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WO2024034652A1 - Dérivé d'amide tertiaire substitué par du carbone quaternaire - Google Patents

Dérivé d'amide tertiaire substitué par du carbone quaternaire Download PDF

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Publication number
WO2024034652A1
WO2024034652A1 PCT/JP2023/029183 JP2023029183W WO2024034652A1 WO 2024034652 A1 WO2024034652 A1 WO 2024034652A1 JP 2023029183 W JP2023029183 W JP 2023029183W WO 2024034652 A1 WO2024034652 A1 WO 2024034652A1
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Prior art keywords
alkyl
group
methyl
optionally substituted
same
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Japanese (ja)
Inventor
惇一郎 上杉
正児 上岡
仁志 坂
雄介 今▲崎▼
雄介 亀井
秀明 荻原
麻里子 佐々木
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National Cancer Center Japan
Sumitomo Pharma Co Ltd
National Cancer Center Korea
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Sumitomo Pharmaceuticals Co Ltd
National Cancer Center Japan
Sumitomo Pharma Co Ltd
National Cancer Center Korea
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Publication of WO2024034652A1 publication Critical patent/WO2024034652A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present disclosure provides pharmaceutically useful quaternary carbon-substituted tertiary amide derivatives and pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them, or CBP/P300 containing these compositions.
  • the present invention relates to therapeutic agents or preventive agents for related pathological conditions.
  • Chromosomes change their higher-order structure through methylation of their component DNA and various modifications (acetylation, methylation, phosphorylation, ubiquitination, etc.) of histones (histones H2A, H2B, H3, H4). , dynamically controls gene replication and transcription (Non-Patent Document 1).
  • Histone acetylation is a post-translational modification that frequently occurs in eukaryotes, and works to promote gene transcription.
  • Histone acetyltransferase which functions in the acetylation modification of histones, is an enzyme that transfers an acetyl group to the lysine side chain of histones, and there are four main types based on amino acid sequence homology, higher-order structure, and its function. are categorized.
  • CBP/P300 E1A binding protein p300/CREB Binding Protein
  • GCN5/PCAF general control nonrepressed-protein 5/P 300/CBP-associated factor
  • MYST MOZ, Ybf2/Sas3, Sas2, and Tip60
  • Rtt109 Regulator of Tyl Transposition gene production 109.
  • P300 and its paralog CBP have over 90% amino acid sequence homology, and in addition to the HAT domain, there are CH1/CH2/CH3 domains (cysteine-histidine rich domains), KIX domain, and bromodomain ( Non-patent document 2).
  • CBP/P300 was discovered as a binding partner of E1A adenoviral protein and cAMP-regulated enhancer binding protein, respectively (Non-Patent Documents 3-5). Subsequently, it was found that CBP/P300 has HAT activity (Non-patent Documents 6, 7), and its substrate specificity was investigated, and , p53 (Non-Patent Document 8), MyoD (Non-Patent Document 9), STAT3 (Non-Patent Document 10), Androgen receptor (Non-Patent Document 11), etc. were also reported to be acetylated. Furthermore, CBP/P300 is also involved in many biological reactions such as division, proliferation, and differentiation (Non-Patent Document 12).
  • CBP/P300 plays an important role in the growth of various cancers. Examples include prostate cancer (Non-Patent Documents 13, 14), liver cancer (Non-Patent Documents 15, 16), lung cancer (Non-Patent Documents 17, 18, 19), breast cancer (Non-Patent Documents 20), and large intestine cancer.
  • Non-patent Document 21 gastric cancer
  • Non-patent Document 22, 23 pancreatic cancer
  • Non-patent Document 24 bladder cancer
  • Non-patent Document 25 gastrointestinal stromal tumor
  • Patent Document 26 NUT midline carcinoma
  • Non-Patent Document 27 ovarian cancer
  • Non-Patent Document 28 malignant rhabdoid tumor and epithelioid sarcoma
  • the present disclosure provides compounds that exhibit anticancer effects by inhibiting CBP/P300, which is reported to be highly expressed, mutated, or hyperactive in various cancers.
  • CBP/P300 which is reported to be highly expressed, mutated, or hyperactive in various cancers.
  • it has high CBP/P300 inhibitory activity and also has "high water solubility that exhibits anticancer effects when administered intravenously" and "high oral absorption that exhibits anticancer effects when administered orally.”
  • the present invention provides a very useful compound as an anticancer agent that can be expected to be applied to the treatment of a wide range of cancer types.
  • the present inventors found that the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "compound of the present disclosure")
  • the present disclosure was completed based on the discovery that the present invention exhibits excellent anticancer activity by having a strong inhibitory effect on the HAT domain of /P300, and exhibits high oral absorption and water solubility suitable for oral and intravenous administration. I ended up letting it happen.
  • B is the following formula (B-1): [In the formula, * represents the bonding position with the nitrogen atom of the hydantoin ring], Ring Q represents an optionally substituted 6- to 10-membered aromatic hydrocarbon ring or an optionally substituted 5- to 10-membered aromatic heterocycle, Z is -O-, -N(R 7a )-, an optionally substituted 6- to 10-membered divalent aromatic ring group, an optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, an optionally substituted 4- to 10-membered divalent aromatic ring group represents a divalent non-aryl heterocyclic group, R 1 is optionally substituted C 1-6 Alkyl or optionally substituted C 3-10 represents an alicyclic group, R 2a and R 2b are each independently optionally substituted C 1-6 represents alkyl, where R 2a and
  • Nitro may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
  • the groups shown in the alicyclic group and (11) 3- to 10-membered non-aryl heterocyclic group are (a) halogen atom, (b) hydroxyl group, (c)C 6-10 aryl, (d) 5-12 membered heteroaryl, (e)C 1-6 alkyl, (f)C 2-6 alkenyl, (g)C 2-6 alkyn
  • Nitro may be substituted with the same or different 1 to 5 substituents selected from the group consisting of; R 10 However, if there are multiple, each independently, C 1-6 is alkyl, R 11 and R 12 are each independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded, R 13 is a hydrogen atom or C 1-6 is an alkyl, Item 1.
  • R 1 ,R 2a ,R 2b ,R 3 ,R 4 ,R 5 ,R 6a ,R 6b ,R 7a ,R 7b ,R 7c ,R 7d ,R 7e ,R 7f ,R 8 ,R 9a ,R 9b an optionally substituted 6- to 10-membered aromatic hydrocarbon ring in rings Q and Z, an optionally substituted 5- to 10-membered aromatic heterocycle, an optionally substituted 6- to 10-membered aromatic heterocycle, Divalent aromatic hydrocarbon ring group, optionally substituted 5- to 10-membered divalent aromatic heterocyclic group, optionally substituted C 6-10 Aryl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted 4- to 10-membered non-aryl heterocyclic group, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 alkenyl, optionally substituted C 1-6 Alkynyl, optionally substituted C 3-10 Alicyclic group
  • Cyano may be substituted with the same or different 1 to 5 substituents selected from the group consisting of; R 10 However, if there are multiple, each independently, C 1-6 is alkyl, R 11 and R 12 are each independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded, A compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
  • R 6a and R 6b are each independently a fluorine atom or a methyl group, A compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • R 6a and R 6b is a fluorine atom, The compound according to any one of Items 1 to 5 or a pharmaceutically acceptable salt thereof.
  • [Section 9] B is the following formula (B-2), (B-3), or (B-4): [In the formula, * represents the bonding position with the nitrogen atom of the hydantoin ring, a represents 0, 1, or 2, b represents 1 or 2, R 8 is a hydrogen atom or an optionally substituted C 1-6 represents alkyl, R 9a and R 9b are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 represents alkyl], Item 8. A compound according to any one of Items 1 to 8 or a pharmaceutically acceptable salt thereof. [Section 10] R 1 is optionally substituted with 1 to 3 fluorine atoms 1-3 is an alkyl, Item 10.
  • CF 3 is, Item 10. The compound according to any one of Items 1 to 10 or a pharmaceutically acceptable salt thereof.
  • C 6-10 Aryl the aryl is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl
  • 5- to 10-membered heteroaryl said heteroaryl includes a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl
  • R 3 is 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, 3-fluoro-2-thienyl, or 4-fluoro-2-pyridyl, A compound according to any one of Items 1 to 12 or a pharmaceutically acceptable salt thereof.
  • R 3 is 4-fluorophenyl or 4-fluoro-2-pyridyl, A compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof.
  • Ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring includes a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), A compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.
  • Ring Q is a benzene ring, Item 15. The compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof.
  • [Section 17] a is 1 or 2, Item 17.
  • [Section 18] a is 1, Item 18.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkoxy (the al
  • A is CF 2 is, Item 20.
  • Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of),
  • a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 22.
  • Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 23.
  • the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 23.
  • [Section 25] R 5 but, hydrogen atom, halogen atom, Cyano, -NR 7b R 7c , C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 25.
  • Formula (1) becomes the following formula (3): [In the formula, R 3 represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), or 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 5 teeth, hydrogen atom, Cyano, -NR 7b R 7c , C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (option
  • Item 1 The compound according to item 1 or a pharmaceutically acceptable salt thereof.
  • [Section 27] R 4 but, is a 4- to 10-membered divalent non-aryl heterocyclic group, Item 27.
  • [Section 28] R 4 but, is a 4- to 6-membered divalent non-aryl heterocyclic group, Item 28.
  • [Section 29] R 4 but, is azetidinylene, Item 29.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the alkoxy is
  • A is CF 2 is, The compound according to any one of Items 1 to 34 or a pharmaceutically acceptable salt thereof.
  • Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), A 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 36.
  • Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 37.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), R 7d
  • C 1-6 Alkyl (the alkyl is a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), Item 39.
  • R 7d , -CONR 7e R 7f , or 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 7d ,R 7e , and R 7f are each independently, hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), R 11 and R 12 are each independently a hydrogen atom or C 1-6 represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen
  • Item 1 The compound according to item 1 or a pharmaceutically acceptable salt thereof.
  • R 4 but, single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), Item 42.
  • R 4 is a single bond, Item 43.
  • C 1-6 is an alkyl, Item 45.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the al
  • Item 1 The compound according to item 1 or a pharmaceutically acceptable salt thereof.
  • A is CF 2 is, Item 49.
  • Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), A 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 49.
  • Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), Item 51.
  • R 5 but, hydrogen atom, Cyano, -NR 7b R 7c , C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 3-10 Alicyclic group (the alicyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of) Item 53.
  • Formula (1) becomes the following formula (7): [In the formula, R 3 represents 4-fluorophenyl or 4-fluoro-2-pyridyl, R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), or 4- to 10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 5 teeth, hydrogen atom, Cyano, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12
  • Item 1 The compound according to item 1 or a pharmaceutically acceptable salt thereof.
  • R 4 is a 4- to 10-membered divalent non-aryl heterocyclic group, Item 56.
  • SAection 57 R 4 but, is a 4- to 6-membered divalent non-aryl heterocyclic group, Item 57.
  • SAection 58 R 4 but, is azetidinylene, Item 58.
  • Item 65 A medicament containing the compound according to any one of Items 1 to 64 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 65 A pharmaceutical composition containing the compound according to any one of Items 1 to 64 or a pharmaceutically acceptable salt thereof.
  • NAFLD non-alcoholic fatty liver disease
  • Heart disease containing the compound or pharmaceutically acceptable salt thereof as an active ingredient according to any one of Items 1 to 64.
  • a therapeutic and/or prophylactic agent for metabolic diseases a therapeutic and/or prophylactic agent for metabolic diseases.
  • Item 65 A therapeutic and/or prophylactic agent for cancer, comprising the compound according to any one of items 1 to 64 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item 69 The therapeutic and/or preventive agent according to Item 67 or 68, wherein the cancer is at least one type of cancer selected from the group consisting of SMARC-deficient cancer, SS18-SSX fusion cancer, and ARID-deficient cancer.
  • the cancer is malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoma-like/rhabdoid tumor, schwannoma, chordoma-like meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma , chordoma, myoepithelial tumor, extraosseous myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, sinonasal basaloid carcinoma, esophageal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal Stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary cancer, endometrial cancer, myoepithelioma-like tumor in the female genital area, colorectal cancer, mesothelioma
  • NAFLD non-alcoholic fatty liver disease
  • the concomitant drug is at least one selected from the group consisting of hormone therapy agents, chemotherapeutic agents, immunotherapeutic agents, and drugs such as cell growth factors and drugs that inhibit their receptor actions. , or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound according to any one of Items 1 to 64, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is , a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, and a drug such as a cell growth factor and a drug that inhibits its receptor action.
  • a concomitant drug is , a hormonal therapeutic agent, a chemotherapeutic agent, an immunotherapeutic agent, and a drug such as a cell growth factor and a drug that inhibits its receptor action.
  • Nitro may be substituted with the same or different 1 to 5 substituents selected from the group consisting of;
  • the groups shown in the alicyclic group and (11) 3- to 10-membered non-aryl heterocyclic group are (a) halogen atom, (b) hydroxyl group, (c)C 6-10 aryl, (d) 5-12 membered heteroaryl, (e)C 1-6 alkyl, (f)C 2-6 alkenyl, (g)C 2-6 alkyn
  • Nitro may be substituted with the same or different 1 to 5 substituents selected from the group consisting of; R 10 However, if there are multiple, each independently, C 1-6 is alkyl, R 11 and R 12 are each independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded, R 13 is a hydrogen atom or C 1-6 is an alkyl, A compound according to item A1, or a pharmaceutically acceptable salt
  • R 11 R 12 (18) Sulfo, (19) phosphate group, (20) Cyano, and (21) Nitro may be substituted with the same or different 1 to 5 substituents selected from the group consisting of; R 10 However, if there are multiple, each independently, C 1-6 is alkyl, R 11 and R 12 are each independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded, A compound according to any one of Items A1 to A2, or a pharmaceutically acceptable salt thereof.
  • Cyano may be substituted with the same or different 1 to 5 substituents selected from the group consisting of; R 10 However, if there are multiple, each independently, C 1-6 is alkyl, R 11 and R 12 are each independently a hydrogen atom or C 1-6 Represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen atom to which they are bonded, A compound according to any one of Items A1 to A3, or a pharmaceutically acceptable salt thereof.
