WO2021098817A1 - Dérivé de dioxopipérazine, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé de dioxopipérazine, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2021098817A1
WO2021098817A1 PCT/CN2020/130361 CN2020130361W WO2021098817A1 WO 2021098817 A1 WO2021098817 A1 WO 2021098817A1 CN 2020130361 W CN2020130361 W CN 2020130361W WO 2021098817 A1 WO2021098817 A1 WO 2021098817A1
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Prior art keywords
phenyl
chloro
mmol
tert
tetrazol
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PCT/CN2020/130361
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English (en)
Chinese (zh)
Inventor
吴俊军
陆银锁
肖瑛
王延彬
吕洋
邢伟
王汝欢
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深圳信立泰药业股份有限公司
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Priority to CN202080079337.XA priority Critical patent/CN114728914B/zh
Publication of WO2021098817A1 publication Critical patent/WO2021098817A1/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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the invention belongs to the technical field of chemical medicines, and relates to dioxopiperazine derivatives, a preparation method thereof and their application in medicine.
  • the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
  • These compounds are inhibitors of selective factor XIa (Factor XIa, FXIa for short).
  • the present invention also relates to a pharmaceutical composition containing these compounds and the use of the compounds in the treatment of diseases such as thromboembolism.
  • Cardiovascular and cerebrovascular diseases such as cerebrovascular, cerebral infarction, myocardial infarction, coronary heart disease, and arteriosclerosis take the lives of nearly 12 million people worldwide each year, which is close to a quarter of the world's total deaths, becoming the number one enemy of human health. In China, more than 2.6 million people die from cardiovascular disease each year, and 75% of the surviving patients are disabled, of which more than 40% are severely disabled. Thrombosis caused by cardiovascular and cerebrovascular diseases and diabetes and its complications has become an urgent problem to be solved today.
  • the human blood coagulation process is composed of intrinsic pathways, extrinsic pathways and common pathways (Annu.Rev.Med.2011.62:41–57). It is caused by the sequential activation of multiple zymogens. A chain reaction in which the process continues to be strengthened and amplified.
  • the coagulation cascade is initiated by the endogenous pathway (also called the contact activation pathway) and the exogenous pathway (also called the tissue factor pathway) to generate FXa, and then through the common pathway to generate thrombin (FIIa), and finally form fibrin.
  • the endogenous pathway refers to the process by which factor XII is activated to form the XIa-VIIIa-Ca 2+ -PL complex and activate factor X.
  • the exogenous coagulation pathway is the release of tissue factor (TF) to TF-VIIa-
  • the common pathway refers to the process in which the two pathways are combined into one after the formation of factor Xa, which activates prothrombin and finally generates fibrin.
  • FXI is necessary to maintain the endogenous pathway and is in the process of amplification of the coagulation cascade. Play a key role.
  • FXIa activated FXI
  • FXIa is currently an emerging target for inhibiting thrombosis.
  • Patent applications that disclose compounds with FXIa inhibitory activity include WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017/023992, WO2018041122, etc.
  • Bayer's antisense oligonucleotide BAY-2306001 has entered the phase II clinical study.
  • the compounds of the present invention have higher activity.
  • the compound of the present invention exhibits excellent anticoagulant effects on human blood, and has good pharmacokinetic activity, and can be used to effectively treat and/or prevent cardiovascular and cerebrovascular diseases and thrombotic symptoms.
  • the invention provides a series of oxopyridazinamide derivatives, their preparation methods and their medical applications.
  • the present invention provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
  • the present invention also relates to a pharmaceutical composition containing these compounds and the use of the compounds in the treatment of diseases such as thromboembolism.
