WO2023124022A1 - 噻吩[2,3-d]嘧啶衍生物及其用途 - Google Patents

噻吩[2,3-d]嘧啶衍生物及其用途 Download PDF

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WO2023124022A1
WO2023124022A1 PCT/CN2022/106494 CN2022106494W WO2023124022A1 WO 2023124022 A1 WO2023124022 A1 WO 2023124022A1 CN 2022106494 W CN2022106494 W CN 2022106494W WO 2023124022 A1 WO2023124022 A1 WO 2023124022A1
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substituted
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halogen
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陈俐娟
陈永
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成都赜灵生物医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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Definitions

  • the invention belongs to the field of chemical medicine, and in particular relates to a class of thiophene [2,3-d] pyrimidine derivatives, a preparation method thereof and an application in medicine.
  • RIPK2 (RIP2, RICK, CARDIAK, CARD3) is a dual-specificity serine/threonine and tyrosine kinase that regulates pro-inflammatory signaling mediated by NOD1 and NOD2, and is an emerging therapeutic target for autoimmune and inflammatory diseases .
  • Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract (Science 2005,307,731-734) reported that the nucleotide-binding oligomerization domain (NOD) protein family is an important intracellular pattern recognition receptor, NOD1 and NOD2 is the representative two receptors of this protein family.
  • Nod-like proteins in inflammation and disease J.Pathol.2008,214,136-148) and Nod-like proteins in immunity,inflammation and disease (Nat.Immunol.2006,7,1250-1257) reported that RIPK2 was activated It will bind to NOD1 or NOD2, and mainly function as a molecular scaffold, activate NF- ⁇ B and MAPK signaling pathways, and then recruit downstream kinases such as TAK1, IKK ⁇ , IKK ⁇ , IKK ⁇ , etc., causing IL- ⁇ , IL-6, IL- 12. The increase of immune-related signaling factors such as TNF ⁇ .
  • Dysregulation of RIPK2-dependent signaling has been linked to autoimmune diseases. Patients with NOD2 gene mutations are prone to induce Crohn's disease, Blau syndrome, early-onset sarcoidosis, dermatitis, arthritis, etc. Mutations of NOD1 are closely related to asthma and extraintestinal inflammatory diseases. Therefore, pharmacologically targeting the NOD/RIPK2 signaling pathway, by directly inhibiting the kinase activity of RIPK2, weakening the pro-inflammatory signal through the bacterial sensing pathway stimulated by NOD1 and NOD2, reducing the inflammatory response and the damage caused by inflammation, has become a therapeutic method for autoimmunity. Promising new drug target for sexual and inflammatory diseases.
  • the purpose of the present invention is to provide a potent and selective inhibitor of small molecule RIPK2 kinase activity that can specifically block RIPK2-dependent pro-inflammatory signaling, so as to provide therapeutic benefits for the treatment of autoinflammatory diseases.
  • the present invention firstly provides the compound represented by formula I or its pharmaceutically acceptable salt, solvate, hydrate, isomer, ester, acid, metabolite, or its prodrug, and its structure is as follows:
  • One of X and Y is S and the other is N;
  • R is selected from H, halogen
  • R2 is selected from Wherein, Z and W are independently selected from O, S, CR 13 R 14 ;
  • the substituents of the substituted C1-C8 alkyl are selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • the substituents of the substituted 3-8 membered cycloalkyl are selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl groups;
  • R 15 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted C2-C8 alkenyl;
  • the substituent of the substituted C1-C8 alkyl is selected from halogen, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • the substituent of the substituted 3-8 membered cycloalkyl is selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6- 10-membered aryl;
  • the substituent of the substituted C2-C8 alkenyl is selected from halogen, 3-8 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • R 13 and R 14 are independently selected from halogen, hydroxyl, C1-C8 alkyl, C1-C8 alkoxy, or R 13 and R 14 form a 3-8-membered epoxy group.
  • R is selected from H and F.
  • R 3 to R 12 are independently selected from H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl; among R 3 to R 12 , the The 3-6 membered cycloalkyl group contains 0-1 heteroatoms, and the heteroatoms are N, S, O; in R3 - R12 , the substituents of the substituted C1-C6 alkyl groups are selected from halogen, C2-C4 Alkenyl, 3-6 membered cycloalkyl, halogen-substituted or unsubstituted 6-10-membered aryl; R 3 -R 12 , the substituents of the substituted 3-6-membered cycloalkyl are selected from halogen, C1 ⁇ C4 alkyl, C2 ⁇ C4 alkenyl, 3 ⁇ 6 membered cycloalkyl, halogen substituted or unsubsti
  • R 3 -R 12 are independently selected from H, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 5-6 membered cycloalkyl; among R 3 -R 12 , the The 5-6 membered cycloalkyl group contains 0-1 heteroatoms, and the heteroatoms are N, S, O; in R3 - R12 , the substituents of the substituted C1-C4 alkyl groups are selected from F, C2 alkenes group, cyclopropyl, fluorine-substituted or unsubstituted 6-membered aryl group; in R 3 to R 12 , the substituent of the substituted 5-6 membered cycloalkyl group is selected from F, C1-C4 alkyl, C2 alkenes Base, cyclopropyl, fluorine-substituted or unsubstituted 6-10 membered aryl.
  • R 15 is selected from substituted or unsubstituted C1 ⁇ C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C2 ⁇ C6 alkenyl;
  • R 15 the The substituent of the substituted C1 ⁇ C6 alkyl is selected from halogen, C2 ⁇ C4 alkenyl, 3 ⁇ 6 membered cycloalkyl, halogen substituted or unsubstituted 6 ⁇ 10 membered aryl;
  • the substituted The substituents of the 3-6 membered cycloalkyl are selected from halogen, C1-C4 alkyl, C2-C4 alkenyl, 3-6 membered cycloalkyl, halogen substituted or unsubstituted 6-10 membered aryl;
  • R 15 the substituent of the substituted C2-C6 alkenyl is selected from hal
  • R 15 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C2-C4 alkenyl;
  • R 15 The substituents of the substituted C1-C4 alkyl are selected from F, C2 alkenyl, 3-6 membered cycloalkyl, fluorine-substituted or unsubstituted 6-membered aryl; in R 15 , the substituted 3-6
  • the substituent of the membered cycloalkyl is selected from F, C1 ⁇ C4 alkyl, C2 alkenyl, 3 ⁇ 6 membered cycloalkyl, fluorine substituted or unsubstituted 6 membered aryl;
  • the substituted C2 ⁇ The substituent of C6 alkenyl is selected from halogen, 3-6 membered cycloalky
  • R 13 and R 14 are independently selected from halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or R 13 and R 14 form a ring to form a 3-6 membered epoxy group.