  • R 6a and R 6b are each independently a fluorine atom or a methyl group, A compound according to any one of Items A1 to A4 or a pharmaceutically acceptable salt thereof.
  • R 6a and R 6b is a fluorine atom, A compound according to any one of Items A1 to A5 or a pharmaceutically acceptable salt thereof.
  • [Section A9] B is the following formula (B-2), (B-3), or (B-4): [In the formula, * represents the bonding position with the nitrogen atom of the hydantoin ring, a represents 0, 1, or 2, b represents 1 or 2, R 8 is a hydrogen atom or an optionally substituted C 1-6 represents alkyl, R 9a and R 9b are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 represents alkyl], A compound according to any one of Items A1 to A8 or a pharmaceutically acceptable salt thereof.
  • R 1 is optionally substituted with 1 to 3 fluorine atoms 1-3 is an alkyl, A compound according to any one of Items A1 to A9 or a pharmaceutically acceptable salt thereof.
  • CF 3 is, A compound according to any one of items A1 to A10 or a pharmaceutically acceptable salt thereof.
  • C 6-10 Aryl the aryl is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl
  • R 3 is 4-fluorophenyl, A compound according to any one of items A1 to A12 or a pharmaceutically acceptable salt thereof.
  • Ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring includes a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), A compound according to any one of items A1 to A13 or a pharmaceutically acceptable salt thereof.
  • Ring Q is a benzene ring, A compound according to any one of Items A1 to A14 or a pharmaceutically acceptable salt thereof.
  • [Section A16] a is 1 or 2, A compound according to any one of items A1 to A15 or a pharmaceutically acceptable salt thereof.
  • [Section A17] a is 1, A compound according to any one of Items A1 to A16 or a pharmaceutically acceptable salt thereof.
  • [Section A18] b is 1, A compound according to any one of items A1 to A17 or a pharmaceutically acceptable salt thereof.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkoxy (the alk
  • A is CF 2 is, A compound according to any one of items A1 to A19 or a pharmaceutically acceptable salt thereof.
  • Z is a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), A 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), A compound according to any one of Items A1 to A20 or a pharmaceutically acceptable salt thereof.
  • Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), A compound according to any one of items A1 to A21 or a pharmaceutically acceptable salt thereof.
  • Formula (1) becomes the following formula (3): [In the formula, R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), or 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 5 teeth, hydrogen atom, -NR 7b R 7c , C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl
  • a compound according to item A1 or a pharmaceutically acceptable salt thereof is a 4- to 10-membered divalent non-aryl heterocyclic group, A compound according to any one of items A1 to A25 or a pharmaceutically acceptable salt thereof.
  • R 5 but, C 1-6 alkyl, or 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl and A compound according to any one of Items A1 to A28 or a pharmaceutically acceptable salt thereof.
  • R 5 but, C 1-3 alkyl, or 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl and A compound according to any one of Items A1 to A29 or a pharmaceutically acceptable salt thereof.
  • R 5 but, is methyl, A compound according to any one of Items A1 to A30 or a pharmaceutically acceptable salt thereof.
  • R 5 but, is oxetanil, A compound according to any one of Items A1 to A30 or a pharmaceutically acceptable salt thereof.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the al
  • A is CF 2 is, A compound according to any one of Items A1 to A33 or a pharmaceutically acceptable salt thereof.
  • Z is a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), A 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), A compound according to any one of Items A1 to A34 or a pharmaceutically acceptable salt thereof.
  • Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), A compound according to any one of items A1 to A35 or a pharmaceutically acceptable salt thereof.
  • R 5 but, hydrogen atom, Cyano, C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), A compound according to any one of Items A1 to A37 or a pharmaceutically acceptable salt thereof.
  • R 7d , -CONR 7e R 7f , or 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 7d ,R 7e , and R 7f are each independently, hydrogen atom, or C 1-6 Alkyl (the alkyl is a halogen atom and C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), R 11 and R 12 are each independently a hydrogen atom or C 1-6 represents alkyl, R 11 or R 12 If there are multiple R 11 or R 12 may be the same or different, and here, R bonded to the same nitrogen atom 11 and R 12 are both C 1-6 When alkyl, these may form a 3- to 8-membered nitrogen-containing non-aryl heterocyclic group together with the nitrogen
  • a compound according to item A1 or a pharmaceutically acceptable salt thereof A compound according to item A1 or a pharmaceutically acceptable salt thereof.
  • R 4 but, single bond, or C 1-6 Alkylene (the alkylene is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), A compound according to any one of items A1 to A40 or a pharmaceutically acceptable salt thereof.
  • R 4 is a single bond, A compound according to any one of Items A1 to A41 or a pharmaceutically acceptable salt thereof.
  • C 1-6 Alkyl (the alkyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkenyl (the alkenyl is a halogen atom, C 1-6 Alkyl, hydroxyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-6 Alkynyl (the alkynyl is a halogen atom, C 1-6 Alkyl, hydroxyl group and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the alkoxy is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), C 1-3 Alkoxy (the alkoxy
  • a compound according to item A1 or a pharmaceutically acceptable salt thereof is, A compound according to item A1 or a pharmaceutically acceptable salt thereof.
  • A is CF 2 is, A compound according to any one of Items A1 to A47 or a pharmaceutically acceptable salt thereof.
  • Z is a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with 1 to 3 same or different substituents selected from the group consisting of), A 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of) A compound according to any one of Items A1 to A48 or a pharmaceutically acceptable salt thereof.
  • Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of), A compound according to any one of Items A1 to A49 or a pharmaceutically acceptable salt thereof.
  • R 9a and R 9b but, is a fluorine atom, A compound according to any one of Items A1 to A52 or a pharmaceutically acceptable salt thereof.
  • Formula (1) becomes the following formula (7): [In the formula, R 4 teeth, single bond, C 1-6 Alkylene (the alkylene is a halogen atom and a C 1-6 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of alkyl), or 4- to 10-membered divalent non-aryl heterocyclic group (the non-aryl heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R 12 optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 5 teeth, hydrogen atom, Cyano, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, or 4- to 10-membered non-aryl heterocyclic group (the non-aryl hetero
  • R 4 is a 4- to 10-membered divalent non-aryl heterocyclic group, A compound according to any one of Items A1 to A54 or a pharmaceutically acceptable salt thereof.
  • R 4 is a 4- to 6-membered divalent non-aryl heterocyclic group, A compound according to any one of items A1 to A55 or a pharmaceutically acceptable salt thereof.
  • R 4 is azetidinylene, A compound according to any one of Items A1 to A56 or a pharmaceutically acceptable salt thereof.
  • R 5 but, C 1-6 alkyl, or is a 4- to 10-membered non-aryl heterocyclic group, A compound according to any one of Items A1 to A57 or a pharmaceutically acceptable salt thereof.
  • R 5 but, C 1-3 alkyl, or is a 4- to 6-membered non-aryl heterocyclic group, A compound according to any one of Items A1 to A58 or a pharmaceutically acceptable salt thereof.
  • R 5 but, is methyl, A compound according to any one of Items A1 to A59 or a pharmaceutically acceptable salt thereof.
  • [Section A62] A compound according to item A1 or a pharmaceutically acceptable salt thereof selected from the following compounds: N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'- ⁇ 1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-yl ⁇ -2 ,3',5-trioxo-2',3'-dihydrospiro[imidazolidin-4,1'-inden]-1-yl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide (Example 1), N-[(4-fluorophenyl)methyl]-2-[(1'S)-5'- ⁇ 1-[2-(morpholin-4-yl)ethyl]-1H-pyrazol-4-
  • [Section A64] A medicament containing the compound according to any one of items A1 to A63 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • [Section A65] A pharmaceutical composition containing a compound according to any one of Items A1 to A63 or a pharmaceutically acceptable salt thereof.
  • [Section A66] Cancer, non-alcoholic fatty liver disease (NAFLD), acute liver disorder, heart disease, containing the compound or pharmaceutically acceptable salt thereof as an active ingredient according to any one of Items A1 to A63. Or a therapeutic and/or prophylactic agent for metabolic diseases.
  • a therapeutic and/or prophylactic agent for cancer comprising a compound according to any one of items A1 to A63 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Cancer A68 The therapeutic and/or preventive agent according to item A66 or 67, wherein the cancer is at least one type of cancer selected from the group consisting of SMARC-deficient cancer, SS18-SSX fusion cancer, and ARID-deficient cancer.
  • the cancer is malignant rhabdoid tumor, epithelioid sarcoma, atypical teratoma-like/rhabdoid tumor, schwannoma, chordoma-like meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, glioblastoma , chordoma, myoepithelial tumor, extraosseous myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, sinonasal basaloid carcinoma, esophageal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, gastrointestinal Stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary cancer, endometrial cancer, myoepithelioma-like tumor in the female genital area, colorectal cancer, mesotheliom
  • NAFLD non-alcoholic fatty liver disease
  • a pharmaceutical composition comprising a compound according to any one of Items A1 to A63, or a pharmaceutically acceptable salt thereof, in combination with a concomitant drug, wherein the concomitant drug is a hormonal therapy agent, a chemical
  • a pharmaceutical composition comprising at least one selected from the group consisting of therapeutic agents, immunotherapeutic agents, and drugs such as cell growth factors and drugs that inhibit their receptor actions.
  • the present disclosure provides CBP/P300 inhibitors comprising quaternary carbon substituted tertiary amide derivatives and pharmaceutically acceptable salts thereof.
  • the present disclosure provides agents that inhibit CBP/P300 function that are applicable to a wide range of diseases and administration methods.
  • the present disclosure also provides compounds represented by formula (1) that are quaternary carbon-substituted tertiary amide derivatives that can be used as these drugs, and drugs related thereto.
  • the compounds of the present disclosure exhibit excellent CBP/P300 inhibitory activity and are useful as therapeutic agents for diseases involving CBP/P300, specifically cancer, non-alcoholic fatty liver disease (NAFLD), acute It is applicable to patients with liver disorders, heart diseases, metabolic diseases, etc.
  • NASH non-alcoholic fatty liver disease
  • FIG. 1 is a diagram showing the acetylation level of histone H3K27 in recovered tumors detected by Western blotting after repeated oral administration of Examples 46 and 83 to G401 xenograft model mice. .
  • the protein amount of H3 is expressed as a loading control.
  • Figure 2 shows the acetylation level of histone H3K27 in tumors recovered after single administration of Example 46, Example 83, Comparative Example 1, and Comparative Example 2 by tail vein administration to G401 xenograft model mice. It is a figure detected by Western blotting.
  • the Western blotting shown on the left (Comparative Example 1, Comparative Example 2, and Example 46) is the result of intravenous administration at a dose of 5 ml/kg.
  • the Western blotting shown on the right (Comparative Example 1 and Example 83) is the result of intravenous administration at a dose of 10 ml/kg.
  • the protein amount of H3 is expressed as a loading control.
  • the number of substituents in the group defined as “optionally substituted” is not particularly limited as long as they are substitutable.
  • the number of substituents is specified and it is described as “substituted” with that number of substituents, it indicates that it is substituted with that number.
  • substituted with 2 to 5 substituents indicates substitution with 2, 3, 4, or 5 substituents.
  • the description of each group also applies when the group is a part or substituent of another group.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Preferably it is a fluorine atom or a chlorine atom.
  • C 1-6 alkyl means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms
  • C 6 alkyl means an alkyl group having 6 carbon atoms. means. The same applies to other numbers.
  • Preferred examples of C 1-6 alkyl include “C 1-4 alkyl", more preferably “C 1-3 alkyl”.
  • Specific examples of “C 1-3 alkyl” include methyl, ethyl, propyl, 1-methylethyl, and the like.
  • Specific examples of "C 1-4 alkyl” include butyl, 1,1 - dimethylethyl, 1-methylpropyl, 2-methyl Examples include propyl.
  • C 1-6 alkyl include pentyl, 1,1 - dimethylpropyl, 1,2-dimethylpropyl, 1 -Methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.
  • C 2-6 alkenyl means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds.
  • Preferred examples of “C 2-6 alkenyl” include “C 2-4 alkenyl.”
  • Specific examples of “C 2-4 alkenyl” include vinyl, propenyl, methylpropenyl, butenyl, and the like.
  • Specific examples of “C 2-6 alkenyl” include pentenyl, hexenyl, and the like, in addition to those listed above as specific examples of “C 2-4 alkenyl.”
  • C 2-6 alkynyl means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one triple bond.
  • C 2-6 alkynyl preferably includes “C 2-4 alkynyl”.
  • Specific examples of “C 2-4 alkynyl” include propynyl, methylpropynyl, butynyl, and the like.
  • Specific examples of “C 2-6 alkynyl” include methylbutynyl, pentynyl, hexynyl, and the like, in addition to those listed above as specific examples of "C 2-4 alkynyl.”
  • C 1-6 alkoxy means “C 1-6 alkyloxy", and the “C 1-6 alkyl” moiety has the same meaning as the above-mentioned “C 1-6 alkyl”.
  • C 1-6 alkoxy preferably includes “C 1-4 alkoxy”, and more preferably “C 1-3 alkoxy”.
  • Specific examples of “C 1-3 alkoxy” include methoxy, ethoxy, propoxy, 1-methylethoxy, and the like.
  • Specific examples of “C 1-4 alkoxy” include, in addition to those listed above as specific examples of “C 1-3 alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methyl Examples include propoxy.
  • C 1-6 alkoxy examples include pentyloxy, 1,1 - dimethylpropoxy, 1,2-dimethylpropoxy, 1 -methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.
  • C 1-6 alkyl part of “C 1-6 alkylthio” has the same meaning as the above "C 1-6 alkyl”.
  • C 1-6 alkylthio preferably includes “C 1-4 alkylthio", and more preferably “C 1-3 alkylthio”.
  • Specific examples of “C 1-3 alkylthio” include methylthio, ethylthio, propylthio, 1-methylethylthio, and the like.
  • Specific examples of "C 1-4 alkylthio” include butylthio, 1,1 - dimethylethylthio, 1-methylpropylthio, 2 -Methylpropylthio and the like.
  • C 1-6 alkylthio include pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, in addition to those listed above as specific examples of "C 1-4 alkylthio". , 1-methylbutylthio, 2-methylbutylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio, hexylthio, and the like.
  • C 1-6 alkylene means a straight or branched divalent saturated hydrocarbon group having 1 to 6 carbon atoms.