  • the present invention is implemented through the following technical solutions:
  • R 1 is selected from R 3 substituted or unsubstituted tetrazole, R 3 substituted or unsubstituted triazole;
  • R 2 is selected from R 4 substituted or unsubstituted benzene ring, wherein R 4 is selected from -NR 5 -(CH 2 )n-CO-(CH 2 )n-NR 6 R 7 , -NR 5 -SO 2 -NR 6 R 7 ;
  • Ar is selected from at least one of the following groups substituted or unsubstituted by R 8:
  • R 3 is selected from hydrogen, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl;
  • R 5 , R 6 , and R 7 are independently selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy -C 1-4 alkyl, -SO 2 -C 1-4 alkane, -SO 2 -Benzene, -C 1-6 mono or dihydric alcohol, -(CH 2 )nC 3-12 aliphatic ring, or wherein any one or more of NR 5 and NR 6 R 7 form a ring through -(CH 2 )n-; or NR 6 R 7 together form C 3-12
  • R 8 is selected from hydrogen, halogen, C 1-4 alkyl, hydroxyl, -C 1-4 carboxylic acid, -C 1-4 carboxylic acid-C 1-4 alcohol ester;
  • R 9 is selected from hydrogen, -(CH 2 )n-OH, -SO 2 -C 1-4 alkane, -(CH 2 )n-COOH, -amide, cyano, NR 10 R 11 -C 1-4 Alkoxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkyl, -CO-morpholine, -CO-NR 12 -(CH 2 ) n-OH, HOOC-C 1-4 alkoxy,
  • R 10 , R 11 , and R 12 are independently selected from hydrogen or C 1-4 alkyl
  • n 0-6.
  • the -NR 5 -(CH 2 )n-CO-(CH 2 )n-NR 6 R 7 includes Wherein, R 7 and R 9 are as defined above.
  • the C 1-4 alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl;
  • -C 1-4 carboxylic acid is selected from formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid, tert-butyric acid;
  • -C 1-4 carboxylic acid-C 1-4 alcohol ester is selected from methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, propyl Methyl acid, ethyl propionate, propyl propionate, butyl propionate, methyl butyrate, ethyl butyrate, propyl butyrate, butyl butyrate.
  • the halogen is selected from fluorine, chlorine, bromine, and iodine.
  • the C 1-4 alkane is selected from methane, ethane, propane, isopropane, n-butane, isobutane, sec-butane, and tert-butane;
  • the C 1-4 alkoxy group is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy;
  • the -(CH 2 )n-OH is selected from hydroxyl, methanol, ethanol, n-propanol, and n-butanol;
  • the -C 1-6 monohydric or dihydric alcohol is selected from methanol, ethanol, n-propanol, n-butanol, tert-butanol, 1,3-butanediol, 3-methylbutan-1-ol, 3 -Methylpentan-1-ol, 4-methylpentan-1ol, 3-methylhexan-1ol, 4-methylhexan-1ol;
  • the alkoxy group of the NR 10 R 11 -C 1-4 is selected from the group consisting of methylamine methoxy, ethylamine methoxy, propylamine methoxy, butylamine methoxy, methylamine ethoxy, and ethylamine ethoxy.
  • the C 1-4 alkoxy-C 1-4 alkyl group is selected from methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxy Ethyl, butoxyethyl, methoxypropyl, ethoxypropyl, propoxypropyl, butoxypropyl, methoxybutyl, ethoxybutyl, propoxybutyl, butoxybutyl;
  • the -CO-NR 12 -(CH 2 )n-OH is selected from -CO-NH-CH 2 OH, -CO-N(CH 3 )-CH 2 OH, -CO-NH-CH 2 CH 2 OH, -CO-N(CH 3 )-CH 2 CH 2 OH;
  • the HOOC-C 1-4 alkoxy group is selected from HOOC-methoxy, HOOC-ethoxy, HOOC-propoxy, HOOC-isopropoxy, HOOC-n-butoxy, HOOC-isobutoxy Group, HOOC-sec-butoxy, HOOC-tert-butoxy.
  • the C 3-12 aliphatic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.
  • More than one carbon atom of the C 3-12 fat is replaced by 0-2 N, O, S atoms, selected from:
  • n 0,1,2,3,4,5,6.
  • R 1 is selected from tetrazolium and triazole
  • R 2 is selected from benzene ring
  • Ar is selected from the following groups:
  • the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:
  • the pharmaceutically acceptable salt refers to a compound prepared with a pharmaceutically acceptable acid or base.
  • more than one hydrogen atom of the compound is replaced by an isotope deuterium.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts and more than one pharmaceutically acceptable a.