  • R 13 and R 14 are independently selected from halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, or R 13 and R 14 form a 5-6-membered epoxy group.
  • R 13 and R 14 are independently selected from F, hydroxyl, methyl, methoxy, or R 13 and R 14 form a ring of 5-membered epoxy group.
  • R 2 is selected from
  • the present invention also provides some specific compounds, and its structural formula is as follows:
  • the present invention also provides a pharmaceutical composition, which is composed of the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable auxiliary ingredient is added.
  • the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, and the above-mentioned pharmaceutical composition in the preparation of RIPK2 inhibitors.
  • the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt and the above-mentioned pharmaceutical composition in the preparation of medicines for treating autoimmune diseases and/or allergic diseases.
  • the autoimmune disease and/or allergic disease is selected from: inflammatory bowel disease, sepsis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, scleroderma , asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, reactive arthritis, Crohn's disease, ulcerative colitis , uveitis, etc.
  • the present invention also provides pharmaceutically acceptable salts of the above-mentioned thiophene[2,3-d]pyrimidine derivatives.
  • forming a salt with an acid means that it is obtained by reacting the free base of the parent compound with an inorganic acid or an organic acid.
  • Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like.
  • Organic acids include acetic, propionic, acrylic, oxalic, (D) or (L) malic, fumaric, maleic, hydroxybenzoic, gamma-hydroxybutyric, methoxybenzoic, phthalic , methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid, etc.
  • pharmaceutically acceptable means, within the scope of reasonable medical judgment, suitable for use in contact with tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc. Administration to a recipient can directly or indirectly provide a compound or a prodrug of a compound of the present invention.
  • the present invention also provides pharmaceutically acceptable solvates of the above-mentioned thienopyrimidine derivatives.
  • solvate refers to an association of one or more solvent molecules with a compound of the invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and the like.
  • the present invention also provides pharmaceutically acceptable hydrates of the above-mentioned thien[2,3-d]pyrimidine derivatives.
  • hydrate means a compound that further incorporates stoichiometric or non-stoichiometric amounts of water through non-covalent intermolecular forces.
  • the present invention also provides pharmaceutically acceptable isomers of the above-mentioned thien[2,3-d]pyrimidine derivatives.
  • the term "isomer” refers to compounds having the same chemical composition but differing in the arrangement of atoms or groups in space, including diastereomers, enantiomers, regioisomers, structural isomers, rotational isomers Conformers, tautomers, etc.
  • the present invention also provides pharmaceutically acceptable polymorphs of the above-mentioned thiophene[2,3-d]pyrimidine derivatives.
  • polymorph means a solid crystalline form of a compound or complex thereof which can be characterized by physical methods such as X-ray powder diffraction patterns or infrared spectroscopy.
  • the present invention also provides a pharmaceutically acceptable pharmaceutical composition of the above-mentioned thiophene [2,3-d] pyrimidine derivatives, which is composed of 4-amino-5-aryl-7-ring compound represented by formula I
  • the hexyl-pyrimido nitrogen heterocyclic derivative or its salt or hydrate is prepared by adding pharmaceutically acceptable auxiliary components.
  • the auxiliary ingredients are cyclodextrin, arginine or meglumine.
  • the cyclodextrin is selected from ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -cyclodextrin, (C 1-4 alkyl)- ⁇ -Cyclodextrin, (C 1-4 Alkyl)- ⁇ -Cyclodextrin, (Hydroxy-C 1-4 Alkyl)- ⁇ -Cyclodextrin, (Hydroxy-C 1-4 Alkyl)- ⁇ -Cyclodextrin, (Hydroxy-C 1-4 Alkyl)- ⁇ -Cyclodextrin, (hydroxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇ -cyclodextrin, (carboxy-C 1-4 alkyl)- ⁇
  • the auxiliary components also include medically acceptable carriers, adjuvants or vehicles.
  • medically acceptable pharmaceutical compositions are ion exchangers, aluminum oxide, aluminum stearate, lecithin; buffer substances include phosphate, glycine, arginine, sorbic acid and the like.
  • the above-mentioned pharmaceutical composition may be in liquid form or solid form.
  • the liquid form may be in the form of an aqueous solution.
  • the solid form may be in the form of powder, granule, tablet or lyophilized powder.
  • the pharmaceutical composition also contains water for injection, saline solution, glucose aqueous solution, saline for injection/infusion, glucose for injection/infusion, Guernsey's solution or Guernsey's solution containing lactate.
  • the present invention provides a class of thiophene[2,3-d]pyrimidine derivatives, which can be used to prepare potent and selective small-molecule RIPK2 kinase activity inhibitors that specifically block RIPK2-dependent pro-inflammatory signaling, Provides new therapeutic avenues for the treatment of autoimmune diseases and/or allergic conditions.
  • the intermediate M2 (11.6 g, 25 mmol) from the previous step was dissolved in 100 mL of dichloromethane, and 50 mL of trifluoroacetic acid was added in portions. After reacting at room temperature for 0.5 hours, the reaction was complete, and the reaction solution was concentrated. Disperse the concentrated solution in water, add an appropriate amount of potassium hydroxide to adjust the pH until the pH>9, and a large amount of solid precipitates, filter and rinse the filter cake with ether to obtain a high-purity intermediate M3 (CL-1), without further purification.