  • C 1-6 alkylene preferably “C 1-4 alkylene” is mentioned, and more preferably “C 1-3 alkylene” is mentioned.
  • Specific examples of “C 1-3 alkylene” include, for example, methylene group, ethylene group, propylene group, and the like.
  • Specific examples of “C 1-4 alkylene” include, in addition to those listed above as specific examples of “C 1-3 alkylene", butylene group, 1,1-dimethylethylene group, 1,2-dimethylethylene group, etc. group, 1-methyltrimethylene group, 2-methyltrimethylene group, etc.
  • C 1-6 alkylene examples include pentylene group, 1,1 - dimethyltrimethylene group, 1,2-dimethyl Examples include trimethylene group, 1-methylbutylene group, 2-methylbutylene group, 1-methylpentylene group, 2-methylpentylene group, 3-methylpentylene group, hexylene group, and the like.
  • C 2-6 alkenylene means a linear or branched divalent unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 double bonds. do.
  • Preferred examples of “C 2-6 alkenylene” include “C 2-4 alkenylene.”
  • Specific examples of “C 2-4 alkenylene” include vinylene group, vinylidene group, propenylene group, methylpropenylene group, butenylene group, and the like.
  • Specific examples of “C 2-6 alkenyl” include, in addition to those listed above as specific examples of "C 2-4 alkenyl", a pentenylene group, a hexenylene group, and the like.
  • C 3-10 alicyclic group means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure.
  • the "C 3-10 alicyclic group” is preferably a "C 3-7 alicyclic group.” Specific examples of the “C 3-7 alicyclic group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Specific examples of the "C 3-10 alicyclic group” include cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. in addition to those listed as specific examples of the "C 3-7 alicyclic group” above. It will be done.
  • C 3-10 alicyclic group includes a bicyclic group in which the C 3-10 alicyclic group and an aromatic hydrocarbon ring are condensed.
  • Specific examples of the ring-fused compound include the structures shown below.
  • C 3-10 cycloalkylene means a cyclic divalent saturated hydrocarbon group having 3 to 10 carbon atoms, and includes those having a partially unsaturated bond and those having a crosslinked structure.
  • Preferred examples of “C 3-10 cycloalkylene” include “C 3-7 cycloalkylene”.
  • Specific examples of “C 3-7 cycloalkylene” include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like.
  • Specific examples of “C 3-10 cycloalkylene” include, for example, cyclooctylene, cyclononylene, cyclodecylene, adamantylene, etc. in addition to those listed as specific examples of "C 3-7 cycloalkylene”.
  • C 3-10 cycloalkenylene means a cyclic divalent unsaturated hydrocarbon group having 3 to 10 carbon atoms, and includes those with a bridged structure. Specific examples of “C 3-10 cycloalkenylene” include cyclobutenylene, cyclopentenylene, cyclohexenylene, and the like.
  • “3- to 10-membered saturated carbocycle” means a cyclic saturated hydrocarbon having 3 to 10 carbon atoms.
  • the "3- to 10-membered saturated carbocycle” preferably includes "4- to 6-membered saturated carbocycle.”
  • Specific examples of the "4- to 6-membered saturated carbocycle” include, for example, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and the like.
  • the "3- to 10-membered saturated carbocycle” include, in addition to the specific examples of the "4- to 6-membered saturated carbocycle", a cyclopropane ring, a cycloheptane ring, a cyclooctane ring, Examples include cyclononane and cyclodecane.
  • a "4- to 10-membered non-aryl heterocyclic group” is a group consisting of 1 to 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and 2 to 9 carbon atoms. It means a monovalent non-aryl heterocyclic group consisting of a monovalent non-aryl heterocyclic group, and includes those having a partially unsaturated bond and those having a crosslinked structure.
  • the atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO 2 -.
  • the "4- to 10-membered non-aryl heterocyclic group” preferably includes “4- to 6-membered non-aryl heterocyclic group.”
  • Specific examples of the "4- or 5-membered non-aryl heterocyclic group” include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, Examples include oxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, and tetrahydropyranyl.
  • Examples of the "4- to 10-membered non-aryl heterocyclic group” include azepanyl, in addition to those listed as specific examples of the "4- to 6-membered monocyclic non-aryl heterocyclic group”.
  • azetidinylene and the like refer to divalent groups such as “azetidinyl”.
  • the "4- to 10-membered non-aryl heterocyclic group” refers to a fused ring group in which the 4- to 10-membered non-aryl heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring are fused. It also includes bicyclic types that form .
  • the 6-membered aromatic hydrocarbon ring forming the condensed ring group include a benzene ring and the like.
  • Examples of the 6-membered aromatic heterocycle forming the condensed ring group include pyridine, pyrimidine, and pyridazine.
  • bicyclic "4- to 10-membered non-aryl heterocyclic group" forming the condensed ring group include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzo Dioxanyl, isoindolyl, indazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyridinyl, and the like.
  • 4- to 10-membered divalent non-aryl heterocyclic group means 1 to 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and 2 to 9 carbon atoms. It refers to a divalent non-aryl heterocyclic group consisting of the following, and includes those having a partially unsaturated bond and those having a crosslinked structure.
  • the atoms constituting the ring may include oxidized atoms such as -C(O)-, -S(O)-, and -SO 2 -.
  • the "4- to 10-membered divalent non-aryl heterocyclic group” preferably includes "4- to 6-membered divalent non-aryl heterocyclic group.”
  • Specific examples of the "4- to 6-membered divalent non-aryl heterocyclic group” include oxetanylene, azetidinylene, tetrahydrofurylene, pyrrolidinylene, imidazolidinylene, piperidinylene, morpholinylene, thiomorpholinylene, dioxothiomorpholinylene, etc.
  • Nylene hexamethylene iminilene, oxazolidinylene, thiazolidinylene, oxoimidazolidinylene, dioxoimidazolidinylene, oxooxazolidinylene, dioxooxazolidinylene, dioxothiazolidinylene, tetrahydrofuranylene, tetrahydro Examples include pyranylene.
  • Examples of the "4- to 10-membered divalent non-aryl heterocyclic group" include azepanylene, in addition to those listed as specific examples of the "4- to 6-membered divalent non-aryl heterocyclic group”.
  • the "4- to 10-membered divalent non-aryl heterocyclic group” includes the above-mentioned 4- to 10-membered divalent non-aryl heterocyclic group and a 6-membered aromatic hydrocarbon ring or a 6-membered aromatic heterocyclic ring. It also includes a bicyclic type in which the fused ring group is formed.
  • the 6-membered aromatic hydrocarbon ring forming the condensed ring group include a benzene ring and the like.
  • Examples of the 6-membered aromatic heterocycle forming the condensed ring group include pyridine, pyrimidine, and pyridazine.
  • bicyclic "4- to 10-membered divalent non-aryl heterocyclic group" forming the condensed ring group include dihydroindolylene, dihydroisoindolylene, dihydroprinylene, dihydrothiazolo Examples include pyrimidinylene, dihydrobenzodioxanylene, isoindolylene, indazolylene, tetrahydroquinolinylene, tetrahydroisoquinolinylene, and tetrahydronaphthyridinylene.
  • C 6-10 aryl means an aromatic hydrocarbon ring group having 6 to 10 carbon atoms. Specific examples of “C 6-10 aryl” include phenyl, 1-naphthyl, 2-naphthyl, and the like. Preferred is phenyl.
  • C 6-10 aryl refers to a bicyclic group in which the C 6-10 aryl and a C 4-6 alicyclic group or a 5- to 6-membered non-aryl heterocycle form a fused ring group. Also included. Specific examples of the bicyclic "C 6-10 aryl” forming a condensed ring group include the groups shown below.
  • Aromatic hydrocarbon ring means the ring portion of the above “C 6-10 aryl”.
  • 5- to 10-membered heteroaryl means a monocyclic 5- to 7-membered aromatic group containing 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. It means a cyclic heterocyclic group or a bicyclic 8- to 10-membered aromatic heterocyclic group. Preferably, it is a "5- to 7-membered monocyclic heteroaryl.” More preferred are pyridyl, pyrimidinyl, quinolyl, or isoquinolyl. More preferred is pyridyl.
  • 5- to 7-membered monocyclic heteroaryl include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, and triazinyl. , triazolyl, oxadiazolyl, triazolyl, tetrazolyl and the like.
  • 5- to 12-membered heteroaryl include indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, in addition to those listed above as specific examples of "5- to 7-membered monocyclic heteroaryl”. , benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, and the like.
  • Aromatic heterocycle means the ring portion of the above “5- to 12-membered heteroaryl”.
  • 3-10 membered cycloalkane means a cyclic saturated hydrocarbon having 3-10 carbon atoms, including those with partially unsaturated bonds and those with a cross-linked structure, and A part of the ring may be condensed with another ring.
  • Specific examples of the "3- to 10-membered cycloalkane” include cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like.
  • 6- to 10-membered aromatic hydrocarbon ring means a cyclic aromatic hydrocarbon having 6 to 10 carbon atoms, and a part of the ring may be fused with another ring.
  • Specific examples of the "6- to 10-membered aromatic hydrocarbon ring” include, for example, a benzene ring and naphthalene.
  • 5- to 10-membered aromatic heterocycle means a monocyclic 4- to 7-membered heterocycle containing 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. It means an aromatic heterocycle or a bicyclic 8- to 12-membered aromatic heterocycle, and a part of the ring may be fused with another ring.
  • Preferred examples include "5- to 6-membered aromatic heterocycle,” “5-membered aromatic heterocycle,” and “6-membered aromatic heterocycle.”
  • Specific examples of the "5- to 6-membered aromatic heterocycle” include furan, thiophene, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, and pyridazine.
  • Specific examples of the "5-membered aromatic heterocycle” include pyrazole, furan, thiophene, oxazole, and the like.
  • Specific examples of the "6-membered aromatic heterocycle” include pyridine, pyrazine, pyrimidine, pyridazine, and the like.
  • 6- to 10-membered divalent aromatic hydrocarbon ring group means monocyclic and bicyclic divalent aromatic hydrocarbon ring groups having 6 to 10 carbon atoms.
  • the "6- to 10-membered divalent aromatic hydrocarbon ring group” preferably includes a "6-membered divalent aromatic hydrocarbon ring group.”
  • Specific examples of the "6- to 10-membered divalent aromatic hydrocarbon ring group” and the “6-membered divalent aromatic hydrocarbon ring group” include, for example, a divalent benzene ring.
  • "5- to 10-membered divalent aromatic heterocyclic group” means a monocyclic divalent aromatic heterocyclic group containing 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. or a bicyclic divalent 8- to 10-membered aromatic heterocyclic group.
  • a "5- to 6-membered divalent aromatic heterocyclic group” is mentioned, and more preferably a "5-membered divalent aromatic heterocyclic group” is mentioned.
  • Specific examples of the "5-membered divalent aromatic heterocyclic group” include divalent pyrazole, divalent furan, divalent thiophene, and divalent oxazole.
  • Examples of the "5- to 10-membered divalent aromatic heterocyclic group” and “5- to 6-membered divalent aromatic heterocyclic group” include, for example, specific examples of the "5-membered divalent aromatic heterocyclic group” In addition to those listed above, examples include divalent pyridine, divalent pyrimidine, divalent pyrazine, and divalent pyridazine.
  • “Cancer” means a malignant tumor, and includes cancer, sarcoma, and hematological malignant tumor.
  • Specific examples of “cancer” include acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastoid, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic acute T-cell leukemia, basal cell carcinoma, gallbladder/cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, choriocarcinoma, chorioepithelial carcinoma, urothelium Cancer, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myeloid leukemia, colorectal cancer, cystadenocarcinoma, diffuse large B-cell
  • lymphoid malignancies of T-cell or B-cell origin leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma tumor, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendrocytoma, oral cavity cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera , prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous carcinoma, seminoma, skin cancer, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat gland carcinoma , thyroid cancer, Waldenström
  • esophageal adenocarcinoma papillary thyroid cancer, follicular thyroid cancer, gastrointestinal stromal tumor, undifferentiated rhabdoid tumor of the pancreas, gastrointestinal rhabdoid tumor, renal medullary cancer, endometrial cancer, myoepithelium of the female vulvar region
  • examples include tumor-like tumors, colon cancer, and mesothelioma.
  • CBP and P300 in the present disclosure are both histone acetyltransferases involved in chromatin regulation, and are in a paralog relationship.
  • CBP/P300 means “CBP” and "P300”.
  • Histone acetyltransferases are enzymes that primarily, but not exclusively, transfer acetyl groups to lysine residues present on the amino-terminal tails of histone proteins.
  • CBP and P300 primarily, but not exclusively, acetylate histones H2A, H2B, H3, H4.
  • histone H3 primarily, but not exclusively, lysine 18, lysine 27, lysine 56, and lysine 122 (H3K18, H3K27, H3K56, and H3K122, respectively) residues are acetylated.
  • acetylation of histone H3K27 is known as a marker of open chromatin and plays an important role in regulating gene expression (J Hum Genet. 2013 Jul; 58 (7): 439-45).
  • Substrates other than histones include p53 (Cell. 1997 Aug; 90 (4): 595-606), MyoD (J Biol Chem. 2000 Nov; 275 (44): 34359-34364), STAT3 (Science.
  • CBP CBP
  • P300 usually mean a protein, but depending on the situation, they may also refer to a nucleic acid encoding the same or a gene as a concept, and those skilled in the art will understand the context. can be understood appropriately.
  • HAT domains are domains that primarily, but not exclusively, have the activity of transferring acetyl groups to lysine residues present on the amino-terminal tails of histone proteins.
  • Bromodomains are protein domains that recognize primarily, but not exclusively, N-acetylated lysine residues found on the amino-terminal tails of histone proteins.
  • CBP refers to any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. Refers to any natural CBP.
  • the term encompasses unprocessed CBP and any form of CBP that results from processing in the cell.
  • the term also encompasses naturally occurring variants of CBP, such as splice variants or allelic variants.
  • Human CBP is registered as UniProt Accession Number: Q92793.
  • a representative amino acid sequence of human CBP is shown as UniProt Q92793-1 (SEQ ID NO: 1) or UniProt Q92793-2 (SEQ ID NO: 2).
  • P300 is derived from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise specified. Refers to any natural P300. The term encompasses unprocessed P300 and any form of P300 that results from processing in the cell. The term also encompasses naturally occurring variants of P300, such as splice variants or allelic variants.
