WO2022179578A1 - 含有亚磺酰基吡啶结构的化合物以及应用 - Google Patents

含有亚磺酰基吡啶结构的化合物以及应用 Download PDF

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WO2022179578A1
WO2022179578A1 PCT/CN2022/077775 CN2022077775W WO2022179578A1 WO 2022179578 A1 WO2022179578 A1 WO 2022179578A1 CN 2022077775 W CN2022077775 W CN 2022077775W WO 2022179578 A1 WO2022179578 A1 WO 2022179578A1
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compound
mmol
reaction
compounds
acid
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钱文远
杨纯道
胡世尘
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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a class of compounds containing a sulfinylpyridine structure. Specifically disclosed is the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the Janus kinases (JAKs) family is a class of intracellular non-receptor tyrosine kinases, which are mainly responsible for regulating signaling pathways mediated by cytokine receptors. and receptor activation, and participate in important physiological processes such as proliferation, differentiation, apoptosis, angiogenesis and immune regulation of various types of cells.
  • the Janus kinase family includes four different isoforms of JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2) in mammals.
  • TYK2 is also structurally composed of 7 homology domains (JAK homology domain, JH) to form 4 conserved domains, including C-terminal pseudo-kinase domain (pseudo-kinase domain, JH2) and kinase domain ( kinase domain, JH1), and N-terminal FERM (Four.1protein, Ezrin, Radixin, Moesin) region and SH2 domain (srchomology 2 domain).
  • JH JH
  • FERM Flu.1protein, Ezrin, Radixin, Moesin
  • TYK2 forms a dimer with JAK2 in cells to mediate the signal transduction of IL-23 and IL-12, and can also form a dimer with JAK1 to mediate the response of type I interferon, these cytokines are related to psoriasis, inflammatory IBD and systemic lupus erythematosus (SLE) have been implicated in the pathogenesis of various inflammatory and autoimmune diseases. By inhibiting TYK2, the signaling pathway of some inflammatory cytokines can be blocked, so as to achieve the purpose of treating related diseases.
  • Current TYK2 inhibitors mainly include orthosteric inhibitors that inhibit the kinase domain (JH1) and allosteric inhibitors that inhibit the pseudokinase domain (JH2).
  • the orthosteric inhibitor represented by Pfizer's PF-06826647, is used to treat diseases such as plaque and ulcerative colitis, and is currently in phase II clinical trials.
  • the allosteric inhibitor is represented by BMS-986165. The clinical trial for the treatment of massive psoriasis has been advanced to the third phase. The clinical effect is outstanding and the safety is good.
  • Nimbus also has several TYK2 allosteric inhibitors in preclinical screening. Recently, it was reported that Fronthera's TYK2 allosteric inhibitor FTP-637, acquired by Haisco, is preparing to enter Phase I clinical trials.
  • Ring A is cyclopropyl
  • R 1 is H, F, Cl, Br, I, CN or C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
  • R 21 , R 22 and R 23 are each independently H or C 1-3 alkyl
  • R 31 and R 32 are each independently H or C 1-3 alkyl
  • Ra is OH.
  • R 1 is H, F, Cl, Br, I, CN or in, Optionally substituted with 1, 2 or 3 Ra , Ra and other variables as defined herein.
  • R 1 is H, F, Cl, CN or Other variables are as defined in the present invention.
  • R 21 , R 22 and R 23 are each independently H or CH 3 , and other variables are as defined in the present invention.
  • R 31 and R 32 are independently H or CH 3 respectively, and other variables are as defined in the present invention.
  • above-mentioned ring A is cyclopropyl, R 1 , R 21 , R 22 , R 23 , R 31 and R 32 and other variables are as defined herein.
  • the above-mentioned ring A is Other variables are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a related medicine of Tyk2 JH2 inhibitor.
  • the compounds of the present invention have strong Tyk2 pseudokinase domain (Tyk2 JH2) inhibitory activity.
  • 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.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, 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.
  • 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.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • 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 located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced 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 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • 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.
  • reaction solution was slowly poured into 40 mL of water, extracted with dichloromethane (30 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, the desiccant was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Compound 2 was separated by chiral SFC, chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [Neu-ETOH]; B%: 55%-55%, min, to obtain compounds 2A and 2B.