  • CL-1 high-purity intermediate M3
  • Step d The reaction continues to split into two different reaction conditions
  • CLJ-24-CLJ-39 is prepared by the same synthetic method, except that N-Boc-1,2,5,6 - Tetrahydropyridine-4-boronic acid pinacol ester replaced by 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5, 6-dihydropyridine-1(2H)-tert-butyl carboxylate, the structural characterization is shown in Table 3:
  • CLJ-40-CLJ-48 is prepared by the same synthetic method, except that N-Boc-1,2,5,6 - Tetrahydropyridine-4-boronic acid pinacol ester replaced by (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ring Hex-3-en-1-yl) tert-butyl carbamate, structural characterization is as shown in table 4:
  • CLJ-49-CLJ-56 is prepared by the same synthetic method, except that N-Boc-1,2,5,6 - Tetrahydropyridine-4-boronic acid pinacol ester is replaced by 1-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-boronic acid pinacol ester, and the structural characterization is shown in Table 5:
  • Step b Disperse the intermediate in the previous step in 50 mL of water, and add 10 mL of concentrated hydrochloric acid to deprotect the group. After continuing the reaction for 5 hours, a large amount of solids precipitated out, and the filter cake was obtained by suction filtration. The filter cake was dispersed in 50 mL of water, and the pH was adjusted to above 9. After suction filtration, the filter cake was dried to obtain high-purity CLJ-69.
  • Step c CLJ-69 (378 mg, 1 mmol) was weighed and dissolved in 20 mL of methanol, and sodium borohydride (57 mg, 1.5 mmol) was added. After 5 hours of reaction, the reaction was complete. The sample was mixed with crude silica gel and then separated by Flash column to obtain the final product CLJ-70.
  • Step a Dissolve 2-fluoro-5-nitroaniline (15.6g, 100mmol) in 200mL of acetonitrile, add BzCl (12.8mL, 110mol) in batches, heat up to 50°C for 4h. A large amount of solids precipitated out of the system, and the relatively pure intermediate was obtained by suction filtration and washing the filter cake with acetonitrile.
  • Step c The intermediate (13.8g, 60mmol) and KSCN (8.75g, 90mmol) in the previous step were mixed in 100mL acetic acid, and the acetic acid solution containing Br 2 (4.5mL, 90mmol) was added dropwise into the system. After reacting for 5 hours, a large amount of solids precipitated out, and a relatively pure intermediate was obtained after suction filtration.
  • Step d The intermediate (14.3g, 50mmol) from the previous step was dissolved in 150mL THF and placed in an ice bath. Isoamyl nitrite (10 mL, 75 mmol) was added dropwise. After the dropwise addition, the reaction was carried out at room temperature for 2 hours, a large amount of solids were precipitated, and a relatively pure intermediate was obtained after suction filtration.
  • Step e The intermediate from the previous step (10.9 g, 40 mmol) was dissolved in 70% concentrated sulfuric acid (100 mL), and heated to 100 degrees Celsius. After reacting for 4 hours, TLC was performed to detect that the reaction was complete. After cooling the reaction solution to room temperature, it was slowly diluted into ice water, and the pH was adjusted to above 10 with sodium hydroxide. Then, extraction was performed twice with 500 mL of ethyl acetate, and the organic phases were combined and concentrated. The concentrated crude product was dispersed in 100 mL of ether, and a relatively pure product was obtained after suction filtration.
  • RIPK2 was incubated in buffer (20mM MOPS, pH 8.5, 0.2mM EDTA, 10mM MnCl 2 ), and added 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ ⁇ - 33P- ATP], and compounds at different concentrations, then Mg/ATP was added to the reaction to initiate the enzymatic reaction process and incubated at room temperature for 120 minutes.
  • RIPK1 was incubated in buffer (8mM MOPS pH 7.0, 0.2mM EDTA), and 0.33mg/mL myelin basic protein, 10mM magnesium acetate and [ ⁇ - 33P -ATP], and different concentrations of compounds were added, and then Mg/ATP was added to the reaction to start the enzymatic process and incubated at room temperature for 120 min. Finally, dilute to 0.5% concentration with phosphate buffer to stop the reaction, and titrate 10 microliters of the reaction solution onto the P30 membrane, wash with 0.425% phosphate solution four times, each time for 5 minutes, and then wash with methanol Once, finally dry the P30 membrane and perform scintillation counting on it.
  • the scintillation counting value reflects the degree of phosphorylation of the substrate, which can characterize the inhibition of kinase activity.
  • the IC 50 values were fitted according to the inhibition rates of the 9 concentrations, and repeated hole tests were performed. A: 1-10 nM; B: 10-100 nM; C: 100-200 nM; D: 200-500 nM.
  • RIPK2 is IC 50 , nM; RIPK1 inhibition rate is 1 ⁇ M, %.
  • the volume of the incubation system is 100 ⁇ L, the system includes 0.1M PBS pH 7.4, NADPH generation system (1mM NADP, 5mM glucose 6-phosphate, 1U/mL glucose 6-phosphate dehydrogenase, 3.3mM MgCl 2 ); Add 1 ⁇ L of K56 solution (concentration 1 ⁇ M/L), pre-incubate in a 37°C water bath for 5 minutes, add 2.5 ⁇ L of liver microsome solution of various species, continue to incubate for 0, 5, 15, 30, 45, 60 minutes, then add 200 ⁇ L containing The internal standard SAHA 20ng/mL glacial acetonitrile terminated the reaction, vortex mixed for 30s, centrifuged at 13000rpm for 10min, took the supernatant, and injected.
  • NADPH generation system 1mM NADP, 5mM glucose 6-phosphate, 1U/mL glucose 6-phosphate dehydrogenase, 3.3mM MgCl 2 .