  • Human P300 is registered as UniProt Accession Number: Q09472.
  • a representative amino acid sequence of human P300 is shown as UniProt Q09472-1 (SEQ ID NO: 3).
  • CBP/P300 inhibitor is a substance that inactivates, reduces activity, and/or reduces expression of CBP and/or P300. "Reduction of CBP/P300 expression” may act at any stage, including the pre-transcriptional level (e.g., genome stage), transcriptional level, post-transcriptional regulation level, translational level, and post-translational modification level. Good too.
  • the "CBP/P300 inhibitor” is preferably a HAT inhibitor or a BRD inhibitor, more preferably a HAT inhibitor.
  • HAT inhibitor is a compound that inhibits the histone acetyltransferase (HAT) activity of CBP and/or P300.
  • HAT histone acetyltransferase
  • a method of detecting CoA-SH produced as a byproduct during the histone acetyltransferase reaction using fluorescence for example, Gao T. et al. Methods Mol Biol. 2013; 981:229-38
  • a radioisotope detection method for example, Lau OD et al. J Biol Chem. 2000;275(29):21953-9
  • TR-FRET detection of acetylated histone peptides for example, a radioisotope detection method, Lau OD et al. J Biol Chem. 2000;275(29):21953-9.
  • WO2016/044770, WO2016/044771, WO2016/044777, WO2018/235966, WO2019/111980, WO2019/049061, WO2019/161162, WO2019/161157, WO2 Disclosed in 019/201291, WO2020/108500 Examples include compounds.
  • BRD inhibitor is a compound that inhibits the function of CBP and/or P300 bromodomain (BRD).
  • detecting the function of bromodomain for example, a method of detecting the binding between bromodomain and acetylated lysine residue by TR-FRET method (for example, Acta Pharmacol Sin. 2020; 41 (2): 286-292), etc. can be used.
  • 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 enzyme activity that transfers acetyl groups to lysine residues of proteins that serve as substrates.
  • the substrate include histone proteins and p53.
  • a bromodomain is a protein domain that recognizes N-acetylated lysine residues. N-acetylated lysine residues are found, for example, on the amino-terminal tails of histone proteins.
  • More preferred embodiments of A include CR 6a R 6b or C ⁇ O.
  • More preferred embodiments of A include CR 6a R 6b .
  • An even more preferred embodiment of A is CF 2 .
  • a preferred embodiment of B includes the following formula (B-1). [In the formula, * 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). [In the formula, * represents the bonding position with the nitrogen atom of the hydantoin ring]
  • R 1 is a C 1-6 alkyl or a C 3-10 alicyclic group (the alkyl or alicyclic group may be substituted with the same or different 1 to 3 halogen atoms). good).
  • R 1 is a C 1-6 alkyl or a C 3-10 alicyclic group (the alkyl or alicyclic group may be substituted with 1 to 3 fluorine atoms). can be mentioned.
  • R 1 is C 1-3 alkyl optionally substituted with 1 to 3 fluorines.
  • An even more preferred embodiment of R 1 is CF 3 .
  • R 2a and R 2b include C 1-6 alkyl, each of which may be independently substituted with 1 to 3 halogen atoms, which may be the same or different.
  • Another preferred embodiment of R 2a and R 2b is that the carbon atom to which R 2a and R 2b are bonded together is C 3-6 cycloalkylene or a 4- to 6-membered divalent non-aryl heterocycle. Examples include the case where a group is formed (the cycloalkylene or divalent non-aryl heterocyclic group may be substituted with 1 to 3 halogen atoms, which are the same or different).
  • R 2a and R 2b are bonded together is C 3-6 cycloalkylene or a 4- to 6-membered divalent non-aryl heterocycle. Examples include the case where a group is formed (the cycloalkylene or divalent non-aryl heterocyclic group may be substituted with 1 to 3 fluorine atoms).
  • R 3 include C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 alicyclic group, or 4-10 membered non-aryl heterocyclic group (such as aryl, heteroaryl, alicyclic group)
  • the cyclic group or the non-aryl heterocyclic group may be substituted with 1 to 3 same or different substituents selected from the group consisting of a halogen atom and C 1-6 alkyl).
  • R 3 is C 6-10 aryl (the aryl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl). or a 5- to 10-membered heteroaryl (the heteroaryl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl) can be mentioned.
  • R 3 is C 6-10 aryl or 5-10 membered heteroaryl (the heteroaryl is the same or different 1-3 atoms selected from the group consisting of fluorine atoms and C 1-6 alkyl). may be substituted with a substituent).
  • R 3 includes 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 4-chlorophenyl, 3-fluoro-2-thienyl, or 4-fluoro-2-pyridyl. More preferred are 4-fluorophenyl or 4-fluoro-2-pyridyl, and another preferred embodiment is 4-fluorophenyl.
  • R 4 include a single bond, C 1-6 alkylene (the alkylene is substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl). ), C 3-10 cycloalkylene (the cycloalkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl) , or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is the same or different one selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 ) (optionally substituted with up to 3 substituents).
  • R 4 include a single bond, C 1-6 alkylene (the alkylene is substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl). ), or a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is selected from the group consisting of a halogen atom, C 1-6 alkyl and -NR 11 R 12 may be substituted with the same or different 1 to 3 substituents).
  • R 4 is a 4- to 6-membered divalent non-aryl heterocyclic group.
  • R 4 is azetidinylene.
  • R 4 is C 1-6 alkylene (the alkylene is substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl). ) may be mentioned.
  • R 5 include a hydrogen atom, a halogen atom, a hydroxyl group, cyano, -NR 7b R 7c , -SO 2 R 7d or -CONR 7e R 7f , C 1-6 alkyl (the alkyl is a halogen atom, C 1-6 alkyl, hydroxyl group, and -NR 11 R 12 may be substituted with the same or different 1 to 3 substituents), C 1-6 alkenyl (the alkenyl is a halogen atom) , C 1-6 alkyl, hydroxyl group and -NR 11 R 12 ), C 1-6 alkynyl (the alkynyl is may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atom, C 1-6 alkyl, hydroxyl group, and -NR 11 R 12 ), C 1-6 alkoxy (the alkoxy may be substituted with the same or different 1 to 3 substituents selected from the
  • R 5 More preferred embodiments of R 5 include a hydrogen atom, a halogen atom, a hydroxyl group, cyano, -NR 7b R 7c , -SO 2 R 7d or -CONR 7e R 7f , C 1-6 alkyl (the alkyl is a halogen atom, may be substituted with the same or different 1 to 3 substituents selected from the group consisting of C 1-6 alkyl, hydroxyl group and -NR 11 atom, C 1-6 alkyl and -NR 11 R 12 ), or a 4- to 10-membered non-aryl heterocyclic group (The non-aryl heterocyclic group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atom, C 1-6 alkyl and -NR 11 R 12 ). .
  • R 5 More preferred embodiments of R 5 include cyano, C 1-6 alkyl (the alkyl is the same or different 1 to 3 selected from the group consisting of a halogen atom, C 1-6 alkyl, a hydroxyl group, and -NR 11 R 12 ). ), or a 4- to 6-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is a halogen atom, C 1-6 alkyl, and -NR 11 R 12 (optionally substituted with 1 to 3 selected substituents, the same or different).
  • R 5 includes C 1-3 alkyl, methyl group, or oxetane.
  • R 6a and R 6b are each independently a fluorine atom or a C 1-6 alkyl (the alkyl is the same or different 1 to 1-6 selected from the group consisting of a halogen atom and a C 1-6 alkyl). (optionally substituted with three substituents).
  • R 6a and R 6b each independently include a fluorine atom or a methyl group.
  • R 6a and R 6b each independently includes a fluorine atom.
  • R 7a , R 7b , R 7c , R 7d , R 7e and R 7f each independently include a hydrogen atom or C 1-6 alkyl (the alkyl is a halogen atom and a C 1-6 alkyl (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of).
  • R 7a , R 7b , R 7c , R 7d , R 7e and R 7f each independently include a hydrogen atom or a methyl group.
  • R 8 is a hydrogen atom or C 1-6 alkyl (the alkyl is substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl). ) can be mentioned.
  • R 8 is C 1-6 alkyl (the alkyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl). good).
  • R 8 is a methyl group.
  • R 9a and R 9b are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl (the alkyl is the same or (optionally substituted with 1 to 3 different substituents).
  • R 9a and R 9b each independently includes a halogen atom.
  • R 9a and R 9b is a fluorine atom.
  • R 10 includes C 1-6 alkyl.
  • R 11 and R 12 each independently include a hydrogen atom or C 1-6 alkyl.
  • R 11 and R 12 are both C 1-6 alkyl, these together with the nitrogen atom bonded to each form 3 Examples include the case where a ⁇ 8-membered nitrogen-containing non-aryl heterocyclic group is formed.
  • a preferred embodiment of ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring has 1 to 3 same or different atoms selected from the group consisting of halogen atoms and C 1-6 alkyl). may be substituted with a substituent).
  • a more preferable embodiment of ring Q is a benzene ring.
  • Preferred embodiments of Z include -O-, a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 may be substituted with the same or different 1 to 3 selected substituents), 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is a halogen atom, C 1 -6 alkyl and -NR 11 R 12 may be substituted with the same or different 1 to 3 substituents), or a 4 to 10-membered divalent non-aryl heterocyclic group (the The divalent non-aryl heterocyclic group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atom, C 1-6 alkyl and -NR 11 R 12 )
  • a more preferred embodiment of Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocycl
  • a further preferred embodiment of Z is a 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 (which may be substituted with 1 to 3 same or different substituents).
  • An even more preferred embodiment of Z is pyrazole.
  • Preferable embodiments of a include 0, 1, or 2.
  • More preferable embodiments of a include 1 and 2.
  • a more preferable embodiment of a is 1.
  • Preferred embodiments of b include 1 and 2.
  • a more preferable embodiment of b includes 1.
  • One embodiment of the compound represented by formula (1) includes the following (A).
  • B is the following formula (B-1): [In the formula, * represents the bonding position with the nitrogen atom of the hydantoin ring], Ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring is substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl) ), and Z is -O-, a 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group is the same group selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12) ; or may be substituted with 1 to 3 different substituents), a 5 to 10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, a C 1-6 al
  • the aryl heterocyclic group may be substituted with 1 to 3 fluorine atoms
  • R 3 is C 6-10 aryl (the aryl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl)
  • R 4 is a single bond
  • C 1-6 alkylene the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl
  • C 3-10 cycloalkylene the cycloalkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl
  • 4 to 10-membered divalent non-aryl heterocyclic group the divalent non-aryl heterocyclic group contains 1 to 3 same or different atoms selected from the group consisting of halogen atoms, C 1-6 alkyl and -NR 11 R 12 )
  • One embodiment of the compound represented by formula (1) includes the following (B).
  • B is the following formula (B-2), (B-3), or (B-4):
  • * represents the bonding position with 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 C 1-6 alkyl (the alkyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl)
  • R 9a and R 9b are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl (the alkyl is the same or different 1 to 3 selected from the group consisting of a halogen atom and a C 1-6 alkyl);
  • Ring Q is a 6- to 10-membered aromatic hydrocarbon ring (the aromatic hydrocarbon ring is substitute
  • One embodiment of the compound represented by formula (2) includes the following (C).
  • One embodiment of the compound represented by formula (2) includes the following (D).
  • A is CF 2
  • Z is a 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is the same or different selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 ); (optionally substituted with 1 to 3 substituents), or a 5 to 10 membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and - NR 11 R 12 ), which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of R 4 is single bond, C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl), or 4- to 10-membered Divalent non-aryl heterocyclic group (the divalent non-
  • R4 is single bond, C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl), or 4- to 10-membered Divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group has 1 to 3 same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl and -NR 11 R 12 ) ), which may be substituted with R5 is hydrogen atom, Cyano, -NR 7b R 7c , C 1-6 alkyl (the alkyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl, a hydroxyl group, and -NR 11 R 12 ), C 1-6 alkoxy (the alkoxy may be substituted with the same or different 1 to 3 substituents selected
  • a compound or a pharmaceutically acceptable salt thereof includes the following (E).
  • R 3 represents 4-fluorophenyl or 4-fluoro-2-pyridyl
  • R 4 is a 4- to 6-membered divalent non-aryl heterocyclic group
  • R 5 is C 1-3 alkyl
  • the non-aryl heterocyclic group has the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl) optionally substituted with a group
  • a compound or a pharmaceutically acceptable salt thereof includes the following (E).
  • R 3 represents 4-fluorophenyl or 4-fluoro-2-pyridyl
  • R 4 is a 4- to 6-membered divalent non-aryl heterocyclic group
  • R 5 is C 1-3 alkyl
  • a 4- to 6-membered non-aryl heterocyclic group has the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl
  • R 4 is azetidinylene
  • R 5 is Methyl or oxetanyl
  • One embodiment of the compound represented by formula (4) includes the following (G).
  • Z is A 6- to 10-membered divalent aromatic ring group (the divalent aromatic ring group includes 1 to 3 same or different atoms selected from the group consisting of halogen atoms, C 1-6 alkyl, and -NR 11 R 12 ) (optionally substituted with a substituent), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl, and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group consisting of R 4 is single bond, C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl), or C 3-10 cyclo alkylene (the cycloalkylene may be substituted with the same or
  • A is CF 2
  • Z is a 4- to 10-membered non-aryl heterocyclic group (the non-aryl heterocyclic group is the same or different 1 to 3 members selected from the group consisting of a halogen atom, C 1-6 alkyl, and -NR 11 R 12 ); (optionally substituted with a substituent) or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group consists of a halogen atom, C 1-6 alkyl and -NR 11 R 12 (optionally substituted with the same or different 1 to 3 substituents selected from the group),
  • R 4 is single bond, C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl), or C 3-10 cyclo alkylene (the cycloalkylene may be substituted with the same or different 1 to
  • R 4 is a single bond, or C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl), R 5 is C 1-6 alkyl or cyano, A compound or a pharmaceutically acceptable salt thereof.