  • the intermediate II (0.25g, 661.64 ⁇ mol) was placed in a microwave reaction tube, 1,4-dioxane (5mL), 2-amino-5-fluoropyridine (77.88mg, 694.72 ⁇ mol), tris(dioxane) (5mL), benzylideneacetone) dipalladium (60.59 mg, 66.16 ⁇ mol), 1,1-bis(diphenylphosphino)ferrocene (73.36 mg, 132.33 ⁇ mol) and potassium phosphate (421.34 mg, 1.98 mmol). Nitrogen replacement for 2 minutes, microwave heating to 110°C and stirring for 1 hour.
  • the compounds of the present invention used in the experiments are all self-made, and their chemical names and structural formulas are shown in the preparation examples of each compound.
  • the enzyme activity test was carried out in Shanghai Runnuo, and the experimental results were provided by the company.
  • nM of TYK2 protein His-TVMV-TYK2 JH2(575-869)
  • 0.2 nM was added to a buffer solution containing 20 mM Hepes pH 7.5, 10 mM MgCl 2 , 0.015% Brij-35, 2 mM DTT and 50 ⁇ g/mL BSA
  • the terbium-labeled His antibody, the fluorescein-labeled kinase tracer at the relevant K d value, and the test compound were incubated at room temperature for 90 minutes.
  • HTRF Homogeneous Time-Resolved Fluorescence
  • the compounds of the present invention have strong inhibitory activity against Tyk2 JH2.

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Abstract

一类含有亚磺酰基吡啶结构的化合物。具体公开了式(Ⅰ)化合物或其药学上可接受的盐。

Description

含有亚磺酰基吡啶结构的化合物以及应用
本申请主张如下优先权：
CN202110209030.3，申请日2021.02.24。
技术领域
本发明涉及一类含有亚磺酰基吡啶结构的化合物。具体公开了式(Ⅰ)化合物或其药学上可接受的盐。
背景技术
Janus激酶(Janus kinases，JAKs)家族是一类细胞内的非受体酪氨酸激酶，它们主要负责调控由细胞因子受体介导的信号传导通路，这些信号通路可由多种细胞因子、生长因子以及受体激活，并参与多种类型细胞的增殖、分化、凋亡，血管生成以及免疫调节等重要的生理过程。Janus激酶家族在哺乳动物体内包括JAK1、JAK2、JAK3和TYK2(tyrosine kinase 2)4个不同的亚型。
和同族的其它激酶一样，TYK2结构上也由7个同源结构域(JAK homology domain，JH)组成4个保守结构域，包括C端的假激酶区(pseudo-kinase domain，JH2)和激酶区(kinase domain，JH1)，以及N端FERM(Four.1protein，Ezrin，Radixin，Moesin)区和SH2结构域(srchomology 2 domain)。
TYK2在细胞内与JAK2形成二聚体介导IL-23、IL-12的信号传导，还可以与JAK1形成二聚体介导I型干扰素的应答，这些细胞因子与银屑病、炎症性肠病(IBD)和系统性红斑狼疮(SLE)等多种炎症和自身免疫性疾病的发病机制有关。通过对TYK2的抑制，可以阻断一些炎性细胞因子的信号传导通路，达到治疗相关疾病的目的。
目前的TYK2抑制剂主要包括抑制激酶区(JH1)的正构抑制剂和抑制假激酶区(JH2)的别构抑制剂。正构抑制剂以Pfizer的PF-06826647为代表，用于治疗斑和溃疡性结肠炎等疾病，目前处于二期临床。而别构抑制剂以BMS-986165为代表，治疗块状银屑病的临床试验已推进至三期，临床效果突出，且安全性好，同时还有包括克罗恩病、银屑病关节炎和系统性红斑狼疮等多种自身免疫类疾病处于临床研究中。除了BMS-986165，Nimbus也有多款TYK2别构抑制剂在临床前筛选中，近期报导的海思科收购的Fronthera的TYK2别构抑制剂FTP-637正在准备进入一期临床。
发明内容
本发明式(Ⅰ)化合物或其药学上可接受的盐，
Figure PCTCN2022077775-appb-000001
其中,
L 1为单键或-C(＝O)；
