WO2021190425A1 - INHIBITEUR DU RÉCEPTEUR DU FACTEUR DE CROISSANCE TRANSFORMANT β - Google Patents

INHIBITEUR DU RÉCEPTEUR DU FACTEUR DE CROISSANCE TRANSFORMANT β Download PDF

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WO2021190425A1
WO2021190425A1 PCT/CN2021/081965 CN2021081965W WO2021190425A1 WO 2021190425 A1 WO2021190425 A1 WO 2021190425A1 CN 2021081965 W CN2021081965 W CN 2021081965W WO 2021190425 A1 WO2021190425 A1 WO 2021190425A1
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cancer
compound
alkyl
cycloalkyl
group
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PCT/CN2021/081965
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English (en)
Chinese (zh)
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俞智勇
李刚
王坤瑶
邱庆崇
季彬
孙钊
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杭州阿诺生物医药科技有限公司
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    • 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
    • A61K31/4353—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 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • the present invention provides a new type of heterocyclic compound, its preparation method and its application as TGF- ⁇ receptor (especially TGF ⁇ RI) antagonist.
  • Transforming growth factor- ⁇ (transforming growth factor- ⁇ , TGF- ⁇ ) is a multifunctional growth factor and cytokine. It is combined with activins, inhibitors, and Mullerian inhibitors. Substance, MIS) and bone morpho-genetic proteins (BMPs) and other related proteins form the transforming growth factor- ⁇ superfamily. It can participate in the regulation of a variety of biological processes, including cell proliferation, differentiation, development, and modification of extracellular matrix (including tumor matrix and immunosuppression, angiogenesis and fibrous tissue generation).
  • MIS transforming growth factor- ⁇
  • BMPs bone morpho-genetic proteins
  • TGF- ⁇ RI type I
  • TGF ⁇ RII type II
  • TGF ⁇ RIII type III
  • the signal transduction in the TGF- ⁇ signaling pathway is mainly through the combination of TGF- ⁇ ligand with the serine/threonine kinase receptor TGF ⁇ RI (ALK5) and TGF ⁇ RII on the cell surface to form a heterotetrameric complex, and then TGF ⁇ RII interacts with TGF ⁇ RI
  • ALK5 serine/threonine kinase receptor
  • TGF ⁇ RII TGF ⁇ RI
  • the glycine/serine region phosphorylates and activates the phosphorylation of TGF ⁇ RI to the intracellular signaling protein Smad protein molecule-Smad2/Smad3 that is connected to it.
  • TGF ⁇ RIII transforming growth factor- ⁇ III receptor
  • TGF- ⁇ plays a key role in the occurrence and progression of fibrosis in different organ systems such as heart, liver, lung, and kidney.
  • Abnormal TGF- ⁇ signaling is related to many human diseases, such as cancer, cardiovascular disease, inflammation, organ fibrotic disease, pancreatic disease, etc.
  • the dysregulation of TGF- ⁇ signaling is very common, which can promote tumor cell growth and differentiation, and regulate extracellular matrix and epithelial-mesenchymal transition.
  • TGF- ⁇ has been proven to play an important role in regulating anti-tumor immunity.
  • TGF- ⁇ has a strong inhibitory effect on the differentiation of T lymphocytes, and has a significant negative effect on dendritic cells, CD8 + T cells and NK cells. At the same time, it can enhance immunosuppressive T reg and bone marrow-derived suppressor cells (MDSC). ), thereby providing a favorable tumor microenvironment for tumor growth and metastasis. Therefore, inhibiting the signal transduction of a certain link in the TGF- ⁇ signaling pathway may become one of the effective methods for the treatment of tumors.
  • MDSC bone marrow-derived suppressor cells
  • TGF ⁇ RI As an important node in the TGF- ⁇ signaling pathway, TGF ⁇ RI (ALK5) is considered to be an important target for tumor treatment. By preventing the binding of TGF ⁇ RI to ligands, it inhibits the phosphoric acid of ALK5 on its downstream signaling protein (Smad2 or Smad3). In order to prevent and treat various related diseases mediated by ALK5, it can affect or block TGF- ⁇ signal transmission.
