepalladium(II).

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

Specific examples of coupling reagents include Z-bound boronic acid and Z-bound boronic acid pinacol.

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

In the production methods described above, starting materials or intermediates for which the production methods are not described can be obtained as commercial products or synthesized from commercially available compounds by methods known to those skilled in the art or in accordance with such methods.

In each reaction of the production method described above, while the use of protecting groups is specifically indicated, protecting groups may be used as needed. For example, if any functional group other than the reactive site is altered under the described reaction conditions, or if the described method is not suitable for carrying out without a protecting group, the functional group other than the reactive site may be protected as needed and then removed after the reaction is completed or after a series of reactions to obtain the target compound.

Protective groups that can be used include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of protecting groups for amino groups include benzyloxycarbonyl, t-butyloxycarbonyl, acetyl, and benzyl groups. Specific examples of protecting groups for hydroxyl groups include trialkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl, acetyl, and benzyl groups.

The introduction and removal of protecting groups can be carried out by methods commonly used in organic synthetic chemistry (e.g., see the aforementioned Protective Groups in Organic Synthesis) or methods therein.

In this specification, protecting groups, condensation agents, etc. are sometimes represented by abbreviations commonly used in the art according to IUPAC-IUB (Institute of Biochemical Nomenclature). Furthermore, the compound names used in this specification do not necessarily follow the IUPAC nomenclature.

Intermediates or target compounds in the production methods described above can also be converted into other compounds included in the present invention by appropriate functional group transformation (e.g., protection and deprotection of the functional groups as needed, and various transformations based on amino groups, hydroxyl groups, carbonyl groups, halogen groups, etc.). Functional group transformations can be carried out by commonly used general methods (e.g., see Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).

The intermediates and target compounds in the production methods described above can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography methods, etc.). Alternatively, the intermediates can be used in the next reaction without further purification.

Protective groups that can be used include those described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999). Specific examples of protecting groups for amino groups include benzyloxycarbonyl, t-butyloxycarbonyl, acetyl, and benzyl groups. Specific examples of protecting groups for hydroxyl groups include trialkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl, acetyl, and benzyl groups.

The introduction and removal of protecting groups can be carried out by methods commonly used in organic synthetic chemistry (e.g., see the aforementioned Protective Groups in Organic Synthesis) or methods therein.

In this specification, protecting groups, condensation agents, etc. are sometimes represented by abbreviations commonly used in the art according to IUPAC-IUB (Institute of Biochemical Nomenclature). Furthermore, the compound names used in this specification do not necessarily follow the IUPAC nomenclature.

Intermediates or target compounds in the production methods described above can also be converted into other compounds included in the present invention by appropriate functional group transformation (e.g., protection and deprotection of the functional groups as needed, and various transformations based on amino groups, hydroxyl groups, carbonyl groups, halogen groups, etc.). Functional group transformations can be carried out by commonly used general methods (e.g., see Comprehensive Organic Transformations, R. C. Larock, John Wiley & Sons Inc. (1999)).

The intermediates and target compounds in the production methods described above can be isolated and purified by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography methods, etc.). Alternatively, the intermediates can be used in the next reaction without further purification.

Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, hydroiodates, nitrates, and phosphates; or organic acid salts such as citrates, oxalates, phthalates, fumarates, cismarates, succinates, malic acids, acetates, formates, propionates, benzoates, trifluoroacetates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, and camphorsulfonates. Examples of base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts; and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. Furthermore, examples of "pharmaceutically acceptable salts" include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamine.

Suitable salts of starting materials and intermediates and salts acceptable as pharmaceutical raw materials are conventional non-toxic salts. Examples of such salts include organic acid salts (e.g., acetate, trifluoroacetate, citric acid salt, fumaric acid salt, citrate, tartaric acid salt, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.) and inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodate, sulfate, nitrate, phosphate, etc.), acid addition salts of amino acids. The industry can appropriately select the salts of arginine, aspartic acid, glutamine, etc., alkali metal salts (such as sodium salts, potassium salts, etc.), alkaline earth metal salts (such as calcium salts, magnesium salts, etc.), ammonium salts, organic alkaline salts (such as trimethylamine salts, triethylamine salts, pyridinium salts, methylpyridinium salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.), etc.

The compounds of the present invention may be substituted with isotopes (e.g., ² H (or D), ³ H (or T), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ³⁵ S, ¹⁸ F, ¹²⁵ I, etc.), and such compounds are also included in the compounds of the present invention.

The present invention includes compounds represented by formulas (1) to (10) or their pharmaceutically acceptable salts. Furthermore, the compounds of the present invention may exist in the form of hydrates and/or solvates with various solvents (e.g., ethanolates), and such hydrates and/or solvates are also included in the compounds of the present invention.

Furthermore, the compounds of the present invention also include all possible isomers, including optical isomers based on optically active centers, configurational isomers based on axial chirality or planar chirality resulting from intramolecular rotational restraint, other stereoisomers, tautomers, geometric isomers, and all possible crystalline forms, as well as mixtures thereof.

In particular, optical isomers or configurational isomers can be obtained as racemates, or, when optically active starting materials or intermediates are used, as optically active isomers. Furthermore, if necessary, at an appropriate stage in the above-described production method, the racemate of the corresponding starting material, intermediate, or final product can be physically or chemically separated into its optical enantiomers by known separation methods such as methods using optically active columns or fractional crystallization. Examples of such separation methods include reacting a racemate with an optically active splitting agent to synthesize two non-mirror isomers, and then separating them by fractional crystallization or other methods based on differences in physical properties.

When a pharmaceutically acceptable salt of the compound of the present invention is to be obtained, when the compound represented by formula (1) to (7) is obtained in the form of a pharmaceutically acceptable salt, it can be directly purified. Alternatively, when it is obtained in a free form, it 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.

The compounds of the present invention may be used in combination with other drugs to enhance their effects. Specifically, the compounds of the present invention may be used in combination with hormonal therapy agents, chemotherapy agents, immunotherapy agents, or agents that inhibit the action of cell growth factors and their receptors. Hereinafter, drugs that can be used in combination with the compounds of the present invention are referred to as concomitant drugs.

Although the compounds of the present invention exhibit excellent anticancer effects when used as a single agent, their effects can be further enhanced or the patient's QOL can be improved by combining them with one or more of the above-mentioned concomitant drugs (multiple-drug combination).

Examples of "hormonal therapy agents" include fosfostilbestrol, diethylstilbestrol, chlortristilbene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asolini, allylestradiol, gestrinone, nomegestrol, tadalafil, mepartricin, raloxifene, ormeloxifene, levomeloxifen, antiestrogens (e.g., tamoxifen citrate, toremifene citrate, etc.), contraceptive preparations, melastane, testosterone, aminoglutethimide, LH-RH derivatives (LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin, etc.), LH-RH antagonists), droloxifene, cyclothiocarbazine, ethinyl estradiol sulfonate, aromatase inhibitors (such as fadrozole hydrochloride, anastrozole, letrozole, exemestane, vorozole, formestane, etc.), antiandrogens (such as flutamide, enzalumide, apalutamide, bicalutamide, nilutamide, etc.), adrenocortical hormone drugs (such as dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (such as abiraterone, etc.), retinoids, and drugs that delay retinoid metabolism (such as liarole, etc.), etc.

Examples of "chemotherapeutic agents" include alkylating agents, metabolic antagonists, anticancer antibiotics, plant-derived anticancer agents, molecularly targeted therapeutic agents, immunomodulators, and other chemotherapeutic agents. Representative examples are listed below.

Examples of the "alkylating agent" include nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambucil, cyclophosphamide, effulamide, thiotepa, carboquinone, improsulfan p-toluenesulfonate, busulfan, nimustine hydrochloride, dibromomannitol, melphalan, dacarbazine, ranimustine, estramustine sodium phosphate, triethylene melamine, carmustine, lomustine, ureazolam, streptomycin, pipobroman, itogluconol, carboplatin, cisplatin, miltplatin, nedaplatin, oxaliplatin, hexamethylmelamine, amidomistine, dibromospiramycin hydrochloride, fotemustine, fennimustine, puromycin, bendamustine hydrochloride, temozolomide, sulsulfuron, cyproconazole, nastatin, adolesin, chimustine, biszelesin, trabectedin, and their DDS preparations.

Examples of the "metabolic antagonist" include: fentopurine, 6-fentopurine nucleoside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine octadecyl phosphate, ancitabine hydrochloride, 5-FU-based drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, galotabine, ethiprole, capecitabine, leucovorin, leucovorin, cladribine, ethidium bromide, fludarabine, gemcitabine, hydroxylamine formamide, pentostatin, piroxetine, iodoxuridine, mitoxantrone, thiazolidinedione, thiazolidinedione, tabloid, buprenorphine, leucovorin, cladribine, ethidium bromide, fludarabine, gemcitabine, hydroxylamine formamide, pentostatin, piroxetine, iodoxuridine, mitoxantrone, thiazolidinedione, tadalafil, bendamustine, and their DDS preparations.