环A为环丙基、
Figure PCTCN2022077775-appb-000002
R 1为H、F、Cl、Br、I、CN或C 1-3烷基，其中C 1-3烷基任选被1、2或3个R a取代；
R 21、R 22和R 23分别独立地为H或C 1-3烷基；
R 31和R 32分别独立地为H或C 1-3烷基；
R a为OH。
本发明的一些方案中，上述R 1为H、F、Cl、Br、I、CN或
Figure PCTCN2022077775-appb-000003
其中，
Figure PCTCN2022077775-appb-000004
任选被1、2或3个R a取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R 1为H、F、Cl、CN或
Figure PCTCN2022077775-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述R 21、R 22和R 23分别独立地为H或CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 31和R 32分别独立地为H或CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述环A为环丙基、
Figure PCTCN2022077775-appb-000006
Figure PCTCN2022077775-appb-000007
R 1、R 21、R 22、R 23、R 31和R 32及其他变量如本发明所定义。
本发明的一些方案中，上述环A为
Figure PCTCN2022077775-appb-000008
Figure PCTCN2022077775-appb-000009
其他变量如本发明所定义。
本发明还提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022077775-appb-000010
本发明的一些方案中，上述的化合物及其药学上可接受的盐，其化合物为
Figure PCTCN2022077775-appb-000011
本发明还提供了上述化合物或其药学上可接受的盐在制备Tyk2 JH2抑制剂的相关药物中的应用。
技术效果
本发明化合物具有较强的Tyk2假激酶区(Tyk2 JH2)抑制活性。
定义与说明
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。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022077775-appb-000012
和楔形虚线键
Figure PCTCN2022077775-appb-000013
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022077775-appb-000014
和直形虚线键
Figure PCTCN2022077775-appb-000015
表示立体中心的相对构型，用波浪线
Figure PCTCN2022077775-appb-000016
表示楔形实线键
Figure PCTCN2022077775-appb-000017
或楔形虚线键
Figure PCTCN2022077775-appb-000018
或用波浪线
Figure PCTCN2022077775-appb-000019
表示直形实线键
Figure PCTCN2022077775-appb-000020
和直形虚线键
Figure PCTCN2022077775-appb-000021
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态 平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都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。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
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 PCTCN2022077775-appb-000022
直形虚线键
Figure PCTCN2022077775-appb-000023
或波浪线
Figure PCTCN2022077775-appb-000024
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 PCTCN2022077775-appb-000025
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 PCTCN2022077775-appb-000026
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 PCTCN2022077775-appb-000027
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 PCTCN2022077775-appb-000028
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022077775-appb-000029
仍包括
Figure PCTCN2022077775-appb-000030