  • Cy represents a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group substituted by 0, 1, 2 or 3 substituents, wherein the substituents are selected from: halogen, C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, halo C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b , -SO 2 R a , -C(O)R a ,- C(O)OR a , -C(O)NR a R b , -P(O)R a R b ;
  • R 1 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl;
  • R 2 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl, -OR a , cyano, Nitro, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -SO 2 NR a R b , -NR a SO 2 R b ;
  • R 3 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl, -OR a , cyanide Group, nitro group, NR a R b , -SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -SO 2 NR a R b , -NR a SO 2 R b ;
  • R 4 represents hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , hydroxyl (C 1 -C 6 alkyl);
  • R 5 represents hydrogen, C 1 -C 6 alkyl, C 2- C 6 alkene Group, C 3 -C 6 cycloalkyl, halo C 1 -C 6 alkyl; or R 4 , R 5 together with the atoms they are connected together form a 5-8 membered saturated and unsaturated ring, and the ring can also Randomly contain 0, 1 or 2 heteroatoms selected from N, O, S;
  • R a and R b each independently represent hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, or halogenated C 1 -C 6 alkyl; or R a, R b form together with the atoms to which they are attached a 5-8 membered ring which may also optionally contain 1 or 2 heteroatoms selected from N, O, S, heteroatoms;
  • n 0, 1, 2 or 3.
  • the compound of formula (I) has the following structure of formula (II):
  • R 1, R 3, R 4 , R 5, R a, R b and n have the meanings according to claim 1;
  • R 2 represents hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, hydroxy (C 1 -C 6 alkyl), halogenated C 1 -C 6 alkyl;
  • W represents CR L or N
  • R 6 represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b ,- SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -P(O)R a R b ;
  • R L represents hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo C 1 -C 6 alkyl, -OR a , cyano, nitro, NR a R b ,- SO 2 R a , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -P(O)R a R b ;
  • o 0, 1, 2 or 3.
  • the compound of the present invention is selected from the following structures:
  • the compounds of the present invention can also be prepared in the form of pharmaceutically acceptable salts, which can be formed using, for example, the following inorganic or organic acids: 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, hydroxyl Benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
  • inorganic or organic acids hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid , Lactic acid,
  • the pharmaceutically acceptable salt of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in an organic solvent miscible with water (such as acetone, methanol, ethanol, and acetonitrile), and adding an excessive amount of organic acid or An aqueous inorganic acid solution is used to precipitate the salt from the resulting mixture, the solvent and remaining free acid are removed therefrom, and then the precipitated salt can be separated.
  • an organic solvent miscible with water such as acetone, methanol, ethanol, and acetonitrile
  • the compound of the present invention may include a solvate form, preferably, the solvate is a hydrate.
  • the present invention also provides the use of the compound of the present invention in the preparation of a medicine for preventing or treating diseases that can be regulated by inhibiting the activity of ALK5.
  • the disease is selected from cancer, tumor, inflammatory disease, autoimmune disease and immune-mediated disease.
  • the present invention provides a pharmaceutical composition for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which comprises the formula of the present invention (I) Compound as active ingredient.
  • the present invention provides a method for preventing or treating cancer, tumor, inflammatory disease, autoimmune disease, neurodegenerative disease, attention-related disease or immune-mediated disease, which includes Of mammals administer the compounds of the invention.
  • cancer or tumors may include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neurocytoma, rectal cancer , Colon cancer, familial adenomatous polyposis cancer, hereditary non-polyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, Papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, Astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, Hodg
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another anticancer agent or checkpoint inhibitor for the treatment of cancer or tumor, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide an enhanced anticancer effect.
  • anticancer agents for the treatment of cancer or tumors may include, but are not limited to, cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carbohydrate Mustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, Mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectidine, dactinomycin, doxorubicin , Epirubicin, daunomycin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxi
  • inflammatory diseases may include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, juvenile arthritis , Other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung disease, lung inflammation, adult respiratory distress syndrome (ARDS) , Pulmonary sarcoidosis, chronic pulmonary inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular disease, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (rubella), multiple sclerosis,
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when administered in combination with another therapeutic agent for the treatment of inflammatory diseases, autoimmune diseases and immune-mediated diseases, the compound of the present invention or a pharmaceutically acceptable salt thereof can provide enhanced Therapeutic effect.
