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WO2023185634A1 - Composé hétérocyclique utilisé comme inhibiteur de la kallicréine plasmatique - Google Patents

Composé hétérocyclique utilisé comme inhibiteur de la kallicréine plasmatique Download PDF

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Publication number
WO2023185634A1
WO2023185634A1 PCT/CN2023/083409 CN2023083409W WO2023185634A1 WO 2023185634 A1 WO2023185634 A1 WO 2023185634A1 CN 2023083409 W CN2023083409 W CN 2023083409W WO 2023185634 A1 WO2023185634 A1 WO 2023185634A1
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Prior art keywords
add
compound
ethyl acetate
hours
synthesis
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PCT/CN2023/083409
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English (en)
Chinese (zh)
Inventor
沈春莉
王廷
吴成德
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2023185634A1 publication Critical patent/WO2023185634A1/fr

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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
    • A61K31/41—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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D403/14—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
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic 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

Definitions

  • the present application belongs to the field of medicine, and specifically relates to compounds of formula (I), their preparation methods, and their applications in the preparation of drugs for the treatment of plasma kallikrein-mediated related diseases.
  • Plasma kallikrein also known as Fletcher factor
  • FXIIa Plasma kallikrein
  • BK bradykinin
  • PKal is often highly expressed in diabetic patients, leading to vasodilation and vasodilation. Increased permeability (RVP), causing diabetic retinopathy (DR) and diabetic macular edema (DME).
  • the main function of plasma kallikrein inhibitors is to reduce the activity level of plasma kallikrein in the body and reduce the activation effect of bradykinin on two receptors, thereby alleviating vascular permeability and inflammation, and achieving the treatment of diabetic retinopathy and diabetes.
  • Important role of macular edema In the clinical stage, the plasma kallikrein inhibitor KVD001 (WO2013005045) developed by KalVista Pharmaceuticals and the bicyclic peptide plasma kallikrein inhibitor developed by Oxurion have both demonstrated significant therapeutic effects in patients who were ineffective in VEGF monoclonal antibody treatment, but the administration The route of administration is intravitreal injection, and patient compliance needs to be improved.
  • the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
  • T 1 is CR 1 or N
  • R 1 is H, F, Cl, Br or I
  • R 2 is H, F, Cl, Br or I
  • R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;
  • R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy
  • R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;
  • R 7 is H, F, Cl, Br or I
  • R a is D, F, Cl or Br.
  • the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof,
  • T 1 is CR 1 or N
  • R 1 is H, F, Cl, Br or I
  • R 2 is H, F, Cl, Br or I
  • R 3 is a C 1-3 alkoxy group, and the C 1-3 alkoxy group is optionally substituted by 1, 2 or 3 R a ;
  • R 4 is F, Cl, Br, I, OH or C 1-3 alkoxy
  • R 5 and R 6 are independently H, F, Cl, Br, I, OH or NH 2 ;
  • R 7 is H, F, Cl, Br or I
  • R a is D, F, Cl or Br.
  • R 1 is F or Cl, and other variables are as defined in the present invention.
  • R 2 is F or Cl, and other variables are as defined in the present invention.
  • R 3 is -OCH 3 or -OCD 3 , and other variables are as defined in the present invention.
  • R 4 is F, Cl, Br, I, OH or -OCH 3 , and other variables are as defined in the present invention.
  • R 5 is H, and other variables are as defined in the present invention.
  • R 6 is H or F, and other variables are as defined in the present invention.
  • R 7 is F or H, and other variables are as defined in the present invention.
  • R 7 is F, and other variables are as defined in the present invention.
  • the present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof:
  • the present invention provides the use of the above compounds or pharmaceutically acceptable salts thereof in the preparation of medicines for treating related diseases mediated by plasma kallikrein.
  • the compounds of the present invention have significant plasma kallikrein inhibitory activity and good oral exposure.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • Treatment encompasses any treatment of a subject's disease that the subject (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also include any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m.
  • a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
  • hydroxyl protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl, Ac); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert. Butyldimethylsilyl (TBS) etc.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • the following abbreviations are used in the present invention: aq represents water; THF represents tetrahydrofuran.
  • Tetrahydrofuran (6200 mL), 3-2 (1.23 kg, 5.64 mol), 3-3 (650.08 g, 5.75 mol) were added to the previously dried reaction. Then add potassium carbonate (1.56kg, 11.27mol). Stir the system at 62°C for 3 hours, cool the system to about 55°C, then filter while hot, rinse the filter cake with 3.1L x 2 of ethyl acetate at 40°C, collect the filtrate, and concentrate to dryness to obtain the crude product.
  • N,N-dimethylformamide 3mL
  • 5-2 0.2g, 479.20 ⁇ mol
  • diisopropylethyl to the pre-dried reaction bottle.
  • Amine (495mg, 3.83mmol)
  • 2-(7-azobenzotriazole)-N,N,N,N-tetramethylurea hexafluorophosphate (273mg, 718.80umo)
  • nitrogen replacement 3 times then 2-1 (110.50 mg, 527.12 ⁇ mol) was added, and the system was stirred at 20°C for 2 hours.
  • PKal reaction buffer 25mM Tris-HCl (trishydroxymethylaminomethane-HCl), pH 8.0, 100mM NaCl, pH 8.5, 0.01% Brij35 (laureth polyoxyethylene ether), and 1% DMSO (final concentration ).
  • PKal R&D Systems Cat#2497-SE
  • Enzyme activation (1) dilute rhPKal to 200 ⁇ g/mL activation buffer (100mM Tris, 10mM CaCl 2 , 150mM NaCl, pH 7.5 (TCN)); (2) dilute thermolysin (Thermolysin) to 20 ⁇ g /mL activation buffer; (3) Mix rhPKal (200 ⁇ g/mL) and thermolysin (20 ⁇ g/mL) in equal volumes; (4) Incubate at 37°C for 30 minutes; (5) Then use 50 ⁇ M EDTA (ethylenediamine Tetraacetic acid) terminates the reaction.
  • EDTA ethylenediamine Tetraacetic acid
  • Matrix (Enzo Cat#P-139): 10 ⁇ M Z-FR-AMC (AMC: 7-amino-4-methylcoumarin).
  • Reaction process (1) Prepare the specified enzyme and substrate in the newly prepared activation buffer; (2) Inject the enzyme solution into the reaction well; (3) Use acoustic technology (Echo 550, LabCyte Inc. Sunnyvale, CA ) Inject the DMSO solution of the test product into the reaction mixture and control it within the nanoliter range; (4) After pre-incubation for 10 minutes, inject the matrix solution into the reaction well to start the reaction; (5) The activity of the enzyme can be measured by fluorescence Indicated by an increase in the fluorescence signal of the labeled peptide matrix, monitor every 5 minutes for 120 minutes at room temperature; (6) Data analysis: measure the slope of the straight line * (fluorescence signal/time), the slope can be calculated by excel, and the curve can be fitted through Prism software .
  • Table 1 The test results of the inhibitory effect of compounds on plasma kallikrein (PKal) are shown in Table 1 below.
  • the compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal).
  • PKal substrate Pro-Phe-Arg-AMC (AMC: 7-amino-4-methylcoumarin) (purchased from GenScript, C882QHC150-1);
  • reaction buffer 50mM Tris-HCl pH7.5, 250mM NaCl
  • substrate Pro-Phe-Arg-AMC working solution to a concentration of 250 ⁇ M
  • Compound addition plate The starting concentration of the positive reference compound and the test compound is 30 ⁇ M, diluted 3 times, and diluted to 10 concentration points. Deliver 0.05 ⁇ L of compound in 100% DMSO into a 384-well plate via acoustic liquid delivery technology (Echo550; nanoliter range);
  • Reading value After the incubation, use a PHERAstar FSX microplate reader (BMG) to read the fluorescence signal (ex380/em460). The activity of the enzyme is indicated by the fluorescence signal intensity of the fluorescently labeled substrate. Use GraphPad Prism software to perform curve fitting and obtain IC50 values.
  • the compound of the present invention has a significant inhibitory effect on plasma kallikrein (PKal) in human plasma.
  • mice Male SD rats were used as test animals, and the LC-MS/MS method was used to determine the drug concentration in the plasma of rats at different times after intravenous and gavage administration of test compounds. Study the pharmacokinetic behavior of compounds in rats and evaluate their pharmacokinetic characteristics.
  • Test drug test compound.
  • the LC-MS/MS method was used to determine the content of the test compound in the plasma of rats after intravenous and intragastric administration.
  • the linear range of the method is 2.00 ⁇ 6000nmol/L; plasma samples are analyzed after being treated with acetonitrile to precipitate proteins.
  • the pharmacokinetic test results of the compounds are shown in Table 3 below.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapport au domaine de la médecine, et concerne en particulier un composé de formule (I), son procédé de préparation et l'utilisation dudit composé dans la préparation d'un médicament pour le traitement de maladies associées à la kallicréine plasmatique.
PCT/CN2023/083409 2022-03-30 2023-03-23 Composé hétérocyclique utilisé comme inhibiteur de la kallicréine plasmatique WO2023185634A1 (fr)