  • Another object of the present invention is to provide the compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, and containing the compound, or its stereoisomers,
  • the pharmaceutical composition of tautomers and pharmaceutically acceptable salts is used in the preparation of pharmaceuticals for the treatment of FXIa-related diseases, in particular, the pharmaceutical uses related to thrombosis-related diseases.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a pharmaceutically acceptable acid or base.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the atoms of the compound molecules of the present invention are isotopes, and isotope derivatization can generally extend the half-life, reduce the clearance rate, enhance the stability of metabolism, and increase the activity in the body. And, an embodiment is included in which at least one atom is substituted with atoms having the same atomic number (number of protons) and different mass numbers (sum of protons and neutrons).
  • isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, which respectively include 2 H, 3 H, 13 C, 14 C, and 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl.
  • radioisotopes that emit radiation as they decay such as 3 H or 14 C, can be used for topographical examinations of pharmaceutical preparations or compounds in the body.
  • the stable isotope neither decays or changes with its amount, nor is it radioactive, so it can be used safely.
  • the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as deuterium ( 2 H), iodine-125 ( 125 I), or C-14 ( 14 C). All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • one or more hydrogen atoms of the compound of the present invention are replaced by the isotope deuterium ( 2 H).
  • the compound of the present invention has the effects of prolonging half-life, reducing clearance, enhancing metabolic stability, and improving in vivo activity.
  • the preparation method of the isotope derivative usually includes a phase transfer catalysis method.
  • the preferred deuteration method uses a phase transfer catalyst (e.g., tetraalkylammonium salt, NBu 4 HSO 4 ).
  • a phase transfer catalyst e.g., tetraalkylammonium salt, NBu 4 HSO 4 .
  • the use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in the use of deuterated silanes (e.g. triethyl deuterated monosilane) or Lewis acids such as trichlorosilane in the presence of an acid (e.g., methanesulfonic acid)
  • Aluminum chloride is reduced with deuterated sodium borate to introduce higher deuterium.
  • pharmaceutically acceptable carrier refers to any preparation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic or side effects to the host or patient.
  • Representative carriers include water and oil. , Vegetables and minerals, cream base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the content of this document is incorporated herein by reference.
  • excipient generally refers to the carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that can effectively treat the target disorder, disease or condition.
  • 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, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • NMR was measured with Bruker AVANCE-III nuclear magnetometer, the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).
  • MS is measured with ISQ EC mass spectrometer (manufacturer: Thermo, model: ISQ EC).
  • HPLC high performance liquid chromatography
  • CombiFlash rapid preparation instrument uses CombiFlash Rf+LUMEN (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Yinlong HSGF254 or GF254 silica gel plate.
  • the size of the silica gel plate used in thin layer chromatography (TLC) is 0.17mm ⁇ 0.23mm, and the size of thin layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the silica gel column chromatography generally uses Rushan Shangbang silica gel 100-200 mesh silica gel as the carrier.
  • Step B Synthesis of (2-((5-chloro-2-nitrophenyl)amino)-2-oxoacetyl)-L-phenylalanine tert-butyl ester
  • Step C Synthesis of (S)-2-(4-(5-chloro-2-nitrophenyl)-2,3-dioxopiperazin-1-yl)-3-phenylpropionic acid tert-butyl ester
  • Step D Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-phenylpropionic acid tert-butyl ester
  • Step E Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -Tert-butyl phenylpropionate
  • Step F Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -Phenylpropionic acid
  • Step G Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-N -(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-phenylpropionamide
  • the reaction was quenched by adding water, a solid was precipitated, filtered, and a filter cake was used to obtain 70 mg of crude product.
  • the crude product was purified by preparative high performance liquid chromatography. The separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido) tert-butyl benzoate
  • Step B Synthesis of (S)-4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)benzoic acid
  • the reaction liquid was distilled under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-N -(3-oxoisoindolin-5-yl)-3-phenylpropionamide
  • the reaction was quenched by adding water, extracted with dichloromethane (10 ml ⁇ 3 times), and distilled under reduced pressure.
  • the residue obtained was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-5-(3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazine- 1-yl)-3-tert-butyl phenylpropoxy)phenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylic acid tert-butyl ester
  • the reaction was quenched by adding water, diluted with ethyl acetate (20 ml), washed with water and brine (10 ml ⁇ 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure.