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Abstract

提供了式Ⅰ所示的噻吩[2,3-d]嘧啶衍生物或其药学上可接受的盐，其能够用于制备RIPK2抑制剂，为制备治疗RIPK2异常激活引起的相关疾病的药物提供了新的选择。

Description

噻吩[2,3-d]嘧啶衍生物及其用途 技术领域
本发明属于化学医药领域，具体涉及一类噻吩[2,3-d]嘧啶衍生物及其制备方法和在医药中的用途。
背景技术
RIPK2(RIP2、RICK、CARDIAK、CARD3)为双特异性丝氨酸/苏氨酸及酪氨酸激酶，调节NOD1和NOD2介导的促炎信号，是自身免疫性和炎性疾病的新兴的治疗靶点。Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract(Science 2005,307,731-734)中报道了核苷酸结合寡聚化结构域(NOD)蛋白家族是重要的细胞内模式识别受体，NOD1和NOD2是该蛋白家族具有代表性的两个受体。Nod-like proteins in inflammation and disease(J.Pathol.2008,214,136-148)及Nod-like proteins in immunity,inflammation and disease(Nat.Immunol.2006,7,1250-1257)报道了RIPK2被激活后就会结合到NOD1或NOD2，并且主要起到分子支架的功能，激活NF-κB和MAPK信号通路，进而招募下游的TAK1、IKKα、IKKβ、IKKξ等激酶，引起IL-β、IL-6、IL-12、TNFα等免疫相关的信号因子的增加。
RIPK2依赖性的信号失调已经证实与自身免疫性疾病相关联。NOD2的基因突变患者容易诱发克罗恩病、Blau综合征、早发性结节病、皮炎、关节炎等。而NOD1的突变与哮喘、肠外炎性疾病有密切关系。因此，从药理上靶向NOD/RIPK2信号通路，通过直接抑制RIPK2的激酶活性减弱通过NOD1及NOD2刺激引发的通过细菌感应途径的促炎信号，减轻炎症反应及炎症造成的损伤，成为治疗自身免疫性和炎症性疾病很有前景的新的药物靶点。
发明内容
本发明的目的是提供可以特异性阻断RIPK2依赖性促炎发信号的强效的、选择性的小分子RIPK2激酶活性抑制剂，为治疗自身炎症性疾病提供治疗益处。
本发明首先提供了式Ⅰ所示化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、酯、酸、代谢物，或其前药，其结构如下：
Figure PCTCN2022106494-appb-000001
Figure PCTCN2022106494-appb-000002
X、Y其中一个为S，另一个为N；
R 1选自H、卤素；
R 2选自
Figure PCTCN2022106494-appb-000003
Figure PCTCN2022106494-appb-000004
其中，Z、W独立地选自O、S、CR 13R 14；
R 3～R 12独立地选自H、取代或未取代的C1～C8烷基、取代或未取代的3～8元环烷基、
Figure PCTCN2022106494-appb-000005
R 3～R 12中，所述3～8元环烷基含有0～2个杂原子，杂原子为N、S、O；n＝0～1；
R 3～R 12中，所述取代的C1～C8烷基的取代基选自卤素、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
R 3～R 12中，所述取代的3～8元环烷基的取代基选自卤素、C1～C6烷基、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
R 15选自取代或未取代的C1～C8烷基、取代或未取代的3～8元环烷基、取代或未取代的C2～C8烯基；
R 15中，所述取代的C1～C8烷基的取代基选自卤素、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
R 15中，所述取代的3～8元环烷基的取代基选自卤素、C1～C6烷基、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
R 15中，所述取代的C2～C8烯基的取代基选自卤素、3～8元环烷基、卤素取代或未取代的6～10元芳基；
R 13、R 14独立地选自卤素、羟基、C1～C8烷基、C1～C8烷氧基，或者R 13和R 14成环为3～8元环氧基。
其中，上述化合物中，R 1选自H、F。
其中，上述化合物中，R 3～R 12独立地选自H、取代或未取代的C1～C6烷基、取代或未取代的3～6元环烷基；R 3～R 12中，所述3～6元环烷基含有0～1个杂原子，杂原子为N、S、O；R 3～R 12中，所述取代的C1～C6烷基的取代基选自卤素、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；R 3～R 12中，所述取代的3～6元环烷基的取代基选自卤素、C1～C4烷基、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基。
优选的，上述化合物中，R 3～R 12独立地选自H、取代或未取代的C1～C4烷基、取代或未取代的5～6元环烷基；R 3～R 12中，所述5～6元环烷基含有0～1个杂原子，杂原子为N、S、O；R 3～R 12中，所述取代的C1～C4烷基的取代基选自F、C2烯基、环丙基、氟取代或未取代的6元芳基；R 3～R 12中，所述取代的5～6元环烷基的取代基选自F、C1～C4烷基、C2烯基、环丙基、氟取代或未取代的6～10元芳基。
其中，上述化合物中，R 15选自取代或未取代的C1～C6烷基、取代或未取代的3～6元环烷基、取代或未取代的C2～C6烯基；R 15中，所述取代的C1～C6烷基的取代基选自卤素、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；R 15中，所述取代的3～6元环烷基的取代基选自卤素、C1～C4烷基、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；R 15中，所述取代的C2～C6烯基的取代基选自卤素、3～6 元环烷基、卤素取代或未取代的6～10元芳基。
优选的，上述化合物中，R 15选自取代或未取代的C1～C4烷基、取代或未取代的3～6元环烷基、取代或未取代的C2～C4烯基；R 15中，所述取代的C1～C4烷基的取代基选自F、C2烯基、3～6元环烷基、氟取代或未取代的6元芳基；R 15中，所述取代的3～6元环烷基的取代基选自F、C1～C4烷基、C2烯基、3～6元环烷基、氟取代或未取代的6元芳基；R 15中，所述取代的C2～C6烯基的取代基选自卤素、3～6元环烷基、氟取代或未取代的6元芳基。
其中，上述化合物中，R 13、R 14独立地选自卤素、羟基、C1～C6烷基、C1～C6烷氧基，或者R 13和R 14成环为3～6元环氧基。
