WO2021104256A1 - 一种杂环衍生物、其药物组合物及用途 - Google Patents

一种杂环衍生物、其药物组合物及用途 Download PDF

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WO2021104256A1
WO2021104256A1 PCT/CN2020/131113 CN2020131113W WO2021104256A1 WO 2021104256 A1 WO2021104256 A1 WO 2021104256A1 CN 2020131113 W CN2020131113 W CN 2020131113W WO 2021104256 A1 WO2021104256 A1 WO 2021104256A1
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pyridyl
heterocyclic derivative
methoxy
halogen
alkyl
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PCT/CN2020/131113
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English (en)
French (fr)
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殷建明
吕裕斌
李邦良
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杭州华东医药集团新药研究院有限公司
杭州澳津生物医药技术有限公司
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Publication of WO2021104256A1 publication Critical patent/WO2021104256A1/zh

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    • 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
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention belongs to the field of medicinal chemistry, and relates to a heterocyclic derivative, its pharmaceutical composition and its use, in particular to a heterocyclic derivative, its pharmaceutical composition and its preparation, prevention and/or treatment and proton pump inhibitory effects Use in drugs that regulate related conditions or diseases.
  • Proton pumps are proteins that actively transport hydrogen ions to biological membranes.
  • the proton pump of the human stomach wall can secrete gastric acid to promote food digestion.
  • Disorders of gastric acid secretion can easily cause gastric mucosal ulcers, erosions, and even gastric bleeding.
  • Proton pump inhibitors can effectively inhibit gastric acid secretion, and are clinically the strongest and most effective class of drugs.
  • common clinical drugs of this type include omeprazole, esomeprazole and rabeprazole, vornorazan, etc.
  • the existing proton pump inhibitors have a short half-life, and are unstable and susceptible under acidic conditions. Drug properties that need to be improved, such as slow effect.
  • the purpose of the present invention is to overcome the defects in the prior art and provide a new type of proton pump inhibitor with long half-life and high efficiency.
  • the invention provides a heterocyclic derivative with a structure represented by the general formula I, II or III
  • M is selected from N atom or C atom
  • A is selected from a sulfone group or a sulfoxide group
  • X is selected from hydrogen or halogen
  • R 1 is selected to be 0, 1 or 2 substituents R a pyridyl group
  • R 2 is selected from pyridyl or phenyl substituted with 0, 1 or 2 R b;
  • R 3 is selected from C1-3 alkyl groups
  • R a is optionally selected from halogen, C1-3 alkyl or methoxy
  • R b is optionally selected from halogen, C1-3 alkyl or methoxy.
  • the heterocyclic derivative has a structure represented by formula I,
  • M is selected from N atom or C atom
  • A is selected from a sulfone group or a sulfoxide group
  • X is selected from hydrogen or halogen
  • R 1 is selected to be 0, 1 or 2 substituents R a pyridyl group
  • R 2 is selected from pyridyl or phenyl substituted with 0, 1 or 2 R b;
  • R 3 is selected from C1-3 alkyl groups
  • R a is optionally selected from halogen, C1-3 alkyl or methoxy
  • R b is optionally selected from halogen, C1-3 alkyl or methoxy.
  • R 1 is selected from 0, 1, or 2 R a substituted 1-pyridyl, 2-pyridyl or 3-pyridyl;
  • R 2 is selected from 0, 1 or 2 substituents R a 1-pyridyl, 2-pyridyl, 3-pyridyl or phenyl.
  • R 3 is selected from methyl or ethyl
  • R a is optionally selected from fluorine, chlorine, methyl or methoxy
  • R b is optionally selected from fluorine, chlorine, methyl or methoxy.