  • the residue obtained was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-N -(4-(5-oxo-2-5-dihydro-1H-pyrazol-3-yl)phenyl)-3-phenylpropionamide
  • the reaction liquid was distilled under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido) tert-butyl benzoate
  • Step B Synthesis of (S)-3-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)benzoic acid
  • the reaction liquid was distilled under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)-1H-benzo[d]imidazole-2-carboxylic acid tert-butyl ester
  • the reaction was quenched by adding water, diluted with ethyl acetate (20 ml), washed with water and brine (10 ml ⁇ 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure.
  • the residue obtained was purified with a TLC plate (ethyl acetate: n-hexane).
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)-1H-benzo[d]imidazole-2-carboxylic acid
  • the reaction liquid was distilled under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • 20 mg of light yellow solid (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxo were obtained.
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • the reaction was quenched by adding water, diluted with ethyl acetate (20 ml), washed with water and brine (10 ml ⁇ 3 times), dried over anhydrous sodium sulfate, and distilled under reduced pressure.
  • the residue obtained was purified with a TLC plate (ethyl acetate: n-hexane).
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)-1H-indole-2-carboxylic acid
  • the reaction liquid was distilled under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(Piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(Piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • the reaction liquid was distilled under reduced pressure.
  • the obtained residue was purified by preparative high performance liquid chromatography.
  • the separation conditions are as follows, chromatographic column: X select C18 19mm*150mm; mobile phase: water (containing 0.05% trifluoroacetic acid) and acetonitrile; flow rate: 25 ml/min; gradient: within 7 minutes, acetonitrile rises from 5% to 100%; detection wavelength: 254nm.
  • chromatographic column X select C18 19mm*150mm
  • mobile phase water (containing 0.05% trifluoroacetic acid) and acetonitrile
  • flow rate 25 ml/min
  • gradient within 7 minutes, acetonitrile rises from 5% to 100%
  • detection wavelength 254nm.
  • Step B Synthesis of 3-chloro-5-nitro-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step C Synthesis of 3-chloro-5-amino-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step D Synthesis of (S)-3-chloro-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazine -1-yl)-3-phenylpropionamide)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step E Synthesis of (S)-3-chloro-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazine -1-yl)-3-phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 1-methyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution, the mixed solution was extracted with ethyl acetate (40 ml ⁇ 3 times), the organic phases were combined, and the organic phase was saturated brine (30 ml ⁇ 3 times), anhydrous sodium sulfate Dry and concentrate under reduced pressure.
  • Step C Synthesis of 1-methyl-5-nitro-1H-indole-2-carboxylic acid tert-butyl ester
  • Step D Synthesis of 1-methyl-5-amino-1H-indole-2-carboxylic acid tert-butyl ester
  • Step E Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(-4-nitrophenyl)propionylamino)-1-methyl-1H-indole-2-carboxylic acid tert-butyl ester
  • the reaction was quenched by adding water to the reaction solution.
  • the mixture was extracted with ethyl acetate (20 ml ⁇ 3 times).
  • the organic phase was combined, and the organic phase was first saturated brine (10 ml ⁇ 3 times), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure.
  • Step F Synthesis of (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3 -Dioxopiperazin-1-yl)propionylamino)-1-methyl-1H-indole-2-carboxylic acid tert-butyl ester
  • Step G Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(-4-(piperidine-1-carboxamido)phenyl)propionamido)-1-methyl-1H-indole-2-carboxylic acid tert-butyl ester
  • Step H Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(Piperidine-1-carboxamido)phenyl)propionamido)-1-methyl-1H-indole-2-carboxylic acid
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-Hydroxypiperidine-1-carboxamido)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step C Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)ureido)phenyl)propionylamino)-1H-indole-1,2- Di-tert-butyl dicarboxylate
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(1,1-dioxotetrahydro-1H-thiopyran-4-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step B Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-Hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propionylamino)-1H-indole-1,2 -Di-tert-butyl dicarboxylate