  • R4 is single bond, C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl), or 4- to 10-membered Divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group has 1 to 3 same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl and -NR 11 R 12 ) ), which may be substituted with R5 is hydrogen atom, hydroxyl group, Cyano, C 1-6 alkyl (the alkyl may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl, a hydroxyl group, and -NR 11 R 12 ), -SO 2 R 7d , -CONR 7e R 7f , or a 4- to 10-
  • R 5 is hydroxyl group, -SO 2 R 7d , C 1-6 alkyl or cyano, R 7d is C 1-6 alkyl; A compound or a pharmaceutically acceptable salt thereof.
  • One embodiment of the compound represented by formula (5) includes the following (I).
  • R 4 is It is a single bond
  • R 5 is Methyl group or cyano
  • R 4 is C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and C 1-6 alkyl), R 5 is Methyl group or cyano, A compound or a pharmaceutically acceptable salt thereof.
  • One embodiment of the compound represented by formula (6) includes the following (K).
  • R 3 represents 4-fluorophenyl or 4-fluoro-2-pyridyl
  • Z is 4- to 10-membered divalent non-aryl heterocyclic group (the divalent non-aryl heterocyclic group is the same or different 1-3 selected from the group consisting of halogen atom, C 1-6 alkyl and -NR 11 R 12 ) ), or a 5- to 10-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group includes a halogen atom, C 1-6 alkyl and -NR 11 R (optionally substituted with 1 to 3 same or different substituents selected from the group consisting of 12 ),
  • R 4 is single bond, C 1-6 alkylene (the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl), or 4- to 10-membered Di
  • One embodiment of the compound represented by formula (6) includes the following (L).
  • A is CF 2
  • Z is 5-membered divalent aromatic heterocyclic group (the divalent aromatic heterocyclic group is composed of 1 to 3 same or different atoms selected from the group consisting of halogen atoms, C 1-6 alkyl and -NR 11 R 12 ) (optionally substituted with a substituent)
  • R 4 is single bond
  • C 1-6 alkylene the alkylene may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen atoms and C 1-6 alkyl
  • 4- to 10-membered Divalent non-aryl heterocyclic group the divalent non-aryl heterocyclic group has 1 to 3 same or different substituents selected from the group consisting of halogen atom, C 1-6 alkyl and -NR 11 R 12
  • R 5 is hydrogen atom, Cyano, -NR 7b R 7c , C 1-6 alkyl (the alkyl may be
  • R 3 represents 4-fluorophenyl
  • R 4 is a 4- to 6-membered divalent non-aryl heterocyclic group
  • R 5 is C 1-3 alkyl, or a 4- to 6-membered non-aryl heterocyclic group
  • a compound or a pharmaceutically acceptable salt thereof includes the following (M).
  • One embodiment of the compound represented by formula (7) includes the following (N).
  • R 3 represents 4-fluorophenyl
  • R 4 is is azetidinylene
  • R 5 is is methyl
  • One embodiment of the compound represented by formula (7) includes the following (O).
  • R 3 represents 4-fluorophenyl
  • R 4 is is azetidinylene
  • R 5 is is oxetanil
  • the administration route of the compound of the present disclosure may be oral administration, parenteral administration, or rectal administration, and the daily dosage varies depending on the type of compound, administration method, patient's condition, age, etc.
  • oral administration it is usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg of human or mammalian body weight, and can be administered in one to several divided doses.
  • parenteral administration such as intravenous injection
  • parenteral administration such as intravenous injection
  • administration schedule include single administration, once a day for three consecutive days, or twice a day for one week.
  • each of the administration methods described above can be repeated at intervals of about 1 day to about 60 days.
  • the compounds of the present disclosure can be administered parenterally or orally, either directly or formulated using a suitable dosage form.
  • dosage forms include, but are not limited to, tablets, capsules, powders, granules, solutions, suspensions, injections, patches, and poultices.
  • the formulation is manufactured by a known method using pharmaceutically acceptable additives. Additives include excipients, disintegrants, binders, flow agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, and sweeteners, depending on the purpose. , fragrance, etc. can be used.
  • lactose lactose, mannitol, crystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearin
  • examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
  • the compounds of the present disclosure can be produced by using known compounds as starting materials, for example, by the following production methods A, B, C, and D, or by methods analogous thereto, or by appropriately combining synthesis methods well known to those skilled in the art. Can be done.
  • the compound (1-11) in which A is CF 2 and Q is a benzene ring can be produced, for example, by the following method.
  • R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and Z have the same meanings as in [Item 1] above. ]
  • Step 1-1 Manufacturing process of compound (1-3)
  • Compound (1-3) is produced by reacting compound (1-1) and compound (1-2) in an inert solvent in the presence of a reducing agent.
  • reducing agent examples include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, and the like.
  • 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, N-methyl-2-pyrrolidinone and the like.
  • 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 Manufacturing step of compound (1-5)
  • Compound (1-5) is subjected to an amidation reaction using compound (1-3) and compound (1-4) in an inert solvent in the presence of a base.
  • the base include inorganic bases such as potassium hydroxide, sodium hydroxide, and sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide.
  • 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; Examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.
  • 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 examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-di
  • 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 Production step of compound (1-6)
  • Compound (1-6) is produced by deprotecting the benzyl group of compound (1-5). For example, catalytic reduction using a metal catalyst such as palladium/carbon or palladium hydroxide/carbon in a hydrogen atmosphere is applied.
  • a metal catalyst such as palladium/carbon or palladium hydroxide/carbon in a hydrogen atmosphere is applied.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0°C to 100°C, preferably 0°C to 25°C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.
  • Step 1-4 Manufacturing process of compound (1-8)
  • Compound (1-8) is produced by reacting commercially available compound (1-7) with 1,2-ethanedithiol in an inert solvent in the presence of an acid. Manufactured by.
  • acids include boron trifluoride diethyl ether complex, p-toluenesulfonic acid, perchloric acid, aluminum chloride, and the like.
  • 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; Examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.
  • 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 examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-di
  • 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 30 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • Step 1-5 Production step of compound (1-9)
  • Compound (1-9) is produced by reacting compound (1-8) with a brominating agent and a fluorinating agent in an inert solvent.
  • 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; Examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, and N,N-dimethylpropylene urea.
  • 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 examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-di
  • brominating agent examples include N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, and the like.
  • fluorinating agent examples include pyridine hydrogen fluoride, potassium fluoride, cesium fluoride, (diethylamino)sulfur trifluoride, and the like.
  • 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 1-6 Manufacturing step of compound (1-10)
  • Compound (1-10) is prepared using Mitsunobu's method using compound (1-6) and compound (1-9) in an inert solvent in the presence of Mitsunobu's reagent. Manufactured by reaction.
  • the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • aromatic hydrocarbons such as toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • Mitsunobu reagent examples include diethyl azodicarboxylate (DEAD), isopropyl azodicarboxylate (DIAD), N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, etc. Cyanomethylenetrimethylphosphorane (Kakuda Reagent) can also be used.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0°C to 100°C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.
  • Step 1-7 Production step of compound (1-11)
  • Compound (1-11) is produced by subjecting compound (1-10) to a palladium-catalyzed cross-coupling reaction using various coupling reagents in an inert solvent. Manufactured by doing.
  • inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; acetonitrile, acetone, methyl ethyl ketone, and N,N-dimethylformamide. , N-methyl-2-pyrrolidinone, N,N-dimethylpropylene urea, and other aprotic polar solvents.
  • aromatic hydrocarbons such as toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane
  • acetonitrile acetone
  • methyl ethyl ketone methyl ethyl ketone
  • N,N-dimethylformamide N-methyl-2-pyrrolidinone
  • N,N-dimethylpropylene urea and other aprotic polar solvents
  • palladium reagents include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butyl phosphine) palladium (0), [1,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloride, and the like.
  • the base include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.
  • the coupling reagent include, for example, Z-bonded boronic acid, Z-bonded boronic acid pinacol ester, and the like.
  • 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.
  • Manufacturing method B Among the compounds represented by formula (1), the compound (1-11) in which A is CF 2 and Q is a benzene ring can also be produced by the following production method. [Wherein, R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and Z have the same meanings as in [Item 1] above. W represents a halogen atom. ]
  • Step 2-1 Production step of compound (2-1)
  • Compound (2-1) is produced by reacting compound (1-3) with an amidating agent in an inert solvent.
  • amidating agents include chloroacetyl chloride, bromoacetyl chloride, chloroacetic anhydride, and the like.
  • 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; Examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,N-dimethylformamide, N-methyl-2-pyrrolidinone, N,N-dimethylpropylene urea, and pyridine.
  • 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 examples include aprotic polar solvents such as acetone, methyl ethyl ketone, N,
  • 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 Production process of compound (1-10)
  • Compound (1-10) is alkylated using compound (2-1) and compound (1-9) in an inert solvent in the presence of a base. Manufactured by reaction.
  • inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; acetonitrile, acetone, methyl ethyl ketone, and N,N-dimethylformamide. , N-methyl-2-pyrrolidinone, N,N-dimethylpropylene urea, and other aprotic polar solvents.
  • aromatic hydrocarbons such as toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane
  • acetonitrile acetone
  • methyl ethyl ketone methyl ethyl ketone
  • N,N-dimethylformamide N-methyl-2-pyrrolidinone
  • N,N-dimethylpropylene urea and other aprotic polar solvents
  • the base include inorganic bases such as potassium carbonate and cesium carbonate; metal alkoxides such as sodium methoxide and potassium tert-butoxide.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0°C to 100°C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.
  • the compound (1-11) in which A is CF 2 and Q is a benzene ring can also be produced by the following production method.
  • R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and Z have the same meanings as in [Item 1] above. ]
  • Step 3-1 Production process of compound (3-1)
  • Compound (3-1) is produced by subjecting compound (1-9) to a palladium-catalyzed cross-coupling reaction using various coupling reagents in an inert solvent. Manufactured by doing.
  • inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; acetonitrile, acetone, methyl ethyl ketone, and N,N-dimethylformamide. , N-methyl-2-pyrrolidinone, N,N-dimethylpropylene urea, and other aprotic polar solvents.
  • aromatic hydrocarbons such as toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane
  • acetonitrile acetone
  • methyl ethyl ketone methyl ethyl ketone
  • N,N-dimethylformamide N-methyl-2-pyrrolidinone
  • N,N-dimethylpropylene urea and other aprotic polar solvents
  • palladium reagents include tetrakis(triphenylphosphine)palladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-tert-butyl phosphine) palladium (0), [1,1'-bis(diphenylphosphino)ferrocene] palladium (II) dichloride, and the like.
  • the base include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, and sodium hydroxide.
  • the coupling reagent include, for example, Z-bonded boronic acid, Z-bonded boronic acid pinacol ester, and the like.
  • 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 Manufacturing process of compound (1-11)
  • Compound (1-11) is produced by Mitsunobu using compound (3-1) and compound (1-6) in an inert solvent in the presence of Mitsunobu's reagent. Manufactured by reaction.
  • the inert solvent include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • aromatic hydrocarbons such as toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • Mitsunobu reagent examples include diethyl azodicarboxylate (DEAD), isopropyl azodicarboxylate (DIAD), N,N,N',N'-tetramethylazodicarboxamide, triphenylphosphine, tributylphosphine, etc. Cyanomethylenetrimethylphosphorane (Kakuda Reagent) can also be used.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0°C to 100°C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.
  • the compound (1-11) in which A is CF 2 and Q is a benzene ring can also be produced by the following production method.
  • R 1 , R 2a , R 2b , R 3 , R 4 , R 5 , and Z have the same meanings as in [Item 1] above.
  • W represents a halogen atom.
  • Step 4-1 Manufacturing step of compound (1-11)
  • Compound (1-11) is alkylated using compound (3-1) and compound (2-1) in an inert solvent in the presence of a base. Manufactured by reaction.
  • inert solvents include aromatic hydrocarbons such as toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; acetonitrile, acetone, methyl ethyl ketone, and N,N-dimethylformamide. , N-methyl-2-pyrrolidinone, N,N-dimethylpropylene urea, and other aprotic polar solvents.
  • aromatic hydrocarbons such as toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane
  • acetonitrile acetone
  • methyl ethyl ketone methyl ethyl ketone
  • N,N-dimethylformamide N-methyl-2-pyrrolidinone
  • N,N-dimethylpropylene urea and other aprotic polar solvents
  • the base include inorganic bases such as potassium carbonate and cesium carbonate; metal alkoxides such as sodium methoxide and potassium tert-butoxide.
  • the reaction temperature is not particularly limited, but is usually selected from the range of 0°C to 100°C.
  • the reaction time is usually 1 hour to 72 hours, preferably 1 hour to 24 hours.
  • a protecting group can be used as necessary, even if the use of a protecting group is not specifically specified. For example, if any functional group other than the reactive site changes under the described reaction conditions or is inappropriate in the absence of a protecting group to carry out the described method, other functional groups other than the reactive site may be protected as necessary. Then, the target compound can be obtained by deprotecting the compound after the completion of the reaction or after performing a series of reactions.
  • protecting group for example, the protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be used. Can be done.
  • Specific examples of amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like.
  • Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, and benzyl.
  • the introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the above-mentioned Protective Groups in Organic Synthesis) or a method analogous thereto.
  • the intermediates or target compounds in the production method explained above should be modified as appropriate by converting their functional groups (e.g., protecting and deprotecting the functional groups as necessary, and using amino, hydroxyl, carbonyl, halogen, etc. as a foothold).
  • Various transformations can also lead to other compounds included in this disclosure. Transformation of the functional group can be performed by a commonly used method (for example, see Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).
  • the intermediates and target compounds in the production method explained above are isolated by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.). Can be purified. Furthermore, the intermediate can be used in the next reaction without being particularly purified.
  • protecting group for example, the protecting groups described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter G. M. Wuts, published by John Wiley & Sons, Inc., 1999) can be used. Can be done.
  • Specific examples of amino protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like.
  • Specific examples of the hydroxyl protecting group include trialkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl, acetyl, and benzyl.
  • the introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (for example, see the above-mentioned Protective Groups in Organic Synthesis) or a method analogous thereto.
  • the intermediates or target compounds in the production method explained above should be modified as appropriate by converting their functional groups (e.g., protecting and deprotecting the functional groups as necessary, and using amino, hydroxyl, carbonyl, halogen, etc. as a foothold).
  • Various transformations can also lead to other compounds included in this disclosure. Transformation of the functional group can be performed by a commonly used method (for example, see Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).
