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WO2024191268A1 - Nouveau composé et composition pharmaceutique le comprenant - Google Patents

Nouveau composé et composition pharmaceutique le comprenant Download PDF

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Publication number
WO2024191268A1
WO2024191268A1 PCT/KR2024/095554 KR2024095554W WO2024191268A1 WO 2024191268 A1 WO2024191268 A1 WO 2024191268A1 KR 2024095554 W KR2024095554 W KR 2024095554W WO 2024191268 A1 WO2024191268 A1 WO 2024191268A1
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WIPO (PCT)
Prior art keywords
thiazol
carboxamide
azetidine
carbonyl
methylsulfonyl
Prior art date
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Pending
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PCT/KR2024/095554
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English (en)
Korean (ko)
Inventor
김성헌
조한원
김현태
이혁주
송인재
이지수
최민우
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Hyundai Pharm Co Ltd
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Hyundai Pharm Co Ltd
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Publication of WO2024191268A1 publication Critical patent/WO2024191268A1/fr
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    • 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
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic 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
    • A61K31/435—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
    • 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
    • A61K31/435—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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—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
    • 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
    • A61K31/535—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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • the present invention relates to a compound having an inhibitory effect on a BAF complex-related disease, particularly on the BAF complex, a method for producing the same, and a use thereof.
  • ATP-dependent chromatin remodeling is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which this gene expression occurs.
  • the human switch/sucrose non-fermentative (SWI/SNF) chromatin remodeling complex also known as the BAF complex (BRG/BRM-Associated Factor complex), contains two SWI2-like ATPases, known as BRG1 (Brahma-related gene-1) and BRM (Brahma).
  • BRG1 Brahma-related gene-1
  • BRM Brahma
  • the transcriptional activator BRG1 also known as the ATP-dependent chromatin remodeler SMARCA4
  • BRG1 is overexpressed in some cancer tumors and is required for cancer cell proliferation.
  • SNF2L2 and/or the ATP-dependent chromatin remodeler BRM also known as the SMARCA2 gene on chromosome 9 have been shown to be essential for tumor cell growth in cells characterized by BRG1 loss-of-function mutations. Inactivation of BRG and/or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.
  • SMARCA2 is one of the proteins that plays an important role in controlling gene expression. It pulls the two ends of chromatin together to expose DNA, allowing it to interact with transcription factors (proteins) required for gene expression. Accordingly, SMARCA2 also plays an important role in cell biological processes such as cell differentiation, cell cycle, and cell proliferation, and SMARCA2 is associated with various diseases.
  • the present invention provides an inhibitor of a BAF complex having a novel structure, and provides a method for preventing or treating a disease related to the BAF complex through a pharmaceutical composition containing the same.
  • the present invention provides a compound having an inhibitory effect on a disease related to the BAF complex, particularly the BAF complex, a method for producing the same, and a use thereof.
  • the present invention provides a pharmaceutical composition comprising the compound as an active ingredient.
  • the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:
  • X is CH, N, O, or S
  • Y is CH, N, O, or S
  • Z is CH, or N
  • L is C 0-4 alkylene
  • R 1 is C 6-10 aryl; C 3-14 heteroaryl comprising at least one selected from the group consisting of N, O and S; or C 8-12 bicyclic monovalent ring comprising at least one selected from the group consisting of N, O and S,
  • R 1 is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, (C 1-4 alkyl)sulfonyl, (C 1-4 alkyl)carbonyl, halogen, cyano, amino, -NH-CO-O-(C 1-4 alkyl), and -CO-CO-N(C 1-4 alkyl) 2 ,
  • R 2 is hydrogen or C 1-4 alkyl
  • R 3 is C 6-10 aryl; C 3-14 heteroaryl comprising at least one selected from the group consisting of N, O and S; C 3-14 heterocycloalkyl comprising at least one selected from the group consisting of N, O, S and B; or C 8-12 bicyclic monovalent ring comprising at least one selected from the group consisting of N, O, S and B,
  • R 3 is unsubstituted or substituted with 1 to 4 substituents each independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 6-10 aryl, amino, amino(C 1-4 alkyl), di(C 1-4 alkyl)amino, halogen, nitro, cyano, -COO-(C 1-4 alkyl), -CONH-(C 3-6 cycloalkyl), -CO-N(C 1-4 alkyl) 2 , -CO-NH 2 , -CO-H, -CO-(C 1-4 alkyl), -SO 2 -NH 2 , -CH 2 -O-(C 1-4 alkyl), -(C 1-4 alkylene)-COOH, and piperazinyl,
  • n is an integer from 1 to 3.