  • Step C Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-Hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propionamido)-1H-indole-2-carboxy acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(Methylsulfonyl)piperidine-1-carboxamido)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(methylsulfonyl)piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(3-(4-(4-(tert-butoxycarbonyl)piperidine-1-carboxamido)phenyl)-2-(4-(5-chloro-2 -(1H-tetrazole)-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)propionamido)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of (S)-5-(3-(4-(4-carboxypiperidine-1-carboxamido)phenyl)-2-(4-(5-chloro-2-(1H-tetrazole) -1-yl)phenyl)-2,3-dioxopiperazin-1-yl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(Methylsulfonyl)ureido)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(methylsulfonyl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propionamido)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(ethylsulfonyl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazine-1- Yl)-3-(4-((S)-3-hydroxypiperidine-1-carboxamido)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-((4-((S)-3-hydroxypiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of methyl 3-(3-oxopiperazin-1-yl)cyclobutane-1-carboxylate
  • Step C Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(4-(3-(Hydroxymethyl))cyclobutyl)-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • Step D Synthesis of (S)-2-(4-(2-amino-5-chloro-phenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(4-( 3-(Hydroxymethyl))cyclobutyl)-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • Step E Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(3-(Hydroxymethyl)cyclobutyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step F Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(-4-(-(3-(hydroxymethyl)cyclobutyl)-2-oxopiperazin-1-yl)phenyl)propionylamino)-1H-indole-1,2 -Di-tert-butyl dicarboxylate
  • Step G Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(3-(hydroxymethyl)cyclobutyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-carboxy acid
  • Step C Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(4-(Tetrahydrofuran-3-yl)methyl-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • Step D Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(4-(tetrahydrofuran) -3-yl)methyl-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • Step E Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(Tetrahydrofuran-3-yl)methyl-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step F Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-((Tetrahydrofuran-3-yl)methyl-2-oxopiperazin-1-yl)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid Tert-butyl ester
  • Step G Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(tetrahydrofuran-3-yl)methyl-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(3-(4-(4-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxamido)phenyl)- 2-(4-(5-)chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)propionamido)-1H-indole -1,2-Di-tert-butyl dicarboxylic acid
  • Step B Synthesis of (S)-5-(3-(4-(4-(carboxymethoxy)piperidine-1-carboxamido)phenyl)-2-(4-(5-chloro-2- (1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-((2-hydroxyethyl)carbamoyl)piperidine-1-carboxamido)phenyl)propionylamino)-1H-indole-1,2-dicarboxy Di-tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-((2-hydroxyethyl)carbamoyl)piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-((2-hydroxyethyl)(methyl)carbamoyl)piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-1, Di-tert-butyl 2-dicarboxylate
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-((2-hydroxyethyl)(methyl)carbamoyl)piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2- carboxylic acid
  • Step A Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(4-Hydroxy-2-methylbut-2-yl)ureido)phenyl)propionamido)-1H-indole-1,2-dicarboxylic acid Butyl
  • Step B Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-(4-hydroxy-2-methylbut-2-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((2S,3S)-1,3-dihydroxybut-2-yl)ureido)phenyl)propionamido)-1H-indole-1,2-di Di-tert-butyl carboxylate
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((2R,3R)-1,3-dihydroxybut-2-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of tert-butyl (S)-2-amino-3-(4-bromophenyl)propionate
  • Step B Synthesis of (S)-3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid tert-butyl ester
  • Piperazine-2-one (11.0 g, 55.5 mmol) was dissolved in a mixed solution of methanol (20.0 mL) and acetic acid (0.5 mL). Subsequently, acetone (6.78 g, 111.0 mmol) and sodium cyanoborohydride (4.19 g, 66.6 mmol) were added to the above solution. Stir overnight at 60 degrees Celsius.
  • Step D Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)propionic acid tert Butyl
  • Step E Synthesis of (S)-2-amino-3-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)propionic acid tert-butyl ester hydrochloride
  • Step F Synthesis of (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4-(4- Isopropyl-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • Step G Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(4-isopropyl-2-oxopiperazine)-tert-butylazin-1-yl)phenyl)tert-butyl propionate
  • Step H Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(4-isopropyl 2-oxopiperazin-1-yl) phenyl) tert-butyl propionate
  • Step I Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step J Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)propionic acid
  • Step K Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step L Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-3-(4-bromophenyl)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido ) Tert-butyl propionate
  • Step B Synthesis of (S)-3-(4-bromophenyl)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazine -1-yl) tert-butyl propionate
  • Piperazine-2-one (1.0 g, 9.9 mmol) was dissolved in a mixed solution of methanol (10.0 mL) and acetic acid (0.2 mL). Subsequently, 4-methylcyclohexan-1-one (2.6 g, 19.9 mmol) and sodium cyanoborohydride (1.3 g, 19.9 mmol) were added to the above solution. Stir overnight at 60 degrees Celsius.