Examples of "anticancer antibiotics" include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pelocycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclamycin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neostatin, leucomycin, saccharomycin, carcinoglucosidase, mitotane, daurubicin hydrochloride, mitoxantrone hydrochloride, idamycin hydrochloride, eribulin, and DDS preparations thereof.

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

Examples of "molecular targeted therapy" 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, abemacilib, brigatinib, neratinib, cupranixib, cobimetinib, ibrutinib, acalabrutinib, conferfenib, bemetinib, baricitinib, fotantinib, larotrectinib, erdafitinib, entrectinib, dacomitinib, sirolimus, everolimus, temsirolimus, olaparib, rucaparib, niraparib, venetoclax, atazacitidine, decitabine, vorinostat, panobinostat, romidepsin, bortezomib, carfilzomib, larotrectinib, and ixazomib, etc.

Examples of "immunomodulators" include lenalidomide and pomalidomide.

Examples of "other chemotherapy agents" include sobuzosine.

Examples of "immunotherapeutic agents (BRMs)" include: Binisu, Clustatin, Schizophyllan, Lentinan, Ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Bacillus thuringiensis, levomethasone, polysaccharide K, aprocodazole, anti-CTLA4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, and toll-like receptor agonists (e.g., TLR7 agonists, TLR8 agonists, TLR9 agonists, etc.).

The cell growth factor used in the drug that inhibits the action of cell growth factors and their receptors may be any substance that promotes cell proliferation. Examples thereof include peptides with a molecular weight of 20,000 or less that can exert their effects at low concentrations by binding to receptors. Specifically, examples include: EGF (epidermal growth factor) or substances having substantially the same activity as the same (e.g., TGFalpha, etc.), insulin or substances having substantially the same activity as the same (e.g., insulin, IGF (insulin-like growth factor)-1, IGF-2, etc.), FGF (fibroblast growth factor) or substances having substantially the same activity as the same (e.g., acidic FGF, alkaline FGF, KGK (keratinocyte growth factor), FGF-10, etc.), and other cell growth factors (e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), etc.). factor, neural 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.

"SMARC-deficient cancers" are cancers characterized by SMARC gene deletion and/or SMARC protein expression loss or attenuation. Preferred are cancers characterized by SMARC gene deletion and/or SMARC gene expression loss. Further preferred are cancers characterized by SMARCB1, SMARCA2, SMARCA4, or SMARCA2/A4 gene deletion. Specifically, the following can be cited: malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid/rhabdoid tumor, neurotheliomas, chordoid meningiomas, neuroepithelial tumors, neurogliomas, craniopharyngiomas, neuroglioblastomas, chordomas, myoepithelioma, unclassified round cell sarcoma, rhabdoid myxoma, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basal cell carcinoma of the nasal sinuses, esophageal adenocarcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumors, and undifferentiated rhabdoid tumor of the pancreas. , gastrointestinal rhabdoid tumor, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumor of the vulva, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung carcinoma, pulmonary neuroendocrine tumor, esophageal cancer, esophagogastric junction cancer, gastric cancer, bladder cancer, squamous cell lung carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver cancer, small cell ovarian carcinoma, mucinous ovarian tumor, endometrial cancer, uterine sarcoma, sinus cancer, thoracic sarcoma, pleomorphic lung carcinoma, thoracic sarcoma, small cell ovarian carcinoma, primary gallbladder tumor, and uterine sarcoma. Malignant rhabdoid tumor and lung adenocarcinoma are preferred.

"SMARCB1-deficient cancer" is a cancer in which the SMARCB1 gene is deleted and/or the expression of the SMARCB1 protein is deleted or weakened. Preferably, it is a cancer in which the SMARCB1 gene is deleted and/or the expression of SMARCB1 is deleted. More preferably, it is a cancer in which the SMARCB1 gene is deleted. Specifically, examples include: malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid/rhabdoid tumor, neurotheliomas, chordoid meningiomas, neuroepithelial tumors, neurogliomas, craniopharyngiomas, neuroglioblastomas, chordomas, myoepithelioma, unclassified round cell sarcoma, rhabdomyosarcoma, extraskeletal myxoid tumors. Chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basal cell carcinoma of the nasal sinuses, esophageal adenocarcinoma, papillary thyroid carcinoma, thyroid follicular carcinoma, gastrointestinal stromal tumor, undifferentiated rhabdomyosarcoma of the pancreas, gastrointestinal rhabdomyosarcoma, renal medullary carcinoma, endometrial carcinoma, myoepithelioma-like tumor of the female vulva, colorectal cancer, and mesothelioma. Malignant rhabdomyosarcoma is preferred.

"SMARCA2-deficient cancers" are cancers characterized by a SMARCA2 gene deletion and/or absent or reduced expression of the SMARCA2 protein. Preferred are cancers characterized by a SMARCA2 gene deletion and/or absent expression of the SMARCA2 protein. Furthermore, SMARCA2-deficient cancers are more preferred. Specifically, examples include lung adenocarcinoma, large cell lung carcinoma, neuroendocrine pulmonary tumor, esophageal cancer, esophagogastric junction cancer, and malignant rhabdomyosarcoma. Lung adenocarcinoma is preferred.

"SMARCA4-deficient cancers" are cancers characterized by a SMARCA4 gene deletion and/or absent or reduced expression of the SMARCA4 protein. Preferred are cancers characterized by a SMARCA4 gene deletion and/or absent expression of the SMARCA4 protein. Furthermore, SMARCA4-deficient cancers are more preferred. Specifically, examples include lung adenocarcinoma, esophageal cancer, esophagogastric junction cancer, gastric cancer, bladder cancer, lung squamous cell carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver cancer, small cell ovarian carcinoma, ovarian mucinous tumor, endometrial cancer, mesothelioma, uterine sarcoma, sinus cancer, rhabdomyosarcoma, and thoracic sarcoma. Lung adenocarcinoma is preferred.

"SMARCA2/A4-deficient cancers" are cancers characterized by a deletion of the SMARCA2 and SMARCA4 genes, and/or a loss or reduction in the expression of the SMARCA2 and SMARCA4 proteins. Preferred are cancers characterized by a deletion of the SMARCA2 and SMARCA4 genes, and/or a loss of the expression of the SMARCA2 and SMARCA4 proteins. Furthermore, preferred are cancers characterized by a deletion of the SMARCA2 and SMARCA4 genes. Specifically, examples include lung adenocarcinoma, pleomorphic lung carcinoma, large cell lung carcinoma, esophageal cancer, esophagogastric junction cancer, thoracic sarcoma, small cell ovarian carcinoma, primary gallbladder tumor, uterine sarcoma, malignant rhabdoid tumor, ovarian granuloma, adrenocortical carcinoma, and small cell lung cancer. Lung adenocarcinoma is preferred.

"ARID-deficient cancers" are cancers characterized by ARID gene deletion and/or ARID protein expression loss or attenuation. Preferred are cancers characterized by ARID gene deletion and/or ARID protein expression loss. More preferably, they are cancers characterized by ARID1A, ARID1B, or ARID1A/1B gene deletion. Specifically, examples include ovarian cancer, gastric cancer, gallbladder cancer, pancreatic cancer, uterine cancer, pediatric neuroblastoma, colorectal cancer, bladder cancer, liver cancer, melanoma, breast cancer, medulloblastoma, and neuroblastoma. Ovarian cancer is preferred.

"ARID1A-deficient cancers" are cancers characterized by ARID1A gene deletion and/or ARID1A protein loss or reduced expression. Preferred are cancers characterized by ARID1A gene deletion and/or ARID1A protein loss. More preferably, these cancers are ARID1A-deficient cancers. Specific examples include ovarian cancer, gastric cancer, gallbladder cancer, pancreatic cancer, uterine cancer, pediatric neuroblastoma, colorectal cancer, and bladder cancer. Ovarian cancer is preferred.

"ARID1B-deficient cancers" are cancers characterized by ARID1B gene deletion and/or ARID1B protein loss or reduced expression. Preferred are cancers characterized by ARID1B gene deletion and/or ARID1B protein loss. More preferably, these are ARID1B-deficient cancers. Specifically, examples include ovarian cancer, colorectal cancer, pancreatic cancer, liver cancer, melanoma, breast cancer, medulloblastoma, uterine cancer, bladder cancer, and gastric cancer. Ovarian cancer is preferred.

"ARID1A/1B-deficient cancers" are cancers characterized by a deletion of the ARID1A and ARID1B genes, and/or a loss or reduction in the expression of the ARID1A and ARID1B proteins. Preferred are cancers characterized by a deletion of the ARID1A and ARID1B genes, and/or a loss of the expression of the ARID1A and ARID1B proteins. Furthermore, preferred are cancers characterized by a deletion of the ARID1A and ARID1B genes. Specific examples include ovarian cancer, colorectal cancer, uterine cancer, neuroblastoma, bladder cancer, and gastric cancer. Ovarian cancer is preferred.

SS18-SSX fusion cancers are cancers in which the SS18 and SSX genes are fused. Specifically, examples include synovial sarcoma and Evan's sarcoma, with synovial sarcoma being preferred.