  • the intermediates and target compounds in the production method explained above are isolated by purification methods commonly used in organic synthetic chemistry (e.g., neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc.). Can be purified. Furthermore, the intermediate can be used in the next reaction without being particularly purified.
  • acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, or citrate, oxalate, phthalate, etc. Fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzene ring sulfonate, para-toluenesulfone
  • organic acid salts such as acid salts and camphorsulfonate salts.
  • base addition salts include inorganic base salts such as sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, and aluminum salts, or trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, and diethanolamine. , triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylamine, and other organic base salts.
  • examples of “pharmaceutically acceptable salts” include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.
  • Suitable salts of the starting materials and intermediates and salts acceptable as pharmaceutical raw materials are customary non-toxic salts. These include, for example, organic acid salts (e.g. acetates, trifluoroacetates, maleates, fumarates, citrates, tartrates, methanesulfonates, benzene ring sulfonates, formates, toluenesulfonates). acid addition salts such as acid salts (e.g. acid salts, etc.) and inorganic acid salts (e.g. hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, etc.), amino acids (e.g.
  • metal salts such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. calcium salts, magnesium salts, etc.), ammonium salts, organic base salts (e.g. trimethylamine salts, triethylamine salts, etc.) salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc.), and can be appropriately selected by those skilled in the art.
  • alkali metal salts e.g. sodium salts, potassium salts, etc.
  • alkaline earth metal salts e.g. calcium salts, magnesium salts, etc.
  • ammonium salts e.g. trimethylamine salts, triethylamine salts, etc.
  • organic base salts e.g. trimethylamine salts, triethylamine salts, etc.
  • pyridine salts
  • Compounds of the present disclosure include isotopic elements such as 2 H (or D), 3 H (or T), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I, etc.), and these compounds are also included in the compounds of the present disclosure.
  • the present disclosure includes compounds represented by formulas (1) to (7) or pharmaceutically acceptable salts thereof. Furthermore, since the compounds of the present disclosure may exist in the form of hydrates and/or solvates with various solvents (ethanolates, etc.), these hydrates and/or solvates are also included in the present invention. Included in the disclosed compounds.
  • the compounds of the present disclosure include optical isomers based on optically active centers, atropisomers based on axial or planar chirality caused by intramolecular rotation constraints, other stereoisomers, tautomers, It includes all possible isomers such as geometric isomers and all forms of crystalline forms, as well as mixtures thereof.
  • optical isomers and atropisomers can be obtained as racemates or as optically active forms when optically active starting materials or intermediates are used.
  • the corresponding raw material, intermediate, or racemic form of the final product may be separated by a known separation method such as a method using an optically active column or a fractional crystallization method. They can be physically or chemically separated into their optical antipodes.
  • separation methods include, for example, reacting a racemate with an optically active resolving agent to synthesize two diastereomers, and then taking advantage of their different physical properties to resolve the diastereomers by methods such as fractional crystallization. Examples include the stereomer method.
  • a pharmaceutically acceptable salt of the compound of the present disclosure when it is desired to obtain a pharmaceutically acceptable salt of the compound of the present disclosure, when the compounds represented by formulas (1) to (7) are obtained in the form of a pharmaceutically acceptable salt, It may be purified as it is, or if it is obtained in a free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or base may be added to form a salt by a conventional method.
  • the compounds of the present disclosure can be used in combination with other drugs for the purpose of enhancing their effects.
  • the compounds of the present disclosure can be used in combination with drugs such as hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors.
  • drugs such as hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, and agents that inhibit the action of cell growth factors and their receptors.
  • a drug that can be used in combination with the compound of the present disclosure will be abbreviated as a concomitant drug.
  • the compound of the present disclosure exhibits excellent anticancer activity even when used as a single agent, but when used in combination with one or more of the above-mentioned concomitant drugs (multidrug combination), the compound can further enhance its effect or improve the patient's health. QOL can be improved.
  • hormone therapy agents include fosfestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, Rinone, Nomegestol, Tadenane, Mepartricin, Raloxifene, Ormeloxifene, Levormeloxifene, Antiestrogens (e.g.
  • chemotherapeutic agents include alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, molecular target therapeutic agents, immunomodulators, and other chemotherapeutic agents. Typical examples are listed below.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mer Faran, dacarbazine, ranimustine, estramustine sodium phosphate, triethylenemelamine, carmustine, lomustine, streptozodin, pipobroman, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine , prednimustine, pumitepa, ribomustine, temozolomide, treosulfan, trophosfamide, dinostatin stimaramer, ado
  • antimetabolites include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, eocitabine, cytarabine, cytarabine oxphosphate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine, etc.), aminopterin, nerzarabine, leucoporin calcium, tabloid, butocin, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarpamide, pentostatin , pyritrexime, idoxyuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS formulations thereof.
  • 5-FU drugs e.g., fluorour
  • anticancer antibiotics include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, pepromycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, and epirubicin hydrochloride.
  • neocarzinostatin mithramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, eribulin, and DDS preparations thereof.
  • plant-derived anticancer drugs include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, DJ-927, vinorelbine, irinotecan, topotecan, and DDS preparations thereof.
  • molecular target therapeutic agents include imatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, nilotinib, lapatinib, pazopanib, ruxolitinib, crizotinib, vemurafenib, vandetanib, ponatinib, cabozantinib, tofacitinib, regorafenib, bosutinib, tinib, dabrafenib , trametinib, nintedanib, idelalisib, ceritinib, lenvatinib, palbociclib, alectinib, afatinib, osimertinib, ribociclib, abemaciclib, brigatinib, neratinib, copanlisib, c
  • immunomodulators examples include lenalidomide and pomalidomide.
  • immunotherapeutic agents include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium Umparvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, Toll-like Receptors agonist (e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.) can be mentioned.
  • TLR7 agonist e.g., TLR7 agonist, TLR8 agonist, TLR9 agonist, etc.
  • the cell growth factor in a drug that inhibits the action of cell growth factors and their receptors may be any substance as long as it promotes cell growth, and is usually a peptide with a molecular weight of 20,000 or less. There are factors that exert their effects at low concentrations due to their binding with the body.
  • EGF epidermal growth factor
  • EGF epidermal growth factor
  • IGF insulin, IGF (insulin- like growth factor)-1, IGF-2, etc.
  • FGF fibroblast growth factor
  • a substance with substantially the same assay as it e.g., acidic FGF, basic FGF, KGK (keratinocyte growth factor) ctor), FGF-10
  • CSF colony stimulating factor
  • EPO erythropoietin
  • IL-2 interleukin-2
  • NGF nerve growth factor
  • PDGF PL. atelet-derived growth factor
  • TGF-beta transforming growth factor beta
  • HGF hepatocyte growth factor
  • VEGF vascular endothelial growth fa) ctor
  • heregulin angiopoietin, etc.
  • SMARC-deficient cancer is a cancer in which the SMARC gene is deleted and/or the expression of SMARC protein is deleted or attenuated. Preferably, it is a cancer in which the SMARC gene is deleted and/or the expression of the SMARC protein is deleted. More preferably, it is a cancer in which the SMARCB1 gene, the SMARCA2 gene, the SMARCA4 gene, or the SMARCA2/A4 gene is deleted.
  • malignant rhabdoid tumor epithelioid sarcoma, atypical teratoid/rhabdoid tumor, schwannoma, chordoma-like meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, and glioblastoma.
  • chordoma myoepithelial tumor, extraosseous myxoid chondrosarcoma, synovial sarcoma, ossifying fibromyxoid tumor, sinonasal basaloid carcinoma, esophageal adenocarcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma, Gastrointestinal stromal tumor, pancreatic undifferentiated rhabdoid tumor, gastrointestinal rhabdoid tumor, renal medullary cancer, endometrial cancer, myoepithelioma-like tumor in the female genital region, colorectal cancer, mesothelioma, lung adenocarcinoma, Large cell lung cancer, lung neuroendocrine tumor, esophageal cancer, gastroesophageal junction cancer, stomach cancer, bladder cancer, lung squamous cell carcinoma, pancreatic cancer, medulloblastoma, renal clear cell carcinoma, liver Cancer, ovarian small cell carcinoma,
  • SMARCB1-deficient cancer is a cancer in which the SMARCB1 gene is deleted and/or the expression of the SMARCB1 protein is deleted or attenuated. Preferably, it is a cancer in which the SMARCB1 gene is deleted and/or the expression of the SMARCB1 protein is deleted. More preferably, it is a cancer in which the SMARCB1 gene is deleted.
  • malignant rhabdoid tumor epithelioid sarcoma, atypical teratoid/rhabdoid tumor, schwannoma, chordoma-like meningioma, neuroepithelial tumor, glioneuronal tumor, craniopharyngioma, and glioblastoma.
  • chordoma myoepithelial tumor
  • extraosseous myxoid chondrosarcoma synovial sarcoma
  • ossifying fibromyxoid tumor sinonasal basaloid carcinoma
  • esophageal adenocarcinoma papillary thyroid carcinoma
  • follicular thyroid carcinoma include gastrointestinal stromal tumors, pancreatic undifferentiated rhabdoid tumors, gastrointestinal rhabdoid tumors, renal medullary cancer, endometrial cancer, myoepithelioma-like tumors in the female vulvar region, colorectal cancer, and mesothelioma.
  • it is a malignant rhabdoid tumor.
  • a "SMARCA2-deficient cancer” is a cancer in which the SMARCA2 gene is deleted and/or the expression of the SMARCA2 protein is deleted or attenuated.
  • it is a cancer in which the SMARCA2 gene is deleted and/or the expression of the SMARCA2 protein is deleted. More preferably, it is a cancer in which the SMARCA2 gene is deleted.
  • Specific examples include lung adenocarcinoma, lung large cell carcinoma, pulmonary neuroendocrine tumor, esophageal cancer, gastroesophageal junction cancer, and malignant rhabdoid tumor.
  • Preferred is lung adenocarcinoma.
  • a "SMARCA4-deficient cancer” is a cancer in which the SMARCA4 gene is deleted and/or the expression of the SMARCA4 protein is deleted or attenuated.
  • it is a cancer in which the SMARCA4 gene is deleted and/or the expression of the SMARCA4 protein is deleted. More preferably, it is a cancer in which the SMARCA4 gene is deleted.
  • small cell carcinoma of the ovary include small cell carcinoma of the ovary, mucinous tumor of the ovary, endometrial cancer, uterine sarcoma, nasal sinus cancer, rhabdoid tumor, and thoracic sarcoma.
  • endometrial cancer include endometrial cancer, uterine sarcoma, nasal sinus cancer, rhabdoid tumor, and thoracic sarcoma.
  • lung adenocarcinoma is preferred.
  • SMARCA2/A4-deficient cancer is cancer in which the SMARCA2 gene and SMARCA4 gene are deleted and/or the expression of the SMARCA2 protein and SMARCA4 protein is deleted or attenuated.
  • it is a cancer in which the SMARCA2 gene and SMARCA4 gene are deleted and/or the expression of the SMARCA2 protein and SMARCA4 protein is deleted. More preferably, it is a cancer in which the SMARCA2 gene and the SMARCA4 gene are deleted.
  • lung adenocarcinoma lung pleomorphic carcinoma, lung large cell carcinoma, esophageal cancer, gastroesophageal junction cancer, thoracic sarcoma, ovarian small cell carcinoma, primary gallbladder tumor, uterine sarcoma, and malignant
  • lung adenocarcinoma preferred is lung adenocarcinoma.
  • ARID-deficient cancer is a cancer in which the ARID gene is deleted and/or the expression of the ARID protein is deleted or attenuated.
  • it is a cancer in which the ARID gene is deleted and/or the expression of the ARID protein is deleted.
  • it is a cancer in which the ARID1A gene, ARID1B gene, or ARID1A/1B gene is deleted.
  • ovarian cancer, stomach cancer, biliary tract cancer, pancreatic cancer, endometrial cancer, neuroblastoma, colorectal cancer, bladder cancer, liver cancer, melanoma, breast cancer, medulloblastoma, and neurological Examples include blastoma.
  • it is ovarian cancer.
  • ARID1A-deficient cancer is cancer in which the ARID1A gene is deleted and/or the expression of ARID1A protein is deleted or attenuated.
  • it is a cancer in which the ARID1A gene is deleted and/or the expression of the ARID1A protein is deleted.
  • it is a cancer in which the ARID1A gene is deleted.
  • Specific examples include ovarian cancer, stomach cancer, biliary tract cancer, pancreatic cancer, endometrial cancer, neuroblastoma, colorectal cancer, and bladder cancer.
  • it is ovarian cancer.
  • ARID1B-deficient cancer is a cancer in which the ARID1B gene is deleted and/or the expression of the ARID1B protein is deleted or attenuated.
  • it is a cancer in which the ARID1B gene is deleted and/or the expression of the ARID1B protein is deleted.
  • it is a cancer in which the ARID1B gene is deleted.
  • Specific examples include ovarian cancer, colon cancer, pancreatic cancer, liver cancer, melanoma, breast cancer, medulloblastoma, endometrial cancer, bladder cancer, and stomach cancer.
  • it is ovarian cancer.
  • ARID1A/1B-deficient cancer is a cancer in which the ARID1A gene and the ARID1B gene are deleted, and/or the expression of the ARID1A protein and the ARID1B protein is deleted or attenuated.
  • it is a cancer in which the ARID1A gene and the ARID1B gene are deleted and/or the expression of the ARID1A protein and the ARID1B protein is deleted.
  • it is a cancer in which the ARID1A gene and the ARID1B gene are deleted.
  • Specific examples include ovarian cancer, colon cancer, endometrial cancer, neuroblastoma, bladder cancer, and stomach cancer.
  • it is ovarian cancer.
  • SS18-SSX fusion cancer is a cancer in which the SS18 gene and the SSX gene are fused. Specific examples include synovial sarcoma and Ewing's sarcoma. Preferably it is synovial sarcoma.
  • Heart disease is a disease caused by some kind of disorder in the heart, resulting in poor blood circulation. Specifically, these include cardiomyopathy, heart failure, and myocardial infarction.
  • Methodabolic diseases are diseases caused by impaired metabolic function. Specifically, these include dyslipidemia and diabetes.
  • the administration period of the compound of the present disclosure and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times. It may also be a combination of the compound of the present disclosure and a concomitant drug.
