WO2021110076A1 - Dérivés d'oxamide, leur procédé de préparation et leur utilisation en médecine - Google Patents

Dérivés d'oxamide, leur procédé de préparation et leur utilisation en médecine Download PDF

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Publication number
WO2021110076A1
WO2021110076A1 PCT/CN2020/133493 CN2020133493W WO2021110076A1 WO 2021110076 A1 WO2021110076 A1 WO 2021110076A1 CN 2020133493 W CN2020133493 W CN 2020133493W WO 2021110076 A1 WO2021110076 A1 WO 2021110076A1
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Prior art keywords
phenyl
amino
mmol
tert
chloro
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PCT/CN2020/133493
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English (en)
Chinese (zh)
Inventor
吴俊军
陆银锁
肖瑛
吕洋
周鹏
洪泽新
黄艺
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 CN202080079342.0A priority Critical patent/CN114728917B/zh
Publication of WO2021110076A1 publication Critical patent/WO2021110076A1/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
    • A61K31/435—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
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom

Definitions

  • the invention belongs to the technical field of chemical medicines, and relates to oxamide derivatives, their preparation methods and their applications 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 diseases 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 is continuously 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 thrombus.
  • Patent applications that disclose compounds with FXIa inhibitory activity include WO96/30396, WO99/41276, WO2013/093484, WO2004/002405, WO2013/056060, WO2017/005725, WO2017/023992, WO2018 /041122 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 oxamide derivatives, their preparation methods and their applications 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.
  • 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, -(CH 2 )n-CO-R 5 , 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 , -NR 5 -SO 2 -R 13 ;
  • 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, phenyl, C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, -SO 2 -C 1-4 alkane , -SO 2 -benzene, -C 1-6 monohydric 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
  • the aliphatic ring; one or more carbon atoms on the aforementioned C 3-12 alicyclic ring are replaced by 0-2 N, O, S atoms, and the aliphatic ring is further replaced by more than one R 9 ;
  • 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, -CO-NR 10 , -CONR 10 R 11 , -CONR 10 -SO 2 -C 1-4 alkane, Cyano, -NR 10 R 11 , NR 10 R 11 -C 1-4 alkoxy, -C 1-4 carboxylic acid, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxy-C 1-4 alkoxy, -CO-morpholine, morpholine, -OC 1-6 mono or dihydric alcohol, HOOC-C 1-4 alkoxy,
  • R 10 , R 11 , and R 12 are independently selected from hydrogen, C 1-4 alkyl, -(CH 2 )n-OH;
  • R 13 is selected from C 1-4 alkyl substituted or unsubstituted phenyl
  • n 0-6.
  • -NR 5 -(CH 2 )n-CO-(CH 2 )n-NR 6 R 7 includes
  • R 7 and R 9 are as defined above.
  • the C 1-4 alkyl group is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, Tert-butyl, cyclobutyl;
  • -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, cyclopropane, n-butane, isobutane, sec-butane, tert-butane, cyclopropane 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 group, methanol, ethanol, n-propanol, 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 NR 10 R 11 is selected from the group consisting of amino, methylamine, ethylamine, propylamine, butylamine, dimethylamine, methylethylamine, methylpropylamine, methylbutylamine, diethylamine, ethylenepropylamine, ethylbutylamine, dipropylamine, propylbutylamine Amine, dibutylamine.
  • 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 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 isotope deuterium.