Heart disease is a condition caused by damage to the heart, which leads to poor blood circulation. Specifically, it includes cardiomyopathy, heart failure, and myocardial infarction.

"Metabolic diseases" are diseases caused by impaired metabolic function. Specifically, they include lipid disorders and diabetes.

The administration time of the compound of the present invention and the concomitant drug is not limited. They can be administered to the subject at the same time or with a time difference. In addition, a combination of the compound of the present invention and the concomitant drug can be prepared. The dosage of the concomitant drug can be appropriately selected based on the dosage used clinically. In addition, the formulation ratio of the compound of the present invention and the concomitant drug can be appropriately selected based on the subject of administration, the route of administration, the target disease, symptoms, combination, etc. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug can be used for 1 part by weight of the compound of the present invention. In addition, it can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep induction agents, and anticonvulsants for the purpose of suppressing its side effects.

In this specification, "or" is used when "at least one or more" is applicable to the examples in the text. The same applies to "or." In this specification, when it is clearly stated that "within the range of two values," the range also includes the two values themselves.

References such as scientific literature, patents, and patent applications cited in this specification are incorporated herein by reference to the same extent as if their respective contents were specifically set forth in their entirety.

The present invention has been described above in its preferred embodiments for easy understanding. The present invention will be described below based on examples. However, the above description and the following examples are provided for illustrative purposes only and are not intended to limit the present invention. Therefore, the scope of the present invention is not limited by the embodiments specifically described in this specification or the examples, but only by the scope of the patent application.

Serial number 1

Serial number 2

Serial number 3 Embodiment

Hereinafter, the present invention will be described in more detail with reference to reference examples, embodiments, and test examples, but the present invention is not limited thereto.

In this specification, the following abbreviations are sometimes used. Me: methyl Et: ethyl Ph: phenyl Bn: benzyl Boc: tert-butyloxycarbonyl DMPU: N,N'-dimethylpropyleneurea n-: normal tert-: tert- p-: para Ac: acetyl dppf: 1,1'-bis(diphenylphosphino)ferrocene X-PHOS: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

The NMR (Nuclear Magnetic Resonance) data used for compound identification were acquired using a JEOL JNM-ECS400 NMR instrument (400 MHz).

As used in NMR, s means singlet, d means doublet, dd means doublet of doublet, t means triplet, td means triplet of doublets, q means quartet, m means multiplet, br means broad, brs means broad singlet, brm means broad multiplet, and J means coupling constant.

Compound identification was performed using LC/MS (Liquid Chromatography-Mass Spectrometry) analysis conditions as described below. Observed mass analysis values [MS (m/z)] are expressed as [M+H] ⁺ , [MH] ^- , or [M+2H] ²⁺ corresponding to single isotopic masses (exact masses consisting solely of the main isotope), and retention times are expressed as Rt (minutes).

LC/MS determination method: Detection equipment: ACQUITY (registered trademark) SQ detector (Waters); HPLC: ACQUITY UPLC (registered trademark); System column: Waters ACQUITY UPLC (registered trademark) B EH C18 (1.7 μm, 2.1 mm × 30 mm); Solvent: Solution A: 0.06% formic acid/ _H2O ; Solution B: 0.06% formic acid/MeCN; Gradient conditions: Linear gradient from 2% to 96% B over 0.0-1.3 min; Flow rate: 0.8 mL/min; UV: 220 nm and 254 nm; Column temperature: 40°C

Reference Example 1 N-(4-fluorobenzyl)-2-hydroxy-N-(3-(trifluoromethyl)oxycyclobutane-3-yl)acetamide [Chemical 26]

a) Preparation of N-(4-fluorobenzyl)-3-(trifluoromethyl)cyclobutane-3-amine (Compound Y1): 3-(Trifluoromethyl)cyclobutane-3-amine hydrochloride (10.0 g) was dissolved in chloroform (188 mL). 4-Fluorobenzaldehyde (7.25 mL) and sodium triacetoxyborohydride (22.4 g) were added at 0°C, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. 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

b) Preparation of 2-(Benzyloxy)-N-(4-fluorobenzyl)-N-(3-(trifluoromethyl)cyclobutan-3-yl)acetamide (Compound Y2): Compound Y1 (7.6 g) was dissolved in DMPU (102 mL), sodium hydroxide (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 the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. 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

c) Preparation of N-(4-fluorobenzyl)-2-hydroxy-N-(3-(trifluoromethyl)oxacyclobutan-3-yl)acetamide: Compound Y2 (15.1 g) was dissolved in methanol (127 mL), and palladium hydroxide-activated carbon (2.1 g) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered through celite, and the residue was washed with methanol. The solvent was then distilled off 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

Reference Examples 2 to 5 The compounds of Reference Examples 2 to 6 were obtained by following the method described in Reference Example 1 using the corresponding starting compounds.

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

Reference Example 8 (3'R,4S)-5'-bromo-3'-fluoro-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-2,5-dione [Chemical 27]

a) Preparation of (3'S,4S)-5'-bromo-3'-hydroxy-2',3'-dihydrospiro[imidazolidin-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 ammonium chloride solution was added to the reaction mixture at 0°C. The reaction mixture was extracted twice with ethyl acetate/methanol. The resulting organic layer was washed with saturated sodium chloride water, dried over magnesium sulfate, filtered, and the solvent was distilled off 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 diethylaminosulfur 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 sodium chloride, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the title compound (15.6 g). LC-MS ([M+H] + /Rt (min)): 299.0/0.681

Reference Example 9 (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl)-N-(4-fluorobenzyl)-N-(3-(trifluoromethyl)oxacyclobutane-3-yl)acetamide [Chemical 28]

The compound of Reference Example 1 (264 mg) was dissolved in tetrahydrofuran (3 mL). (S)-5'-bromo-2',3'-dihydrospiro(imidazolidin-4,1'-indene)-2,5-dione (230 mg), diisopropyl azodicarboxylate (0.56 mL), and triphenylphosphine (279 mg) were added at 0°C and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. 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

Reference Examples 10 to 16 The compounds of Reference Examples 10 to 16 were obtained by following the method described in Reference Example 9 using the corresponding starting compounds.

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

Reference Example 17 (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl)-N-(1-methyl-3-(trifluoromethyl)azetidin-3-yl)acetamide [Chemical 29]

a) The compound of Reference Example 3 (1.83 g) was dissolved in tetrahydrofuran (29 mL). (S)-5'-bromo-2',3'-dihydrospiro(imidazolidin-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 stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound. LC-MS ([M+H] + /Rt (min)): 615.2/1.178 b) Preparation of (S)-2-(5'-bromo-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl)-N-(1-methyl-3-(trifluoromethyl)azetidin-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 distilled off under reduced pressure and subjected to triene azeotropy. The obtained crude product was dissolved in chloroform (21 mL), and a 37% aqueous formalin 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. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C. The reaction mixture was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.16 g). LC-MS([M+H] + /Rt(min)): 583.3/0.778

Reference Examples 18 to 22 The compounds of Reference Examples 18 to 22 were obtained by following the method described in Reference Example 17 using the corresponding starting compounds.

[Table 3]

Example 1: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide [Chemical 30]

The compound of 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-(oxacyclobutane-3-yl)azetidin-3-yl)-1H-pyrazole-4-boronic acid pinacol (68 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloride (14 mg) were added at room temperature and stirred at 90°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform. The obtained organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. 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

Examples 2 to 35 The compounds of Examples 2 to 35 were obtained by following the method described in Example 1 using the compounds of the corresponding reference examples and commercially available compounds as starting materials.

[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]

Comparative example 1 [Chemical 31] 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

Comparative example 2 [Chemical 32] The method described in WO2020/108500 was used to obtain the compound of Comparative Example 2. LC-MS ([M+H] + /Rt(min)): 531.3/0.965

Test Examples The following shows the test results of representative compounds of the present invention and describes the pharmacological properties, chemical properties, and pharmacokinetic properties of the compounds. However, the present invention is not limited to these test examples.

Experimental Example 1 : HAT Activity Inhibition Assay: The HAT activity inhibition ability of HAT inhibitors was evaluated using the SensoLyte HAT (p300) Assay Kit (ANA SPEC, AS-72172). Specifically, 7.5 μL of the compounds from Examples 1-35 diluted in assay buffer was added to 7.5 μL of a recombinant p300 solution diluted 10-fold in assay buffer and incubated at room temperature for 10 minutes. To this solution, 7.5 μL of an acetyl CoA solution diluted 10-fold in assay buffer and 15 μL of a histone H3 peptide diluted 10-fold in assay buffer were added and incubated at 37°C for 30 minutes. The reaction was stopped by adding 37.5 μL of stop solution. Add 75 μL of p300 developer solution diluted 50-fold with assay buffer and incubate at room temperature for 30 minutes under light-shielded conditions. Fluorescence at 513 nm, when excited at 389 nm, was measured using a multifunctional microplate reader. Based on the measured fluorescence intensity, the _IC50 value (IC50) was calculated, corresponding to the compound concentration that exhibited 50% inhibition of the enzymatic reaction. The results are shown in Table 5.