  • the dosage of the concomitant drug can be appropriately selected based on the clinically used dosage.
  • the compounding ratio of the compound of the present disclosure and the concomitant drug can be appropriately selected depending on the subject of administration, administration route, target disease, symptoms, combination, etc. For example, when the subject to be administered is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present disclosure.
  • drugs concomitant drugs
  • it can be used in combination with drugs (concomitant drugs) such as antiemetics, sleep-inducing drugs, and anticonvulsants.
  • NMR (Nuclear Magnetic Resonance) data used for compound identification was obtained using a JNM-ECS400 nuclear magnetic resonance apparatus (400 MHz) manufactured by JEOL Ltd.
  • Symbols used in NMR include s for singlet, d for doublet, dd for doublet, t for triplet, td for triplet doublet, q for quartet, m stands for multiplet, br for broad, brs for broad singlet, brm for broad multiplet and J for coupling constant.
  • the LC/MS (Liquid Chromatography-Mass Spectrometry) analysis conditions used for compound identification are as follows. Among the observed mass spectrometry values [MS (m/z)], the value corresponding to the monoisotopic mass (accurate mass consisting only of the main isotope) is expressed as [M+H] + , [MH] - or [M+2H] 2+ etc., and the retention time is indicated as Rt (minutes).
  • LC/MS measurement method Detection device: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 ⁇ m, 2.1 mm x 30 mm) Solvent: A solution: 0.06% formic acid/H 2 O, B solution: 0.06% formic acid/MeCN Gradient condition: 0.0-1.3min Linear gradient from B 2% to 96% Flow rate: 0.8mL/min UV: 220nm and 254nm Column temperature: 40°C
  • Reference examples 2 to 5 According to the method described in Reference Example 1, the compounds of Reference Examples 2 to 5 were obtained using the corresponding raw material compounds.
  • the compound of Reference Example 1 (200 mg) was dissolved in tetrahydrofuran (3 mL), and (4S)-5'-bromospiro(imidazolidine-4,1'-indene)-2,3',5(2'H)-trione was dissolved in tetrahydrofuran (3 mL). (200 mg), N,N,N',N'-tetramethylazodicarboxamide (140 mg) and tributylphosphine (0.20 mL) were added at 0°C, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Reference examples 10 to 13 According to the method described in Reference Example 9, the compounds of Reference Examples 10 to 13 were obtained using the corresponding starting compounds.
  • the compound of Reference Example 1 (7.3 g) was dissolved in tetrahydrofuran (118 mL), and the compound of Reference Example 8 (8.3 g) and N,N,N',N'-tetramethylazodicarboxamide (6.1 g) were dissolved. and tributylphosphine (8.9 mL) were added at 0°C, and the mixture was stirred at room temperature for 2 hours. 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 off, and the solvent was distilled off under reduced pressure.
  • Reference examples 19-21, 35-37 According to the method described in Reference Example 18, the compounds of Reference Examples 19 to 21 and 35 to 37 were obtained using the corresponding starting compounds.
  • Reference example 25 4-bromo-1-(1-(oxetan-3-yl)azetidin-3-yl)-1H-pyrazole
  • Reference example 27 4-bromo-1-(1-(2,2-difluoroethyl)azetidin-3-yl)-1H-pyrazole
  • Examples 2 to 11 According to the method described in Example 1, the compounds of Examples 2 to 11 were obtained using the corresponding compounds of Reference Examples and commercially available compounds as raw materials.
  • Example 12 1-(4-bromo-1H-pyrazol-1-yl)cyclopropane-1-carbonitrile (100 mg) was dissolved in 1,4-dioxane (2 mL), and potassium acetate (139 mg) was dissolved. , X-PHOS (15 mg), bis(pinacolato)diboron (240 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (26 mg) were added at room temperature, and the mixture was stirred at 100°C for 1 hour. did.
  • Examples 13-15 According to the method described in Example 12, the compounds of Examples 13 to 15 were obtained using the corresponding compounds of Reference Examples and commercially available compounds as raw materials.
  • the compound of Reference Example 23 (190 mg) was dissolved in 1,4-dioxane (2 mL), and potassium acetate (146 mg), X-PHOS (24 mg), bis(pinacolato)diboron (213 mg) and [1,1'-bis (Diphenylphosphino)ferrocene]palladium(II) dichloride (40 mg) was added at room temperature, and the mixture was stirred at 100°C for 1 hour. Water (0.4 mL), potassium carbonate (137 mg), and the compound of Reference Example 10 (281 mg) were added to the reaction mixture at room temperature, and the mixture was stirred at 100°C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform.
  • Examples 17-31 According to the method described in Example 16, the compounds of Examples 17 to 31 were obtained using the corresponding compounds of Reference Examples as raw materials.
  • the compound of Reference Example 19 (108 mg) was dissolved in 1,2-dimethoxyethane (0.9 mL) and water (0.2 mL), potassium carbonate (51 mg), 1-(2-morpholinoethyl)-1H-pyrazole -4-boronic acid pinacol ester (84 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (15 mg) were added at room temperature, and the mixture was stirred at 90°C for 4 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 off, and the solvent was distilled off under reduced pressure.
  • Examples 33-43 According to the method described in Example 32, the compounds of Examples 33 to 43 were obtained using the corresponding compounds of Reference Examples and commercially available compounds as raw materials.
  • Example 44 Production of Example 44 Compound Y12 (100 mg) was dissolved in 1,2-dimethoxyethane (0.7 mL) and water (0.1 mL), potassium carbonate (45 mg), 1-methyl-1H-pyrazole-4 -boronic acid pinacol ester (50 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (13 mg) were added at room temperature, and the mixture was stirred at 90°C for 1 hour. 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 off, 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 (51 mg). LC-MS ([M+H] + /Rt(min)): 621.3/0.816
  • Example 46 2-[(1'S)-3',3'-difluoro-5'- ⁇ 1-[1-(oxetan-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-(trifluoro Methyl)oxetan-3-yl]acetamide
  • the compound of Reference Example 25 (128 mg) was dissolved in 1,4-dioxane (1.4 mL), and potassium acetate (97 mg), X-PHOS (31 mg), bis(pinacolato)diboron (142 mg) and [1,1' -bis(diphenylphosphino)ferrocene]palladium(II) dichloride (27 mg) was added at room temperature, and the mixture was stirred at 100°C for 1 hour. Water (0.3 mL), potassium carbonate (91 mg), and the compound of Reference Example 18 (200 mg) were added to the reaction mixture at room temperature, and the mixture was stirred at 100°C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted twice with chloroform.
  • Examples 47-51 According to the method described in Example 46, the compounds of Examples 47 to 51 were obtained using the corresponding compounds of Reference Examples as raw materials.
  • Example 52 Production of Example 52 Compound Y13 (72 mg) was dissolved in chloroform (2 mL), trifluoroacetic acid (0.5 mL) was added at room temperature, and the mixture was stirred 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 magnesium sulfate, filtered off, 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 (80 mg).
  • Example 54 2-[(1'S)-3',3'-difluoro-5'-(3-methoxyazetidin-1-yl)-2,5-dioxo-2',3'-dihydrospiro[imidazolidine- 4,1'-indene]-1-yl]-N-[(4-fluorophenyl)methyl]-N-[3-(trifluoromethyl)oxetan-3-yl]acetamide
  • the compound of Reference Example 18 (50 mg) was dissolved in 1,4-dioxane (1.0 mL), and cesium carbonate (107 mg), X-PHOS (12 mg), 3-methoxyazetidine hydrochloride (15 mg) and tris(dioxane) Benzylideneacetone)dipalladium(0) (8 mg) was added at room temperature, and the mixture was stirred at 100°C for 4 hours. 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 off, and the solvent was distilled off under reduced pressure.
  • Example 56 Production of Example 56 Compound Y15 (241 mg) was dissolved in chloroform (3 mL), trifluoroacetic acid (3 mL) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture evaporated under reduced pressure was dissolved in chloroform (3 mL), formaldehyde (0.16 mL) and sodium triacetoxyborohydride (699 mg) were added at 0°C, and the mixture was stirred at room temperature 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 magnesium sulfate, filtered off, 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 (333 mg). LC-MS ([M+H] + /Rt(min)): 597.3/0.770
  • Example 57 Compound Y16 (105 mg) was dissolved in 1,2-dimethoxyethane (0.8 mL) and water (0.2 mL), potassium carbonate (51 mg), 1-(2-morpholinoethyl) -1H-pyrazole-4-boronic acid pinacol ester (85 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (15 mg) were added at room temperature, and the mixture was stirred at 90°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Example 58 Production of Example 58 Compound Y17 (171 mg) was dissolved in 1,2-dimethoxyethane (1.2 mL) and water (0.2 mL), potassium carbonate (81 mg), 1-(2-morpholinoethyl) -1H-pyrazole-4-boronic acid pinacol ester (136 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (24 mg) were added at room temperature, and the mixture was stirred at 90°C for 4 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • Example 59 Compound Y18 (249 mg) was dissolved in toluene (1.7 mL), azobisisobutyronitrile (66 mg) and tributyltin hydride (146 mg) were added at room temperature, and the mixture was stirred under heating under reflux for 2 hours. did. The reaction mixture was purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (26 mg). LC-MS ([M+H] + /Rt(min)): 617.3/0.823
  • Examples 60-62 According to the method described in Example 54, the compounds of Examples 60 to 62 were obtained using the compound of Reference Example 18 and commercially available compounds as raw materials.
  • Examples 63-99 According to the method described in Example 46, the compounds of Examples 63 to 99 were obtained using the corresponding compounds of Reference Examples as raw materials.
  • Comparative example 1 The compound of Comparative Example 1 was obtained using the method described in WO2016/044770. LC-MS ([M+H] + /Rt(min)): 619.4/0.938
  • Comparative example 2 A compound of Comparative Example 2 was obtained using the method described in WO2020/108500. LC-MS ([M+H] + /Rt(min)): 531.3/0.965
  • test results will be shown for representative compounds of the present disclosure, and the pharmacological characteristics, chemical characteristics, and pharmacokinetics of the compounds will be explained; however, the present disclosure is not limited to these test examples. do not have.
  • Test Example 1 HAT activity inhibition experiment SensoLyte HAT (p300) Assay Kit (ANASPEC, AS-72172) was used to evaluate the ability of HAT inhibitors to inhibit HAT activity. Specifically, 7.5 ⁇ L of the recombinant p300 solution diluted 10 times with assay buffer was added to 7.5 ⁇ L of the compounds of Examples 1 to 59 diluted with assay buffer, and the mixture was incubated at room temperature for 10 minutes. Thereto, 7.5 ⁇ L of an acetyl-CoA solution diluted 10 times with assay buffer and 15 ⁇ L of histone H3 peptide diluted 10 times with assay buffer were added, and the mixture was incubated at 37° C. for 30 minutes.
  • Test Example 2 Cell proliferation inhibition experiment G-401 cells (derived from malignant rhabdoid tumor) were obtained from the American Type Culture Collection (ATCC). G-401 cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37° C. and 5% CO 2 conditions.
  • G-401 cells which are cells derived from malignant rhabdoid tumors.
  • Examples 3, 5-8, 12-14, 21, 23, 26-27, 34, 38, 41, 43-46, 51, 78, 89, 92, 95, 98, 99 are strong It showed cell proliferation inhibitory effect.
  • Test Example 3 Solution Stability Test Regarding Example 32, Example 46, Example 51, Example 57, Example 58, Example 59, Example 83, Comparative Example 1 and Comparative Example 2, stability in buffer solution The gender was evaluated. Test compounds were added to buffer solutions of pH 3.0, 4.0, 5.0, 7.4, and 9.0 at a concentration of 10 ⁇ mol/L, respectively, and stored in a constant temperature warehouse at 40°C. Purity (area percentage of compound peak) was determined by HPLC measurement on the first day of storage and 1 to 7 days after storage. The buffer solutions used at each pH are as follows.
  • Examples 32, 46, 51, 57, 58 and 83 maintained their purity for 7 days at pH 3-5 and were stable in solution.
  • Comparative Example 1 which is a compound described in WO2016/044770, the purity decreased over time at any pH of 3.0, 4.0, 5.0, 7.4, and 9.0.
  • Tables 20 and 21 it became clear that the hydroxide of Comparative Example 1 increased as the purity of Comparative Example 1 decreased. That is, in Comparative Example 1, it was suggested that fluorine at the benzyl position was hydrolyzed to a hydroxyl group in the aqueous solution, and toxic hydrogen fluoride was generated within the system.
  • Comparative Example 2 which is a compound described in WO2020/108500, the purity decreased over time at pH 7.4 and pH 9.0.
  • Examples 32, 46, 51, 57, 58, and 83 have extremely high stability in solution compared to Comparative Example 1 and Comparative Example 2. Stable solution formulations can be created.
  • Test Example 4 Solubility Test Solubility was measured for Example 12, Example 46, Example 51, Example 83, Comparative Example 1, and Comparative Example 2. The test compound was added to 10 mmol/L glycine buffer (pH 2.0) and 10 mmol/L citrate buffer (pH 3.0) and stored in a thermostatic chamber at 5°C. After standing overnight, it was filtered with a membrane filter, and the filtrate concentration was measured by HPLC. The HPLC measurement conditions are as follows.
  • Example 12 Example 46, Example 51 and Example 83 showed good solubility.
  • Example 46 and Example 83 showed high solubility of 5 mg/mL or more at pH 2.0.
  • Comparative Example 1 showed extremely low solubility of 0.002 mg/mL and 0.005 mg/mL
  • Comparative Example 2 also showed extremely low solubility of 0.004 mg/mL and 0.005 mg. It showed an extremely low solubility of /mL.
  • the test results showed that Example 12, Example 46, Example 51, and Example 83 were compounds that showed exceptional effects on solubility.
  • Test example 5 Membrane permeability test
  • the membrane permeability of the test compounds was tested by artificial membrane permeability assay (PAMPA) as follows. 200 ⁇ L of System solution (pION inc.) containing the test compound and 4 ⁇ L of GIT Lipid-0 (pION inc.) were added to the donor plate. 200 ⁇ L of Acceptor Sink Buffer (pION inc.) was added to the Acceptor plate. After stacking both plates and incubating at 37° C. for 4 hours, the UV of the acceptor side and donor side solutions was measured using a UV plate reader (190-500 nm). Compounds with poor UV absorption were measured by LC-MS. The permeability coefficient Pe (10 ⁇ 6 cm/sec) of the drug was calculated using the following formula.