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，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能 团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
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 PCTCN2022077775-appb-000031
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。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022077775-appb-000032
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通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。
中间体I
Figure PCTCN2022077775-appb-000033
合成路线：
Figure PCTCN2022077775-appb-000034
步骤1：化合物I-B的合成
将化合物I-A(5g,25.36mmol)，碳酸钾(7.01g,50.72mmol)溶于N,N-二甲基甲酰胺(50mL)中，向其中加入碘甲烷(7.20g,50.72mmol)，缓慢升温至60℃(内温)，反应在60℃(内温)下搅拌1小时。将反应液冷却至18℃，倒入碎冰(约50g)中，加入水(至总体积200mL)。过滤，滤饼用100mL水冲洗，收集滤饼，干燥，得到化合物I-B。
1H NMR(400MHz,CDCl 3)δ8.04(dd,J＝1.8,7.8Hz,1H),7.92(dd,J＝1.8,8.3Hz,1H),7.31-7.26(m,1H),4.01(s,3H),3.97(s,3H)。
步骤2：化合物I-C的合成
将化合物I-B(4.76g,22.54mmol)加入氨水(28mL,浓度25％)中，向其中加入氨的甲醇溶液(120mL,7M)，反应在13～18℃下搅拌15小时，将反应液减压浓缩得到粗品。向粗品中加入100mL水，在0～10℃下搅拌0.5小时，过滤，收集滤饼，干燥后得到化合物I-C。
1H NMR(400MHz,DMSO-d 6)δ8.02-7.86(m,2H),7.76(br dd,J＝1.5,7.5Hz,2H),7.36(t,J＝7.8Hz,1H),3.87(s,3H)。
步骤3：化合物I-E的合成
将化合物I-D(23.69g,198.82mmol)加入化合物I-C(3.9g,19.88mmol)中，缓慢升温至95℃，反应在95℃下搅拌0.5小时。将其冷却至30℃后，减压浓缩后得到黄色油状物，溶于乙醇(20mL)中待用。将乙醇(80mL)和醋酸(20mL)加入250mL的三颈瓶中，将其降温至0℃，在0～10℃下向其中缓慢加入水合肼(11.71g,198.82mmol)，然后在0～10℃下缓慢加入上述乙醇溶液并搅拌。缓慢升温至18℃，反应在18℃下搅拌4小时。将反应液减压浓缩除去大部分乙醇，并向其中加入约40mL水，过滤，收集滤饼，干燥后得到化合物1-E。
MS m/z:220.9[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ8.54(s,1H),8.21(dd,J＝1.8,8.0Hz,1H),7.98(dd,J＝1.6,8.2Hz,1H), 7.45(t,J＝8.0Hz,1H),3.80(s,3H)。
步骤4：化合物I-F的合成
将化合物I-E(5.13g,23.30mmol)溶于N,N-二甲基甲酰胺(60mL)中，向其中加入碳酸钾(9.66g,69.90mmol)，缓慢降温至0℃，在0～5℃下向其中缓慢加入碘甲烷(4.30g,30.29mmol)，缓慢升温至20℃，反应在20℃(室温)下搅拌4小时。向反应液中缓慢加入200mL水淬灭，用二氯甲烷(50mLх3)萃取，有机相用无水硫酸钠干燥，过滤干燥剂，将滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/四氢呋喃＝1/0～1/1)纯化，到化合物I-F。
MS m/z:235.1[M+H] +。
步骤5：中间体I的合成
将化合物I-F(2.6g,11.10mmol)溶于四氢呋喃(30mL)中，向其中加入钯碳(1g,钯含量10％)，用氮气置换三次，反应在30℃，氢气氛围及15Psi下搅拌15小时。反应液用硅藻土过滤，滤液减压浓缩得到中间体I。
MS m/z:204.9[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ8.47(s,1H),6.95(dd,J＝1.8,7.8Hz,1H),6.86(t,J＝7.8Hz,1H),6.74(dd,J＝1.8,7.8Hz,1H),4.97(s,2H),3.91(s,3H),3.66(s,3H)。
中间体II
Figure PCTCN2022077775-appb-000035
合成路线：
Figure PCTCN2022077775-appb-000036
步骤1：化合物II-B的合成