  • therapeutic agents for the treatment of inflammatory diseases, autoimmune diseases, and immune-mediated diseases may include, but are not limited to, steroid drugs (e.g., prednisone, hydroprednisolone, methylhydroprednisolone) Pine, cortisone, hydroxycortisone, betamethasone, dexamethasone, etc.), methotrexate, leflunomide, anti-TNF ⁇ agents (e.g., Etanercept, Infliximab, Adali Monoclonal antibodies, etc.), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.) and antihistamines (e.g., diphenhydramine, hydroxyzine, loratadine, ebas , Ketotifen, cetirizine, levocetirizine, fexofenadine, etc.), and at least one therapeutic agent selected from them may be included in the pharmaceutical composition of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered orally or parenterally as an active ingredient, and its effective amount ranges from 0.1 to 2,000 mg/kg body weight/day in the case of mammals including humans (body weight of about 70 kg). It is preferably 1 to 1,000 mg/kg body weight/day, and administered in a single or 4 divided doses per day, or following/not following a predetermined time.
  • the dosage of the active ingredient can be adjusted according to a number of relevant factors (such as the condition of the subject to be treated, the type and severity of the disease, the rate of administration, and the doctor's opinion). In some cases, an amount less than the above dosage may be appropriate. If it does not cause harmful side effects, an amount larger than the above dose can be used and the amount can be administered in divided doses per day.
  • the pharmaceutical composition of the present invention can be formulated into dosage forms for oral administration or parenteral administration (including intramuscular, intravenous and subcutaneous routes) according to any of the conventional methods, such as tablets, granules, powders, capsules, syrups , Emulsion, microemulsion, solution or suspension.
  • the pharmaceutical composition of the present invention for oral administration can be prepared by mixing the active ingredient with a carrier such as the following: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.
  • a carrier such as the following: cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, hard Magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers and diluents.
  • carriers used in the injection composition of the present invention are water, salt solution, glucose solution, glucose-like solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester,
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the field of organic synthesis, and the compounds of the present invention can be synthesized using synthetic methods known in the field of organic synthetic chemistry or through variations known to those skilled in the art. .
  • the desired reaction can be carried out in a solvent or solvent mixture suitable for the kit materials used and suitable for the transformation achieved.
  • the present invention describes the cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention, and they can be separated into a mixture of isomers or separate isomer forms.
  • the compounds of the present invention can be isolated in optically active or racemic form.
  • the compounds of the present invention may exist in a variety of tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are thus rearranged. It should be understood that all tautomeric forms that may exist are included in the present invention.
  • substituent is selected from, for example, the following substituents such as alkyl, cycloalkyl, aryl, heterocyclyl, halogen, hydroxy, Alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine groups (two of the amino substituents are selected (From alkyl, aryl or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thio, alkyl Thio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsul
  • substituents such as alkyl, cycloalkyl,
  • alkyl or "alkylene” as used herein is intended to include branched or straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C 6 alkyl means an alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, tert-butyl) and Pentyl (e.g., n-pentyl, isopentyl, neopentyl).
  • Preferred alkyl groups are C 1 -C 6 alkyl groups, and more preferred alkyl groups are C 1 -C 4 alkyl groups.
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds and usually having a length of 2 to 20 carbon atoms.
  • C 2 -C 8 alkenyl contains two to eight carbon atoms.
  • Alkenyl includes, but is not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • a preferred alkenyl group is a C 2 -C 8 alkenyl group, and a more preferred alkenyl group is a C 2 -C 6 alkenyl group.
  • alkynyl means a straight or branched hydrocarbon group containing one or more triple bonds and usually having a length of 2 to 20 carbon atoms.
  • C 2 -C 8 alkynyl contains two to eight carbon atoms.
  • a preferred alkynyl group is a C 2 -C 8 alkynyl group, and a more preferred alkenyl group is a C 2 -C 6 alkynyl group.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C 1 -C 6 alkoxy (or alkyloxy) is intended to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
  • a preferred alkoxy group is a C 1 -C 6 alkoxy group, and a more preferred alkoxy group is a C 1 -C 4 alkoxy group.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (such as n-propoxy and isopropoxy), and tert-butoxy.
  • alkylthio or “thioalkoxy” means an alkyl group, as defined above, with the specified number of carbon atoms connected via a sulfur bridge; for example, methyl-S- and ethyl-S-.