  • Examples 44, 45, 46, 51, and 83 were found to exhibit good membrane permeability equivalent to Comparative Examples 1 and 2.
  • Test Example 6 Mouse Pharmacokinetic Study The compound of the present disclosure was administered intravenously in a 50% PEG solution (0.01 mol/L HCl) to 7-week-old female BALB/c (BALB/cAnN CrlCrlj) mice ( Administration dose: 1 mg/kg) or 0.5% methylcellulose aqueous solution was administered orally (administration dose: 10 mg/kg), and blood was collected at the following times. Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours after administration Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration and 24 hours
  • the collected blood was centrifuged at 3000 rpm for 10 minutes using a refrigerated centrifuge set at 4°C, and the resulting plasma was measured by LC-MS.
  • a calibration curve was created from the value obtained by dividing the peak area of the test substance in MS by the peak area of the internal standard substance (peak ratio) and the concentration of the plasma calibration curve sample. The concentration in the sample was calculated from the peak ratio of each sample and the calibration curve.
  • Table 25 shows the test results for Examples 2, 7, 19, 44, 46, 51, and 83.
  • Examples 44, 46, 51, and 83 exhibited excellent oral absorption properties that enabled them to exhibit anticancer effects through oral administration.
  • Test Example 7 Intratumoral and plasma pharmacokinetic studies using G-401 xenograft model mice 4-6 week old female BALB/cAnNCrj-nu/nu mice (CAnN.Cg-Foxn1 ⁇ nu>/CrlCrlj, G-401 cells (ATCC) were intradermally transplanted into a mouse (Jackson Laboratory Japan) at 5 ⁇ 10 5 cells/mouse.
  • the tumor volume was calculated using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo) using the following formula.
  • Tumor volume [mm 3 ] 0.5 x short axis [mm] x (long axis [mm]) 2
  • the test compound was orally administered (dose: 30 or 10 mg/kg) in a 0.5% methylcellulose aqueous solution to mice whose tumor volume reached 100 mm 3 to 200 mm 3 .
  • the drug was administered twice a day for a total of 3 doses, and blood and tumor samples were collected 4 hours after the final dose.
  • the collected blood was centrifuged at 3000 rpm for 10 minutes using a refrigerated centrifuge set at 4°C to obtain a plasma fraction.
  • a tumor homogenate was prepared by adding methanol in an amount 4 times the weight of the tumor to the collected tumor, and crushing the tumor using a bead homogenizer at 4200 rpm for 20 seconds under cooling.
  • the obtained plasma and tumor homogenate were measured by LC-MS.
  • a calibration curve was created from the value obtained by dividing the peak area of the test substance in MS by the peak area of the internal standard substance (peak ratio) and the concentration of the calibration curve sample of plasma or tumor. The concentration in the sample was calculated from the peak ratio of each sample and the calibration curve.
  • Example 46 The test results for Example 46 and Comparative Example 1 are shown in Table 26.
  • Example 1 As the dose increased from 10 mg/kg to 30 mg/kg, both the plasma concentration and the intratumoral concentration increased, and at 10 mg/kg and 30 mg/kg, the tumor metastasis was almost the same ( The ratio of plasma concentration to tumor concentration) was shown.
  • Example 46 As the dose increased from 10 mg/kg to 30 mg/kg, the concentration in the tumor decreased while the concentration in the tumor increased significantly, and was higher at 30 mg/kg than at 10 mg/kg. The drug had the unexpected effect of showing tumor metastasis.
  • Example 46 compared to Comparative Example 1, exhibited a different and particularly remarkable tumor metastasis that could exhibit a strong anticancer effect.
  • Test Example 8 Drug efficacy evaluation test by oral administration using G-401 xenograft model mice 4-7 week old BALB/cAnNCrj-nu/nu mice (CAnN.Cg-Foxn1 ⁇ nu>/CrlCrlj, Jackson Laboratory) G-401 cells (ATCC) were intradermally transplanted into a mouse (Japan) at 5 ⁇ 10 5 cells/mouse. After confirming the engraftment of G-401 cells 20 to 40 days after transplantation, a test compound suspended in a solvent such as 0.5% methylcellulose solution was orally administered at a dose of 1 to 100 mg/kg twice a day.
  • a solvent such as 0.5% methylcellulose solution
  • the tumor volume was measured over time from the start of administration, and the tumor volume reduction effect due to administration of the test compound was evaluated.
  • the tumor volume can be calculated by the following formula using the short axis and long axis of the tumor measured with an electronic caliper (Mitutoyo).
  • Tumor volume [mm 3 ] 0.5 x short axis [mm] x (long axis [mm]) 2
  • T/C (Tumor volume at the end of administration in the test compound administration group - Tumor volume at the start of administration in the test compound administration group) / (Tumor volume at the end of administration in the control administration group - Administration in the control administration group Starting tumor volume) x 100
  • Example 46 and Example 83 The test results for Example 46 and Example 83 are shown in Table 27. From the results of this test, Examples 46 and 83 showed strong antitumor effects in the G-401 xenograft model, which is a cell derived from malignant rhabdoid tumor.
  • Test Example 9 PD response test by intravenous administration using G-401 xenograft model mice 4-7 week old BALB/cAnNCrj-nu/nu mice (CAnN.Cg-Foxn1 ⁇ nu>/CrlCrlj, Jackson Laboratory) G-401 cells (ATCC) were intradermally transplanted into a mouse (Japan) at 5 ⁇ 10 5 cells/mouse. After confirming the engraftment of G-401 cells 20 to 40 days after transplantation, inject the test compound suspended in a solvent such as 10 mmol/L glycine buffer (pH 2.0) at a maximum dissolution volume of 5 ml/kg or 10 ml/kg.
  • a solvent such as 10 mmol/L glycine buffer (pH 2.0)
  • a tumor homogenate was prepared by collecting a tumor, adding RIPA buffer, and crushing the tumor using a bead homogenizer. Acetylation of histone H3K27 was detected by Western blotting. For detection of acetylated H3K27, anti-acetylated H3K27 antibody (Cell Signaling Technology, 8173) was used.
  • Examples 46 and 83 reduced intratumoral histone H3K27 acetylation levels by tail vein administration at the maximum lysis amount.
  • Comparative Examples 1 and 2 did not cause any change in the histone H3K27 acetylation level within the tumor, even though they were administered at the maximum dissolution amount. From the above, it was shown that Examples 46 and 83 inhibit HAT activity, which is a function of CBP/P300, even when administered through the tail vein.
  • Test Example 10 Evaluation of Dopamine Receptor Inhibitory Activity
  • the binding evaluation assay was carried out outsourced to Eurofins. Specifically, CHO-S/hDAT cells were homogenized using an incubation buffer consisting of 50 mmol/L Tris-HCl, pH 7.4, 100 mmol/L NaCl, 1 ⁇ mol/L Leupeptin, and 10 ⁇ mol/L PMSF. The membrane pellet obtained by centrifugation was resuspended in incubation buffer to prepare a membrane preparation. Test compound (1-10 ⁇ mol/L DMSO solution), membrane formulation and 0.15 nmol/L 3 H Paroxetine were mixed and incubated for 180 minutes at 4°C.
  • the cell membrane and 125 I RTI-55 complex was bound to the GF/B filter mat by suction filtration, and washed with 50 mmol/L Tris-HCl, pH 7.4. The effects on receptors were evaluated by measuring radioactivity using a scintillation counter.
  • Test Example 11 Evaluation of serotonin receptor inhibitory activity
  • the binding evaluation assay was commissioned to Eurofins. Specifically, HEK293/hSERT cells were homogenized using a buffer solution consisting of 100 mmol/L NaCl, 1 ⁇ mol/L Leupeptin, 10 ⁇ mol/L PMSF, 50 mmol/L Tris-HCl, pH 7.4.
  • the membrane pellet obtained by centrifugation was resuspended in an incubation buffer consisting of 50 mmol/L Tris-HCl, pH 7.4, 120 mmol/L NaCl, and 5 mmol/L KCl to prepare a membrane preparation.
  • Test compound (1-10 ⁇ mol/L DMSO solution), membrane preparation and 0.4 nmol/L 3 H Paroxetin were mixed and incubated for 60 minutes at 25°C.
  • the cell membrane and 3 H Paroxetin complex was bound to the GF/B filter mat by suction filtration, and washed with 50 mmol/L Tris-HCl, pH 7.4.
  • the effects on receptors were evaluated by measuring radioactivity using a scintillation counter.
  • the compound disclosed in the present application exhibited a strong HAT inhibitory activity (Test Example 1) and a strong cancer cell proliferation suppressive effect (Test Example 2). Furthermore, the compounds of the present disclosure have high solution stability (Test Example 3), excellent solubility (Test Example 4), high membrane permeability (Test Example 5), good pharmacokinetics (Test Example 6), and exceptionally pronounced and It exhibited a unique tumor metastasis (Test Example 7) and an exceptional antitumor effect (Test Example 8). Furthermore, even when administered intravenously, the compound disclosed in the present application exhibits exceptional HAT inhibitory activity within tumors (Test Example 9), and also exhibits strong inhibitory activity against off-target dopamine receptors and serotonin receptors. There was no difference in safety, indicating particularly remarkable and heterogeneous safety (Test Examples 10 and 11).
  • the present inventors have newly found a problem in Comparative Examples 1 and 2 that intravenous administration is difficult because they have low solubility and are unstable in solution. In general, structural changes that increase solubility reduce fat solubility and impair membrane permeability.
  • the compounds represented by formulas (2) to (7) in particular have a unique effect of having both excellent solubility (Test Example 4) and high membrane permeability (Test Example 5). , is an excellent CBP/P300 inhibitor that can be administered orally and intravenously.
  • Example 46 included in formula (2) and formula (3), and Example 83 included in formula (6) and formula (7) exhibited strong HAT inhibitory activity (Test Example 1 ), showed a strong cancer cell proliferation inhibitory effect (Test Example 2).
  • Examples 46 and 83 have a particularly remarkable effect showing superior solution stability (Test Example 3) compared to Comparative Examples 1 and 2.
  • Test Example 4 when structural changes are made to increase solubility, fat solubility is weakened and membrane permeability is impaired, but Examples 46 and 83 have better solubility (Test Example 4) than Comparative Examples 1 and 2.
  • it has a different effect of having the same membrane permeability as Comparative Examples 1 and 2 (Test Example 5).
  • Examples 46 and 83 showed excellent pharmacokinetics (Test Example 6). Moreover, Example 46 also has a particularly remarkable and different effect showing higher tumor metastasis than Comparative Example 1 (Test Example 7). Examples 46 and 83 show exceptional antitumor effects when administered orally (Test Example 8), and even when administered intravenously, they show exceptionally significant HAT inhibitory activity within tumors that Comparative Examples 1 and 2 cannot achieve ( Test Example 9) is a CBP/P300 inhibitor with a profile suitable for oral and intravenous administration. Furthermore, while Comparative Example 2 shows strong inhibitory activity against dopamine receptors and serotonin receptors, which are off-targets, Examples 46 and 83 do not show strong inhibitory activity. (Test Examples 10 and 11).
  • the compounds of the present disclosure and their pharmaceutically acceptable salts are useful as therapeutic or preventive agents for pathological conditions involving CBP/P300 by strongly inhibiting CBP/P300.

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Abstract

La présente divulgation concerne : un dérivé d'amide tertiaire substitué par du carbone quaternaire qui est utile en tant que médicament et un sel pharmaceutiquement acceptable du dérivé d'amide tertiaire ; une composition pharmaceutique comprenant ces composants ; et un agent thérapeutique ou prophylactique pour un état pathologique dans lequel le CBP/P300 est impliqué, l'agent thérapeutique ou prophylactique comprenant la composition. Plus particulièrement, la présente invention concerne un composé représenté par la formule (1) [dans laquelle A représente CR6aR6b, C=O, C=CH2 ou S(=O)2 ; B représente la formule (B-1) ; le cycle Q représente un cycle hydrocarboné aromatique de 6 à 10 chaînons éventuellement substitué ou un cycle hétérocyclique aromatique de 5 à 10 chaînons éventuellement substitué ; Z représente -O-,-N(R7a)-, un groupe cyclique aromatique bivalent de 6 à 10 chaînons éventuellement substitué, un groupe cyclique hétérocyclique aromatique bivalent de 5 à 10 chaînons éventuellement substitué, un groupe cyclique non arylhétérocyclique bivalent de 4 à 10 chaînons éventuellement substitué ; et R1, R2a et R2b, R3, R4 et R5 sont tels que décrits dans la description] ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2023/029183 2022-08-10 2023-08-09 Dérivé d'amide tertiaire substitué par du carbone quaternaire Ceased WO2024034652A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160235716A1 (en) * 2014-09-18 2016-08-18 Abbvie Inc. Spirocyclic hat inhibitors and methods for their use
JP2021522317A (ja) * 2018-04-20 2021-08-30 中国科学院上海薬物研究所 ヒストンアセチルトランスフェラーゼ（ｈａｔ）阻害剤及びその用途
JP2022510874A (ja) * 2018-11-27 2022-01-28 ヒノバ ファーマシューティカルズ インコーポレイテッド ヒストンアセチラーゼｐ３００阻害剤及びその用途
JP2022512900A (ja) * 2018-11-02 2022-02-07 ダナ－ファーバー キャンサー インスティテュート，インコーポレイテッド アセチル化ライター阻害剤の開発およびその使用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160235716A1 (en) * 2014-09-18 2016-08-18 Abbvie Inc. Spirocyclic hat inhibitors and methods for their use
JP2021522317A (ja) * 2018-04-20 2021-08-30 中国科学院上海薬物研究所 ヒストンアセチルトランスフェラーゼ（ｈａｔ）阻害剤及びその用途
JP2022512900A (ja) * 2018-11-02 2022-02-07 ダナ－ファーバー キャンサー インスティテュート，インコーポレイテッド アセチル化ライター阻害剤の開発およびその使用
JP2022510874A (ja) * 2018-11-27 2022-01-28 ヒノバ ファーマシューティカルズ インコーポレイテッド ヒストンアセチラーゼｐ３００阻害剤及びその用途

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