优选的，上述化合物中，R 13、R 14独立地选自卤素、羟基、C1～C4烷基、C1～C4烷氧基，或者R 13和R 14成环为5～6元环氧基。
更优选的，上述化合物中，R 13、R 14独立地选自F、羟基、甲基、甲氧基，或者R 13和R 14成环5元环氧基。
最优选的，上述化合物中，R 2选自
Figure PCTCN2022106494-appb-000006
Figure PCTCN2022106494-appb-000007
本发明还提供了一些具体化合物，其结构式如下：
Figure PCTCN2022106494-appb-000008
Figure PCTCN2022106494-appb-000009
Figure PCTCN2022106494-appb-000010
本发明还提供了一种药物组合物，其由上述化合物或其药学上可接受的盐为活性成分，添加药学上可接受的辅助性成分组成。
本发明还提供了上述化合物或其药学上可接受的盐、上述药物组合物在制备RIPK2抑制剂中的用途。
本发明还提供了上述化合物或其药学上可接受的盐、上述药物组合物在制备治疗自体免疫疾病和/或过敏性病症药物中的用途。
进一步的，上述用途中，所述自体免疫疾病和/或过敏性病症选自：炎症性肠病、脓毒症、类风湿性关节炎、牛皮癣、全身性红斑狼疮、狼疮性肾炎、硬皮病、哮喘、过敏性鼻炎、过敏性湿疹、多发性硬化症、青少年类风湿性关节炎、青少年特发性关节炎、牛皮癣性关节炎、反应性关节炎、克罗恩氏病、溃疡性结肠炎、葡萄膜炎等。
本发明还提供了上述噻吩[2,3-d]嘧啶衍生物药学上可接受的盐。其中与酸成盐是指，通过母体化合物的游离碱与无机酸或有机酸的反应而得。无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等。有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
本发明所用的术语“药学上可接受的”是指在在合理的医学判断范围，能适于用来与 人类和其他哺乳动物的组织接触，而没有不当毒性、刺激、过敏反应等，其在对受者给药时能直接或间接地提供本发明的化合物或化合物的前药。
本发明还提供了上述噻吩并嘧啶衍生物药学上可接受的溶剂化物。术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但不限于，水、异丙醇、乙醇、甲醇、二甲基亚砜、乙酸乙酯、乙酸等。
本发明还提供了上述噻吩[2,3-d]嘧啶衍生物药学上可接受的水合物。术语“水合物”表示进一步通过非共价分子间作用力结合化学计量或非化学计量的水的化合物。
本发明还提供了上述噻吩[2,3-d]嘧啶衍生物药学上可接受的异构体。术语“异构体”是指化学组成相同但是原子或基团在空间排列上不同的化合物，包括非对映异构体、对映异构体、区域异构体、结构异构体、旋转异构体、互变异构体等。
本发明还提供了上述噻吩[2,3-d]嘧啶衍生物药学上可接受的多晶型物。术语“多晶型物”表示化合物或其复合物的固体结晶形式，其可以通过物理方法，例如X射线粉末衍射图或红外光谱进行表征。
本发明还提供了上述噻吩[2,3-d]嘧啶衍生物药学上可接受的药物组合物，这种药物组合物是由式Ⅰ所示的4-氨基-5-芳基-7-环己基-嘧啶并氮杂环衍生物或其盐或水合物添加药学上可以接受的辅助性成分制备而成的。所述的辅助性成分如环糊精、精氨酸或葡甲胺。所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、(C 1-4烷基)-α-环糊精、(C 1-4烷基)-β-环糊精、(C 1-4烷基)-γ-环糊精、(羟基-C 1-4烷基)-α-环糊精、(羟基-C 1-4烷基)-β-环糊精、(羟基-C 1-4烷基)-γ-环糊精、(羧基-C 1-4烷基)-α-环糊精、(羧基-C 1-4烷基)-β-环糊精、(羧基-C 1-4烷基)-γ-环糊精、α-环糊精的糖类醚、β-环糊精的糖类醚、γ-环糊精的糖类醚、α-环糊精的磺丁基醚、β-环糊精的磺丁基醚和γ-环糊精的磺丁基醚。所述的辅助性成分还包含医学上可接受的载体、佐剂或媒剂。可用于药学上可接受的药物组合物还离子交换剂、氧化铝、硬脂酸铝、卵凝脂；缓冲物质包括磷酸盐、甘氨酸、精氨酸、山梨酸等。
上述药物组合物可以为液体形式或固体形式。其中，所述的液体形式可以为水溶液形式。所述的固体形式可以为粉末、颗粒、片剂或冻干粉形式。该药物组合物还含有注射用水、盐水溶液、葡萄糖水溶液、注射/输注用盐水、注射/输注用葡萄糖、格林氏溶液或含有乳酸盐的格林氏溶液。
本发明中，当Z、W选自CR 7R 8，且R 7、R 8同时为OH时，会脱除一分子水，此时表示Z和W共同形成羰基。
本发明的有益效果：
本发明提供了一类噻吩[2,3-d]嘧啶衍生物，其能够用于制备特异性阻断RIPK2依赖性促炎发信号的强效的、选择性的小分子RIPK2激酶活性抑制剂，为治疗自体免疫疾病和/或过敏性病症提供新的治疗途径。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。实施例中无特殊说明，反应的温度为室温，即20-30℃。
一般合成方法如下所描述：CLJ-1-CLJ-23的制备方法
Figure PCTCN2022106494-appb-000011
步骤a：中间体M1的制备
称量原料SM1(25g,100mmol)、SM2(16.5,110mmol)和对甲苯磺酸(1.7g,10mmol)加入到500mL圆底烧瓶内，并计入异丙醇250mL，将温度设置为80℃。反应2h后TLC检测反应完全，并有大量固体析出。过滤后用***淋洗滤饼就可以得到高纯度的中间体M1。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),9.32(s,1H),8.78(d,J＝2.1Hz,1H),8.56(s,1H),8.28(s,1H),8.09(d,J＝8.8Hz,1H),7.90(dd,J＝8.8,2.2Hz,1H).
步骤b：中间体M2的制备
将上一步中间体M1(18.2g,50mmol)、SM3(N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯)(17g,55mmol)、碳酸钾(13.8g,100mmol)和dppf(Pd 2Cl 2)(1.8g,2.5mmol)加入到500mL三颈瓶内，加入二氧六环/乙醇/水＝7:3:4(共计200mL)作为溶剂，置换氮气三次后转入80℃的油浴内反应2h。反应结束后有大量固体析出，过滤后用少量乙醇淋洗滤饼就可以得到高纯度的中间体M2。 1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.73(d,J＝2.1Hz,1H),8.45(s,1H),8.05(d,J＝8.9Hz,1H),7.84–7.79(m,2H),6.21(s,1H),4.12–3.99(m,2H),3.60(t,J＝5.7Hz,2H),2.57(s,2H),1.44(s,9H).