[Table 5] Embodiment HAT activity inhibition IC ₅₀ (μM) 1 0.016 2 0.019 3 0.0006 4 0.0005 5 0.0061 6 0.0198 7 0.0009 8 0.0172 9 0.0006 10 0.0004 11 0.0021 12 0.0063 13 0.0052 14 0.1236 15 0.0061 16 0.0536 17 0.0023 18 0.0582 19 0.0072 20 0.0017 twenty one 0.052 twenty two 0.011 twenty three 0.009 twenty four 0.0098 25 0.0057 26 0.0092 27 0.0068 29 0.0028 30 0.0015 31 0.0010 32 0.0004 33 0.0002 34 0.0002 35 0.0052

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

Experimental Example 2 : Cell Proliferation Inhibition Assay Using G-401 Cells G-401 cells (derived from malignant rhabdoid tumor) were obtained from the American College of Cell Culture Collection (ATCC). G-401 cells were cultured in McCoy's 5a medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin at 37°C and 5% _CO₂ .

500 cells were seeded per well in a 384-well plate. One day after seeding, Examples 1-35 were added to a final DMSO concentration of 0.1% and cultured for 3 days. After completion of the culture, cell viability was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). Based on the viability curves, the _IC50 value was calculated as the concentration of the evaluated compound that exhibited 50% inhibition of cell proliferation. The results are shown in Table 6.

[Table 6] Embodiment Cell proliferation inhibition IC ₅₀ (μM) 1 0.181 2 0.089 3 0.044 4 0.043 5 0.088 6 0.391 7 0.044 8 0.247 9 0.038 10 0.01 11 0.01 12 0.082 13 0.02 14 0.677 15 0.033 16 0.31 17 0.025 18 0.292 19 0.024 20 0.036 twenty one 0.353 twenty two 0.068 twenty three 0.082 twenty four 0.036 25 0.059 26 0.014 27 0.022 29 0.017 30 0.002 31 0.001 32 0.005 33 0.004 34 0.005 35 0.072

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

Experimental Example 3 : Cell Proliferation Inhibition Experiment Using Kuramochi Cells Kuramochi cells (derived from ovarian cancer) were obtained from the JCRB (Japanese Collection of Research Bioresources) cell bank. Kuramochi cell line 1 was cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin at 37°C in the presence of 5% _CO₂ .

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 a final DMSO concentration of 0.1% and cultured for 6 days. After completion of the culture, cell viability was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). Based on the viability curves, the _IC50 value was calculated as the concentration of the evaluated compound that exhibited 50% inhibition of cell proliferation. The results are shown in Table 7.

[Table 7] Embodiment Cell proliferation inhibition IC ₅₀ (μM) 3 0.091 7 0.298 9 0.184 10 0.066 11 0.048 20 0.320 twenty three 0.591 twenty four 0.399 25 0.424 30 0.010 31 0.008 32 0.053 33 0.024 34 0.045

Experimental Example 4 : Cell Proliferation Inhibition Experiment Using RMGI Cells RMGI cells (derived from ovarian cancer) were obtained from the JCRB Cell Bank. RMGI cells were cultured in Ham's F12 medium containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37°C in the presence of 5% CO ₂ .

200 cells were seeded per well in a 384-well plate. One day after seeding, Examples 3, 7, 9, 10, 11, 20, and 23-25 were added to a final DMSO concentration of 0.1% and cultured for 6 days. After completion of the culture, cell viability was determined using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, G7570). Based on the viability curves, the _IC50 value was calculated as the concentration of the evaluated compound that exhibited 50% inhibition of cell proliferation. The results are shown in Table 8.

[Table 8] Embodiment Cell proliferation inhibition IC ₅₀ (μM) 3 0.018 7 0.035 9 0.024 10 0.006 11 0.005 20 0.043 twenty three 0.054 twenty four 0.037 25 0.041

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

The test results are shown in Table 9. Examples 7, 10, 20, 23, 24, and 30-34 exhibited high solubility. On the other hand, Comparative Examples 1 and 2 exhibited extremely low solubilities of 0.002 mg/mL, 0.004 mg/mL, and 0.005 mg/mL at pH 2.0 and pH 3.0, respectively. These test results demonstrate that Examples 7, 10, 20, 23, 24, and 30-34 exhibited a particularly strong solubility effect.

[Table 9] Compound Solubility in pH 2.0 buffer (mg/mL) Solubility in pH 3.0 buffer (mg/mL) Example 7 >10 4.6 Example 10 >10 1.6 Example 20 >10 8.6 Example 23 >10 8.6 Example 24 >10 >10 Example 30 8.8 1.7 Example 31 7.1 1.4 Example 32 >10 >10 Example 33 >10 8.6 Example 34 >10 8.1 Comparative example 1 0.002 0.005 Comparative example 2 0.004 0.005

Test Example 6 : Membrane permeability test

Membrane permeability tests of test compounds were performed using an artificial membrane permeability assay (PAMPA) in the following manner. 200 μL of the 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 receptor absorption buffer (pION inc.) was added to the receptor plate. The two plates were overlapped and incubated at 37°C for 4 hours. After incubation, UV absorption of the solutions on the receptor and donor sides was measured using a UV plate reader (190-500 nm). Compounds lacking UV absorption were measured using LC-MS. The permeability coefficient Pe ( ^10-6 cm/sec) of the drug was calculated using the following formula. V _D = donor well volume _VA = acceptor well volume t = transit time τ ^SS = steady-state time R = retention _CD and _CA = concentrations in the donor and acceptor wells

The test results are shown in Table 10.

[Table 10] Embodiment pH 5.0 Pe (10 ^-6 cm/s) pH 7.4 Pe (10 ^-6 cm/s) 1 16.2 20.6 2 7.4 19.0 3 14.9 17.7 4 25.7 31.2 5 25.4 28.4 6 3.1 5.5 7 3.0 5.1 8 13.5 14.3 9 13.3 15.3 10 23.9 28.6 11 24.1 27.2 12 24.0 28.9 13 26.2 26.9 14 26.1 27.9 15 30.0 33.3 16 29.2 32.0 17 28.1 32.2 18 28.6 31.8 19 24.4 28.9 20 7.8 21.9 twenty one 6.2 21.2 twenty two 21.2 23.0 twenty three 3.2 7.0 twenty four 1.6 8.2 25 1.0 6.1 26 10.2 16.3 27 0.6 3.5 8 25.7 30.0 29 23.9 28.3 30 30.6 35.0 31 31.3 34.9 32 15.4 26.0 33 22.6 27.0 34 24.4 34.9 35 31.2 33.7 Comparative example 1 21.3 20.8

Experimental Example 7 : Mouse Drug Dynamics Study. Seven-week-old female BALB/c (BALB/cAnN CrlCrlj) mice were administered the test compound intravenously (dosage: 1 mg/kg) using a 50% PEG solution (0.01 mol/L HCl) or orally (dosage: 10 mg/kg) using a 0.5% methylcellulose aqueous solution. Blood was collected at the following times. Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration. Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration. Blood was collected by centrifugation at 3000 rpm for 10 minutes in a cooled centrifuge set at 4°C. The resulting plasma was analyzed by LC-MS. A calibration curve was generated based on the peak area of the test sample divided by the peak area of the internal standard in the MS analysis (peak ratio) and the concentration of the plasma calibration curve samples. The sample concentration was calculated based on the peak ratio of each sample and the calibration curve.

Table 11 shows the test results for Examples 1, 3-5, 7, 9-12, 20, and 23-25. These test results demonstrate that the compounds of the present invention exhibit excellent pharmacokinetic properties and are also effective in vivo.

[Table 11] Embodiment Administration method Half-life (hr) CL (mL/min/kg) V _dss (L/kg) AUG (ng•hr/mL) BA (%) C _max (ng/mL) 1 MS 1.10 28,6 1.8 575 Oral 4351 75.7 3767 3 vein 1.80 20,6 2.0 764 Oral 3890 50.9 2673 4 vein 2.30 6.8 1.2 2103 Oral 28657 136.3 8303 5 vein 1.75 17.6 2.1 875 Oral 7297 83.4 3500 7 1.41 19.9 1.3 819 Oral 8242 100.6 6140 9 vein 2.43 11.9 2.0 1201 Oral 13103 109.1 5373 10 vein 1.16 33.5 1.8 491 Oral 3480 70.8 3243 11 2.12 33.7 4.1 446 Oral 2505 56.2 1717 12 vein 0.97 35.7 1.6 465 Oral 1396 30.0 1293 20 vein 1.34 31.1 1.6 528 Oral 1521 28.8 1337 twenty three 4.10 9.8 1.8 1689 Oral 8401 49.7 8137 twenty four vein 1.15 53.0 2.1 313 Oral 1471 47.0 1474 25 vein 672 Oral 1314 19.6 1627

Experimental Example 8 : Oral Drug Efficacy Evaluation Using a G-401 Xenograft Mouse Model 4-7 week-old BALB/cAnNCrj-nu/nu mice (CAnN.Cg-Foxn1<nu>/CrlCrlj, THE JACKSON LABORATORY JAPAN) were intradermally transplanted with G-401 cells (ATCC) at a density of 5×10 ⁵ cells/mouse. Ten to 40 days after transplantation, once G-401 cell survival was confirmed, the test compound, suspended in a solvent such as 0.5% methylcellulose solution, was orally administered twice daily at a dose of 1-100 mg/kg. Tumor volume was measured periodically after the start of administration to evaluate the tumor volume reduction effect of the test compound. Tumor volume was calculated using the short diameter and long diameter of the tumor measured with an electronic vernier caliper (Mitutoyo) using the following formula: Tumor volume [mm ³ ] = 0.5 × short diameter [mm] × (long diameter [mm]) ²

The anti-tumor effect was evaluated by comparing the control group (administered only with a 0.5% methylcellulose solution or other solvent) with the test compound-administered group. The T/C ratio was calculated using the following formula. T/C (%) = (tumor volume at the end of administration in the test compound-administered group - tumor volume at the start of administration in the test compound-administered group) / (tumor volume at the end of administration in the control group - tumor volume at the start of administration in the control group) × 100

Table 12 shows the test results for Examples 7, 10, 20, and 23. These test results demonstrate that Examples 7, 10, 20, and 23 exhibit potent anti-tumor effects in the G-401 xenograft model, which utilizes cells derived from malignant rhabdomyosarcoma.