  • the R 1 is selected from
  • the R 2 is selected from:
  • the R 1 is selected from
  • the R 2 is selected from:
  • the heterocyclic derivative has a structure represented by formula II,
  • M is N atom
  • A is a sulfone group
  • R 1 is selected to be 0, 1 or 2 substituents R a pyridyl group
  • R 2 is selected from pyridyl or phenyl substituted with 0, 1 or 2 R b;
  • R 3 is selected from C1-3 alkyl groups
  • R a is optionally selected from halogen, C1-3 alkyl or methoxy
  • R b is optionally selected from halogen, C1-3 alkyl or methoxy.
  • the heterocyclic derivative has a structure represented by formula III,
  • A is selected from sulfone group
  • R 1 is selected to be 0, 1 or 2 substituents R a pyridyl group
  • R 2 is selected from pyridyl or phenyl substituted with 0, 1 or 2 R b;
  • R 3 is selected from C1-3 alkyl groups
  • R a is optionally selected from halogen, C1-3 alkyl or methoxy
  • R b is optionally selected from halogen, C1-3 alkyl or methoxy.
  • heterocyclic derivatives include:
  • heterocyclic derivatives of the present invention can be prepared by synthetic routes similar to those well-known in the chemical field, especially the compounds of the present invention are synthesized according to the description contained herein. Reagents are generally obtained from commercial sources or easily prepared using methods well known to those skilled in the art.
  • the present invention also provides a pharmaceutical composition, which contains the heterocyclic derivative and a pharmaceutically acceptable carrier.
  • the present invention also provides a use of the heterocyclic derivative in the preparation of a medicament for preventing and/or treating diseases or diseases related to the regulation of proton pump inhibition.
  • the diseases or diseases related to the regulation of proton pump inhibition include ulcers, esophagitis, gastritis, gastroesophageal reflux and Helicobacter pylori infection, gastric cancer, etc.
  • the indications related to the regulation of proton pump inhibition are Including other diseases related to the mechanism of proton pump inhibition.
  • the compound provided by the present invention is a novel heterocyclic derivative, which has a strong inhibitory effect on the proton pump, has a high ulcer inhibition rate, and has a long half-life. Therefore, the compounds of the present invention can be used to prepare drugs for the treatment or prevention of various indications related to the regulation of proton pump inhibition.
  • This embodiment provides a compound represented by formula I-1:
  • Step 1-2
  • This embodiment provides a compound represented by formula (II-1):
  • This embodiment provides a compound represented by formula (II-2):
  • This embodiment provides a compound represented by formula (III-1):
  • This embodiment provides a compound represented by formula (III-2):
  • This embodiment provides a compound represented by formula (III-3):
  • step 4-2 refers to steps 4-2 to 4-6 in Example 4, and replace the solvent in step 4-2 with acetonitrile to obtain a yellow solid compound (2-(2-fluorophenyl)-1-(pyridine) -3-ylsulfonyl)-1H-indol-5-yl)(methyl)tert-butyl carbamate (221 mg, 20.1%).
  • This embodiment provides a compound represented by formula (III-4):
  • Example 4 Using the intermediate (2-(2-fluorophenyl)-1H-indol-6-yl)(methyl) t-butyl carbamate of Example 5 as a raw material, refer to 4-6 and 4- in Example 4 Step 7 and replace pyridine-3-sulfonyl chloride with 6-chloropyridine-3-sulfonyl chloride to finally obtain 1-((6-chloropyridin-3-yl)sulfonyl)-2-(2-fluorobenzene Yl)-N-methyl-1H-indole-6-amine (90 mg, 80%), as a yellow-green solid.