  • X is S.
  • Y is CH. More preferably, X is S and Y is CH.
  • L is C 0-1 alkylene. This may indicate that R 1 is directly bonded to the carbonyl group without the intervention of alkylene.
  • the term 'bicyclic' means two rings fused together, wherein each of the two rings is an aromatic ring, a heteroaromatic ring, an aliphatic ring, or a heteroaliphatic ring.
  • R 1 is phenyl, pyridinyl, pyrrolyl, pyrazolyl, thiazolyl, isoxazolyl, indolyl, pyrrolidinyl, 1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepinyl, or 1-oxido-2,3,4,5-tetrahydrobenzo[b]thiepinyl,
  • R 1 is unsubstituted or substituted with 1 to 3 substituents each independently selected from the group consisting of methyl, trideuteriomethyl (CD 3 ), ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, trifluoromethyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, fluoro, bromo, chloro, cyano, and amino, -NH-CO-O-(methyl), -NH-CO-O-(ethyl), -NH-CO-O-(propyl), -NH-CO-O-(isopropyl), and -CO-CO-N(methyl) 2 .
  • substituents each independently selected from the group consisting of
  • R 1 is phenyl, pyridinyl, pyrrolyl, pyrazolyl, thiazolyl, isoxazolyl, or 1-oxido-2,3,4,5-tetrahydrobenzo[b]thiepinyl, wherein R 1 is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, trifluoromethyl, methylsulfonyl, methylcarbonyl, fluoro, bromo, chloro, cyano, and amino.
  • R 2 is hydrogen or methyl.
  • R 3 is phenyl, pyridinyl, morpholino, dioxaborolanyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2-azabicyclo[2.2.2]octanyl, 3,6-dihydro-2H-pyranyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, piperazinyl, pyrimidinyl, pyrrolidinyl, quinolinyl, or thiophenyl,
  • R 3 is unsubstituted or; Or substituted with 1 to 4 substituents each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, ethenyl, methoxy, ethoxy, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, amino, aminomethyl, dimethylamino, fluoro, bromo, chloro, nitro, cyano, -COO-(methyl), -COO-(ethyl), -COO(propyl), -COO-(isopropyl), -CONH-(cyclopropyl), -CONH-(cyclobutyl), -CO-N(methyl) 2 , -CO-NH 2 , -CO-H, -CO-(methyl), -CO-(ethyl), -CO-(propyl), -
  • R 3 is phenyl, pyridinyl, morpholino, dioxaborolanyl, or 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, wherein R 3 is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, trifluoromethyl, aminomethyl, fluoro, bromo, chloro, and piperazinyl.
  • n 1
  • the chemical formula 1 is represented by the following chemical formula 2:
  • the chemical formula 1 is represented by the following chemical formula 3:
  • R 2 , R 3 and n are as defined above,
  • R' 1 is hydrogen, C 1-4 alkyl, or (C 1-4 alkyl)sulfonyl
  • R' 2 is hydrogen, C 1-4 alkyl, or halogen
  • R' 3 is hydrogen or C 1-4 alkyl.
  • the compound of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt.
  • a salt there may be used without limitation any salt commonly used in the art, such as an acid addition salt formed by a pharmaceutically acceptable free acid.
  • pharmaceutically acceptable salt of the present invention means any organic or inorganic addition salt of the compound represented by the chemical formula 1, which has a relatively non-toxic and harmless effective effect at a concentration that is harmless to the patient, and the side effects due to the salt do not reduce the beneficial effects of the compound represented by the chemical formula 1.