[Table 12] Embodiment Dosage (mg/kg) Dosage period (days) T/C(%) 7 10 34 31 7 30 34 80 10 3 twenty one 53 10 10 twenty one 102 20 20 twenty one 80 20 30 twenty one 89 twenty three 20 twenty one 81

Experimental Example 9 : Intravenous Drug Efficacy Evaluation Using a G-401 Xenograft Mouse Model. 4-7 week-old BALB/cAnNCrj-nu/nu mice (CAnN.Cg-Foxn1<nu>/CrlCrlj, THE JACKSON LABORATORY JAPAN) were intradermally transplanted with G-401 cells (ATCC) at a density of 5×10 ⁵ cells/mouse. Ten to 40 days after transplantation, after confirming the survival of the G-401 cells, the test compound, suspended in a 10 mmol/L glycine buffer (pH 2.0) or similar solvent, was administered via the tail vein at a dose of 0.015-20 mg/kg at least once a week. Tumor volume was measured periodically after the start of administration to evaluate the reduction in tumor volume caused by the test compound. Tumor volume was calculated using the short and long diameters of the tumor, measured using an electronic vernier caliper (Mitutoyo), using the following formula: Tumor volume [mm ³ ] = 0.5 × short diameter [mm] × (long diameter [mm]) ^2. A control group administered with only a solvent such as 10 mmol/L glycine buffer (pH 2.0) was compared with the test compound-administered group, and the T/C ratio was calculated using the following formula to evaluate the antitumor effect. T/C (%) = (tumor volume at the end of administration of the test compound-tumor volume at the beginning of administration of the test compound) / (tumor volume at the end of administration of the control group-tumor volume at the beginning of administration of the control group) × 100

Table 13 shows the test results for Examples 7, 10, 20, 23, and 24, and Comparative Example 1. According to these test results, Examples 7, 10, 20, 23, and 24 demonstrated potent antitumor effects even after intravenous administration in the G-401 xenograft model, which utilizes cells derived from malignant rhabdoid tumors. On the other hand, Comparative Example 1 demonstrated no antitumor effects despite administration at the maximum concentration.

[Table 13] Embodiment Dosage (mg/kg) Dosage period (days) T/C(%) 7 20 14 40 10 10 14 73 20 10 14 53 twenty three 20 14 54 twenty four 20 14 44 Comparative example 1 0.015 14 -1.1

Experimental Example 10 : Evaluation of Dopamine Receptor Inhibitory Activity . The combined evaluation assay was commissioned by Eurofins. Specifically, CHO-S/hDAT cells were homogenized in a culture buffer containing 50 mmol/L tris(OH)2Cl (pH 7.4), 100 mmol/L NaCl, 1 μmol/L anti-fibrotic peptide, and 10 μmol/L PMSF. The membrane pellet obtained by centrifugation was resuspended in the culture buffer to prepare a membrane preparation. Test compounds (1-10 μmol/L DMSO solution), membrane preparation, and 0.15 nmol/L [3H]k paroxetine were mixed and incubated at 4°C for 180 minutes. The cell membranes and [125I]RTI-55 complexes were bound to GF/B filter mats by filtration and washed with 50 mmol/L trihydroxymethylaminomethane hydrochloride (pH 7.4). Radioactivity was measured using a flash counter to assess receptor effects.

The test results are shown in Table 14.

[Table 14] Compound Inhibitory activity at 10 μM (%) Example 7 7 Example 10 6 Example 20 46 Example 23 7 Example 24 6 Example 25 9 Comparative example 2 88

Experimental Example 11 : Evaluation of Serotonin Receptor Inhibitory Activity . The combined evaluation assay was commissioned by Eurofins. Specifically, HEK293/hSERT cells were homogenized in a buffer containing 100 mmol/L NaCl, 1 μmol/L anti-fibrotic peptide, 10 μmol/L PMSF, and 50 mmol/L tris(OH)2Cl (pH 7.4). The membrane pellet obtained by centrifugation was resuspended in a culture buffer containing 50 mmol/L tris(OH)2Cl (pH 7.4), 120 mmol/L NaCl, and 5 mmol/L KCl to prepare a membrane preparation. Test compounds (1-10 μmol/L DMSO solution), membrane preparation, and 0.4 nmol/L [3H]paroxetine were mixed and incubated at 25°C for 60 minutes. The cell membranes and [3H]paroxetine complexes were bound to GF/B filter mats by filtration and washed with 50 mmol/L trihydroxymethylaminomethane hydrochloride (pH 7.4). Radioactivity was measured using a flash counter to assess receptor effects.

The test results are shown in Table 15.

[Table 15] Compound Inhibitory activity at 10 μM (%) Example 7 -1 Example 10 -5 Example 20 -1 Example 23 3 Example 24 15 Example 25 2 Comparative example 2 76

The results of Test Examples 10 and 11 confirm that the compounds of the present invention do not act on off-targets, which are of safety concern. Furthermore, the results of Comparative Example 2 clearly demonstrate a strong inhibitory effect on dopamine and serotonin receptors.

Based on the results of Test Examples 1-11, the compounds disclosed herein exhibited potent HAT inhibitory activity (Test Example 1) and potent cancer cell proliferation inhibitory effects (Test Examples 2-4). Furthermore, the compounds disclosed herein exhibited excellent solubility (Test Example 5), high membrane permeability (Test Example 6), favorable pharmacokinetic properties (Test Example 7), and significant anti-tumor effects (Test Example 8). Furthermore, the compounds disclosed herein also demonstrated significant anti-tumor effects in a xenograft mouse model when administered intravenously (Test Example 9) and showed no strong inhibitory activity against off-target dopamine and serotonin receptors, demonstrating a particularly remarkable and unique safety profile (Test Examples 10 and 11).

The inventors have discovered that the low solubility of Comparative Examples 1 and 2 makes intravenous administration difficult. Generally speaking, if structural transformation is performed to increase solubility, lipid solubility will be reduced, which may impair membrane permeability. However, among the compounds of the present invention, the compounds represented by formulas (2) to (7) in particular have the unique effect of having both 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.

Among the compounds of the present invention, Examples 7, 10, 20, 23, 24, 25, 30-34 encompassed by Formula (2), Formula (3), Formula (5), or Formula (6) exhibited potent HAT inhibitory activity (Test Example 1) and potent cancer cell proliferation inhibitory effects (Test Examples 2-4). Furthermore, although structural transformation to enhance solubility generally results in decreased lipid solubility and consequently decreased membrane permeability, Examples 7, 10, 20, 23, 24, 30-34 exhibited the unique effect of exhibiting superior solubility compared to Comparative Example 1 and Comparative Example 2 (Test Example 5) and comparable membrane permeability to Comparative Example 1 and Comparative Example 2 (Test Example 6). Furthermore, Examples 7, 10, 20, 23, and 24 exhibited excellent pharmacokinetic properties (Test Example 7). Examples 7, 10, 20, and 23 demonstrated significant antitumor effects upon oral administration (Test Example 8). Even upon intravenous administration, they exhibited a particularly significant antitumor effect within the tumor, which was not achieved in Example 1 (Test Example 9). These CBP/P300 inhibitors are suitable for both oral and intravenous administration. Furthermore, while Comparative Example 2 exhibited stronger inhibitory activity against off-target dopamine receptors and serotonin receptors, Examples 7, 10, 20, 23, 24, and 25 did not exhibit stronger inhibitory activity, demonstrating a particularly remarkable and unique safety profile (Test Examples 10 and 11). (Note) As described above, the present invention has been exemplified using preferred embodiments thereof. However, it should be understood that the scope of the present invention is to be construed solely within the scope of the patent applications. Patents, patent applications, and literature cited in this specification are to be incorporated herein by reference as if their contents were specifically set forth herein. Industrial Applicability

The compounds of the present invention and their pharmaceutically acceptable salts can be used as therapeutic or preventive agents for CBP/P300-related diseases by potently inhibiting CBP/P300.