将二甲基二硫醚(2.41g,25.58mmol)，亚硝酸叔丁酯(1.90g,18.40mmol)溶于二氯甲烷(10mL)中，用氮气置换三次，缓慢降温至0℃，在0～5℃下缓慢加入化合物II-A(2g,12.27mmol)的二氯甲烷(10mL)溶液，缓慢升温至18℃，并搅拌2小时。将反应液缓慢倒入40mL水中，用二氯甲烷(30mLх2)萃取，有机相用无水硫酸钠干燥，过滤干燥剂，将滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1/0～20/1)纯化，得到化合物II-B。
MS m/z:193.7[M+H] +。
步骤2：化合物II-C的合成
将化合物II-B(788mg,4.06mmol)溶于二氯甲烷(10mL)中，降温至-5℃，在-5～0℃下分批加入80％间氯过氧化苯甲酸(1.31g,6.09mmol)，反应在-5～0℃下搅拌40分钟。在0～5℃下向反应液中缓慢加入20mL饱和碳酸氢钠溶液淬灭，用二氯甲烷(30mLх2)萃取，有机相用无水硫酸钠干燥，过滤干燥剂，滤液减压浓缩得到粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到化合物II-C。
MS m/z:209.7[M+H] +。
步骤3：中间体II的合成
将化合物II-C(150mg,714.01μmol)和中间体I(160.40mg,785.41μmol)溶于四氢呋喃(8mL)中，用氮气置换三次，缓慢降温至0℃，在0～5℃下缓慢加入双(三甲基硅基)胺基锂的四氢呋喃溶液(2.14mL,1M)，反应在0～5℃、氮气保护下搅拌1.5小时。在0～5℃下向反应液中缓慢滴加饱和氯化铵溶液(20mL)进行淬灭，用二氯甲烷(40mL)萃取，有机相用无水硫酸钠干燥，过滤干燥剂，将滤液减压浓缩得到粗品。粗品经硅胶柱层析(二氯甲烷/四氢呋喃＝1/0～1/1)纯化得到中间体II。
MS m/z:378.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.34(s,1H),8.56(s,1H),8.27(s,1H),7.73(d,J＝7.8Hz,1H),7.51(d,J＝8.0Hz,1H),7.34-7.26(m,1H),6.76(s,1H),3.94(s,3H),3.66(s,3H),3.04(s,3H)。
实施例1：化合物1
Figure PCTCN2022077775-appb-000037
合成路线：
Figure PCTCN2022077775-appb-000038
步骤1：化合物1的合成
将中间体II(104mg,275.24μmol)，环丙甲酰胺(28.11mg,330.29μmol)，磷酸钾(175.27mg,825.73μmol)，1,1-双(二苯基膦)二茂铁(30.52mg,55.05μmol)和三(二亚苄基丙酮)二钯(25.20mg,27.52μmol)溶于二氧六环(3mL)中，用氮气置换三次，反应混合物在微波130℃下搅拌1小时。冷却后，反应液用硅藻土过滤，滤液减压浓缩，得到粗品。粗品经硅胶柱层析(二氯甲烷/甲醇＝1/0～30/1)纯化，得到化合物1。
MS m/z:427.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.84(s,1H),9.32(s,1H),8.55(s,1H),8.18(s,1H),8.03(s,1H),7.62(br d,J＝7.5Hz,1H),7.50(br d,J＝7.8Hz,1H),7.25(t,J＝7.9Hz,1H),3.94(s,3H),3.67(s,3H),3.02(s,3H),1.98(br t,J＝5.4Hz,1H),0.77(br d,J＝8.0Hz,4H)。
实施例2：化合物2、2A、2B
Figure PCTCN2022077775-appb-000039
合成路线：
Figure PCTCN2022077775-appb-000040
步骤1：化合物2的合成
将中间体II(230.60mg,610.31μmol)，2-氨基吡啶(63.18mg,671.34μmol)，磷酸钾(388.64mg,1.83mmol)，1,1-双(二苯基膦)二茂铁(67.67mg,122.06μmol)，三(二亚苄基丙酮)二钯(55.89mg,61.03μmol)溶于二氧六环(10mL)中，用氮气置换三次，反应混合物在微波110℃下搅拌1小时。将反应液用硅藻土过滤，滤液减压浓缩，得到粗品。粗品经硅胶柱层析(二氯甲烷/甲醇＝1/0～30/1)纯化，得到化合物2。
MS m/z:436.0[M+H] +。
1H NMR(400MHz,CDCl 3)δ9.40(s,1H),8.23(d,J＝3.8Hz,1H),8.13(s,1H),8.07(s,1H),7.81-7.75(m,2H),7.67(d,J＝8.0Hz,1H),7.64-7.57(m,1H),7.37(br d,J＝8.3Hz,1H),7.28-7.25(m,1H),6.88(dd,J＝5.3,6.8Hz,1H),4.03(s,3H),3.83(s,3H),3.06(s,3H)。
步骤2：化合物2A、2B的制备
化合物2用手性SFC分离，色谱柱：DAICEL CHIRALPAK AD(250mm*30mm,10um)；流动相：[Neu-ETOH]；B％:55％-55％,min，得到化合物2A和2B。
2A：保留时间：1.35分钟，ee值：99.06％
1H NMR(400MHz,CDCl 3)δ9.38(s,1H),8.21(br d,J＝3.8Hz,1H),8.11(s,1H),8.05(s,1H),7.80-7.72(m,2H),7.64(d,J＝8.0Hz,1H),7.59(br t,J＝7.8Hz,1H),7.34(br d,J＝8.3Hz,1H),7.26-7.22(m,1H),6.86(dd,J＝5.1,7.2Hz,1H),4.01(s,3H),3.81(s,3H),3.04(s,3H)。
