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WO2025155167A1 - Nouveau composé utilisé en tant qu'inhibiteur de cbp/p300, et composition pharmaceutique pour la prévention ou le traitement du cancer, de troubles inflammatoires ou de maladies auto-immunes le comprenant en tant que principe actif - Google Patents

Nouveau composé utilisé en tant qu'inhibiteur de cbp/p300, et composition pharmaceutique pour la prévention ou le traitement du cancer, de troubles inflammatoires ou de maladies auto-immunes le comprenant en tant que principe actif

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Publication number
WO2025155167A1
WO2025155167A1 PCT/KR2025/099056 KR2025099056W WO2025155167A1 WO 2025155167 A1 WO2025155167 A1 WO 2025155167A1 KR 2025099056 W KR2025099056 W KR 2025099056W WO 2025155167 A1 WO2025155167 A1 WO 2025155167A1
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methyl
dihydro
oxo
sulfonamide
dimethyl
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Korean (ko)
Inventor
김리라
박경아
이소윤
조중희
함영진
황유선
윤홍빈
김병규
김학중
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LG Chem Ltd
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LG Chem Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds used as CBP/p300 inhibitors, and pharmaceutical compositions containing them as active ingredients for preventing or treating cancer, inflammatory disorders or autoimmune diseases.
  • CBP and p300 have been associated with several diseases, particularly malignancies.
  • CBP and p300 bind to chromatin through BRD and HAT and acetylate histones at the enhancer sites of oncogenes, which relaxes the chromatin structure and allows transcriptional proteins, including RNA polymerase II, to assemble.
  • oncogenes such as MYC and IRF4 in tumor cells, leading to tumor formation and growth.
  • HAT domain Inhibition of the HAT domain causes an overall decrease in acetylation, which is important for transcription, and acts equally not only in tumor cells but also in normal cells, especially stem cells. Because it has been reported that securing a therapeutic window is difficult and toxicity may be induced, it is expected that these concerns can be overcome through a bromodomain inhibitor strategy.
  • CCS1477 a CBP/p300 bromodomain inhibitor developed by CellCentric
  • CCS1477 is in phase 1b/2a clinical trials for the treatment of hematological malignancies and advanced drug-resistant prostate cancer
  • various CBP/p300 activity modulators are also disclosed in the following patent documents 1 to 3.
  • Patent Document 2 WO2019191667
  • Patent Document 3 WO2017205538
  • One object of the present invention is to provide a novel compound used as a CBP/p300 inhibitor.
  • Another object of the present invention is to provide an isomer of the compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, inflammatory disorders or autoimmune diseases, comprising at least one of the compound, an isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof and a solvate thereof as an active ingredient.
  • W, X or Y are each independently C or N,
  • heterocycloalkenyl means an unsaturated hydrocarbon group containing one or more heteroatoms selected from O, N, P and S as a reducing group and forming a single or fused ring.
  • the heteroatoms may be 1, 1 to 2 or 1 to 3. Examples thereof include, but are not limited to, tetrahydropyridinyl.
  • heteroaryls include pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, tetrazolyl, isothiazolyl, furyl, thienyl, pyridinyl, pyridyl N-oxide, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, isoquinolinyl, thiophenyl, acridyl, indazolyl, carbazolyl, benzimidazolyl, benzocarbazolyl, benzofuranyl, benzothiophenyl, dibenzothiophenyl, pyrazolopyrimidinyl, ind
  • oxy refers to a substituent which can be represented as “-OR oxy ”, wherein R oxy can be, but is not limited to, a substituted or unsubstituted C 1-10 alkyl, a substituted or unsubstituted C 2-10 alkenyl, a substituted or unsubstituted C 3-10 carbocycle, a substituted or unsubstituted C 3-10 cycloalkyl, a substituted or unsubstituted C 6-30 aryl, a substituted or unsubstituted 3- to 30-membered heterocycle, a substituted or unsubstituted C 1-10 haloalkyl.
  • “Carbonyl” can be referred to as a “ketone”, and depending on its substituent and bonding site, it can be referred to as an “alkylketone”.
  • thio refers to a substituent which can be represented as “-SR thio ”, wherein R thio can be, but is not limited to, a substituted or unsubstituted C 1-10 alkyl, a substituted or unsubstituted C 2-10 alkenyl, a substituted or unsubstituted C 3-10 carbocycle, a substituted or unsubstituted C 3-10 cycloalkyl, a substituted or unsubstituted C 6-30 aryl, a substituted or unsubstituted 3- to 30-membered heterocycle, a substituted or unsubstituted C 1-10 haloalkyl.