步骤c：中间体M3(CLJ-1)的制备
将上一步的中间体M2(11.6g,25mmol)溶解在100mL二氯甲烷中，并分批加入三氟乙酸50mL。于室温下反应0.5小时后反应完全，并将反应液进行浓缩。将浓缩液分散在水中，加入适量氢氧化钾调节pH直至pH>9，并有大量固体析出，过滤并用***淋洗滤饼得到高纯度的中间体M3(CL-1)，无需进一步纯化。 1H NMR(400MHz,DMSO-d6)δ9.77(s,1H),9.40(s,1H),8.74(d,J＝2.1Hz,1H),8.52(s,1H),8.14(d,J＝8.7Hz,1H),7.88(dd,J＝8.8,2.1Hz,1H),7.83(s,1H),6.29(t,J＝3.5Hz,1H),3.41(d,J＝3.1Hz,2H), 2.97(t,J＝5.6Hz,2H),2.46(s,2H).ESI-MS m/z:366.1[M+H] +
步骤d：该反应继续拆分为两个不同的反应条件
反应条件1：实施例CLJ-2的合成
称量中间体M3(183mg,0.5mmol)和多聚甲醛(150mg,5mmol)并溶解在10mL甲醇中。反应2h后，加入NaBH3CN(63mg，1mmol)。反应2h后检测反应完全，用粗硅胶进行拌样后进行Flash柱进行分离得到终产物CLJ-2。 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),9.40(s,1H),8.76(d,J＝2.0Hz,1H),8.52(s,1H),8.13(d,J＝8.7Hz,1H),7.94–7.88(m,2H),6.22(s,1H),3.07(d,J＝3.2Hz,2H),2.65–2.57(m,4H),2.30(s,3H).ESI-MS m/z:380.1[M+H] +
其他化合物参照CLJ-2的合成方法进行制备，只是将甲醛换做其他的相应的醛或酮，结构表征如表1所示：
表1化合物CLJ-3～CLJ-10
Figure PCTCN2022106494-appb-000012
Figure PCTCN2022106494-appb-000013
另一部分产物采取以下制备方法：将上一步的中间体M3(183mg,0.5mmol)溶解在二氯甲烷中，再将相应的酸酐或异氰酸酯加入体系内。反应0.5h后进行检测反应完全，并析出大量固体。抽滤得到滤饼并用***淋洗得到纯净的终产物CLJ-11-CLJ-23。结构表征表2所示：
表2化合物CLJ-11至CLJ-23
Figure PCTCN2022106494-appb-000014
Figure PCTCN2022106494-appb-000015
Figure PCTCN2022106494-appb-000016
一般合成方法如下所描述：CLJ-24-CLJ-39的制备方法
Figure PCTCN2022106494-appb-000017
参照实施例CLJ-1、CLJ-2和CLJ-11的合成路线，CLJ-24-CLJ-39采纳同样的合成方法进行制备，只是在反应b中将N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯替换成3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯，结构表征如表3所示：
表3化合物CLJ-24至CLJ-39
Figure PCTCN2022106494-appb-000018
Figure PCTCN2022106494-appb-000019
Figure PCTCN2022106494-appb-000020
Figure PCTCN2022106494-appb-000021
一般合成方法如下所描述：CLJ-40-CLJ-48的制备方法
Figure PCTCN2022106494-appb-000022
参照实施例CLJ-1、CLJ-2和CLJ-11的合成路线，CLJ-40-CLJ-48采纳同样的合成方法进行制备，只是在反应b中将N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯替换成(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环己-3-烯-1-基)氨基甲酸叔丁酯，结构表征如表4所示：
表4化合物CLJ-40至CLJ-48
Figure PCTCN2022106494-appb-000023
Figure PCTCN2022106494-appb-000024
Figure PCTCN2022106494-appb-000025
一般合成方法如下所描述：CLJ-49-CLJ-56的制备方法
Figure PCTCN2022106494-appb-000026
参照实施例CLJ-1、CLJ-2和CLJ-11的合成路线，CLJ-49-CLJ-56采纳同样的合成方法进行制备，只是在反应b中将N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯替换成1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯，结构表征如表5所示：
表5化合物CLJ-49至CLJ-56
Figure PCTCN2022106494-appb-000027
Figure PCTCN2022106494-appb-000028
一般合成方法如下所描述：CLJ-57-CLJ-63的制备方法
Figure PCTCN2022106494-appb-000029
该系列化合物的制备方法与制备实施例CLJ-1的方法相同，只是将SM3(1,3-苯并噻唑-5-胺)替换为SM4(6-氨基苯并噻唑)，结构表征如表6所示：
表6化合物CLJ-57至CLJ-63
Figure PCTCN2022106494-appb-000030
Figure PCTCN2022106494-appb-000031
一般合成方法如下所描述：CLJ-64-CLJ-68的制备方法
Figure PCTCN2022106494-appb-000032
该系列化合物的制备方法与制备实施例CLJ-1的方法相同，只是将N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯替换成相应的硼酸频哪醇酯，结构表征如表7所示：
表7化合物CLJ-64至CLJ-68
Figure PCTCN2022106494-appb-000033
Figure PCTCN2022106494-appb-000034
一般合成方法如下所描述：CLJ-69-CLJ-71的制备方法
Figure PCTCN2022106494-appb-000035
步骤a：将中间体M1(3.63g,10mmol)、1,4-二氧杂-螺[4,5]癸-7-烯-8-硼酸频哪醇酯(2.93g,11mmol)、碳酸钾(2.76g,20mmol)和dppf(PdCl 2)(366mg,0.5mmol)加入到100mL三颈瓶内，加入二氧六环/乙醇/水＝7:3:4(共计50mL)作为溶剂，置换氮气三次后转入80℃的油浴内反应2h。反应结束后有大量固体析出，过滤后用少量乙醇淋洗滤饼就可以得到高纯度的CLJ-71，无需进一步纯化。 1H NMR(400MHz,DMSO-d 6)δ9.75(s,1H),9.41(s,1H),8.75(d,J＝2.0Hz,1H),8.52(s,1H),8.14(d,J＝8.7Hz,1H),7.89(dd,J＝8.8,2.1Hz,1H),7.83(s,1H),6.14(t,J＝4.1Hz,1H),3.57(s,4H),2.69(d,J＝6.8Hz,2H),2.47–2.41(m,2H),1.90(t,J＝6.5Hz,2H)。
步骤b：将上一步的中间体分散在50mL水中，加入10mL浓盐酸进行脱保护基。持续反应5h后，有大量固体析出，抽滤得滤饼，并将滤饼分散在50mL水中，并将pH调至9以上，抽滤后对滤饼进行干燥得高纯度的CLJ-69。 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.41(s,1H),8.75(d,J＝2.1Hz,1H),8.55(s,1H),8.15(d,J＝8.7Hz,1H),7.98(s,1H),7.90(dd,J＝8.7,2.1Hz,1H),6.31(t,J＝4.1Hz,1H),3.11(dd,J＝4.2,2.1Hz,2H),3.00–2.94(m,2H),2.64(t,J＝6.9Hz,2H).