  • Another object of the present invention provides 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 isotopic derivatization can generally prolong 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 examination 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 each 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 C Synthesis of methyl 2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetate
  • Step D Synthesis of 2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetic acid
  • Step F Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl ) Tert-butyl propionate
  • Step G Synthesis of (S)-2-amino-3-(4-(4-(3-methoxypropyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step H Synthesis of (S)-2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(3-methoxypropyl)-2-oxopiperazin-1-yl)phenyl ) Tert-butyl propionate
  • Step I Synthesis of (S)-2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(3-methoxypropyl)-2-oxopiperazin-1-yl)phenyl ) Propionic acid
  • Step J Synthesis of (S)-4-(2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(3-methoxypropyl)-2-oxopiperazin-1-yl )Phenyl)propionamido)-1-tert-butoxycarbonyl-indole-2-acid tert-butyl ester
  • Step K Synthesis of (S)-4-(2-amino-3-(4-(4-(3-methoxypropyl)-2-oxopiperazin-1-yl)phenyl)propionamido) -1H-Indole-2-acid tert-butyl ester
  • Step L Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(3-Methoxypropyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid tert-butyl ester
  • Step M Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(3-methoxypropyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid
  • Step B Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl ) Tert-butyl propionate
  • Step C Synthesis of (S)-2-amino-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step D Synthesis of (S)-2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl ) Tert-butyl propionate
  • Step E Synthesis of (S)-2-((Fluorenylmethoxycarbonyl)amino)-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl ) Propionic acid
  • Step F Synthesis of (S)-4-(2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl )Phenyl)propionamido)-1-tert-butoxycarbonyl-indole-2-acid tert-butyl ester
  • Step G Synthesis of (S)-4-(2-amino-3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido) -1H-Indole-2-acid tert-butyl ester
  • Step H Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid tert-butyl ester
  • Step I Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(2-ethoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid
  • Step B Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazine-1- (Yl)phenyl)tert-butyl propionate
  • Step C Synthesis of (S)-2-amino-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl)propionic acid tert Butyl
  • Step D Synthesis of (S)-2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazine-1- (Yl)phenyl)tert-butyl propionate
  • Step E Synthesis of (S)-2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazine-1- (Yl)phenyl)propionic acid
  • Step F Synthesis of (S)-4-(2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazine -1-yl)phenyl)propionamido)-1-tert-butoxycarbonyl-indole-2-acid tert-butyl ester
  • Step G Synthesis of (S)-4-(2-amino-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl) Propionamido)-1H-indole-2-acid tert-butyl ester
  • Step H Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid tert-butyl ester
  • Step I Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid
  • Step B Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl)propane Tert-butyl ester
  • Step C Synthesis of (S)-2-amino-3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step D Synthesis of (S)-2-((Fluorenylmethoxycarbonyl)amino)-3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl)propane Tert-butyl ester
  • Step E Synthesis of (S)-2-((Fluorenylmethoxycarbonyl)amino)-3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl)propane acid
  • Step F Synthesis of (S)-4-(2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)benzene Yl)propionamido)-1-tert-butoxycarbonyl-indole-2-acid tert-butyl ester
  • Step G Synthesis of (S)-4-(2-amino-3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H -Indole-2-acid tert-butyl ester
  • Step H Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid tert-butyl ester
  • Step I Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(tetrahydrofuran-3-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid
  • Step B Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl ) Tert-butyl propionate
  • Step C Synthesis of (S)-2-amino-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl) tert-butyl propionate
  • Step D Synthesis of (S)-2-((Fluorenylmethoxycarbonyl)amino)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl ) Tert-butyl propionate
  • Step E Synthesis of (S)-2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl ) Propionic acid
  • Step F Synthesis of (S)-4-(2-((fluorenylmethoxycarbonyl)amino)-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl )Phenyl)propionamido)-1-tert-butoxycarbonyl-indole-2-acid tert-butyl ester
  • Step G Synthesis of (S)-4-(2-amino-3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionamido) -1H-Indole-2-acid tert-butyl ester
  • Step H Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid tert-butyl ester
  • Step I Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(4-methoxycyclohexyl)-2-oxopiperazin-1-yl)phenyl)propionamido)-1H-indole-2-acid