  • amino is intended to encompass monovalent primary amines, monovalent secondary amines, and monovalent tertiary amines. That is, amino refers to both monovalent groups having two hydrogen atoms bonded to a nitrogen atom and monovalent groups having at least one hydrogen atom substituted with another substituent.
  • the group having two hydrogen atoms bonded to a nitrogen atom may be an unsubstituted amino, and the group having at least one hydrogen atom substituted with another substituent may be a substituted amino.
  • dialkylamino the alkyl moieties may be the same or different.
  • Sulfinyl may also be used interchangeably with “thiocarbonyl”, and in a narrower sense, when R s2 is alkyl, it may also be referred to as alkylthiocarbonyl.
  • R, R a to R f , A and Z may each be substituted or unsubstituted with substituent group I-1:
  • Substituent group I-1 substituted or unsubstituted C 1-5 alkyl, substituted or unsubstituted C 3-5 cycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted C 6-8 aryl, substituted or unsubstituted 3- to 9-membered heterocycloalkyl, substituted or unsubstituted 3- to 11-membered heteroaryl, substituted or unsubstituted C 1-3 haloalkyl, substituted or unsubstituted C 1-3 alkoxy, hydroxy, halogen, aldehyde, cyano, substituted or unsubstituted amide.
  • the compound of formula I may be represented by any one of the following formulae I-1 to I-5:
  • R 112 , R 313 , R 114 , R 314 , R 215 , R 315 , R 116 , R 216 and R 316 are the same or different from each other, and each independently represents SO 2 NHR c , CONHR d , SO 2 R e , CO 2 R f , C 1-4 haloalkyl, or 3 to 9 membered heteroaryl, each of which is unsubstituted or substituted with a substituent group I,
  • R c , R d , R e , R f , A, Z and m may each be as defined above.
  • the chemical formula I-2 may be represented by any one of the following chemical formulas I-2-1 to I-2-3:
  • R 322 , R 223 and R 323 may be the same or different and each independently be NR a R b , SO 2 NHR c , CONHR d , C 1-4 alkyl, or 3- to 9-membered heteroaryl, each of which is unsubstituted or substituted with a substituent group I,
  • R a , R b , R c , R d , A, Z and m may each be as defined above.
  • R 132 , R 333 , R 134 and R 334 may be the same or different and may each independently be NR a R b or halogen, and each is unsubstituted or substituted with a substituent group I,
  • R a , R b , A, Z and m may each be as defined above.
  • chemical formula I-4 may be represented by any one of the following chemical formulas I-4-1 to I-4-6:
  • R 142 , R 243 , R 344 , R 145 , R 345 , R 146 , R 246 and R 346 may be the same or different and may each independently be NR a R b or CONHR d , each of which is unsubstituted or substituted with a substituent group I,
  • R a , R b , R d , A, Z and m may each be as defined above.
  • chemical formula I-5 may be represented by any one of the following chemical formulas I-5-1 to I-5-3:
  • R 352 , R 153 and R 353 may be the same or different and may each independently be NR a R b or halogen, and each is unsubstituted or substituted with a substituent group I,
  • R a , R b , A, Z and m may each be as defined above.
  • each R can be independently NR a R b , SO 2 NHR c , CONHR d , SO 2 R e , CO 2 R f , chloro, C 1-2 haloalkyl, or pyrazolyl, wherein each of R a to R f is independently hydrogen, methyl, ethyl, propyl, pyrrolidinyl, or morpholinyl, and each of R a to R f can be unsubstituted or substituted with substituent group I-1-1, and wherein R can be unsubstituted or substituted with substituent group I-1-2:
  • Substituent group I-1-1 substituted or unsubstituted C 1-3 alkyl, substituted or unsubstituted C 3-5 cycloalkyl, substituted or unsubstituted amino, substituted or unsubstituted C 6-8 aryl, substituted or unsubstituted 3- to 9-membered heterocycloalkyl, substituted or unsubstituted 3- to 11-membered heteroaryl;
  • Substituent group I-1-2 Substituted or unsubstituted C 1-3 alkyl.