步骤c：称量CLJ-69(378mg,1mmol)并溶于20mL的甲醇中，加入硼氢化钠(57mg,1.5mmol)。反应5h后反应完全，用粗硅胶进行拌样后进行Flash柱进行分离得到终产物CLJ-70。 1H NMR(400MHz,DMSO-d 6)δ9.73(s,1H),9.36(s,1H),8.71(d,J＝1.9Hz,1H),8.48(d,J＝0.9Hz,1H),8.10(d,J＝8.7Hz,1H),7.84(dd,J＝8.7,2.0Hz,1H),7.77(s, 1H),6.12(t,J＝4.1Hz,1H),4.78(d,J＝4.0Hz,1H),4.52(s,1H),3.81(s,1H),2.66–2.56(m,1H),2.42(s,0H),2.14–2.04(m,1H),1.95–1.86(m,1H).
6-氟-5-氨基-1,3-苯并噻唑的制备过程如下：
Figure PCTCN2022106494-appb-000036
步骤a：将2-氟-5-硝基苯胺(15.6g,100mmol)溶于200mL乙腈中，分批加入BzCl(12.8mL,110mol),升温至50摄氏度反应4h。体系析出大量固体，抽滤并用乙腈淋洗滤饼后的较纯的中间体。
步骤b：将上一步得到的中间体(22.1g,85mmol)、Fe粉(9.5g,170mmol)和氯化铵(9.1g,170mmol)混合在甲醇/水＝4:1的混合溶剂中，加热至65摄氏度。1h后TLC检测反应完毕，将反应混悬液通过硅藻土过滤，保留母液。将母液浓缩后分散在100mL水中进行打浆，抽滤后得到较纯的中间体。
步骤c：将上一步的中间体(13.8g,60mmol)和KSCN(8.75g,90mmol)混合于100mL醋酸中，往体系内滴加含有Br 2(4.5mL,90mmol)的醋酸溶液。反应5h后，有大量固体析出，抽滤后得到较纯的中间体。 1H NMR(400MHz,DMSO-d 6)δ10.16(s,1H),8.66(s,2H),7.99–7.91(m,2H),7.78(d,J＝9.9Hz,1H),7.66(d,J＝6.5Hz,1H),7.61–7.55(m,1H),7.51(t,J＝7.5Hz,2H).
步骤d：将上一步的中间体(14.3g,50mmol)溶于150mL四氢呋喃中，并至于冰浴条件下。滴加亚硝酸异戊酯(10mL,75mmol)。滴加完毕后转至室温反应2h，有大量固体析出，抽滤后得到较纯的中间体。
步骤e：将上一步的中间体(10.9g,40mmol)溶解在70％的浓硫酸中(100mL),并加热至100摄氏度。反应4h后进行TLC检测反应完全，将反应液冷却至室温后缓慢稀释至冰水中，并用氢氧化钠调节pH至10以上。然后用乙酸乙酯500mL进行萃取两次，合并有机相后进行浓缩。将浓缩后的粗品分散在100mL***中，抽滤后得到较纯的产物。 1H NMR(400MHz,DMSO-d 6)δ9.13(d,J＝1.1Hz,1H),7.77(d,J＝10.9Hz,1H),7.35(dd,J＝8.2,1.1Hz,1H),5.35(s,2H).
一般合成方法如下所描述：CLJ-72-CLJ-77的制备方法
Figure PCTCN2022106494-appb-000037
该系列化合物与实施列CLJ-1和CLJ-11的合成方法相似，只是将起始原料SM2(1,3-苯并噻唑-5-胺)替换为6-氟-5-氨基-1,3-苯并噻唑,其他反应条件均一致，结构表征如表8所示：
表8化合物CLJ-72至CLJ-77
Figure PCTCN2022106494-appb-000038
Figure PCTCN2022106494-appb-000039
一般合成方法如下所描述：CLJ-78-CLJ-83的制备方法
Figure PCTCN2022106494-appb-000040
该系列化合物与实施列CLJ-1和CLJ-11的合成方法相似，只是N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯替换成(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)环己-3-烯-1-基)氨基甲酸叔丁酯,其他反应条件均一致，结构表征如表9所示：
表9化合物CLJ-78至CLJ-83
Figure PCTCN2022106494-appb-000041
Figure PCTCN2022106494-appb-000042
一般合成方法如下所描述：CLJ-84-CLJ-90的制备方法
Figure PCTCN2022106494-appb-000043
该系列化合物与实施列CLJ-1和CLJ-11的合成方法相似，只是N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯替换成3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯,其他反应条件均一致，结构表征如表10所示：
表10化合物CLJ-84至CLJ-90
Figure PCTCN2022106494-appb-000044
Figure PCTCN2022106494-appb-000045
药效学实验部分
以下代表性实验(不限于此)用于分析本发明化合物的生物活性。
体外激酶抑制实验
在一个反应管内，RIPK2在缓冲液(20mM MOPS,pH 8.5,0.2mM EDTA,10mM MnCl 2)中进行孵育,并加入0.33mg/mL髓磷脂碱性蛋白，10mM醋酸镁和[γ- 33P-ATP]，以及不同浓度的化合物，然后向反应中加入Mg/ATP以启动酶反应过程，并在室温下孵育120分钟。RIPK1在缓冲液(8mM MOPS pH 7.0,0.2mM EDTA)中进行孵育,并加入 0.33mg/mL髓磷脂碱性蛋白，10mM醋酸镁和[γ- 33P-ATP]，以及不同浓度的化合物，然后向反应中加入Mg/ATP以启动酶反应过程，并在室温下孵育120分钟。最终用磷酸盐缓冲液稀释到0.5％的浓度来终止反应，并把10微升的反应液滴定到P30膜上，用0.425％的磷酸盐溶液洗四次，每次5分钟，再用甲醇洗一次，最后干燥P30膜并对其进行闪烁计数，闪烁计数值得大小反映了底物被磷酸化的程度，从而可以表征激酶活性抑制情况。根据9个浓度的抑制率拟合IC 50值，复孔测试。A：1-10nM；B：10-100nM；C：100-200nM；D：200-500nM。
表11本发明化合物RIPK2激酶的抑制活性
Figure PCTCN2022106494-appb-000046
Figure PCTCN2022106494-appb-000047
注：RIPK2为IC 50，nM；RIPK1抑制率为1μM，％。
结果表明，本发明大部分化合物对RIPK2具有较好的体外酶学抑制活性，其IC 50处于1-100nM范围内，而且对同家族成员RIPK1激酶具有高选择性。
代谢稳定性试验
