WO2022002210A1 - 嘧啶并吡咯基类氘代化合物 - Google Patents

嘧啶并吡咯基类氘代化合物 Download PDF

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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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compound
pharmaceutically acceptable
acceptable salt
present
compounds
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PCT/CN2021/104064
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English (en)
French (fr)
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付志飞
罗妙荣
张杨
黎健
陈曙辉
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南京明德新药研发有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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.

Abstract

公开了一系列含嘧啶并吡咯结构的氘代化合物，具体公开了式(I)所示化合物及其药学上可接受的盐。

Description

嘧啶并吡咯基类氘代化合物
本发明主张如下优先权：
CN202010633910.9，申请日：2020年07月02日。
技术领域
本发明公开了一系列含嘧啶并吡咯结构的氘代化合物，具体公开了式(I)所示化合物及其药学上可接受的盐。
背景技术
蛋白激酶作为一类重要的酶，已经显示可作为用于治疗性干预的靶标。具体而言，细胞蛋白酪氨酸激酶的JAK家族在细胞因子信号传导中起主要作用。细胞因子在与受体结合后，激活JAK，然后JAK磷酸化细胞因子受体，从而为信号传导分子建立对接位点。JAK3是包含JAK1、JAK2、JAK3和TYK2的Janus家族蛋白激酶的成员，并且在所有组织中以不同水平表达。动物研究表明在免疫***的发育、功能和稳态中的牵涉JAK3，通过抑制JAK3激酶活性来调节免疫活性可证明在治疗多种免疫病症中的用途，同时避免JAK2依赖性红细胞生成素(EPO)和血小板生成素(TP0)信号传导。
辉瑞公司研发的PF-06651600是一款JAK3的激酶抑制剂，已在临床中展现出良好的药效，但由于其在人体中的稳定性不够，给药剂量较高，需要研发更稳定、更可靠的替代药物，以更低的给药剂量，实现同等或更好的疗效。
Figure PCTCN2021104064-appb-000001
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021104064-appb-000002
其中，
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和R 14、R 13和R 14分别独立地选自H和D，且其中至少有一个选自D；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自
Figure PCTCN2021104064-appb-000003
其中，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和R 14如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 1选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 1选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 2和R 3选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 2和R 3选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 4和R 5选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 4和R 5选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 6和R 7选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 6和R 7选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 8、R 9和R 10选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 8、R 9和R 10选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 11选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 11选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 12选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 12选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 13选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 13选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 14选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 14选自H，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其中，R 12、R 13和R 14选自D，其他变量如本发明所定义。
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021104064-appb-000004
其中，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和R 14如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明还提供了下列所示化合物或其药学上可接受的盐，其选自
Figure PCTCN2021104064-appb-000005
在本发明的一些方案中，所述化合物或其药学上可接受的盐，其选自
Figure PCTCN2021104064-appb-000006
本发明还提供了所述的化合物或其药学上可接受的盐在制备治疗与JAK3相关疾病的药物中的应用。本发明还提供了下了合成方法：
方法1：
Figure PCTCN2021104064-appb-000007
方法2：
Figure PCTCN2021104064-appb-000008
Figure PCTCN2021104064-appb-000009
方法3：
Figure PCTCN2021104064-appb-000010
相关定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸 加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2021104064-appb-000011
直形虚线键
Figure PCTCN2021104064-appb-000012
或波浪线
Figure PCTCN2021104064-appb-000013
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2021104064-appb-000014
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2021104064-appb-000015
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2021104064-appb-000016
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2021104064-appb-000017
Figure PCTCN2021104064-appb-000018
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021104064-appb-000019
仍包括
Figure PCTCN2021104064-appb-000020
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
除非另有规定，本发明所述D代表氘( 2H)。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021104064-appb-000021
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021104064-appb-000022
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物可有效抑制JAK3，在全血及肝微粒体中具有优异的稳定性，有优异的药代动力学性质。
具体实施方式
下面经过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2021104064-appb-000023
步骤1：化合物001-2的合成
在500mL三口瓶中加入搅拌子，抽换氮气三次后加入ZnCl 2(1.0M,52.50mL,3eq)，再缓慢加入氘代甲基碘化镁的***溶液(280mL,140mmol,0.5M,8eq)，混合物在25℃下搅拌反应1小时。之后再加入001-1(4.78g,17.50mmol,1eq)和Pd(PPh 3) 4(2.02g,1.75mmol,0.1eq)以及1,4-二氧六环(100mL)，反应混合物在60℃下继续反应11小时。反应结束后冷却至室温，加入500mL水后乙酸乙酯萃取(300mL*3)，有机相合并后用饱和食盐水洗涤(300mL*4)，有机相用无水硫酸钠干燥后旋蒸除去溶剂得粗品。粗品通过 快速柱层析纯化(石油醚：乙酸乙酯＝2:1–1:1)得化合物001-2。