  • aryl alone or as part of a larger part such as “aralkyl”, “aralkoxy” or “aryloxyalkyl”, refers to a monocyclic ring having a total of 5 to 12 ring members , A bicyclic or tricyclic ring system, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • a monocyclic aromatic group refers to a phenyl group
  • a bicyclic or more aromatic group refers to naphthyl, anthracenyl, etc.
  • the aryl bicyclic ring can also be a benzene ring fused with a cycloalkyl group or a ring Alkenyl, or fused with a cycloalkynyl group.
  • the preferred aryl group is a C 6 -C 12 aryl group.
  • "aryl" refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthalene base.
  • aralkyl or "arylalkyl” refers to an alkyl residue attached to an aryl ring. Non-limiting examples include benzyl, phenethyl, and the like.
  • the fused aryl group may be connected to another group at a suitable position on the cycloalkyl ring or aromatic ring.
  • Example The arrow line drawn from the ring system indicates that the bond can be connected to any suitable ring atom.
  • cycloalkyl refers to a monocyclic or bicyclic cyclic alkyl group.
  • the monocyclic cyclic alkyl group refers to a C 3 -C 8 cyclic alkyl group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornanyl.
  • Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl”.
  • the bicyclic cyclic alkyl group includes a bridged ring, a spiro ring, or a fused ring cycloalkyl group.
  • the preferred cycloalkyl group is a C 3 -C 6 cycloalkyl group.
  • cycloalkenyl refers to a monocyclic or bicyclic cyclic alkenyl.
  • the monocyclic cyclic alkenyl group refers to a C 3 -C 8 cyclic alkenyl group, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl.
  • Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are included in the definition of "cycloalkenyl”.
  • the bicyclic cyclic alkenyl group includes a bridged ring, a spiro ring, or a fused ring cyclic alkenyl group.
  • hydroxyalkyl refers to a branched and straight chain saturated aliphatic hydrocarbon group with the specified number of carbon atoms and at least one -OH is attached to the carbon atom of the hydrocarbon group.
  • hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoromethyl Propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” intended to include branched and straight chain saturated aliphatic hydrocarbon groups having a designated number of carbon atoms and substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group as defined above with the specified number of carbon atoms connected via an oxygen bridge.
  • C 1 -C 6 haloalkoxy is meant to include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 haloalkoxy.
  • Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” means a haloalkyl group as defined above that has the specified number of carbon atoms connected by a sulfur bridge; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • heteroaryl means a stable 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered aromatic monocyclic or aromatic bicyclic ring or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered , 13-membered or 14-membered aromatic polycyclic heterocyclic ring, which is fully unsaturated, partially unsaturated, and contains carbon atoms and 1, 2, 3 or 4 independently selected from N, O and S And includes any of the following polycyclic groups in which any heterocyclic ring as defined above is fused with a benzene ring. Nitrogen and sulfur heteroatoms can optionally be oxidized.
  • the nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined).
  • the heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocyclic group described herein may be substituted on a carbon or nitrogen atom.
  • the nitrogen in the heterocyclic ring can optionally be quaternized.
  • the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other.
  • the total number of S and O atoms in the heterocyclic ring is not more than one.
  • Preferred heteroaryl groups are 5-12 membered heteroaryl groups.
  • heteroaryl groups include, but are not limited to, acridinyl, azetidinyl, azetidinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothienyl, benzoxazole Group, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH -Carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3 -b] Tetrahydrofuryl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H
  • heterocycloalkyl refers to a monocyclic heterocycloalkyl system, or a bicyclic heterocycloalkyl system, and also includes spiro heterocycles or bridged heterocycloalkyls.
  • the monocyclic heterocycloalkyl refers to a 3-8 membered, and at least one saturated or unsaturated but not aromatic cyclic alkyl system selected from O, N, S, and P.
  • the bicyclic heterocycloalkyl system refers to a heterocycloalkyl group fused to a phenyl group, or a cycloalkyl group, or a cycloalkenyl group, or a heterocycloalkyl group, or a heteroaryl group.
  • a preferred heterocycloalkyl group is a 3-12 membered heterocycloalkyl group.
  • substitution means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that the normal valence is maintained and the substitution results in a stable compound.