  • test compound and 0.25 ⁇ g/mL enzyme were pre-incubated at 37°C for 15 minutes in a modified Bis-Tris-Acteate buffer pH 5.5. The reaction was initiated by adding 0.1 mM ATP for 60 minutes of incubation. A sample was taken to determine the amount of inorganic phosphate formed spectrophotometrically at 630 nm by the biomol green reagent. The IC50 value is determined by non-linear least squares regression analysis using MathIQTM (UK ID Business Solutions Ltd.).
  • the compound of the present invention has obvious inhibitory activity on H+/K+-ATPase.
  • HP- ⁇ -CD Hydroxypropyl- ⁇ -cyclodextrin
  • Solvent preparation DMSO, Solutol HS15, 20% HP- ⁇ -CD are mixed and prepared at a weight-volume ratio of 5:10:85.
  • Example 1 The compound of Example 1 was prepared at 20 mg/kg; 8 mg was dissolved in 4 mL of solvent to obtain a 2 mg/mL solution.
  • Example 1 Preparation of 10 mg/kg compound: Take 1 mL of the prepared 2 mg/mL solution and add 1 mL of solvent to obtain a 1 mg/mL solution.
  • mice After adaptive feeding, male ICR mice were randomly divided into 4 groups, namely: blank control group, model group, the compound of Example 1 (10mg/kg) intravenously administered group, and the compound of Example 1 (20mg/kg) orally administered Group: Except for the blank control group, which has 5 animals, the other groups have 10 animals. All animals were fasted without water for 24 hours, and the animals in each group were given the corresponding liquid medicine once. After 30 minutes of administration, the mice were given 0.15 mL of absolute ethanol orally. One hour later , the animals were killed by CO 2 inhalation. The pylorus was ligated, and 1 mL of 1% formaldehyde solution was injected into the stomach through the esophagus.
  • the cardia was ligated and the stomach was taken out. Put it in a 1% formaldehyde solution and fix it for 15 minutes. Cut along the greater curvature of the stomach, clean the stomach contents with normal saline, and calculate the ulcer index and ulcer inhibition rate after tiling.
  • Ulcer index If the length of the cord-like injury is greater than 1mm, measure the length and count 1 point per millimeter; if the width is greater than 1mm, double the score by the width in millimeters; if the length is less than 1mm, 0.5 points are counted, and the scores are added. Get the ulcer index of the animal.
  • Ulcer inhibition rate% (model group ulcer index-drug administration group ulcer index) / model group ulcer index ⁇ 100%
  • mice in the model group showed obvious damage in the stomach after 1 hour of administration of 0.15ml absolute ethanol, and the ulcer index was higher (P ⁇ 0.01 vs. blank control group), indicating that the mouse gastric ulcer model was successful.
  • the compound of Example 1 administered by tail vein injection at 10 mg/kg can significantly reduce the gastric ulcer index of mice (P ⁇ 0.01), and its ulcer inhibition rate is about 67%; oral administration of 20 mg/kg
  • the compound of Example 1 can also significantly reduce the gastric ulcer index of mice (P ⁇ 0.01), and its ulcer inhibition rate is as high as 85%.
  • mice weighing 21-25g, males, a total of 18; oral and intravenous injection each group of 9 each, a total of 3 for each collection point.
  • test product The compound of Example 1 was formulated into 2.5 mg/mL (for intravenous administration) and 2.0 mg/mL (for oral administration), and set aside.
  • Route of administration oral/intravenous injection.
  • Administration 1mL/kg (tail vein injection) or 5mL/kg (oral), single administration.
  • Sample collection Blood was collected at the following time points, 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr and 24hr after administration.
  • Sample analysis Use the LC-MS/MS method to detect the collected samples.
  • the instrument model used is UPLC-MS/MS-02 (Triple QuadTM 4000).
  • test results show that the compound of the present invention has good pharmacokinetic characteristics.