  • a pharmaceutically acceptable salt can be obtained by a conventional method using an inorganic acid or an organic acid.
  • the compound represented by the above chemical formula 1 can be dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an organic or inorganic acid can be added, and the precipitated crystals can be filtered to prepare and dried to obtain a pharmaceutically acceptable salt.
  • the salt can be prepared by depressurizing a solvent or an excess acid in a reaction mixture to which an acid has been added, drying the residue, or by adding another organic solvent and filtering the precipitated salt.
  • preferable salts include salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like.
  • a pharmaceutically unacceptable salt or solvate of a compound represented by chemical formula 1 can be used as an intermediate in the production of a compound represented by chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof.
  • the compound represented by the chemical formula 1 of the present invention includes not only its pharmaceutically acceptable salt but also all possible enantiomers, stereoisomers, solvates, polymorphs, or isotope derivatives that can be prepared therefrom.
  • the compound represented by chemical formula 1 according to the present invention can be prepared in a crystalline form or an amorphous form, and when the compound represented by chemical formula 1 is prepared in a crystalline form, it can be optionally hydrated or solvated.
  • the present invention may include not only a stoichiometric hydrate of the compound represented by chemical formula 1, but also a compound containing various amounts of water.
  • the solvate of the compound represented by chemical formula 1 according to the present invention includes both a stoichiometric solvate and a non-stoichiometric solvate.
  • the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 1, for example.
  • the above step 1 is a Suzuki coupling reaction, which is preferably performed in the presence of a palladium catalyst and a base, and the reactor for the Suzuki coupling reaction can be changed as known in the art.
  • the above step 2 is an amidation reaction, and the catalyst and solvent for the amidation reaction can be changed as known in the art.
  • the above step 3 is a deprotection group reaction, and the solvent for this can be changed as known in the art.
  • the above step 4 is an amidation reaction, and the catalyst and solvent for the amidation reaction can be changed as known in the art.
  • the above manufacturing method can be more specifically described in the manufacturing examples described below.
  • the present invention provides a pharmaceutical composition for preventing or treating a disease associated with a BAF complex, for example, a disease associated with an alteration of BRG1 and/or BRM, comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotope derivative thereof as an active ingredient.
  • BAF complex refers to a BRG1- and/or HBRM-associated factor complex in human cells
  • BAF complex-associated disease refers to a disease caused or affected by the level and/or activity level of the BAF complex.
  • the BAF complex-associated disease includes cancer, viral infection, Coffin Siris syndrome, neurofibromatosis (e.g., NF-1, NF-2 or schwannomatosis), or multiple meningiomas.
  • the cancer includes non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, penile cancer, bone cancer, hematological cancer, or eye cancer.
  • the viral infection includes an infection with a virus of the Retroviridae family, a virus of the Hepadnaviridae family, a virus of the Flaviviridae family, a virus of the Adenoviridae family, a virus of the Herpeviridae family, a virus of the Papillomaviridae family, a virus of the Parvoviridae family, a virus of the Poliomaviridae family, a virus of the Paramyxoviridae family, or a virus of the Togaviridae family.
  • prevention of the present invention means any act of inhibiting or delaying the occurrence, spread and recurrence of the disease by administration of the composition of the present invention
  • treatment means any act of improving or beneficially changing the symptoms of the disease by administration of the composition of the present invention.
  • the prevention or treatment is due to reducing the level and/or activity of the BAF complex in a cell or a subject.
  • the prevention or treatment is due to inhibiting BRM in a cell or a subject.
  • the prevention or treatment is due to inhibiting BRG1 in a cell or a subject.
  • composition of the present invention can be formulated into an oral or parenteral administration form according to standard pharmaceutical practice.
  • formulations may contain additives such as pharmaceutically acceptable carriers, adjuvants, or diluents in addition to the active ingredient.
  • Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate; and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine.
  • the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions.
  • the compounds of the present invention can be formulated as ointments or creams for topical action.