  • nitrogen atoms such as amines
  • these nitrogen atoms can be converted into N-oxides by treatment with an oxidizing agent (such as m-CPBA and/or hydrogen peroxide) to obtain the present invention
  • an oxidizing agent such as m-CPBA and/or hydrogen peroxide
  • any variable occurs more than once in any composition or formula of a compound, its definition at each occurrence is independent of its definition at every other occurrence.
  • the group may be optionally substituted with up to three R groups, and R is independently selected from R at each occurrence. definition.
  • substituents and/or variables are only allowed if the above-mentioned combinations produce stable compounds.
  • solvate means the physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be able to be separated.
  • the solvent molecules in the solvate can be arranged in regular and/or disordered arrangements.
  • Solvates may contain stoichiometric or non-stoichiometric solvent molecules.
  • “Solvate” encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrate, ethanolate, methanolate, and isopropanolate. Solvation methods are well known in the art.
  • patient refers to an organism that is treated by the method of the present invention.
  • organisms preferably include, but are not limited to, mammals (e.g., murine, ape/monkey, horse, cow, pig, dog, cat, etc.) and most preferably refer to humans.
  • an effective amount means the amount of a drug or agent (ie, a compound of the present invention) that will elicit a biological or medical response of a tissue, system, animal, or human sought by, for example, a researcher or clinician.
  • therapeutically effective amount means an amount that results in an improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or reduction in disease, compared to a corresponding subject who has not received the above-mentioned amount. Or the rate of progression of the disease.
  • the effective amount can be given in one or more administrations, administrations or doses and is not intended to be limited by a particular formulation or route of administration. The term also includes within its scope an effective amount for enhancing normal physiological functions.
  • treatment includes any effect that leads to amelioration of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration or elimination, or amelioration of its symptoms.
  • a certain compound or pharmaceutical composition can improve a certain disease, symptom or condition after administration, especially its severity is improved, the onset is delayed, the progression of the disease is slowed, or the duration of the disease is reduced. Regardless of fixed administration or temporary administration, continuous administration or intermittent administration, it can be attributed to or related to the administration.
  • prevention refers to preventing, blocking, eliminating the occurrence of a disease or interfering with or slowing the development of a disease before the occurrence of a disease or symptom.
  • composition refers to a combination of an active agent and an inert or active carrier, so that the composition is particularly suitable for in vivo or ex vivo diagnosis or treatment.
  • bases include, but are not limited to, alkali metal (e.g., sodium) hydroxide, alkaline earth metal (e.g., magnesium) hydroxide, ammonia, and the like.
  • alkali metal e.g., sodium
  • alkaline earth metal e.g., magnesium hydroxide
  • ammonia e.g., sodium
  • salt of the compound of the present invention is intended for therapeutic use, and the salt of the compound of the present invention is expected to be pharmaceutically acceptable.
  • salts of non-pharmaceutical acids and bases can also be used, for example, in the preparation or purification of pharmaceutical compounds.
  • immediate is used herein to refer to the following compounds, substances, compositions and/or dosage forms: within the scope of reasonable medical judgment, they are suitable for use in contact with human and animal tissues without excessive toxicity or irritation Sex, allergic reactions, and/or other problems or complications, and are commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable carrier” and “pharmaceutically acceptable carrier” mean pharmaceutical substances, compositions or vehicles, such as liquid or solid fillers, diluents, excipients, manufacturing aids (e.g. Lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid) or solvent encapsulated substances, which involve carrying or transporting the active compound from one organ or part of the body to another organ or Parts of the body.
  • manufacturing aids e.g. Lubricants, talc, magnesium stearate, calcium stearate or zinc stearate or stearic acid
  • solvent encapsulated substances which involve carrying or transporting the active compound from one organ or part of the body to another organ or Parts of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient.
  • acceptable refers to a prescription component or active ingredient that does not have undue harmful effects on the health of the general treatment target.
  • cancer refers to an abnormal growth of cells that cannot be controlled and which can metastasize (spread) under certain conditions.
  • This type of cancer includes, but is not limited to, solid tumors (such as bladder, intestine, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovary, pancreas or other endocrine organs (such as thyroid), prostate , Skin (melanoma) or hematoma (such as non-leukemic leukemia).
  • co-administration refers to administering several selected therapeutic drugs to a patient in the same or different modes of administration at the same or different times.