2B：保留时间：1.65分钟，ee值：97.68％
1H NMR(400MHz,CDCl 3)δ9.37(s,1H),8.21(d,J＝3.8Hz,1H),8.11(s,1H),8.05(s,1H),7.79-7.71(m,2H),7.64(d,J＝7.8Hz,1H),7.59(br t,J＝7.2Hz,1H),7.34(d,J＝8.3Hz,1H),7.26-7.22(m,1H),6.86(dd,J＝5.4,6.9Hz,1H),4.01(s,3H),3.81(s,3H),3.04(s,3H)。
实施例3：化合物3
Figure PCTCN2022077775-appb-000041
合成路线：
Figure PCTCN2022077775-appb-000042
步骤1：化合物3-B的合成
将化合物3-A(2g,10.10mmol)溶于四氢呋喃(20mL)中，温度降至0℃，加入60％钠氢(605.94mg，15.15mmol)，逐渐升至20℃，搅拌0.5小时。加入对甲苯磺酰氯(2.31g，12.12mmol)，在20℃下反应13小时。反应结束后，将反应液降至0℃，加入20mL饱和氯化铵水溶液淬灭反应。搅拌5分钟，加入30mL水，用乙酸乙酯150mL(50mLх3)萃取。有机相用饱和食盐水洗涤一次，用无水硫酸钠干燥。过滤，滤液减压浓缩，粗品经硅胶柱层析分离(石油醚/乙酸乙酯：1/0～5/1)得到化合物3-B。
MS m/z:353.7[M+H] +。
步骤2：化合物3-C的合成
将化合物3-B(3.62g,10.28mmol)置于三口瓶中，加入1,4-二氧六环(40mL)。向混合物中加入氨基甲酸叔丁酯(1.81g,15.42mmol)，碳酸钾(4.26g,30.83mmol)，醋酸钯(230.75mg,1.03mmol)和[(4,5-双 (二苯基膦)-9,9-二甲基氧杂蒽)-2-(2-氨基联苯)]钯(II)(1.19g,2.06mmol)。氮气置换3次，加热至105℃，搅拌3小时。反应结束后将反应液通过硅藻土过滤，得滤液并减压浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯：1/0～5/1)分离，得到化合物3-C。
MS m/z:332.9[M+H] +。
步骤3：化合物3-D的合成
将化合物3-C(4g,10.30mmol)溶于乙酸乙酯(40mL),加入4M盐酸/乙酸乙酯(6mL,24mmol),加热至50℃，搅拌5小时。反应结束后将反应液置于冰浴中，加入饱和碳酸钠水溶液调节pH约为7左右，用乙酸乙酯210mL(70mLх3)萃取，有机相用饱和食盐水洗涤一次。用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品加入20mL的石油醚和乙酸乙酯的混合液(石油醚/乙酸乙酯＝3/1)搅拌，过滤，滤饼用石油醚(10mL)冲洗，得到化合物3-D。
MS m/z:288.9[M+H] +。
步骤4：化合物3的合成
将中间体II(0.3g，793.97μmol)置于微波反应管中，加入1,4-二氧六环(6mL)，再加入三(二亚苄基丙酮)二钯(72.71mg，79.40μmol)，1,1-双(二苯基膦基)二茂铁(88.03mg，158.79μmol)和磷酸钾(505.60mg，2.38mmol)。氮气置换一分钟，微波加热至110℃反应1小时。反应结束后，将反应液通过硅藻土过滤，滤液减压浓缩。粗品经硅胶柱层析分离(甲醇/二氯甲烷＝0/1～1/20)，得到化合物3。
MS m/z:476.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.81(br s,1H),9.96(s,1H),9.40(s,1H),8.55(s,1H),8.39(s,1H),8.22(s,1H),8.12(s,1H),7.74(br d,J＝7.8Hz,1H),7.71-7.59(m,2H),7.37(t,J＝7.9Hz,1H),6.32(br s,1H),3.94(s,3H),3.71(s,3H),3.04(s,3H)。
实施例4：化合物4
Figure PCTCN2022077775-appb-000043
合成路线：
Figure PCTCN2022077775-appb-000044
步骤1：化合物4的合成
将中间体II(0.25g,661.64μmol)置于微波反应管中，加入1,4-二氧六环(5mL)，1,5-二甲基-1-氢-吡唑-3-胺(77.21mg,694.72μmol),三(二亚苄基丙酮)二钯(60.59mg,66.16μmol)，1,1-双(二苯基膦基)二茂铁(73.36mg,132.33μmol)和磷酸钾(421.34mg,1.98mmol)。氮气置换2分钟，微波加热至110℃搅拌1小时。反应结束后将反应液通过硅藻土过滤，滤液减压浓缩。粗品经制备HPLC分离(色谱柱：Welch Xtimate C18 150*25mm*5μm；流动相：[10mM NH 4HCO 3的水溶液-ACN]；梯度:ACN(29％-59％),9min)，得到化合物4。
MS m/z:453.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.32(d,J＝2.3Hz,2H),8.55(s,1H),8.00(s,1H),7.66-7.60(m,1H),7.57(dd,J＝1.4,7.8Hz,1H),7.51(br s,1H),7.28(t,J＝7.9Hz,1H),5.95(s,1H),3.94(s,3H),3.69(s,3H),3.33(s,3H),2.99(s,3H),2.18(s,3H)。