  • A may be acetamide, carbamide, hydroxy, isoxazolyl, hydropyranyl or tetrahydropyranyl, or two As may be fused to each other to form imidazolidinonyl, lactamyl, piperazinedioneyl or pyrrolyl together with the atoms bonded thereto, and A may be optionally substituted with a substituent group I-1-3:
  • said Z can be hydrogen, methyl, hydroxy, amide, phenyl, naphthalenyl, tetrahydrofuranyl, lactamyl, tetrahydropyranyl, pyrrolyl, thiazolyl, imidazolyl, thiophenyl, isoxazolyl, pyrazolyl, pyridinyl, benzimidazolyl, indolyl, azaindolyl, indazolyl, benzofuranyl, benzothiophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyridinyl, quinolinyl or isoquinolinyl, and said Z can be unsubstituted or substituted with substituent group I-1-4:
  • Substituent group I-1-4 substituted or unsubstituted C 1-5 alkyl, substituted or unsubstituted C 3-5 cycloalkyl, C 1-3 haloalkyl, substituted or unsubstituted C 6-8 aryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted 4- to 8-membered heterocycloalkyl, substituted or unsubstituted 3- to 8-membered heterocycloalkenyl, substituted or unsubstituted C 1-3 alkoxy, hydroxy, halogen, aldehyde, cyano, substituted or unsubstituted amide.
  • the compound represented by the chemical formula I may be any one selected from Table 2 below.
  • the above CBP/p300 induces histone H3 lysine 27 acetylation (H3K27ac) at target gene promoters, enhancers and super enhancers, and recognizes acetylated histones via BRD to activate gene transcription.
  • H3K27ac histone H3 lysine 27 acetylation
  • the above CBP/p300 is overexpressed in cancer cells and drug-resistant cancer cells, it activates oncogene transcription and induces cancer cell proliferation, survival, tumor formation, metastasis, immune evasion or drug resistance. Therefore, it is necessary to inhibit the overexpression of CBP/p300 in cancer cells, etc.
  • the use of the compound represented by chemical formula I in the present specification as a CBP/p300 inhibitor may mean that it has the overexpression inhibition activity of CBP/p300 as described above.
  • the present invention also provides an isomer of the compound represented by the above chemical formula I, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solvate thereof.
  • the term “isomer” may include enantiomers, diastereomers thereof, tautomers thereof, and geometrical isomers thereof.
  • enantiomers refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • diastereomers refer to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis and chromatography.
  • MPLC Medium pressure liquid chromatography, CombiFlash Nextgen 300+
  • prepHPLC Thermo Ultimate 3000 equipped with a diode array detector, UV detection: 215 nm, 254 nm, 280 nm
  • 3-Bromoaniline (4.8 g, 27.9 mmol) was dissolved in 1,4-dioxane (100 mL) and (3,5-dimethylisoxazol-4-yl)boronic acid (5.90 g, 41.9 mmol) and sodium carbonate (2 M in water) (27.9 mL, 55.8 mmol) were added under nitrogen, and nitrogen was bubbled for 5 minutes.
  • Tetrakis(triphenylphosphine)palladium(0) (0.967 g, 0.837 mmol) was added to the reaction solution, and the mixture was stirred at 90 °C for 24 h. Water was added to the reaction solution, and extracted with ethyl acetate. The oil layer was washed with brine, concentrated under reduced pressure, and then separated by MPLC to obtain the desired material (5.05 g, 26.8 mmol, 96% yield).
  • 1,1,3-Trimethyl-3-(3-nitrophenyl)urea (146.9 mg, 0.658 mmol) was dissolved in methanol (6.6 mL), palladium/carbon (210 mg, 0.197 mmol) was added, and the mixture was stirred under a hydrogen balloon at room temperature for 18 h. After the reaction was completed, the mixture was passed through a celite filter, and the filtrate was concentrated. After MPLC purification, the title compound was obtained (140 mg, 0.724 mmol, 110% yield).
  • N-Methyl-5-nitro-1H-indole-3-carboxamide (310 mg, 1.414 mmol) was dissolved in methanol (7.1 mL) and tetrahydrofuran (7.1 mL), palladium/carbon (452 mg, 0.424 mmol) was added, and the mixture was stirred under a hydrogen balloon at room temperature for 18 h. After the reaction was completed, the mixture was passed through a celite filter, and the filtrate was concentrated to obtain the title compound (264 mg, 1.395 mmol, 99% yield).
  • 1,4-Dimethyl-5-nitro-1,4-dihydroquinoxaline-2,3-dione 71.3 mg, 0.303 mmol was dissolved in methanol (3 mL) and 1,4-dioxane (3 mL), palladium/carbon (32.3 mg, 0.030 mmol) was added, and the mixture was stirred under a hydrogen balloon at room temperature for 18 h. After the reaction was completed, the mixture was passed through a celite filter, and the filtrate was concentrated to obtain the title compound (50 mg, 0.244 mmol, 80 % yield).