  • an “enhance” or “enhance”, as used herein, means that the expected result can be increased or prolonged in terms of potency or duration. Therefore, in terms of enhancing the therapeutic effect of a drug, the term “enhanced” refers to the ability of the drug to increase or extend the potency or duration of the drug in the system. "Synergy value” as used herein refers to the ability of another therapeutic drug to be maximized in an ideal system.
  • immune disease refers to a disease or symptom that produces an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually cell dysfunction, or destruction and dysfunction, or destruction of organs or tissues that may produce immune symptoms.
  • subject or “subject” includes mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cows, horses, goats, sheep, pigs; domestic animals such as rabbits and dogs; laboratory animals include rodents, Such as rats, mice and guinea pigs.
  • Non-mammalian animals include, but are not limited to, birds, fish, etc.
  • the selected mammal is a human.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, and otic administration , Nasal administration and local administration.
  • parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
  • the mode of administration of the compounds described herein is a local rather than a systemic mode of administration.
  • the long-acting formulation is administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered through a targeted drug delivery system.
  • liposomes encapsulated by organ-specific antibodies In this specific embodiment, the liposomes are selectively targeted to specific organs and absorbed.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of the present invention formulated together with one or more pharmaceutical carriers (additives) and/or diluents, and optionally one One or more of the above-mentioned other therapeutic agents.
  • the compound of the present invention can be administered by any suitable means for any of the above-mentioned purposes, for example, oral administration, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried Dispersions), syrups and emulsions; sublingually; buccal; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (for example, in a sterile injectable aqueous or non-aqueous solution or suspension Liquid form); nasal, including administration to the nasal membranes, such as by inhalation spray; topical, such as in the form of creams or ointments; or transrectally, such as in the form of suppositories. They can be administered alone, but are usually administered using a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.
  • the pharmaceutical carrier is formulated according to many factors within the scope of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; the subject to whom the composition containing the active agent is to be administered; the expected route of administration of the composition; and the targeted therapeutic indication.
  • Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.
  • the above-mentioned carrier may include many different ingredients and additives in addition to the active agent, and the above-mentioned other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizing active agents, binders, and the like.
  • suitable pharmaceutical carriers and the factors involved in the selection of carriers please refer to many easily available sources, such as Allen LVJr.et al. Remington: The Science and Practice of Pharmacy(2Volumes), 22nd Edition (2012) ), Pharmaceutical Press.
  • the dosage regimen of the compound of the present invention varies depending on known factors, such as the pharmacodynamic properties of the specific agent and its administration mode and route; the species, age, sex, health status, medical condition and weight of the recipient. ; The nature and degree of symptoms; the types of simultaneous treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the desired effect.
  • the daily oral dose of each active ingredient should be about 0.001 mg/day to about 10-5000 mg/day, preferably about 0.01 mg/day to about 1000 mg/day, and most preferably The ground is about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose should be about 0.01 mg/kg/min to about 10 mg/kg/min.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compound is usually selected as a suitable pharmaceutical diluent, excipient or carrier (herein Administered in the form of a mixture of drugs collectively referred to as drug carriers).
  • a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will usually be present in an amount of about 0.1-95% by weight based on the total weight of the composition.
  • a typical capsule for oral administration contains at least one compound of the present invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture was passed through a 60-mesh screen and packed into No. 1 gelatin capsules.
  • a typical injectable preparation can be prepared by aseptically placing at least one compound of the present invention (250 mg) in a bottle, aseptically lyophilizing and sealing. For use, the contents of the bottle are mixed with 2 mL of physiological saline to produce an injectable preparation.
  • the scope of the present invention includes (alone or in combination with a pharmaceutical carrier) pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the present invention as an active ingredient.
  • the compound of the present invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).
  • the compound of the present invention (which can be used in a suitable hydrated form) and/or the pharmaceutical composition of the present invention is formulated into a pharmaceutical dosage form by conventional methods known to those skilled in the art.
  • the actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed, so as to obtain the amount of the active ingredient that is effective for realizing the desired therapeutic response, composition, and administration mode of a specific patient without being toxic to the patient.
  • the selected dosage level will depend on many factors, including the activity of the particular compound of the invention or its ester, salt or amide used; route of administration; time of administration; excretion rate of the particular compound used; rate and extent of absorption The duration of treatment; other drugs, compounds and/or substances used in combination with the specific compound used; the age, sex, weight, condition, general health and previous medical history of the patient being treated and other factors well known in the medical field.