实施例5：化合物5
Figure PCTCN2022077775-appb-000045
合成路线：
Figure PCTCN2022077775-appb-000046
步骤1：化合物5的合成
将中间体II(0.25g,661.64μmol)置于微波反应管中，加入1,4-二氧六环(5mL)，2-氨基-5-氟吡啶(77.88mg,694.72μmol),三(二亚苄基丙酮)二钯(60.59mg,66.16μmol)，1,1-双(二苯基膦基)二茂铁(73.36mg,132.33μmol)和磷酸钾(421.34mg,1.98mmol)。氮气置换2分钟，微波加热至110℃搅拌1小时。反应结束后将反应液通过硅藻土过滤，滤液减压浓缩。粗品经制备HPLC分离(色谱柱：Welch Xtimate C18 150*25mm*5μm；流动相：[10mM NH 4HCO 3的水溶液-ACN]；ACN:29％-59％,9min)，得到化合物5。
MS m/z:453.9[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),9.36(s,1H),8.56(s,1H),8.17(d,J＝3.0Hz,1H),8.11(s,1H),7.80(dd,J＝3.9,8.9Hz,1H),7.69-7.63(m,2H),7.61(t,J＝7.8Hz,2H),7.34-7.27(m,1H),3.94(s,3H),3.69(s,3H),3.02(s,3H)。
实施例6：化合物6
Figure PCTCN2022077775-appb-000047
合成路线：
Figure PCTCN2022077775-appb-000048
步骤1：化合物6的合成
将中间体II(0.22g,582.24μmol)置于微波反应管中，加入1,4-二氧六环(6mL)，2-氨基-6-氰基吡啶(72.83mg,611.36μmol),三(二亚苄基丙酮)二钯(53.35mg,58.22μmol)，1,1-双(二苯基膦基)二茂铁(64.56mg,116.45μmol)和磷酸钾(370.77mg,1.75mmol)。氮气置换2分钟，微波加热至110℃搅拌1小时。反应结束后将反应液通过硅藻土过滤，滤液减压浓缩。粗品经制备HPLC分离(色谱柱：Welch Xtimate C18 150*25mm*5μm；流动相：[10mM NH 4HCO 3的水溶液-ACN]；ACN:29％-59％,9min)，得到化合物6。
MS m/z:461.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.33(s,1H),9.56(s,1H),8.56(s,1H),8.16(s,1H),7.90(s,1H),7.87(d,J＝6.8Hz,1H),7.85-7.81(m,1H),7.71(dd,J＝1.3,8.0Hz,1H),7.60(dd,J＝1.4,7.9Hz,1H),7.52(dd,J＝1.1,6.9Hz,1H),7.36(t,J＝7.9Hz,1H),3.95(s,3H),3.70(s,3H),3.04(s,3H)。
实施例7：化合物7
Figure PCTCN2022077775-appb-000049
合成路线：
Figure PCTCN2022077775-appb-000050
步骤1：化合物7的合成
将中间体II(0.36g,952.76μmol)置于微波反应管中，加入1,4-二氧六环(5mL)，4-氨基-2,6-二甲基嘧啶(123.20mg,1.00mmol),三(二亚苄基丙酮)二钯(87.25mg,95.28μmol)，1,1-双(二苯基膦基)二茂铁(105.64mg,190.55μmol)和磷酸钾(606.73mg,2.86mmol)。氮气置换2分钟，微波加热至110℃搅拌1小时。反应结束后将反应液通过硅藻土过滤，滤液减压浓缩。粗品经制备HPLC分离(色谱柱：Welch Xtimate C18 150*25mm*5μm；流动相：[10mM NH 4HCO 3的水溶液-ACN]；ACN:29％-59％,9min)，得到化合物7。
MS m/z:465.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ10.11(s,1H),9.40(s,1H),8.55(s,1H),8.16(s,1H),8.08(s,1H),7.64(t,J＝6.5Hz,2H),7.29(t,J＝7.9Hz,1H),7.12(s,1H),3.94(s,3H),3.70(s,3H),3.04(s,3H),2.35(s,3H),2.28(s,3H)。
实施例8：化合物8
Figure PCTCN2022077775-appb-000051
合成路线：
Figure PCTCN2022077775-appb-000052
步骤1：化合物8-B的合成
将化合物8-A(0.2g,1.31mmol)溶于四氢呋喃(10mL)中，用氮气置换3次。温度降至0℃，向反应液中加入3M甲基溴化镁(4.37mL，13.10mmol)，逐渐升至室温20℃并继续搅拌16小时。反应结束后，向反应液中加入10mL饱和氯化铵水溶液淬灭反应。用乙酸乙酯150mL(50mLх3)萃取，合并的有机相用饱和食盐水洗涤一次，用无水硫酸钠干燥。过滤，滤液减压浓缩，得化合物8-B。
MS m/z:152.8[M+H] +。
步骤2：化合物8的合成