  • Step 2 Preparation of 5-((5-amino-6-((3-(azepan-1-yl)propyl)(methyl)amino)pyrimidin-4-yl)amino)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
  • Step 3 Preparation of 5-(6-((3-(azepan-1-yl)propyl)(methyl)amino)-8-(1H-pyrrolo[2,3-b]pyridin-2-yl)-9H-purin-9-yl)-1,3-dimethyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
  • Step 2 Preparation of 1,3-dimethyl-5-((6-(methyl(2-(m-tolyloxy)ethyl)amino)-5-nitropyrimidin-4-yl)amino)-1,3-dihydro-2H-benzo[d]imidazol-2-one
  • Step 2) Preparation of 1',3'-dimethyl-2-(6-methyl-1H-indol-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)-1',3'-dihydro-2'H-[1,5'-bibenzo[d]imidazole]-2'-one
  • Tetrakis(triphenylphosphine)palladium(0) (0.819 mg, 0.709 ⁇ mol) was added to the reaction solution, and nitrogen was bubbled for 5 min. The reaction solution was reacted at 90 °C for 24 h. Add water to the reaction solution, extract the oil layer with ethyl acetate, and wash with brine. The oil layer was concentrated under reduced pressure and separated by MPLC to obtain the title compound. (3 mg, 5.04 ⁇ mol, 35.5% yield)
  • N-Methyl-4-nitro-3-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)benzenesulfonamide (56 mg, 0.154 mmol) was added to dimethyl sulfoxide (1 mL), and 1-methyl-1H-imidazole-5-carbaldehyde (25.5 mg, 0.231 mmol) and sodium hydrosulfite (95 mg, 0.462 mmol) were added. The reaction solution was stirred at 90 °C for 3 hours.
  • the reaction solution was cooled to 0 °C, diluted with water and ethyl acetate, adjusted to pH 9-11 by adding 25% ammonium hydroxide, and then the oil layer was extracted with ethyl acetate. The oil layer was concentrated under reduced pressure and separated by PTLC to obtain the title compound. (20 mg, 0.047 mmol, 30.6% yield)
  • Examples 2 ⁇ 19, 28 ⁇ 29, 38, 40 ⁇ 42, 51, 60 ⁇ 64, 67 ⁇ 71, 76, 79, 88, 94, 115 ⁇ 116, 118, 123 ⁇ 124, 128 ⁇ 135, 153 ⁇ 165 are Synthesis Method A
  • Examples 43, 45 ⁇ 46, 75 are Synthesis Method B
  • Examples 22 ⁇ 27, 30 ⁇ 33, 39, 136 ⁇ 140 are Synthesis Method C
  • Examples 35 ⁇ 37 are Synthesis Method D
  • Examples 47, 72 ⁇ 73 are Synthesis Method F
  • Examples 53 ⁇ 54, 65 ⁇ 66, 82, 85 ⁇ 87, 89, 91 ⁇ 93, 95 ⁇ 100, 102, 106 ⁇ 112, 114, 141 ⁇ 152 were similarly prepared according to Synthesis Method I
  • Examples 57, 59, 119 ⁇ 122 were similarly prepared according to Synthesis Method J
  • Example 78 was similarly prepared according to Synthesis Method M
  • Example 84 was similarly prepared according to Synthesis Method P
  • Example 103 was similarly prepared according to Synthesis Method Q
  • Example 105 was similarly prepared according to
  • the CBP bromodomain activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) experiments.
  • the assay was performed in a final volume of 14 ⁇ l and optimized based on the CREBBP Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay Kit (BPS Bioscience, cat. 32619) to maximize the assay window and performed in a total final volume of 14 ⁇ l.
  • TR-FRET fluorescence acceptor and Tb donor were diluted in assay buffer containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (assay buffer, BPS Bioscience, cat. 33012), and 3 ⁇ l of each solution was transferred to all wells of a white 384-low-volume well plate (Corning, cat. 4513).
  • % Activity ((FRETcompound - FRETLow av) / (FRETHigh av - FRETLow av)) ⁇ 100.
  • IC50 analysis was determined by standard four-parameter curve fitting according to the algorithm using GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are presented as mean ⁇ standard error of the mean (SEM).