  • a doctor or veterinarian with ordinary skill in the art can easily determine and prescribe an effective amount of the required pharmaceutical composition.
  • the physician or veterinarian can start a competition of the compound of the present invention used in the pharmaceutical composition at a level lower than the required level, and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of the compound of the invention will be the amount of the compound that is the lowest dose effective to produce a therapeutic effect.
  • Such effective doses usually depend on the above-mentioned factors.
  • oral, intravenous, intracerebroventricular, and subcutaneous doses of the compound of the present invention for patients range from about 0.01 to about 50 mg/kg body weight/day.
  • the effective daily dose of the active compound can be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form.
  • the medication is administered once a day.
  • the compound of the present invention can be administered alone, it is preferable to administer the compound in the form of a pharmaceutical preparation (composition).
  • kits/product packaging is also described here.
  • kits can be composed of a conveyor, a medicine pack or a container box.
  • the container box can be divided into multiple compartments to accommodate one or more containers, such as vials, test tubes, and the like.
  • Each container contains all A single component in the method described. Suitable containers include bottles, vials, syringes and test tubes.
  • the container is made of acceptable materials such as glass or plastic.
  • the container may contain one or more of the compounds described herein.
  • the compounds may exist in the form of pharmaceutical components, or they may exist as a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an intravenous infusion bag or a bottle, and the stopper may be pierced by a hypodermic syringe needle).
  • kits may contain a compound, and instructions, labels, or operating instructions for the method of use described herein.
  • a typical kit may include one or more containers.
  • each container contains one or more materials (such as reagents, or concentrated mother liquor, and/ Or equipment).
  • materials include, but are not limited to, buffers, diluents, filters, needles, syringes, conveyors, bags, containers, bottles and/or test tubes, with a list of contents and/or instructions for use, and instructions for the built-in packaging. The entire set of instructions must be included.
  • the label can be displayed on the container or closely related to the container.
  • the appearance of a label on a container means that the label letters, numbers or other features are pasted, molded, or engraved on the container; the label can also appear in a container box or shipping box containing a variety of containers, such as in a product insert.
  • a label can be used to indicate a specific therapeutic use of the contents.
  • the label may also indicate instructions for use of the content, such as described in the above method.
  • the unit of weight-volume percentage in the present invention is well known to those skilled in the art, for example, refers to the weight of the solute in a 100 ml solution. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the content described can be applied to the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.
  • the relevant intermediates are commercially available (for example from Sigma Aldrich, Alfa).
  • the LC-MS experiment is measured under the following conditions:
  • Preparative HPLC usually uses an acidic method (gradient of acetonitrile and water, each containing 0.1% formic acid) with Thermo U3000 AFC-3000; column: Globalsil C-18 12nm, 250x 20mm, 10 ⁇ m, or equivalent; flow rate: 20mL/min, Separate.
  • N-bromosuccinimide (549 mg, 3.1 mmol) was added to N, N-dimethylformamide (5 mL) in which compound INT-1a (500 mg, 3.1 mmol) was dissolved, The resulting reaction liquid was stirred at the same temperature for 1.5 hours.
  • the reaction solution was poured into water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3); the combined organic phase was washed with water and saturated brine (100 mL each), dried over anhydrous sodium sulfate, and concentrated.
  • the reaction solution was quenched with a little water, poured into water (50mL), and extracted with ethyl acetate (50mL ⁇ 3); the combined organic phase was washed with water and saturated brine (100mL each), dried over anhydrous sodium sulfate, and concentrated .
  • Cyclopropyl methyl ketone (160mg, 1.9mmol) was added to a solution of sodium hydrogen (37mg, 1.6mmol, 60% w/w in kerosene) in tetrahydrofuran (10mL), and the resulting reaction solution was stirred at room temperature for half an hour After heating, it was raised to reflux; then, a solution of 4-fluoroacetophenone (250 mg, 1.6 mmol) in tetrahydrofuran (3 mL) was added dropwise. The resulting reaction solution was further stirred for half an hour under reflux.