  • Step D Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(4-(4-Methoxycyclohexyl))-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • N,N-dimethylethyl-1,2-diamine (292 mg, 3.22 mmol)
  • cuprous iodide (315 mg, 1.66 mmol)
  • cesium carbonate (1 g, 3.22 mmol).
  • Step E Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(4-(4 -Methoxycyclohexyl)-2-oxopiperazin)-1-yl)phenyl)tert-butyl propionate
  • Step F Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step G Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(4-(methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionic acid
  • Step H Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionylamino)-1H-indole-1,2-dicarboxy Di-tert-butyl ester
  • Triazole N,N,N',N'-tetramethylurea hexafluorophosphate (245 mg, 0.64 mmol), N,N-diisopropylethylamine (111 mg, 0.86 mmol) , Stir at room temperature for 18 hours.
  • Step I Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Piperazine-2-one (2.0 g, 20.0 mmol) was dissolved in acetonitrile (20.0 mL). Subsequently, 1-bromo-2-methoxyethane (5.6 g, 40.0 mmol) and potassium carbonate (5.5 g, 40.0 mmol) were added to the above solution. Stir overnight at 100 degrees Celsius.
  • Step B Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(4-(2-Methoxyethyl)-)2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • Step C Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(4-(2 -Methoxyethyl)-2-oxopiperazin)-1-yl)phenyl)tert-butyl propionate
  • Step D Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(2-Methoxyethyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step E Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(2-(Methoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionic acid
  • Step F Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(2-Methoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-1,2-dicarboxy Di-tert-butyl ester
  • Triazole N,N,N',N'-tetramethylurea hexafluorophosphate (171 mg, 0.45 mmol), N,N-diisopropylethylamine (77 mg, 0.60 mmol) , Stir at room temperature for 18 hours.
  • Step G Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(2-methoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Piperazine-2-one 500 mg, 2.5 mmol was dissolved in a mixed solution of methanol (10.0 mL) and acetic acid (0.2 mL). Subsequently, tetrahydro-4H-pyran-4-one (788 mg, 5.0 mmol) and sodium cyanoborohydride (317 mg, 5.0 mmol) were added to the above solution. Stir overnight at 60 degrees Celsius.
  • Step B Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(2-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl) tert-butyl propionate
  • N,N-dimethylethyl-1,2-diamine (292 mg, 3.3 mmol), cuprous iodide (315 mg, 1.6 mmol) and cesium carbonate (1.08 g, 3.3 mmol). Stir at 110 degrees Celsius for 18 hours.
  • Step C Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(2-oxo -4-(Tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)tert-butyl propionate
  • Step D Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(2-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)tert-butyl propionate
  • Step E Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(2-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)propionic acid
  • Step F Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(2-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)propionamido)-1H-indole-1, Di-tert-butyl 2-dicarboxylate
  • Step G Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(2-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)phenyl)propionamido)-1H-indole-2- carboxylic acid
  • Piperazine-2-one (1.5 g, 7.5 mmol) was dissolved in a mixed solution of methanol (20.0 mL) and acetic acid (0.4 mL). Subsequently, 4-hydroxycyclohexane-1-one (1.7 g, 15.0 mmol) and sodium cyanoborohydride (951 mg, 15.0 mmol) were added to the above solution. Stir overnight at 60 degrees Celsius.
  • Step B Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(4-(4-Hydroxycyclohexyl))-2-oxopiperazin-1-yl)phenyl)tert-butyl propionate
  • N,N-dimethylethane-1,2-diamine (175 mg, 1.99 mmol)
  • cuprous iodide 189 mg, 0.99 mmol
  • cesium carbonate 645 mg, 1.99 mmol
  • Step C Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(4-(4 -Hydroxycyclohexyl)-2-oxopiperazin)-1-yl)phenyl)tert-butyl propionate
  • Step D Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(4-Hydroxycyclohexyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step E Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-(4-Hydroxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionic acid
  • Step F Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(4-Hydroxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionylamino)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step G Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(4-(4-hydroxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-carboxylic acid compound
  • Piperazine-2-one 500 mg, 4.9 mmol was dissolved in a mixed solution of methanol (10.0 mL) and acetic acid (0.2 mL). Subsequently, dihydro-2H-pyran-3(4H)-one (1.0 g, 10.0 mmol) and sodium cyanoborohydride (627 mg, 10.0 mmol) were added to the above solution. Stir overnight at 60 degrees Celsius.
