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WO2022002210A1 - Composés deutérés de pyrimidopyrrolyle - Google Patents

Composés deutérés de pyrimidopyrrolyle Download PDF

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Publication number
WO2022002210A1
WO2022002210A1 PCT/CN2021/104064 CN2021104064W WO2022002210A1 WO 2022002210 A1 WO2022002210 A1 WO 2022002210A1 CN 2021104064 W CN2021104064 W CN 2021104064W WO 2022002210 A1 WO2022002210 A1 WO 2022002210A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
present
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/104064
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English (en)
Chinese (zh)
Inventor
付志飞
罗妙荣
张杨
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Original Assignee
Medshine Discovery Inc
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Filing date
Publication date
Application filed by Medshine Discovery Inc filed Critical Medshine Discovery Inc
Publication of WO2022002210A1 publication Critical patent/WO2022002210A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention discloses a series of deuterated compounds containing a pyrimidopyrrole structure, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
  • JAK family of cellular protein tyrosine kinases plays a major role in cytokine signaling. Cytokines, upon binding to the receptors, activate JAKs, which then phosphorylate the cytokine receptors, creating docking sites for signaling molecules.
  • JAK3 is a member of the Janus family of protein kinases comprising JAK1, JAK2, JAK3 and TYK2 and is expressed at different levels in all tissues.
  • PF-06651600 developed by Pfizer is a JAK3 kinase inhibitor, which has shown good efficacy in clinical practice. A reliable alternative medicine that achieves equal or better efficacy at lower doses.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 , R 13 and R 14 each independently is selected from H and D, and at least one of which is selected from D;
  • the carbon atoms with "*" are chiral carbon atoms, which exist as (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 1 is selected from D the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 1 is selected from H the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof wherein R 2 and R 3 are selected from H, and the other variables are as defined herein.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 4 and R 5 is selected from D the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 6 and R 7 is selected from D the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 11 is selected from D the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 11 is selected from H the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 12 is selected from D the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof, wherein, R 12 is selected from H the other variables are as defined in the present invention.
  • the compound or a pharmaceutically acceptable salt thereof wherein R 12 , R 13 and R 14 are selected from D, and the other variables are as defined herein.
  • the compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof, which are selected from
  • the compound, or a pharmaceutically acceptable salt thereof is selected from
  • the present invention also provides the use of the compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating JAK3-related diseases.
  • the present invention also provides the following synthetic method:
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds 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 isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not positioned and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • C n-n + m or C n -C n + m to n + m comprises n number of any one particular case of carbon, such as C 1-12 include C 1, C 2, C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring
  • D in the present invention represents deuterium ( 2 H).
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • the compounds of the present invention can effectively inhibit JAK3, have excellent stability in whole blood and liver microsomes, and have excellent pharmacokinetic properties.
  • reaction mixture was extracted with ethyl acetate (300 mL*3), the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a crude product.
  • Reaction buffer The preparation of buffers including: 50 mM HEPES (pH 7.5), 0.01% Brij-35 , 10 mM MgCl 2 , 1 mM EDTA, 1 mM DTT.
  • JAK1, 2, 3 and TYK2 were used in this experiment method for activity detection.
  • the enzyme, ULight-labeled polypeptide substrate, ATP, and detection compound are mixed and the reaction incubated.
  • EDTA was added to stop the reaction, and Eu-labeled antibody was added at the same time.
  • kinase assays the binding of europium-labeled anti-phosphorylated substrate antibodies to phosphorylated ULight-labeled substrates enables donor and acceptor molecules to approach each other. After irradiation with 320nm wavelength light, the kinase reacts, the energy of the europium donor is transferred to the ULight acceptor dye, and the 665nm wavelength light is generated.
  • the emission intensity of light is proportional to the phosphorylation level of the ULight matrix.
  • the final test concentration of the test compounds was from 1 ⁇ M to 0.017 nM, 3-fold serial dilution, 11 concentrations.
  • Final tested concentrations of the reference compound Tofacitinib ranged from 1 ⁇ M to 0.017 nM, 3-fold serial dilution, 11 concentrations.
  • the content of DMSO in the detection reaction was 1%.
  • the compounds of the present invention can effectively inhibit JAK3 kinase.
  • Rat blood was collected from 4 male Sprague-Dawley rats (200-250 g, Charles River Laboratories), fresh rat blood was collected into K2-EDTA tubes and kept on ice, and an aliquot of blood was transferred into microtubes , preheated at 37°C for 10min in a water bath, then added the test compound (final concentration 2 ⁇ M) and incubated in duplicate for 120min at 37°C, removing an aliquot of the incubation mixture at a specified time point during the incubation process and adding it to the Mixed with an aliquot of acetonitrile containing the internal standard, vortexed and centrifuged, the resulting supernatant was removed and analyzed by LC-MS/MS to determine the parent compound concentration, and the peak area ratio of the parent compound to the internal standard was used to determine the relative Percentage of parent compound remaining at incubation time.
  • T60 incubation plate Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
  • microsomal working solution concentration of liver microsomal protein: 0.56 mg/mL
  • stop solution containing 200 ng/mL tolbutamide and 200 ng/mL labetalol
  • CD-1 mice male, 20-27g
  • Intravenous and oral vehicles are a certain proportion of hydroxypropyl ⁇ -cyclodextrin aqueous solution or physiological saline solution. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times the volume of acetonitrile solution containing the internal standard to precipitate the protein, centrifuge to take the supernatant, add an equal volume of water, and then centrifuge to take the supernatant.
  • LC-MS/MS analysis method was used to quantitatively analyze the blood drug concentration, and the pharmacokinetic parameters, such as peak concentration, peak time, clearance rate, half-life, area under the drug-time curve, bioavailability, etc., were calculated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une série de composés deutérés contenant une structure de pyrimidopyrrole, et spécifiquement un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2021/104064 2020-07-02 2021-07-01 Composés deutérés de pyrimidopyrrolyle Ceased WO2022002210A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010633910 2020-07-02
CN202010633910.9 2020-07-02