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-(oxetan-3-yl)-2-oxopiperazine-1 -Yl)phenyl)propionamido)tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-amino-3-(4-(4-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)propionamide Yl) tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(oxetan-3-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazine -1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-amino-3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl) (Propionamido) tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(Tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(tetrahydro-2H-pyran-4-yl)-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-hydroxy-2-oxopiperidin-1-yl)phenyl)propionamido )Tert-Butyl Benzoate
  • Step C Synthesis of tert-butyl (S)-4-(2-amino-3-(4-(4-hydroxy-2-oxopiperidin-1-yl)phenyl)propionamido)benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4-(4-hydroxy-2-oxopiperidin-1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4--(4-hydroxy-2-oxopiperidin-1-yl)phenyl)propionamido)benzoic acid
  • Step A Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(3-oxo-8-oxa-2-azaspiro[4.5]decane- 2-yl)phenyl)propionamido)tert-butyl benzoate
  • Step B Synthesis of (S)-4-(2-amino-3-(4-(3-oxo-8-oxa-2-azaspiro[4.5]decane-2-yl)phenyl)propane Amido) tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4-(3-oxo-8-oxa-2-azaspiro[4.5]decane-2-yl)phenyl)propionamido)tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4--(3-oxo-8-oxa-2-azaspiro[4.5]decane-2-yl)phenyl)propionamido)benzoic acid
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-(2,2,2-trifluoroethyl)-2-oxopiperazine- 1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-amino-3-(4-(4-(2,2,2-trifluoroethyl)-2-oxopiperazin-1-yl)phenyl)propane Amido) tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(2,2,2-trifluoroethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(2,2,2-trifluoroethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • Step A Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(3-oxo-2-azaspiro[4.5]decane-2-yl)benzene (Yl) propionamido) tert-butyl benzoate
  • Step B Synthesis of (S)-4-(2-amino-3-(4-(3-oxo-2-azaspiro[4.5]decane-2-yl)phenyl)propionamido)benzoic acid Tert-butyl ester
  • Step C Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4-(3-oxo-2-azaspiro[4.5]decane-2-yl)phenyl)propionamido)tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4--(3-oxo-2-azaspiro[4.5]decane-2-yl)phenyl)propionamido)benzoic acid
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1 -Yl)phenyl)propionamido)tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-amino-3-(4-(((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)phenyl)propionamide Yl) tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4--(((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)phenyl)propionamido) tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(2-oxo-4--(((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)phenyl)propionamido)benzoic acid
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-(2-methoxyethyl)-2-oxopiperazin-1-yl )Phenyl)propionamido)tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-amino-3-(4-(4-(2-methoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido) Tert-butyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(2-Methoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(2-methoxyethyl)-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • Step C Synthesis of methyl 2-((5,6-dichloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetate
  • Step D Synthesis of 2-((5,6-Dichloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetic acid
  • Step E Synthesis of (S)-4-(2-(2-(((5,6-Dichloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamide Yl)-3-phenylpropionamido) tert-butyl benzoate
  • Step F Synthesis of (S)-4-(2-(2-(((5,6-Dichloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamide Yl)-3-phenylpropionamido)benzoic acid
  • Step C Synthesis of methyl 2-((5-chloro-2-(cyclopropylmethyl)phenyl)amino)-2-oxoacetate
  • Step D Synthesis of 2-((5-chloro-2-(cyclopropylmethyl)phenyl)amino)-2-oxoacetic acid
  • Step E Synthesis of (S)-4-(2-(2-(((5-chloro-2-(cyclopropylmethyl)phenyl)amino)-2-oxoacetamido)-3-benzene Propyl propionamido) tert-butyl benzoate
  • Step F Synthesis of (S)-4-(2-(2-(((cyclopropylmethyl)phenyl)amino)-2-oxoacetamido)-3-phenylpropionamido)benzoic acid
  • Step A Synthesis of (S)-2-amino-N-(1-oxoisoindol-5-yl)-3-phenylpropionamide
  • Step B Synthesis of (S)-N 1 -(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N 2 -(1-oxo-1-((3-oxoiso Indol-5-yl)amino)-3-phenylpropan-2-yl)oxalamide
  • Step A Synthesis of (S)-2-amino-N-(1-oxoisoindol-5-yl)-3-phenylpropionamide
  • Step B Synthesis of (S)-N 1 -(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N 2 -(1-oxo-1-((1-oxoiso Indol-5-yl)amino)-3-phenylpropan-2-yl)oxalamide
  • Step A Synthesis of (S)-2-amino-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3-phenylpropionamide
  • Step B Synthesis of (S)-N 1 -(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N 2 -(1-oxo-1-((2-oxo- 2,3-Dihydro-1H-benzo[d]imidazol-5-yl)amino)-3-phenylprop-2-yl)oxamide
  • Step A Synthesis of methyl (S)-4-(3-(4-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionamido)benzoate
  • Step B Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido ) Methyl benzoate
  • Step C Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-Methyl-2-oxopiperazin-1-yl)phenyl)propionamido)methyl benzoate
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-Methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • Step A Synthesis of tert-butyl (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(pyridin-3-yl)propionamido)benzoate