  • Step B Synthesis of (2S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -(2-oxo-4-(tetrahydro)-2H-pyran-3-yl)piperazin-1-yl)phenyl)tert-butyl propionate
  • N,N-dimethylethane-1,2-diamine (175 mg, 1.99 mmol)
  • cuprous iodide 189 mg, 0.99 mmol
  • cesium carbonate 645 mg, 1.99 mmol
  • Step C Synthesis of (2S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(2-oxo -4-(Tetrahydro-2H-pyran-3-yl)piperazin-1-yl)phenyl)tert-butyl propionate
  • Step D Synthesis of (2S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(2-oxo-4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl)phenyl) tert-butyl propionate
  • (2S)-2-(4-(2-Amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-(2-oxo-4- (Tetrahydro-2H-pyran-3-yl)piperazin-1-yl)phenyl)tert-butyl propionate (260 mg, 0.4 mmol) and triethyl orthoformate (430 mg, 2.9 mmol) Dissolve in acetic acid (5.0 ml). Subsequently, sodium azide (188 mg, 2.9 mmol) was added to the above solution. Stir at 70 degrees Celsius for 1 hour.
  • Step E Synthesis of (2S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(2-oxo-4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl)phenyl)propionic acid
  • Step F Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(2-oxo-4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl)phenyl)propionamido)-1H-indole-2- Tert-butyl carboxylate
  • Step G Synthesis of 5-((2S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(2-oxo-4-(tetrahydro-2H-pyran-3-yl)piperazin-1-yl)phenyl)propionamido)-1H-indole-2- carboxylic acid
  • Step A Synthesis of 6-nitro-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of 6-amino-1H-indole-2-carboxylic acid tert-butyl ester
  • Step C Synthesis of (S)-6-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-6-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-Phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-3-(4-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxide Piperazin-1-yl) tert-butyl propionate
  • Step B Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-((phenoxycarbonyl)yl)amino)phenyl)tert-butyl propionate
  • Step C Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-Cyanopiperidine-1-carboxamido)phenyl) tert-butyl propionate
  • Step D Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-(4-Cyanopiperidine-1-carboxamido)phenyl)propionic acid
  • Step E Synthesis of (S)-N-(4-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazine- 1-yl)-3-((4-hydroxy-2-oxo-1,2-dihydroquinolin-6-yl)amino)-3-oxopropyl)phenyl)-4-cyanopiper Pyridine-1-carboxamide
  • Step A Synthesis of tert-butyl (S)-2-amino-3-(4-nitrophenyl)propionate
  • Step B Synthesis of tert-butyl (S)-2-(2-methoxy-2-oxoacetamido)-3-(4-nitrophenyl)propionate
  • Step C Synthesis of (S)-2-((1-(tert-butoxy)-3-(4-nitrophenyl)-1-oxopropan-2-yl)amino)-2-oxoacetic acid
  • Step E Synthesis of N 1 ,N 1 -diallyl-4-chlorobenzene-1,2-diamine
  • N,N-diallyl-4-chloro-2-nitroaniline (27.5 g, 108.8 mmol) to ethyl acetate, and add stannous chloride dihydrate in batches under ice bath (122.8 g, 544.0 mmol), under N 2 protection, react at room temperature overnight.
  • Step F Synthesis of (S)-2-(2-((5-chloro-2-(diallylamino)phenyl)amino)-2-oxoacetamido)-3-(4-nitrobenzene Base) tert-butyl propionate
  • Step G Synthesis of (S)-2-(4-(5-chloro-2-(diallylamino)phenyl)-2,3-dioxopiperazin-1-yl)-3-(4 -Nitrophenyl) tert-butyl propionate
  • the pad was suction filtered with anhydrous sodium sulfate, the filter cake was washed with 200 ml of ethyl acetate, the filtrate was extracted with ethyl acetate (100 ml ⁇ 3 times), the organic phases were combined, and the organic phase was first used with saturated brine (100 ml ⁇ 2 times) washing, then drying with anhydrous sodium sulfate, and finally concentrating under reduced pressure.