孵育体系体积为100μL，体系包括0.1M pH 7.4的PBS，NADPH发生***(1mM NADP，5mM的6-磷酸葡萄糖，1U/mL 6-磷酸葡萄糖脱氢酶，3.3mM的MgCl 2)；在冰浴上加入1μL k56溶液(浓度1μM/L)，采用37℃水浴预孵育5min，加入2.5μL各种属肝微粒体溶液，继续温孵0，5，15，30，45，60min后加200μL的含内标SAHA20ng/mL的冰乙腈终止反应，涡旋混匀30s,13000rpm离心10min，取上清液，进样。
表12部分化合物的肝微粒体稳定性数据
Figure PCTCN2022106494-appb-000048
Figure PCTCN2022106494-appb-000049
结果表明，部分化合物具有良好的体外肝微粒体稳定性，具有较佳的药代动力学性质。

Claims (10)

  1. 式Ⅰ所示化合物或其药学上可接受的盐，其特征在于，结构如下：
    Figure PCTCN2022106494-appb-100001
    X、Y其中一个为S，另一个为N；
    R 1选自H、卤素；
    R 2选自
    Figure PCTCN2022106494-appb-100002
    Figure PCTCN2022106494-appb-100003
    其中，Z、W独立地选自O、S、CR 13R 14；
    R 3～R 12独立地选自H、取代或未取代的C1～C8烷基、取代或未取代的3～8元环烷基、
    Figure PCTCN2022106494-appb-100004
    R 3～R 12中，所述3～8元环烷基含有0～2个杂原子，杂原子为N、S、O；n＝0～1；
    R 3～R 12中，所述取代的C1～C8烷基的取代基选自卤素、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
    R 3～R 12中，所述取代的3～8元环烷基的取代基选自卤素、C1～C6烷基、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
    R 15选自取代或未取代的C1～C8烷基、取代或未取代的3～8元环烷基、取代或未取代的C2～C8烯基；
    R 15中，所述取代的C1～C8烷基的取代基选自卤素、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
    R 15中，所述取代的3～8元环烷基的取代基选自卤素、C1～C6烷基、C2～C6烯基、3～8元环烷基、卤素取代或未取代的6～10元芳基；
    R 15中，所述取代的C2～C8烯基的取代基选自卤素、3～8元环烷基、卤素取代或未取代的6～10元芳基；
    R 13、R 14独立地选自卤素、羟基、C1～C8烷基、C1～C8烷氧基，或者R 13和R 14成环为3～8元环氧基。
  2. 如权利要求1所述的化合物，其特征在于，R 1选自H、F。
  3. 如权利要求1或2所述的化合物，其特征在于，
    R 3～R 12独立地选自H、取代或未取代的C1～C6烷基、取代或未取代的3～6元环烷基；R 3～R 12中，所述3～6元环烷基含有0～1个杂原子，杂原子为N、S、O；R 3～R 12中，所述取代的C1～C6烷基的取代基选自卤素、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；R 3～R 12中，所述取代的3～6元环烷基的取代基选自卤素、C1～C4烷基、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；
    优选的，R 3～R 12独立地选自H、取代或未取代的C1～C4烷基、取代或未取代的5～6元环烷基；R 3～R 12中，所述5～6元环烷基含有0～1个杂原子，杂原子为N、S、O；R 3～R 12中，所述取代的C1～C4烷基的取代基选自F、C2烯基、环丙基、氟取代或未取代的6元芳基；R 3～R 12中，所述取代的5～6元环烷基的取代基选自F、C1～C4烷基、C2烯基、环丙基、氟取代或未取代的6～10元芳基。
  4. 如权利要求1或2所述的化合物，其特征在于，
    R 15选自取代或未取代的C1～C6烷基、取代或未取代的3～6元环烷基、取代或未取代的C2～C6烯基；R 15中，所述取代的C1～C6烷基的取代基选自卤素、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；R 15中，所述取代的3～6元环烷基的取代基选自卤素、C1～C4烷基、C2～C4烯基、3～6元环烷基、卤素取代或未取代的6～10元芳基；R 15中，所述取代的C2～C6烯基的取代基选自卤素、3～6元环烷基、卤素取代或未取代的6～10元芳基；
    优选的，R 15选自取代或未取代的C1～C4烷基、取代或未取代的3～6元环烷基、取代或未取代的C2～C4烯基；R 15中，所述取代的C1～C4烷基的取代基选自F、C2烯基、3～6元环烷基、氟取代或未取代的6元芳基；R 15中，所述取代的3～6元环烷基的取代基选自F、C1～C4烷基、C2烯基、3～6元环烷基、氟取代或未取代的6元芳基；R 15中，所述取代的C2～C6烯基的取代基选自卤素、3～6元环烷基、氟取代或未取代的6元芳基。
  5. 如权利要求1或2所述的化合物，其特征在于，
    R 13、R 14独立地选自卤素、羟基、C1～C6烷基、C1～C6烷氧基，或者R 13和R 14成环为3～6元环氧基；
    优选的，R 13、R 14独立地选自卤素、羟基、C1～C4烷基、C1～C4烷氧基，或者R 13和R 14成环为5～6元环氧基；
    更优选的，R 13、R 14独立地选自F、羟基、甲基、甲氧基，或者R 13和R 14成环5元环氧基。
  6. 如权利要求1或2所述的化合物，其特征在于，
    R 2选自
    Figure PCTCN2022106494-appb-100005
    Figure PCTCN2022106494-appb-100006
  7. 如权利要求1～6任一项所述的化合物，其特征在于，结构式如下：
    Figure PCTCN2022106494-appb-100007
    Figure PCTCN2022106494-appb-100008
    Figure PCTCN2022106494-appb-100009
  8. 药物组合物，由权利要求1～7任一项所述化合物或其药学上可接受的盐为活性成分，添加药学上可接受的辅助性成分组成。
  9. 权利要求1～7任一项所述化合物或其药学上可接受的盐、权利要求8所述的药物组合物在制备RIPK2抑制剂中的用途。
  10. 权利要求1～7任一项所述化合物或其药学上可接受的盐、权利要求8所述的药物组合物在制备治疗自体免疫疾病和/或过敏性病症药物中的用途。
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