  • 2,4-Dinitrophenylhydroxylamine (3.1g, 15.4mmol) was added to a solution of 4-(tert-butoxycarbonylamino)pyridine (3.0g, 15.4mmol) in 2-methyltetrahydrofuran (15mL); The resulting reaction solution was stirred at 40°C for 4 hours, then cooled to room temperature and stirred overnight. The reaction solution was filtered to obtain a yellow solid INT-4a (6.1 g, yield: 99.6%).
  • Diethyl oxalate (554mg, 3.8mmol) was added to a tetrahydrofuran (20mL) solution mixed with sodium hydrogen (74mg, 3.2mmol, 60% w/w in kerosene), and the resulting reaction solution was stirred at room temperature for half an hour. Heat to reflux; then add dropwise a solution of 4-fluoroacetophenone (500 mg, 3.6 mmol) in tetrahydrofuran (6 mL) previously dissolved. The resulting reaction solution was further stirred for half an hour under reflux.
  • Aqueous sodium hydroxide solution (3M, 1 mL) was added to a solution of compound 1a (147 mg, 0.31 mmol) in methanol (5 mL); the resulting reaction solution was stirred at 60° C. for 2 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to 3-4 with 1M aqueous hydrochloric acid, and extracted with ethyl acetate (20 mL ⁇ 2). The combined organic phase was washed with saturated sodium bicarbonate and saturated brine (30 mL each), dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oil 3a (122 mg, yield: 88.1%). MS(ESI): m/z 453.2(M+H) + .
  • TGF ⁇ RI kinase was purchased from Carna (Cat#09-141). Add 2 ⁇ l of enzyme solution prepared with kinase buffer (40mM Tris PH 7.5, 20mM MgCl 2 , 1mM DTT, 1mg/ml BSA) into a 384-well plate (Greiner, Cat#784075) (TGF ⁇ RI kinase is 25nM in the final reaction system) ). For the negative control, 2 ⁇ l kinase buffer was added. The compound was prepared as a 10 mM stock solution with DMSO, and the compound was diluted twice with DMSO according to the requirement of the initial concentration before the compound was detected.
  • p38 ⁇ kinase was purchased from SignalChem (Cat#M39-10BG). Add 2 ⁇ l of enzyme solution (p38 ⁇ kinase in the final reaction system) prepared with kinase buffer (40mM Tris PH 7.5, 20mM MgCl 2 , 0.05mM DTT, 0.1mg/ml BSA) into a 384-well plate (Greiner, Cat#784075) 0.8ng/ul). For the negative control, 2 ⁇ l kinase buffer was added. The compound was prepared as a 10 mM stock solution with DMSO, and the compound was diluted twice with DMSO according to the requirement of the initial concentration before the compound was detected.
  • HEK-Blue TGF ⁇ cells (Invivogen, Cat#hkb-tgfb), adjust the cell density to 1.25 ⁇ 10 6 cells/ml with 10% FBS DMEM, and add 40 ⁇ l per well to a 96-well plate.
  • the compound was prepared as a 10 mM stock solution with DMSO, and the compound was diluted twice with DMSO according to the requirement of the initial concentration before the compound was detected. Add 2.5 ⁇ l of the compound to 1 ml of complete medium, mix by pipetting, and dilute the compound 3-fold with DMEM medium containing 0.25% DMSO (the DMSO concentration in a 100 ⁇ l system is 0.1%).
  • SEAP detection uses Great EscApe SEAP chemiluminescence KIT (Clontech, Cat#631738) for detection, and cell viability detection uses CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat#G7573) for detection.
  • CellTiter-Glo Luminescent Cell Viability Assay Promega, Cat#G7573
  • Use Molecular Devices, SpectraMax i3x. to read the final chemiluminescence signal.
  • XLFIT data obtained using the 4-parameter curve fitting is performed aggregated IC 50.

Abstract

L'invention concerne un composé de formule (I) et une composition pharmaceutique le comprenant. Le composé de formule (I) peut être utilisé en tant qu'inhibiteur du récepteur TGF-β, en particulier un inhibiteur de TGFβRI, et peut être utilisé pour prévenir ou traiter, par exemple, diverses maladies associées induites par TGFβRI(ALK5). Drawing_references_to_be_translated:
PCT/CN2021/081965 2020-03-24 2021-03-22 INHIBITEUR DU RÉCEPTEUR DU FACTEUR DE CROISSANCE TRANSFORMANT β WO2021190425A1 (fr)

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