  • Step H Synthesis of (S)-2-(4-(2-amino-5-chlorophenyl)-2,3-dioxopiperazin-1-yl)-3-(4-nitrophenyl) Tert-butyl propionate
  • Step I Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-Nitrophenyl) tert-butyl propionate
  • Step J Synthesis of (S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)-3 -(4-Nitrophenyl)propionic acid
  • Step K Synthesis of 5-nitro-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step L Synthesis of 5-amino-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step M Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(-4-nitrophenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step N Synthesis of (S)-5-(3-(4-aminophenyl)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3 -Dioxopiperazin-1-yl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step O Synthesis of (S)-5-(2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(-4-((phenoxycarbonyl)amino)phenyl)propionylamino)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step P Synthesis of 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-(5 -Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)propionamido)-1H-indole-1,2-dicarboxylic acid Di-tert-butyl ester
  • Step Q Synthesis of 5-((2S)-3-(4-(3-((1,4-dioxan-2-yl)methyl)ureido)phenyl)-2-(4-(5 -Chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((R)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1H-indole-1,2-dicarboxylic acid di-tert-butyl ester
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((S)-4-hydroxybut-2-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1H-indole-1,2-di Di-tert-butyl carboxylate
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((S)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1H-indole-1,2-di Di-tert-butyl carboxylate
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((R)-1-hydroxy-3-methylbut-2-yl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((3-Methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1H-indole-1,2-di Di-tert-butyl carboxylate
  • Step B Synthesis of 5-((S)-2-(4-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-2,3-dioxopiperazin-1-yl )-3-(4-(3-((3-Methyloxetan-3-yl)methyl)ureido)phenyl)propionamido)-1H-indole-2-carboxylic acid

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Abstract

La présente invention concerne un dérivé de dioxopipérazine, son procédé de préparation et son utilisation pharmaceutique. En particulier, l'invention concerne des composés de formule (I) ou un stéréoisomère, un tautomère, un sel pharmaceutiquement acceptable de ceux-ci. Les composés sont des inhibiteurs du facteur XIa sélectif (facteur XIa, en abrégé FXIa). La présente invention concerne également une composition pharmaceutique comprenant les composés et une utilisation des composés dans des médicaments pour le traitement de maladies telles que la thromboembolie.
PCT/CN2020/130361 2019-11-21 2020-11-20 Dérivé de dioxopipérazine, son procédé de préparation et son utilisation pharmaceutique WO2021098817A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1101039A (zh) * 1993-05-14 1995-04-05 第一制药株式会社 哌嗪衍生物
CN101218227A (zh) * 2005-07-08 2008-07-09 阿斯利康(瑞典)有限公司 作为因子Xa的抑制剂的杂环磺酰胺衍生物
CN102026996A (zh) * 2008-03-13 2011-04-20 百时美施贵宝公司 作为凝血因子xia抑制剂的哒嗪衍生物
WO2014009872A1 (fr) * 2012-07-09 2014-01-16 Lupin Limited Dérivés tétrahydroquinazolinone utilisés comme inhibiteurs de parp

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE040226T2 (hu) * 2014-01-31 2019-02-28 Bristol Myers Squibb Co Makrociklusok heterociklusos P2' csoportokkal XIA faktor inhibitorokként
RU2742771C2 (ru) * 2016-08-31 2021-02-10 Цзянсу Хэнжуй Медицин Ко., Лтд. Производное оксопиколинамида, способ его получения и его фармацевтическое применение
CN107793396B (zh) * 2016-08-31 2021-02-26 江苏恒瑞医药股份有限公司 环氧基取代的氧代吡啶类衍生物、其制备方法及其在医药上的应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1101039A (zh) * 1993-05-14 1995-04-05 第一制药株式会社 哌嗪衍生物
CN101218227A (zh) * 2005-07-08 2008-07-09 阿斯利康(瑞典)有限公司 作为因子Xa的抑制剂的杂环磺酰胺衍生物
CN102026996A (zh) * 2008-03-13 2011-04-20 百时美施贵宝公司 作为凝血因子xia抑制剂的哒嗪衍生物
WO2014009872A1 (fr) * 2012-07-09 2014-01-16 Lupin Limited Dérivés tétrahydroquinazolinone utilisés comme inhibiteurs de parp

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