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WO2022002210A1 true WO2022002210A1 (fr) 2022-01-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116496280A (zh) * 2023-06-25 2023-07-28 北京科翔中升医药科技有限公司 氘代丙烯酰胺类jak3抑制剂药物及用途
WO2023165562A1 (fr) * 2022-03-02 2023-09-07 南京明德新药研发有限公司 Composé hétérocyclique contenant de l'azote et son utilisation
CN119552162A (zh) * 2025-01-26 2025-03-04 药康众拓(北京)医药科技有限公司 氘代jak3抑制剂药物及用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106061973A (zh) * 2013-12-05 2016-10-26 辉瑞公司 吡咯并[2,3‑d]嘧啶基、吡咯并[2,3‑b]吡嗪基和吡咯并[2,3‑d]吡啶基丙烯酰胺
WO2020007698A1 (fr) * 2018-07-06 2020-01-09 Leo Pharma A/S Nouveaux dérivés d'amino-imidazopyrimidine utilisés en tant qu'inhibiteurs de janus kinase et leur utilisation pharmaceutique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106061973A (zh) * 2013-12-05 2016-10-26 辉瑞公司 吡咯并[2,3‑d]嘧啶基、吡咯并[2,3‑b]吡嗪基和吡咯并[2,3‑d]吡啶基丙烯酰胺
WO2020007698A1 (fr) * 2018-07-06 2020-01-09 Leo Pharma A/S Nouveaux dérivés d'amino-imidazopyrimidine utilisés en tant qu'inhibiteurs de janus kinase et leur utilisation pharmaceutique

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023165562A1 (fr) * 2022-03-02 2023-09-07 南京明德新药研发有限公司 Composé hétérocyclique contenant de l'azote et son utilisation
CN116496280A (zh) * 2023-06-25 2023-07-28 北京科翔中升医药科技有限公司 氘代丙烯酰胺类jak3抑制剂药物及用途
CN116496280B (zh) * 2023-06-25 2023-09-08 北京科翔中升医药科技有限公司 氘代丙烯酰胺类jak3抑制剂药物及用途
CN119552162A (zh) * 2025-01-26 2025-03-04 药康众拓(北京)医药科技有限公司 氘代jak3抑制剂药物及用途

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