  • the compounds of the present invention can be formulated as injectables by dissolving, suspending or emulsifying the compounds in a water-soluble solvent such as normal saline, about 5% dextrose, or in a water-insoluble solvent such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol.
  • a water-soluble solvent such as normal saline, about 5% dextrose, or in a water-insoluble solvent such as synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol.
  • the formulations of the present invention can contain conventional additives such as solubilizing agents, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
  • compositions of the present invention can be used alone or in combination with other pharmaceutically active compounds as well as in appropriate combinations.
  • the preferred dosage of the compound of the present invention varies depending on the patient's condition and weight, the degree of the disease, the form of the drug, the route and period of administration, and can be appropriately selected by those skilled in the art. However, for a desirable effect, it is recommended to administer the compound of the present invention at about 0.0001 to 100 mg/kg (body weight) per day, preferably about 0.001 to 100 mg/kg (body weight).
  • the administration can be administered once a day or in divided doses via oral or parenteral routes.
  • the composition can contain about 0.001 to 99 wt%, preferably about 0.01 to 60 wt%, of the compound of the present invention.
  • the pharmaceutical composition of the present invention can be administered to mammals including rats, mice, livestock, and humans by various routes. All modes of administration can be envisaged, for example, oral, rectal, or intravenous, intramuscular, subcutaneous, intrauterine epidural, or intracerebroventricular injection.
  • the compound represented by chemical formula 1 of the present invention a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotope derivative thereof, can be usefully used for the prevention or treatment of diseases related to the BAF complex.
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid 38.1 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 3-(methylsulfonyl)benzoic acid 40.3 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 5-(methylsulfonyl)nicotinic acid 40.5 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (21.4 mg, yield: 31%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-bromopicolinic acid 40.6 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (5.5 mg, yield: 8%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 5-fluoronicotinic acid 28.4 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (18.6 mg, yield: 30%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-fluoropicolinic acid 28.4 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (20.3 mg, yield: 33%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-fluoronicotinic acid 28.4 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (7.5 mg, yield: 12%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-(trifluoromethyl)nicotinic acid 38.4 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 2-(trifluoromethyl)nicotinic acid 38.4 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 2-chloronicotinic acid 31.7 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (25.7 mg, yield: 40%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 2-(4-(methylsulfonyl)phenyl)acetic acid (43.1 mg, 0.20 mmol)
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 5-chloronicotinic acid 31.7 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (6.5 mg, yield: 10%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-chloropicolinic acid 31.7 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (4.5 mg, yield: 7%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 2-chloroisonicotinic acid 31.7 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-chloro-3-(trifluoromethyl)picolinic acid 45.4 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 4-cyanobenzoic acid 29.6 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • distilled water 5 mL
  • EA 20 mL
  • the extracted organic layer was dried with MgSO 4 and filtered under reduced pressure.
  • the filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (32.7 mg, yield: 47%).
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 5-chloro-1H-pyrrole-3-carboxylic acid 29.3 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DMF 0.5 mL
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 3-((tert-butoxycarbonyl)amino)benzoic acid 47.7 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • Step 1) Preparation of tert-butyl-(4-(2-oxo-2-(2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)carbamoyl)azetidin-1-yl)ethyl)phenyl)carbamate
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 2-(4-((tert-butoxycarbonyl)amino)phenyl)acetic acid 50.5 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 4-((tert-butoxycarbonyl)amino)benzoic acid 47.7 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 6-((tert-butoxycarbonyl)amino)nicotinic acid 47.9 mg, 0.20 mmol
  • HATU 76.4 mg, 0.20 mmol
  • DIPEA 0.094 mL, 0.54 mmol
  • the solution was cooled to room temperature, distilled water (5 mL) was added, and extracted with EA (20 mL). The extracted organic layer was dried over MgSO 4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (29.0 mg, yield: 51%).
  • Example 49 Preparation of (S)-N-(4-(3'-carbamoyl-[1,1'-biphenyl]-3-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide.
  • Example 50 Preparation of (S)-N-(4-(4'-formyl-3',5'-dimethyl-[1,1'-biphenyl]-3-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide.