步骤2：化合物001-3的合成
将化合物001-2(5.98g,28.3mmol,1.0eq)溶于冰醋酸(70mL)中，加入二氧化铂(0.65g,2.83mmol,0.1eq)，体系抽换氢气后在55℃，45psi下反应48小时。冷却至室温后用硅藻土过滤，甲醇洗涤滤渣，滤液旋蒸除去溶剂后得粗品001-3。
步骤3：化合物001-4的合成
将化合物001-3(5.9g,27.15mmol,1eq)溶于四氢呋喃(70mL)和水(70mL)的混合溶剂中，再加入NaHCO 3(15.96g,190.04mmol,7.0eq)，之后缓慢向溶液中滴加氯甲酸苄酯(6.95g,40.72mmol,5.79mL,1.5eq)，反应混合物在25℃下反应2小时。反应结束后，反应混合物用乙酸乙酯萃取(300mL*3)，有机相合并后用无水硫酸钠干燥，旋蒸除去溶剂后得粗品。粗品通过快速柱层析纯化(石油醚：乙酸乙酯＝10:1)得到化合物001-4。
步骤4：化合物001-5的合成
将化合物001-4(4g,11.38mmol,1eq)溶于二氯甲烷(100mL)中，加入氯化氢的二氧六环溶液(4M,20.72mL,7.28eq)后混合物在25℃下搅拌反应4小时。反应结束后旋蒸除去溶剂，得到化合物001-5的粗品直接用于下一步反应。
步骤5：化合物001-7的合成
将化合物001-5(2.8g,11.14mmol,1eq)和001-6(2.30g,12.25mmol,1.1eq)溶于正丁醇(50mL)中，再加入二异丙基乙胺(7.20g,55.70mmol,9.70mL,5.0eq)，混合物在140℃下反应8小时。反应结束后冷却至室温，加入500mL水，乙酸乙酯萃取(300mL*3)，有机相合并后用无水硫酸钠干燥，旋蒸除去溶剂后得到的粗品通过快速柱层析纯化(石油醚：乙酸乙酯＝3:1-2:1)得到目标化合物001-7。
步骤6：化合物001-8的合成
将化合物001-7(2.5g,6.21mmol,1eq)溶于甲醇(80mL)中，加入湿钯碳(0.66g,0.62mmol,10％含量,0.1eq)后抽换氢气三次，混合物置于45℃，45psi下反应24小时。反应冷却至室温后用硅藻土过滤，200mL甲醇洗涤滤渣。滤液旋蒸除去溶剂后得粗品001-8，可直接用于下一步。
步骤7：化合物001的合成
将化合物001-8(0.37g,1.58mmol,1eq)溶于四氢呋喃(25mL)和饱和碳酸氢钠水溶液(25mL)中，冰浴冷却至0℃后缓慢滴加丙烯酰氯(171.50mg,1.89mmol,154.51μL,1.2eq)，反应混合物在0℃下继续反应2小时。反应结束后乙酸乙酯萃取(300mL*3)，有机相合并后用无水硫酸钠干燥，旋蒸除去溶剂后得粗品。粗品通过快速柱层析纯化(石油醚：乙酸乙酯＝4:1–2:1)得化合物001。MS(ESI)m/z:289.1[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 8.20–8.15(m,1H),7.15–7.05(m,1H),6.90–6.80(m,1H),6.70–6.55(m, 1H),6.25–6.15(dd,J＝16.8,2.0Hz,1H),5.80–5.72(dd,J＝10.4,2.0Hz,1H),4.80–4.10(m,3H),3.15–3.0(t,J＝11.92Hz,0.5H),2.85–2.72(t,J＝11.92Hz,0.5H),2.05–1.70(m,4H)。
生物测试
实验例1：化合物对JAK1,JAK2,JAK3和TYK2酶活性的抑制效应
JAK1(Invitrogen,Cat.No PV4775),JAK2(Invitrogen,Cat.No PV4288),JAK3(Invitrogen,Cat.No PV4080),TYK2(Invitrogen,Cat.No PR8440C),ATP(Sigma,Cat.No.A7699-1G),DMSO(Sigma,Cat.No.D2650),DTT(Sigma,Cat.No.43815),384孔板_测试板(Perkin Elmer,Cat.No.6007299),LANCE Ultra ULight TM-JAK-1peptide(Perkin Elmer,Cat.No.TRF0121),LANCE Eu-W1024Anti-phosphotyrosine(PT66)(Perkin Elmer,Cat.No.AD0069),LANCE TM Detection Buffer(Perkin Elmer,Cat.No.CR97-100)。
反应缓冲液：缓冲液的配制，缓冲液包括:50mM HEPES(pH 7.5)，0.01％Brij-35，10mM MgCl 2，1mM EDTA，1mM DTT。
本次试验中JAK1,2,3和TYK2使用
Figure PCTCN2021104064-appb-000024
方法进行活性检测。在检测板中，将酶、ULight标记的多肽底物、ATP以及检测化合物混合，孵育反应。反应后，加入EDTA终止反应，并同时加入Eu标记的抗体。在
Figure PCTCN2021104064-appb-000025
激酶检测中，铕标记的抗磷酸化基质抗体与磷酸化的ULight标记的基质结合可使供体和受体分子相互趋近。经过320nm波长光的照射后，激酶发生反应，铕供体的能量将转移到ULight受体染料中，并生成波长665nm的光。光的发射强度与ULight基质的磷酸化水平成比例。受试化合物最终测试浓度从1μM到0.017nM，3倍梯度稀释，11个浓度。参考化合物Tofacitinib的最终测试浓度从1μM到0.017nM，3倍梯度稀释，11个浓度。DMSO在检测反应中的含量为1％。
JAK1测试：
在缓冲液中，将2nM JAK1和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加38μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
JAK2测试：
在缓冲液中，将0.03nM JAK2和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加12μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
JAK3测试：
在缓冲液中，将0.08nM JAK3和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加4μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
TYK2测试：
在缓冲液中，将4nM TYK2和50nM底物与预先稀释配制的不同浓度化合物混合一起预孵育15分钟。添加15μM ATP开始反应，在室温下孵育90分钟。反应完毕加入抗体检测，室温孵育60分钟后Evnvision检测，采集数据。
数据分析：
根据％inhibition vs.log[compound concentration],使用XLfit5软件mode205进行数据分析。
Fit＝(A+((B-A)/(1+((C/x)^D))))
Res＝(y-fit)
表1.本发明化合物体外筛选试验结果
化合物 JAK3(IC 50nM)
化合物001 0.477
结论：本发明化合物能有效抑制JAK3激酶。
实验例2：化合物的全血稳定性测试
大鼠血液收集自4只雄性Sprague-Dawley大鼠(200-250g,Charles River Laboratories)，将大鼠新鲜血液收集到K2-EDTA管中，并保存在冰上，将一份血液转移入微管中，在水浴锅中于37摄氏度下预热10min，然后加入测试化合物(终浓度2μM)，并一式两份的在37摄氏度下孵育120min，在孵育过程中指定时间点移出一份孵育混合物，将其与一份含有内标的乙腈混合，涡旋并离心，移除所得的上清液，进行LC-MS/MS分析，以测定母体化合物浓度，将母体化合物相对于内标的峰面积比率用于测定相对于孵育时间，母体化合物剩余的百分比。
实验例3：化合物的体外微粒体稳定性测试
3.1肝微粒体
人和动物微粒体购买于Corning或Xenotech，储存于-80℃冰箱。还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)，供应商：Chem-impex international，货号：00616。对照化合物：睾酮，双氯芬酸，普罗帕酮3.2实验步骤
3.2.1工作液的配制
储备液：10mM DMSO溶液
工作浓度配制：100％乙腈稀释到100μM(有机相含量：99％ACN，1％DMSO)
3.2.2实验步骤
准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。
在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。
预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)和6μL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在T60孵育板上每孔添加44μL NADPH再生体系工作液启动反应。在Blank板中只添加54μL微粒体工作液、6μL的NADPH再生体系工作液和180μL的终止液。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。孵育适当时间(如5、15、30、45和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL甲苯磺丁脲和200ng/mL拉贝洛尔的乙腈溶液)，之后从T60孵育板中取出60μL样品以终止反应。
实验例4：化合物的药代动力学评价
实验目的：测试化合物在CD-1小鼠体内药代动力学
实验材料：
CD-1小鼠(雄性,20-27g)
实验操作：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予小鼠单次静脉注射及口服给药。静注及口服溶媒为一定比例的羟丙基β环糊***溶液或生理盐水溶液。收集24小时内的全血样品，3000g离心15分钟，分离上清得血浆样品，加入4倍体积含内标的乙腈溶液沉淀蛋白，离心取上清液加入等倍体积的水再离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。