  • Step B Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(Pyridin-3-yl) propionamido) tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3- (Pyridin-3-yl)propionamido)benzoic acid
  • Step A Synthesis of (S)-5-(2-((tert-butoxycarbonyl)amino)-3-phenylpropionamido)-1H-indole-2-carboxylic acid ethyl ester
  • Step B Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -Phenylpropionamido)-1H-indole-2-carboxylic acid ethyl ester
  • Step C Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -Phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step B Synthesis of tert-butyl 5-(4-nitrophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate
  • Step C Synthesis of tert-butyl 5-(4-aminophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate
  • Step D Synthesis of (S)-3-(4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamide (Phenyl)-3-phenylpropionamido)phenyl)-5-oxo-2,5-dihydro-1H-pyrazole-1-carboxylic acid tert-butyl ester
  • Step E Synthesis of (S)-N 1 -(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-N 2 -(1-oxo-1-((4-(5- Oxo-2,5-dihydro-1H-pyrazol-3-yl)phenyl)amino)-3-phenylprop-2-yl)oxamide
  • Step A Synthesis of 2-((5-chloro-2-(trifluoromethoxy)phenyl)amino)-2-oxoacetic acid
  • Step B Synthesis of (S)-4-(2-(2-(((5-chloro-2-(trifluoromethoxy)phenyl)amino)-2-oxoacetamido)-3-benzene Propyl propionamido) tert-butyl benzoate
  • Step C Synthesis of (S)-4-(2-(2-((5-chloro-2-(trifluoromethoxy)phenyl)amino)-2-oxoacetamido)-3-phenylpropane Amido) benzoic acid
  • Step C Synthesis of methyl 2-((5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl)amino)-2-oxoacetate
  • Step D Synthesis of 2-((5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl)amino)-2-oxoacetic acid
  • Step E Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl)amino)-2-oxy (Acetamido)-3-phenylpropionamido) tert-butyl benzoate
  • Step F Synthesis of (S)-4-(2-(2-((((5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl)amino)-2-oxy (Acetamido)-3-phenylpropionamido)benzoic acid
  • Step A Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(Piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(Piperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(3-(4-(1H-imidazole-1-carboximido)phenyl)-2-(2-((5-chloro-2-(1H-tetra (Azol-1-yl)phenyl)amino)-2-oxoacetamido)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-Cyanopiperidine-1-carboximidamido)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step C Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino))-2-oxoacetamido) -3-(4-(4-Cyanopiperidine-1-carboximidylamino)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S,Z)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido) -3-(4-(((cyanoamino)(phenoxy)methyl)amino)phenyl)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S,Z)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido) -3-(4-(N',4-dicyanopiperidine-1-carboximidodiamino)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step C Synthesis of (S,Z)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido) -3-(4-(N',4-dicyanopiperidine-1-carboximiddiamino)phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of phenyl isocyanate
  • triphosgene (240.37 mg, 0.81 mmol) was added dropwise to ethyl acetate (5.0 ml) containing aniline (50.0 mg, 0.54 mmol), the dripping was completed, and the reaction was carried out at 80 degrees Celsius for 4 hours.
  • Step B Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(3-phenylureido)phenyl)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step C Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(3-phenylureido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step C Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(2-oxopyrrolidin-1-yl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-(2-oxopyrrolidin-1-yl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(3-(1,1-tetrahydro-2H-thiopyran-4-yl)ureido)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(3-(1,1-tetrahydro-2H-thiopyran-4-yl)ureido)phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(methylsulfonyl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(methylsulfonyl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of 1-oxa-8-azaspiro[4.5]decane-3-ol trifluoroacetate
  • N-tert-butoxycarbonyl-1-oxa-8-azaspiro[4.5]decan-3-ol 100 mg, 0.39 mmol
  • dichloromethane 2.0 mL
  • Trifluoroacetic acid 1.0 mL
  • Step B Synthesis of 5-((2S)-2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(3-Hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step C Synthesis of 5-((2S)-2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(3-Hydroxy-1-oxa-8-azaspiro[4.5]decane-8-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of tert-butyl 4-((methylsulfonyl)carbamoyl)piperidine-1-carboxylate
  • tert-butyl 4-((methylsulfonyl)carbamoyl)piperidine-1-carboxylate 700 mg, 2.3 mmol was added to dichloromethane (2.0 mL), and trifluoroacetic acid ( 1.0 ml), react at room temperature for 3 hours.
  • Step C Synthesis of (S)-5-(3-(4-(4-carbamoylpiperidine-1-carboxamido)phenyl)-2-(2-((5-chloro-2-(1H -Tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-5-(3-(4-(4-carbamoylpiperidine-1-carboxamido)phenyl)-2-(2-((5-chloro-2-(1H -Tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of tert-butyl 4-((methylsulfonyl)carbamoyl)piperidine-1-carboxylate
  • tert-butyl 4-((methylsulfonyl)carbamoyl)piperidine-1-carboxylate 1.5 g, 5.0 mmol was added to dichloromethane (2.0 mL), and trifluoroacetic acid ( 1.0 ml), react at room temperature for 3 hours.