将中间体II(0.1g,264.66μmol)置于微波反应管中，加入1,4-二氧六环(5mL)，8-B(44.31mg,291.12μmol),三(二亚苄基丙酮)二钯(24.24mg,26.47μmol)，1,1-双(二苯基膦基)二茂铁(29.34mg,52.93μmol)和磷酸钾(168.53mg,793.97μmol)。氮气置换2分钟，微波加热至110℃搅拌1小时。反应结束后将反应液通过硅藻土过滤，滤液减压浓缩。粗品经硅胶柱层析分离(二氯甲烷/甲醇＝0/1～1/20)，得到化合物8。
MS m/z:494.0[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ9.77(br s,1H),9.36(s,1H),8.55(s,1H),8.25(d,J＝2.0Hz,1H),8.10(s,1H),7.86(br s,1H),7.72(dd,J＝2.4,8.7Hz,1H),7.64(br d,J＝7.0Hz,1H),7.61-7.52(m,2H),7.33-7.25 (m,1H),7.33-7.25(m,1H),5.04(s,1H),3.94(s,3H),3.70(s,3H),3.02(s,3H),1.42(s,6H)。
生物活性评价：
实验例1：体外酶活性评价
供实验用的本发明化合物均为自制，其化学名称和结构式见各化合物的制备实施例，酶活性测试在上海润诺进行，实验结果由该公司提供。
Tyk2 JH2酶活性测试实验过程
在包含20mM Hepes pH 7.5、10mM MgCl 2、0.015％Brij-35、2mM DTT和50μg/mL BSA的缓冲溶液中加入0.5nM的TYK2蛋白(His-TVMV-TYK2 JH2(575-869))、0.2nM的铽标记的His抗体、在相关K d值下的荧光素标记的激酶示踪剂，以及待测化合物，测试体系在室温下孵化90分钟。随后，在Envision平板阅读器上测量产生的HTRF(均相时间分辨荧光)信号，即荧光素受体(520nm)和铽供体(495nm)在发射波长处的荧光强度之比，并以此为基础计算得出IC 50值。
表1：本发明化合物体外酶活性测定结果(IC 50)
化合物编号 Tyk2 JH2(IC50nM)
化合物1 7.17
化合物2 2.21
化合物2A 1.73
化合物2B 89.48
化合物3 2.45
化合物4 11.27
化合物5 2.32
化合物6 0.62
化合物7 1.1
化合物8 2.75
结论：本发明化合物有较强的Tyk2 JH2的抑制活性。

Claims (10)

  1. 式(Ⅰ)化合物或其药学上可接受的盐，
    Figure PCTCN2022077775-appb-100001
    其中,
    L 1为单键或-C(＝O)；
    环A为环丙基、
    Figure PCTCN2022077775-appb-100002
    R 1为H、F、Cl、Br、I、CN或C 1-3烷基，其中C 1-3烷基任选被1、2或3个R a取代；
    R 21、R 22和R 23分别独立地为H或C 1-3烷基；
    R 31和R 32分别独立地为H或C 1-3烷基；
    R a为OH。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1为H、F、Cl、Br、I、CN或
    Figure PCTCN2022077775-appb-100003
    其中
    Figure PCTCN2022077775-appb-100004
    任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，R 1为H、F、Cl、CN或
    Figure PCTCN2022077775-appb-100005
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 21、R 22和R 23分别独立地为H或CH 3。
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 31和R 32分别独立地为H或CH 3。
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，环A为环丙基、
    Figure PCTCN2022077775-appb-100006
    Figure PCTCN2022077775-appb-100007
  7. 根据权利要求6所述化合物或其药学上可接受的盐，其中，环A为
    Figure PCTCN2022077775-appb-100008
    Figure PCTCN2022077775-appb-100009
  8. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022077775-appb-100010
  9. 根据权利要求1所述的化合物及其药学上可接受的盐，其化合物为
    Figure PCTCN2022077775-appb-100011
  10. 根据权利要求1～9任意一项所述化合物或其药学上可接受的盐在制备Tyk2JH2抑制剂的相关药物中的应用。
PCT/CN2022/077775 2021-02-24 2022-02-24 含有亚磺酰基吡啶结构的化合物以及应用 WO2022179578A1 (zh)

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