  • BRD4 inhibitory activity was measured using time-resolved fluorescence resonance energy transfer (TR-FRET) experiments to verify BRD4 bromodomain activity.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • the assay was performed in a final volume of 14 ⁇ l and optimized based on the CREBBP Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay Kit (BPS Bioscience, cat. 32613) to maximize the assay window and performed in a total final volume of 14 ⁇ l.
  • TR-FRET fluorescence acceptor and Tb donor were diluted in assay buffer containing 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (assay buffer, BPS Bioscience, cat. 33012), and 3 ⁇ l of each solution was transferred to all wells of a white 384-low-volume well plate (Corning, cat. 4513).
  • % Activity ((FRETcompound - FRETLow av) / (FRETHigh av - FRETLow av)) ⁇ 100.
  • IC50 analysis was determined by standard four-parameter curve fitting according to an algorithm using GraphPad Prism 7.0 (GraphPad Software Inc., La Jolla, CA, USA). All data are expressed as mean ⁇ standard error of the mean (SEM).
  • the activity value is 0 or more and 500 nM or less, it is marked as '+++', if it is more than 500 and 5 uM or less, it is marked as '++', and if it is more than 5 uM, it is marked as '+'.
  • Example BRD4 (BD1) IC 50 Example BRD4 (BD1) IC 50 1 N.D 84 N.D 2 ++ 85 + 3 ++ 86 + 4 N.D 87 + 5 + 88 N.D 6 N.D 89 + 7 ++ 90 + 8 ++ 91 + 9 N.D 92 + 10 ++ 93 + 11 + 94 + 12 N.D 95 + 13 N.D 96 + 14 N.D 97 + 15 N.D 98 + 16 ++ 99 + 17 + 100 + 18 + 101 + 19 ++ 102 + 20 + 103 + 21 N.D 104 + 22 + 105 + 23 N.D 106 N.D 24 N.D 107 N.D 25 N.D 108 N.D 26 N.D 109 N.D 27 N.D 110 N.D 28 N.D 111 N.D 29 + 112 N.D 30 N.D 113 N.D 31 N.D 114 N.D 32 ++ 115 N.D 33 ++ 116 N.D 34 N.D 117 N

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Abstract

La présente invention concerne un nouveau composé utilisé en tant qu'inhibiteur de CBP/p300, un isomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, un hydrate de celui-ci, et un solvate de celui-ci, et concerne une composition pharmaceutique pour prévenir ou traiter le cancer, un trouble inflammatoire ou une maladie auto-immune, la composition pharmaceutique comprenant le composé, l'isomère, le sel, l'hydrate ou le solvate en tant que principe actif.
PCT/KR2025/099056 2024-01-17 2025-01-16 Nouveau composé utilisé en tant qu'inhibiteur de cbp/p300, et composition pharmaceutique pour la prévention ou le traitement du cancer, de troubles inflammatoires ou de maladies auto-immunes le comprenant en tant que principe actif Pending WO2025155167A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080610A1 (fr) * 2002-03-22 2003-10-02 Glaxo Group Limited Derives d'imidazopyridine en tant qu'inhibiteurs de kinase
WO2011106168A1 (fr) * 2010-02-24 2011-09-01 Dcam Pharma Inc Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes
KR20170140382A (ko) * 2015-04-29 2017-12-20 얀센 파마슈티카 엔.브이. 아자벤즈이미다졸 및 ampa 수용체 조절제로서의 이의 용도
WO2019043217A1 (fr) * 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Dihydrobenzimidazolones
WO2020181232A1 (fr) * 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
WO2023239750A1 (fr) * 2022-06-06 2023-12-14 C4 Therapeutics, Inc. Liants de céréblon de glutarimide à substitution bicyclique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003080610A1 (fr) * 2002-03-22 2003-10-02 Glaxo Group Limited Derives d'imidazopyridine en tant qu'inhibiteurs de kinase
WO2011106168A1 (fr) * 2010-02-24 2011-09-01 Dcam Pharma Inc Composés de purine pour le traitement de maladies auto-immunes et démyélinisantes
KR20170140382A (ko) * 2015-04-29 2017-12-20 얀센 파마슈티카 엔.브이. 아자벤즈이미다졸 및 ampa 수용체 조절제로서의 이의 용도
WO2019043217A1 (fr) * 2017-09-04 2019-03-07 F. Hoffmann-La Roche Ag Dihydrobenzimidazolones
WO2020181232A1 (fr) * 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
WO2023239750A1 (fr) * 2022-06-06 2023-12-14 C4 Therapeutics, Inc. Liants de céréblon de glutarimide à substitution bicyclique

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