  • Step 1) Preparation of tert-butyl (S)-2-methyl-2-(4-(3-(2-(1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamido)thiazol-4-yl)phenyl)pyridin-2-yl)propanoate
  • Step 2 Preparation of (S)-2-methyl-2-(4-(3-(2-(1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamido)thiazol-4-yl)phenyl)pyridin-2-yl)propanoic acid
  • Step 2 Preparation of (S)-N-(4-(3'-(aminomethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide hydrochloride
  • the solution was cooled to room temperature, distilled water (5 mL) was added, and extracted with EA (20 mL). The extracted organic layer was dried over MgSO 4 and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (54.7 mg, yield: 99%).
  • Step 2 Preparation of tert-butyl-2-((4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate
  • N-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid 28.3 mg, 0.15 mmol
  • HATU 71.0 mg, 0.19 mmol
  • DMF 0.5 mL
  • DIPEA 0.087 mL, 0.50 mmol
  • N-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride 50 mg, 0.13 mmol
  • 5-(methylsulfonyl)nicotinic acid 30.1 mg, 0.15 mmol
  • HATU 71.0 mg, 0.19 mmol
  • DMF 0.5 mL
  • DIPEA 0.087 mL, 0.50 mmol
  • Example 80 Preparation of tert-butyl (S)-(5-(2-((4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)carbamoyl)azetidine-1-carbonyl)thiophen-2-yl)carbamate
  • 6-Fluoropicolinoyl chloride 13.50 g, 84.60 mmol was dissolved in 1,4-dioxane (150 mL) cooled to 0 °C. 2 M trimethylsilyl diazomethane solution (in hexane; 9.60 g, 84.6 mmol) was slowly added to the reaction solution using a dropping funnel and stirred at 25 °C for 10 h. Then, 4 N hydrochloric acid solution (in 1,4-dioxane; 150 mL, 0.60 mol) was added to the reaction solution, stirred for 2 h, and concentrated under reduced pressure.

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Abstract

La présente invention concerne un composé représenté par la formule chimique 1 dans la description ou un sel pharmaceutiquement acceptable de celui-ci. La composition pharmaceutique comprenant le composé en tant que principe actif peut être avantageusement utilisée pour la prévention ou le traitement de maladies liées au complexe BAF.
PCT/KR2024/095554 2023-03-15 2024-03-15 Nouveau composé et composition pharmaceutique le comprenant Pending WO2024191268A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115863A1 (en) * 1999-12-17 2002-08-22 Dinesh Patel Novel succinate compounds, compositions and methods of use and preparation
US20020119962A1 (en) * 1999-12-17 2002-08-29 Jacobs Jeffrey W. Novel urea compounds, compositions and methods of use and preparation
KR20070085395A (ko) * 2004-10-19 2007-08-27 사노피-아벤티스 2-아미도-4-페닐티아졸 유도체, 그의 제조 방법 및 치료적용도
KR20110028661A (ko) * 2008-07-15 2011-03-21 노파르티스 아게 Ｄｇａｔ１ 억제제로서의 헤테로아릴 유도체
WO2022109426A1 (fr) * 2020-11-20 2022-05-27 Foghorn Therapeutics Inc. Composés et utilisations associées

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020115863A1 (en) * 1999-12-17 2002-08-22 Dinesh Patel Novel succinate compounds, compositions and methods of use and preparation
US20020119962A1 (en) * 1999-12-17 2002-08-29 Jacobs Jeffrey W. Novel urea compounds, compositions and methods of use and preparation
KR20070085395A (ko) * 2004-10-19 2007-08-27 사노피-아벤티스 2-아미도-4-페닐티아졸 유도체, 그의 제조 방법 및 치료적용도
KR20110028661A (ko) * 2008-07-15 2011-03-21 노파르티스 아게 Ｄｇａｔ１ 억제제로서의 헤테로아릴 유도체
WO2022109426A1 (fr) * 2020-11-20 2022-05-27 Foghorn Therapeutics Inc. Composés et utilisations associées

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