Claims (15)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021104064-appb-100001
    其中，
    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和R 14分别独立地选自H和D，且其中至少有一个选自D；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2021104064-appb-100002
    其中，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和R 14如权利要求1所定义。
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 1选自D。
  4. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 2和R 3选自D。
  5. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 4和R 5选自D。
  6. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 6和R 7选自D。
  7. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 8、R 9和R 10选自D。
  8. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 11选自D。
  9. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 12选自D。
  10. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 13选自D。
  11. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 14选自D。
  12. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2021104064-appb-100003
    其中，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和R 14如权利要求1～11任意一项所定义。
  13. 下列所示化合物或其药学上可接受的盐，其选自
    Figure PCTCN2021104064-appb-100004
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2021104064-appb-100005
  15. 根据权利要求1～14任意一项所述的化合物或其药学上可接受的盐在制备治疗与JAK3相关疾病的药物中的应用。
PCT/CN2021/104064 2020-07-02 2021-07-01 嘧啶并吡咯基类氘代化合物 WO2022002210A1 (zh)

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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 (zh) * 2022-03-02 2023-09-07 南京明德新药研发有限公司 含氮杂环类化合物及其应用

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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 (en) * 2018-07-06 2020-01-09 Leo Pharma A/S Novel amino-imidazopyrimidine derivatives as janus kinase inhibitors and pharmaceutical use thereof

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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
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WO2023165562A1 (zh) * 2022-03-02 2023-09-07 南京明德新药研发有限公司 含氮杂环类化合物及其应用
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