TW202532410A_113105163_SEQL.xml

Claims (103)

A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: [wherein, A represents CHF or CH ₂ , and B represents the following formula (B-1): [Chemical 2] [wherein, * represents the bonding position to the nitrogen atom of the hydantoin ring], Ring Q represents an optionally substituted 6- to 10-membered aromatic hydrocarbon ring, or an optionally substituted 5- to 10-membered aromatic heterocyclic ring, Z represents -O-, -N(R ^7a )-, an optionally substituted 6- to 10-membered divalent aromatic cyclic group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, or an optionally substituted 4- to 10-membered divalent non-aromatic heterocyclic group, R ¹ represents an optionally substituted C _1-6 alkyl group, or an optionally substituted C _3-10 alicyclic group, R ^2a and R ^2b each independently represent an optionally substituted C _1-6 alkyl group, wherein R ^2a and R ^2b , together with the carbon atoms to which they are bonded, may form an optionally substituted C R represents a C _3-6 cycloalkylene group, or an optionally substituted 4-6 membered divalent non-aromatic heterocyclic group; ^R represents a C _6-10 aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted C _3-10 alicyclic group, or an optionally substituted 4-10 membered non-aromatic heterocyclic group; ^R represents a single bond, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, or an optionally substituted 4-10 membered divalent non-aromatic heterocyclic group; ^R represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _1-3 alkoxy group, or -NR ^7b R ^7c , -SO ₂ R ^7d , -CONR ^7e R ^7f , an optionally substituted C _3-10 alicyclic group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _6-10 aryl group, or an optionally substituted 5-10 membered heteroaryl group, R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or an optionally substituted C _1-6 alkyl group]. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein 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 , ring Q, and Z are an optionally substituted 6-10 membered aromatic alkyl ring, an optionally substituted 5-10 membered aromatic heterocyclic ring, an optionally substituted 6-10 membered divalent aromatic alkyl ring, an optionally substituted 5-10 membered divalent aromatic heterocyclic ring, an optionally substituted C The _6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _3-10 alicyclic group, an optionally substituted C _3-6 cycloalkylene group, an optionally substituted 4-6 membered divalent non-aryl heterocyclic group, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, an optionally substituted 4-10 membered divalent non-aryl heterocyclic group, or an optionally substituted C _1-3 alkoxy group may be independently selected from (1) a halogen atom, (2) a hydroxyl group, (3) a C _6-10 aryl group, (4) 5-12 membered heteroaryl, (5) C _1-6 alkyl, (6) C _2-6 alkenyl, (7) C _2-6 alkynyl, (8) C _1-6 alkoxy, (9) C _1-6 alkylthio, (10) C _3-10 alicyclic group, (11) 3-10 membered non-aromatic heterocyclic group, (12) carboxyl, (13) -COR ¹⁰ , (14) -CO ₂ R ¹⁰ , (15) -CONR 11 R 12 , (16) -NR ¹¹ R ¹² , (17) -NR ¹³ COR ¹⁰ , (18) -NR ¹³ CO ² _R ¹⁰ , (19) -NR ¹³ SO ₂ R ¹⁰ , (20) -NR ¹³ CONR ¹¹ R ^{12 ,} (21) -NR ¹³ SO ₂ NR ¹¹ R ¹² , (22) -SO ₂ R ¹⁰ , (23) -SO ₂ NR ¹¹ R ¹² , (24) -OCOR ¹⁰ , (25) -OCO ₂ R ¹⁰ , (26) -OCONR ¹¹ R ¹² , (27) sulfo, (28) phosphate, (29) cyano, and (30) nitro, wherein the above-mentioned (3) C _6-10 aryl, (4) 5-12 membered heteroaryl, (5) C _1-6 alkyl, (6) C _2-6 alkenyl, (7) C _2-6 alkynyl, (8) C _1-6 alkoxy, (9) C _1-6 alkylthio, (10) C The group represented by the _3-10 membered alicyclic group and (11) the 3-10 membered non-aromatic heterocyclic group may be selected from (a) a halogen atom, (b) a hydroxyl group, (c) a C _6-10 aryl group, (d) a 5-12 membered heteroaryl group, (e) a C _1-6 alkyl group, (f) a C _2-6 alkenyl group, (g) a C _2-6 alkynyl group, (h) a C _1-6 alkoxy group, (i) a C _3-10 alicyclic group, (j) a 3-10 membered non-aromatic heterocyclic group, (k) a carboxyl group, (l) -COR ¹⁰ , (m) -CO ₂ R ¹⁰ , (n) -CONR ¹¹ R ¹² , (o) -NR ¹¹ R ¹² , (p) -NR ¹³ COR ¹⁰ , (q) -NR ¹³ SO ₂ R ¹⁰ , (r)-SO ₂ R ¹⁰ , (s)-SO ₂ NR ¹¹ R ¹² , 1 to 5 substituents selected from the group consisting of (t) sulfo, (u) phosphate, (v) cyano, and (w) nitro, R ¹⁰ when there are plural R 10s are each independently a C _1-6 alkyl group, R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group, and when there are plural R ¹¹ or R ¹² , R ^{11 or R 12 may be the same or different. Here, when R 11 and R 12 bonded to} the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded, and R ¹³ is a hydrogen atom or C _1-6 alkyl. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein 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 , ring Q, and Z are an optionally substituted 6-10 membered aromatic alkyl ring, an optionally substituted 5-10 membered aromatic heterocyclic ring, an optionally substituted 6-10 membered divalent aromatic alkyl ring group, an optionally substituted 5-10 membered divalent aromatic heterocyclic ring group, an optionally substituted C The _6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _3-10 alicyclic group, an optionally substituted C _3-6 cycloalkylene group, an optionally substituted 4-6 membered divalent non-aryl heterocyclic group, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, an optionally substituted 4-10 membered divalent non-aryl heterocyclic group, or an optionally substituted C _1-3 alkoxy group may be independently selected from (1) a halogen atom, (2) a hydroxyl group, (3) a C _6-10 aryl group, (4) 5-12 membered heteroaryl group, (5) C _1-6 alkyl group which may be substituted with 1-3 halogen atoms, (6) C _2-6 alkenyl group, (7) C _2-6 alkynyl group, (8) C _1-6 alkoxy group, (9) C _3-10 alicyclic group, (10) 3-10 membered non-aromatic heterocyclic group, (11) carboxyl group, (12) -COR ¹⁰ , (13) -CO ₂ R ¹⁰ , (14) -CONR ¹¹ R ¹² , (15) -NR ¹¹ R ¹² , (16) -SO ₂ R ¹⁰ , (17) -SO ₂ NR ¹¹ R ¹² , (18) sulfo group, (19) phosphate group, (20) cyano, and (21) nitro, substituted by 1 to 5 substituents, which may be the same or different, from the group consisting of: (20) cyano, and ( ²¹⁾ nitro; ^R10 , when present in plural, each independently represents a _C1-6 alkyl group; ^R11 and ^{R12 ,} when present in plural, each independently represents a hydrogen atom or a _C1-6 alkyl group; ^R11 or ^R12 , when present in plural, may be the same or different; herein, when ^R11 and ^R12 bonded to the same nitrogen atom are both _C1-6 alkyl, they may form together with the nitrogen atom to which they are bonded a 3-8 membered nitrogen-containing non-aromatic heterocyclic group. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein 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 , ring Q, and Z are an optionally substituted 6-10 membered aromatic alkyl ring, an optionally substituted 5-10 membered aromatic heterocyclic ring, an optionally substituted 6-10 membered divalent aromatic alkyl ring group, an optionally substituted 5-10 membered divalent aromatic heterocyclic ring group, an optionally substituted C The _6-10 membered aryl group, an optionally substituted 5-10 membered heteroaryl group, an optionally substituted 4-10 membered non-aryl heterocyclic group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkenyl group, an optionally substituted C _1-6 alkynyl group, an optionally substituted C _3-10 alicyclic group, an optionally substituted C _3-6 cycloalkylene group, an optionally substituted 4-6 membered divalent non-aryl heterocyclic group, an optionally substituted C _1-6 alkylene group, an optionally substituted C _3-10 cycloalkylene group, an optionally substituted 4-10 membered divalent non-aryl heterocyclic group, or an optionally substituted C _1-3 alkoxy group may be independently selected from (1) a halogen atom, (2) a hydroxyl group, (3) a phenyl group, (4) a 5-6 membered heteroaryl group, (5) C _1-6 alkyl which may be substituted with 1 to 3 halogen atoms, (6) C _1-6 alkoxy, (7) C _3-7 alicyclic group, (8) 3-7 membered non-aromatic heterocyclic group, (9) -COR ¹⁰ , (10) -CO ₂ R ¹⁰ , (11) -CONR ¹¹ R ¹² , (12) -NR ¹¹ R ¹² , (13) -SO ₂ R ¹⁰ , (14) -SO ₂ NR ¹¹ R ¹² , and (15) cyano, substituted with 1 to 5 substituents which are the same or different, wherein R ¹⁰ , when present in plural, is independently C _1-6 alkyl, R ¹¹ and R ¹² are independently hydrogen or C _1-6 alkyl, R ¹¹ or R When there are multiple R ¹¹ or R ¹² , each R ¹¹ or R 12 may be the same or different. Here, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein B is the following formula (B-2), (B-3), or (B-4): [Chemical 3] [In the formula, * represents the bonding position to the nitrogen atom of the hydantoin ring, a represents 0, 1, or 2, b represents 1, or 2, R ⁸ represents a hydrogen atom or an optionally substituted C _1-6 alkyl group, and R ^9a and R ^9b each independently represent a hydrogen atom, a halogen atom, or an optionally substituted C _1-6 alkyl group]. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-3 alkyl group which may be substituted with 1 to 3 fluorine atoms. The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R ¹ is CF ₃ . The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R ³ is a C _6-10 aryl group (the aryl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group which may be substituted), or a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl, 4-(trifluoromethyl)phenyl, or 4-fluoro-2-pyridyl. The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl or 4-fluoro-2-pyridyl. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein ring Q is a 6-10 membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein ring Q is a benzene ring (the benzene ring may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein a is 1, 2, or 3. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein a is 1. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein b is 1. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein a is 1 and b is 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (2): [Chemical 4] [In the formula, A represents CHF or CH ₂ , R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents -O-, a 6- to 10-membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 ^R4 represents a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to ³ substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents ^which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group ^{, -NR7bR7c} , -SO ₂ R ^7d , -CONR ^7e R ^7f , C _1-6 alkyl (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkenyl (the alkenyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkynyl (the alkynyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), C _1-6 alkoxy (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 1-6 alkyl and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by ^1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR 11 R 12), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of -NR 11 R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁶ represents a hydrogen atom or a halogen atom, R ^7b , R ^7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group, when there are plural R ¹¹ or R ¹² , R ^{R 11} or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein A is CHF. The compound of claim 17 or 18 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom. The compound of any one of claims 17 to 19, or a pharmaceutically acceptable salt thereof, wherein Z is a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 17 to 20 or a pharmaceutically acceptable salt thereof, wherein Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 17 to 21 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ). The compound of any one of claims 17 to 22 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a halogen atom, a cyano group, -NR ^7b R ^7c , a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group and -NR ¹¹ R ¹² ), a C _1-6 alkoxy group (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 ). ¹² and 1 to 3 substituents which are the same or different). The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (3): [Chemical 5] [In the formula, R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R 1-6 alkyl group and -NR ₁₁ R ¹² ), or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 same or different substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R 11 or R ¹² , each R ¹¹ or R ¹² may be the same or different. Herein, when R ¹¹ and R ¹² bonded to the _{same nitrogen atom are both C 1-6} ^alkyl groups, they may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded]. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl. The compound of claim 24 or 25 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluoro-2-pyridyl. The compound of any one of claims 24 to 26 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-10 membered divalent non-aryl heterocyclic group. The compound of any one of claims 24 to 27 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-6 membered divalent non-aryl heterocyclic group. The compound of any one of claims 24 to 28 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is azetidinyl or piperidinyl. The compound of any one of claims 24 to 29 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-6 alkyl group or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 24 to 30, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-3 alkyl group, or a 4-6 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 24 to 31 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl. The compound of any one of claims 24 to 31 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is oxacyclobutyl. The compound of any one of claims 24 to 33 or a pharmaceutically acceptable salt thereof, wherein R ¹¹ and R ¹² are methyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (4): [Chemical 6] [In the formula, R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ); R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group; when there are plural R ¹¹ or R ¹² groups, each R ¹¹ or R ¹² may be the same or different; herein, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may, together with the nitrogen atom to which they are bonded, form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-10 membered divalent non-aryl heterocyclic group. The compound of claim 35 or 36 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-6 membered divalent non-aryl heterocyclic group. The compound of any one of claims 35 to 37 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is azetidinyl. The compound of any one of claims 35 to 38, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-6 alkyl group, or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 35 to 39, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a C _1-3 alkyl group, or a 4-6 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 35 to 40 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is oxacyclobutyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (5): [Chemical 7] [In the formula, A represents CHF or CH ₂ , R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6-10 membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 ^R4 represents a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to ³ substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents ^which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group ^{, -NR7bR7c} , -SO ₂ R ^7d , -CONR ^7e R ^7f , C _1-6 alkyl (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkenyl (the alkenyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkynyl (the alkynyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-3 alkoxy (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 1-6 alkyl and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by ^1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR 11 R 12), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 1-6 alkyl group and -NR 11 ^{R 12} ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), R ⁶ represents a hydrogen atom or a halogen atom, R ^7a , R ^7b , R 7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group) ^, R ⁸ represents a hydrogen atom or a C _{1-6 alkyl group (the alkyl group may be substituted by 1-3 substituents selected from the group consisting of a halogen atom and a C 1-6} alkyl group R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R 11 or R ¹² , each R ¹¹ or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl ^groups , they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to _which they are bonded]. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein A is CHF. The compound of claim 42 or 43 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom. The compound of any one of claims 42 to 44, or a pharmaceutically acceptable salt thereof, wherein Z is a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof, wherein Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 42 to 46, or a pharmaceutically acceptable salt thereof, wherein ^R4 is a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a _C1-6 alkylene group), or a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a _C1-6 alkylene group). The compound of any one of claims 42 to 47, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a hydroxyl group, a cyano group, a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ^7d is a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 42 to 48 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is C _1-6 alkyl. The compound of any one of claims 42 to 49 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is methyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (6): [Chemical 8] [In the formula, R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a hydroxyl group, a cyano group, a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C a _3-10 membered alicyclic group (the alicyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R ¹¹ or R ¹² , each R ¹¹ or R ¹² may be the same or different. Here, when R ¹¹ and R ¹² are bonded to the same nitrogen atom, they are both C _1-6 alkyl groups, they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded]. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl. The compound of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluoro-2-pyridyl. The compound of any one of claims 51 to 53 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond or a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 51 to 54 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond. The compound of any one of claims 51 to 54 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 51 to 56 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydroxy, cyano, C _1-6 alkyl, C _3-10 alicyclic, or 4-10 membered non-aromatic heterocyclic group. The compound of any one of claims 51 to 57 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl. The compound of any one of claims 51 to 57 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is oxacyclobutyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (7): [Chemical 9] [In the formula, R ³ represents a 4-fluorophenyl group or a 4-fluoro-2-pyridyl group, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a cyano group, a C _{1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C 1-6 alkyl} group, a hydroxyl group, and -NR ¹¹ R 1-6 alkyl group and -NR ₁₁ R ¹² ), or a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1-3 same or different substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group and -NR ¹¹ R ¹² ), R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural R 11 or R ¹² , each R ¹¹ or R ¹² may be the same or different. Herein, when R ¹¹ and R ¹² bonded to the _{same nitrogen atom are both C 1-6} ^alkyl groups, they may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded]. The compound of claim 60 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond or a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of claim 60 or 61 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond. The compound of any one of claims 60 to 62, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _1-6 alkylene group (the alkylene group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group). The compound of any one of claims 60 to 63 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is C _1-6 alkyl or cyano. The compound of any one of claims 60 to 64 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl. The compound of any one of claims 60 to 64 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is cyano. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (8): [Chemical 10] [In the formula, A represents CHF or CH ₂ , R ³ represents 4-fluorophenyl or 4-fluoro-2-pyridyl, Z represents a 6-10 membered divalent aromatic cyclic group (the divalent aromatic cyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 ^R4 represents a single bond, a _C1-6 alkylene group (the alkylene group may be substituted by 1 to ³ substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), a _C3-10 cycloalkylene group (the cycloalkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a _C1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents ^which are the same or different and selected from the group consisting of a halogen atom, a _C1-6 alkyl group, and ^-NR11R12 ), ^R5 represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group ^{, -NR7bR7c} , -SO ₂ R ^7d , -CONR ^7e R ^7f , C _1-6 alkyl (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkenyl (the alkenyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-6 alkynyl (the alkynyl group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), C _1-3 alkoxy (the alkoxy group may be substituted by 1 to 3 substituents which are the same or different and are selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 1-6 alkyl and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by ^1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR 11 R 12), a C _6-10 aryl group (the aryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R ¹² ), a 5-10 membered heteroaryl group (the heteroaryl group may be substituted by 1-3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group and -NR ¹¹ R 12 _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom, a C 1-6 alkyl group, and -NR 11 R ¹² ), R ⁶ represents a hydrogen atom or a halogen atom, R ^7a , R ^7b , R ^7c , R ^7d , R ^7e , and R ^7f each independently represent a hydrogen atom or a C _1-6 alkyl group (the alkyl group may be substituted with 1 to 3 substituents which may be the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), R ^9a and R ^9b each independently represent a hydrogen atom, a halogen atom, or a C _wherein R ¹¹ and R ¹² are C _1-6 alkyl groups (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group); R 11 and R ¹² each independently represent a hydrogen atom or a C 1-6 alkyl group; when there are plural R ¹¹ or R ¹² , each R ¹¹ or R 12 may be the same or different; herein, when R ¹¹ and R ¹² bonded to the same nitrogen atom are both C _1-6 alkyl groups, they may form together with the nitrogen atom to which they are bonded a 3-8 membered nitrogen-containing non-aromatic heterocyclic group]. The compound of claim 67 or a pharmaceutically acceptable salt thereof, wherein A is CHF. The compound of claim 67 or 68 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom. The compound of any one of claims 67 to 69, or a pharmaceutically acceptable salt thereof, wherein Z is a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 5-10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 67 to 70, or a pharmaceutically acceptable salt thereof, wherein Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group may be substituted with 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 67 to 71, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10 membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group may be substituted by 1 to 3 substituents, which may be the same or different, selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ). The compound of any one of claims 67 to 72, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom, a cyano group, -NR ^7b R ^7c , a C _1-6 alkyl group (the alkyl group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, a hydroxyl group, and -NR ¹¹ R ¹² ), a C _3-10 alicyclic group (the alicyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), or a 4-10 membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 ). ¹² and 1 to 3 substituents which are the same or different). The compound or pharmaceutically acceptable salt thereof as described in any one of claims 67 to 73, wherein R ^9a and R ^9b are fluorine atoms. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (9): [Chemical 11] [In the formula, R ³ represents a 4-fluorophenyl group or a 4-fluoro-2-pyridyl group, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkenyl group, a C _1-6 alkynyl group, or a 4-10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural ^{R 11 or R 12, each R 11 or R 12 may be the same or different. Here, when R 11 and R 12 bonded to} the same nitrogen atom are both C _1-6 alkyl ^groups , they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded]. The compound of claim 75 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluorophenyl. The compound of claim 75 or 76 or a pharmaceutically acceptable salt thereof, wherein R ³ is 4-fluoro-2-pyridyl. The compound of any one of claims 75 to 77 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-10 membered divalent non-aromatic heterocyclic group. The compound of any one of claims 75 to 78 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-6 membered divalent non-aryl heterocyclic group. The compound of any one of claims 75 to 79 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is azetidinyl. The compound of any one of claims 75 to 80 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a 4-10 membered non-aryl heterocyclic group. The compound of any one of claims 75 to 81 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a 4-6 membered non-aryl heterocyclic group. The compound of any one of claims 75 to 82 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is oxacyclobutyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the formula (1) is the following formula (10): [Chemical 12] [In the formula, R ³ represents a 4-fluorophenyl group or a 4-fluoro-2-pyridyl group, R ⁴ represents a single bond, a C _1-6 alkylene group (the alkylene group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom and a C _1-6 alkyl group), or a 4-10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R ¹² ), R ⁵ represents a hydrogen atom, a cyano group, a C _1-6 alkyl group, a C _1-6 alkenyl group, a C _1-6 alkynyl group, or a 4-10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group may be substituted by 1 to 3 substituents which are the same or different and selected from the group consisting of a halogen atom, a C _1-6 alkyl group, and -NR ¹¹ R 12 R ¹¹ and R ¹² each independently represent a hydrogen atom or a C _1-6 alkyl group. When there are plural ^{R 11 or R 12, each R 11 or R 12 may be the same or different. Here, when R 11 and R 12 bonded to} the same nitrogen atom are both C _1-6 alkyl ^groups , they may form a 3-8 membered nitrogen-containing non-aromatic heterocyclic group together with the nitrogen atom to which they are bonded]. The compound of claim 84 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-10 membered divalent non-aromatic heterocyclic group. The compound of claim 84 or 85 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a 4-6 membered divalent non-aromatic heterocyclic group. The compound of any one of claims 84 to 86 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is azetidinyl. The compound of any one of claims 84 to 87 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a 4-10 membered non-aryl heterocyclic group. The compound of any one of claims 84 to 88 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a 4-6 membered non-aryl heterocyclic group. The compound of any one of claims 84 to 89 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is oxacyclobutyl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, 2-[(1'S)-5'-{1-[(3-fluoro-1-methylazetidin-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-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-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]acetamide, N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, N-[3,3-difluoro-1-(trifluoromethyl)cyclobutyl]-N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-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-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-5'-[1-(2-cyanopropane-2-yl)-1H-pyrazol-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)azetidin-3-yl]acetamide, N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S)-5'-[1-(2-cyanopropane-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrrolidone-3-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxacyclobutane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S)-5'-(5-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-Fluoro-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S)-5'-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(trifluoromethyl)-4-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, N-[(5-fluoropyridin-2-yl)methyl]-2-[(1'S)-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-{[3-(dimethylamino)oxacyclobutane-3-yl]methyl}-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxacyclobutane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxocyclobutane-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxocyclobutane-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-5'-[1-(2-cyanopropane-2-yl)-1H-pyrazol-4-yl]-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'R,3'S)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3',6'-difluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propane-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propane-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]-N-{[4-(trifluoromethyl)phenyl]methyl}acetamide. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds: 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)azetidin-3-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-(1-methyl-1H-pyrazol-4-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[1-(oxocyclobutane-3-yl)piperidin-4-yl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[3-(trifluoromethyl)oxocyclobutane-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-5'-[1-(oxocyclobutane-3-yl)-1H-pyrazol-4-yl]-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-3'-fluoro-5'-{1-[(oxocyclobutane-3-yl)methyl]-1H-pyrazol-4-yl}-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propane-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(4-fluorophenyl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-ethyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-{(1'S,3'R)-3'-fluoro-2,5-dioxo-5'-[1-(propane-2-yl)-1H-pyrazol-4-yl]-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl}-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide, 2-[(1'S,3'R)-5'-(1-cyclobutyl-1H-pyrazol-4-yl)-3'-fluoro-2,5-dioxo-2',3'-dihydrospiro[imidazolidin-4,1'-indene]-1-yl]-N-[(5-fluoropyridin-2-yl)methyl]-N-[1-methyl-3-(trifluoromethyl)azetidin-3-yl]acetamide. A medicament comprising the compound of any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition comprising the compound of any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof. A therapeutic and/or preventive agent for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease, comprising a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic and/or preventive agent for cancer, comprising the compound of any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof as an active ingredient. The therapeutic and/or preventive agent of claim 95 or 96, wherein the cancer is at least one cancer selected from the group consisting of SMARC-deficient cancer, SS18-SSX fusion cancer, and ARID-deficient cancer. The therapeutic agent and/or preventive agent of any one of claims 95 to 97, wherein the cancer is selected from malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoid/rhabdoid tumor, neurothelial tumor, chordoid meningioma, neuroepithelial tumor, neuroglioma, craniopharyngioma, neuroglioblastoma, chordoma, Myoepithelioma, extraskeletal myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, basal cell carcinoma of the nasal sinuses, esophageal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal stromal tumor, undifferentiated rhabdomyosarcoma of the pancreas, gastrointestinal rhabdomyosarcoma, renal medullary carcinoma, endometrial cancer, myoepithelioma-like tumor of the vulva Tumor, colorectal cancer, mesothelioma, lung adenocarcinoma, large cell lung carcinoma, pulmonary neuroendocrine tumor, esophagogastric junction cancer, gastric cancer, bladder cancer, squamous cell lung carcinoma, pancreatic cancer, medulloblastoma, clear cell kidney carcinoma, liver cancer, pleomorphic lung carcinoma, thoracic sarcoma, small cell ovarian carcinoma, primary gallbladder tumor, uterine sarcoma, ovarian granuloma At least one cancer selected from the group consisting of: small cell lung cancer, adrenocortical carcinoma, small cell lung cancer, ovarian cancer, corpus uteri cancer, neuroblastoma, mucinous ovarian tumor, sinus cancer, thoracic sarcoma, gallbladder cancer, pediatric neuroblastoma, melanoma, breast cancer, unclassified round cell sarcoma, rhabdomyosarcoma, and Evan's sarcoma. A method for treating or preventing cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease, comprising administering a therapeutically or preventively effective amount of a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof to a patient in need of treatment or prevention. Use of a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or preventive drug for cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease. A compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof, for use in treating or preventing cancer, non-alcoholic fatty liver disease (NAFLD), acute liver injury, heart disease, or metabolic disease. A compound according to any one of claims 1 to 92, or a pharmaceutically acceptable salt thereof, for use in combination with a concomitant drug or a pharmaceutically acceptable salt thereof for the treatment of cancer, wherein the concomitant drug is at least one selected from the group consisting of hormonal therapy agents, chemotherapy agents, immunotherapy agents, and agents that inhibit the action of cell growth factors and their receptors. A pharmaceutical composition comprising a compound according to any one of claims 1 to 92 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is in combination with a concomitant drug, wherein the concomitant drug is at least one selected from the group consisting of hormonal therapy agents, chemotherapy agents, immunotherapy agents, and agents that inhibit the action of cell growth factors and their receptors.