Applications Claiming Priority (4)

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CN202210334521 2022-03-30
CN202210334521.5 2022-03-30
CN202210431376 2022-04-22
CN202210431376.2 2022-04-22

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105143201A (zh) * 2013-01-08 2015-12-09 卡尔维斯塔制药有限公司 苄胺衍生物
CN105452240A (zh) * 2013-05-23 2016-03-30 卡尔维斯塔制药有限公司 杂环衍生物
CN107108576A (zh) * 2014-11-27 2017-08-29 卡尔维斯塔制药有限公司 作为血浆激肽释放酶抑制剂的n‑((杂)芳基甲基)‑杂芳基‑甲酰胺化合物
TW201925188A (zh) * 2017-11-29 2019-07-01 英商卡爾維斯塔製藥有限公司 酶抑制劑
WO2021175290A1 (fr) * 2020-03-04 2021-09-10 南京明德新药研发有限公司 Composé hétérocyclique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105143201A (zh) * 2013-01-08 2015-12-09 卡尔维斯塔制药有限公司 苄胺衍生物
CN105452240A (zh) * 2013-05-23 2016-03-30 卡尔维斯塔制药有限公司 杂环衍生物
CN107108576A (zh) * 2014-11-27 2017-08-29 卡尔维斯塔制药有限公司 作为血浆激肽释放酶抑制剂的n‑((杂)芳基甲基)‑杂芳基‑甲酰胺化合物
TW201925188A (zh) * 2017-11-29 2019-07-01 英商卡爾維斯塔製藥有限公司 酶抑制劑
WO2021175290A1 (fr) * 2020-03-04 2021-09-10 南京明德新药研发有限公司 Composé hétérocyclique

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