  • Step C Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-((Methylsulfonyl)carbamoyl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-((methylsulfonyl)carbamoyl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of tert-butyl 4-(3-hydroxyazetidine-1-carbonyl)piperidine-1-carboxylate
  • Step B Synthesis of (3-hydroxyazetidin-1-yl)(piperidin-4-yl)methanone trifluoroacetate
  • tert-butyl 4-((methylsulfonyl)carbamoyl)piperidine-1-carboxylate 1. g, 4.9 mmol
  • dichloromethane 2.0 mL
  • trifluoroacetic acid 1.0 ml
  • Step C Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(3-Hydroxyazetidine-1-carbonyl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step D Synthesis of (S)-5-(2-(2-((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)-3 -(4-(4-(3-Hydroxyazetidine-1-carbonyl)piperidine-1-carboxamido)phenylpropionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid
  • reaction solution was quenched with 1M hydrochloric acid, adjusted to pH 3, diluted with ethyl acetate (200 ml), washed with water (30 ml ⁇ 2 times) and saturated brine (30 ml), and used for the organic phase After drying with anhydrous sodium sulfate, filtering and concentrating, the crude product (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid was directly used in the next reaction.
  • Step B Synthesis of tert-butyl (S)-4-(3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionamidobenzoate
  • Step C Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-(3-(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamide Yl) tert-butyl benzoate
  • Step D Synthesis of tert-(S)-4-(2-amino-3-(3-(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido tert-butyl)benzoic acid Butyl
  • Step E Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- Tert-Butyl 3-(3-(4-methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoate
  • Step F Synthesis of (S)-4-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(3-(4-Methyl-2-oxopiperazin-1-yl)phenyl)propionamido)benzoic acid
  • reaction solution was quenched with water (10 mL), the tetrahydrofuran was evaporated to dryness, the remaining aqueous solution was diluted with ethyl acetate (100 mL), and the mixture was washed with water (20 mL ⁇ 2 times) and saturated brine (20 mL). The phase was dried with anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was directly used in the next reaction.
  • Step B Synthesis of 4-chloro-2-amino-1-(2,2,2-trifluoroethoxy)benzene
  • reaction solution was diluted with ethyl acetate (100 ml), water (20 ml ⁇ 2 times) and saturated brine (20 ml) respectively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was used directly in the next step reaction.
  • Step C Synthesis of 2-((5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)amino)-2-oxoacetic acid
  • reaction solution was diluted with ethyl acetate (100 ml), respectively, with water (20 ml ⁇ 2 times) and saturated brine (20 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product and lithium hydroxide ( 1.0 g, 24.0 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL)/water (10 mL), and reacted at room temperature for 5 hours.
  • Step D Synthesis of (S)-4-(2-(2-((5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)amino)-2-oxoacetamido )-3-Phenylpropionamido) tert-butyl benzoate
  • Step E Synthesis of (S)-4-(2-(2-((5-chloro-2-(2,2,2-trifluoroethoxy)phenyl)amino)-2-oxoacetamido )-3-Phenylpropionamido)benzoic acid
  • Step A Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-Cyanopiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-Cyanopiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid
  • Step A Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-morpholinylpiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid tert-butyl ester
  • Step B Synthesis of (S)-5-(2-(2-(((5-chloro-2-(1H-tetrazol-1-yl)phenyl)amino)-2-oxoacetamido)- 3-(4-(4-morpholinylpiperidine-1-carboxamido)phenyl)propionamido)-1H-indole-2-carboxylic acid

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Abstract

La présente invention concerne le domaine de la chimie médicale et concerne des dérivés d'oxamide, leur procédé de préparation et leur utilisation en médecine. En particulier, l'invention concerne un composé de formule (I) ou un stéréoisomère, un tautomère et un sel pharmaceutiquement acceptable de celui-ci. Ces composés sont des inhibiteurs du facteur XIa sélectif (facteur XIa, abrégé FXIa). La présente invention concerne également une composition pharmaceutique comprenant ces composés et l'utilisation du composé dans un médicament pour le traitement de maladies telles que des thromboembolies.
PCT/CN2020/133493 2019-12-04 2020-12-03 Dérivés d'oxamide, leur procédé de préparation et leur utilisation en médecine WO2021110076A1 (fr)

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