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Abstract

式I、式II、式III所示的新型杂环衍生物、含有其的药物组合物及在制备预防和/或治疗与质子泵抑制作用调节有关的适应症的药物中的用途。所述杂环衍生物药效强、半衰期长，是理想的高效质子泵抑制剂，可用于治疗或预防需要质子泵抑制作用调节的病症或疾病，例如溃疡、食管炎、胃炎、胃食管反流、幽门螺杆菌感染、胃癌等。

Description

一种杂环衍生物、其药物组合物及用途
本申请要求申请日为2019年11月25日，申请号为201911163438.0的中国发明专利申请的优先权。
技术领域
本发明属于药物化学领域，涉及一种杂环衍生物、其药物组合物及用途，具体涉及一种杂环衍生物、其药物组合物及其在制备预防和/或治疗与具有质子泵抑制作用调节有关的病症或疾病的药物中的用途。
背景技术
质子泵为生物膜主动运输氢离子的蛋白质。人胃壁质子泵可分泌胃酸以促进食物消化。胃酸分泌的失常易引发胃黏膜溃疡、糜烂，甚至胃出血。
质子泵抑制剂能够有效地抑制胃酸分泌，是临床上抑酸作用最强、疗效最好的一类药物。目前临床常见的本类药物有奥美拉唑、埃索美拉唑和雷贝拉唑、沃诺拉赞等，但现有的质子泵抑制剂具有半衰期短，在酸性条件下不稳定和起效慢等需要改进的药物属性。
发明内容
本发明的目的在于克服现有技术中的缺陷，提供一种新型的半衰期长、高效质子泵抑制剂。
本发明提供了一种具有通式I、II或III所示结构的杂环衍生物
Figure PCTCN2020131113-appb-000001
其中：
M选自N原子或C原子；
A选自砜基或亚砜基；
X选自氢或卤素；
R 1选自被0、1或2个R a取代的吡啶基；
R 2选自被0、1或2个R b取代的吡啶基或苯基；
R 3选自C1-3的烷基；
R a任选自卤素、C1-3的烷基或甲氧基；
R b任选自卤素、C1-3的烷基或甲氧基。
作为优选，所述的杂环衍生物具有式I所示结构，
Figure PCTCN2020131113-appb-000002
其中：
M选自N原子或C原子；
A选自砜基或亚砜基；
X选自氢或卤素；
R 1选自被0、1或2个R a取代的吡啶基；
R 2选自被0、1或2个R b取代的吡啶基或苯基；
R 3选自C1-3的烷基；
R a任选自卤素、C1-3的烷基或甲氧基；
R b任选自卤素、C1-3的烷基或甲氧基。
进一步优选：
所述R 1选自被0、1或2个R a取代的1-吡啶基、2-吡啶基或3-吡啶基；
所述R 2选自被0、1或2个R a取代的1-吡啶基、2-吡啶基、3-吡啶基或苯基。
进一步优选：
R 3选自甲基或乙基；
R a任选自氟、氯、甲基或甲氧基；
R b任选自氟、氯、甲基或甲氧基。
进一步优选：
所述R 1选自
Figure PCTCN2020131113-appb-000003
所述R 2选自:
Figure PCTCN2020131113-appb-000004
进一步优选：
所述R 1选自
Figure PCTCN2020131113-appb-000005
所述R 2选自:
Figure PCTCN2020131113-appb-000006
作为优选，所述的杂环衍生物具有式II所示结构，
Figure PCTCN2020131113-appb-000007
其中：
M是N原子；
A是砜基；
R 1选自被0、1或2个R a取代的吡啶基；
R 2选自被0、1或2个R b取代的吡啶基或苯基；
R 3选自C1-3的烷基；
R a任选自卤素、C1-3的烷基或甲氧基；
R b任选自卤素、C1-3的烷基或甲氧基。
作为优选，所述的杂环衍生物具有式III所示结构，
Figure PCTCN2020131113-appb-000008
其中：
A选自砜基；
R 1选自被0、1或2个R a取代的吡啶基；
R 2选自被0、1或2个R b取代的吡啶基或苯基；
R 3选自C1-3的烷基；
R a任选自卤素、C1-3的烷基或甲氧基；
R b任选自卤素、C1-3的烷基或甲氧基。
作为优选，所述的杂环衍生物包括：
Figure PCTCN2020131113-appb-000009
Figure PCTCN2020131113-appb-000010
Figure PCTCN2020131113-appb-000011
本发明杂环衍生物的制备可以通过化学领域众所周知的那些类似的方法的合成途径，特别是根据本文包含的描述合成本发明的化合物。试剂一般从商业来源获得或易于使用本领域技术人员众所周知的方法制备。
本发明还提供了一种药物组合物，含有所述的杂环衍生物和药学上可接受的载体。
本发明还提供了一种所述杂环衍生物在制备预防和/或治疗与具有质子泵抑制作用调节有关的病症或疾病的药物中的用途。
作为优选，所述与具有质子泵抑制作用调节有关的病症或疾病包括溃疡、食管炎、胃炎、胃食管反流和幽门螺杆菌感染、胃癌等，所述与质子泵抑制调节有关的适应症还包括其他和质子泵抑制机理相关的疾病。
本发明的技术方案与现有技术相比具有如下优点：
本发明提供的化合物是新型的杂环衍生物，其对质子泵具有强效的抑制作用，溃疡抑制率高，同时半衰期长。因此本发明化合物可用于制备治疗或预防各种与质子泵抑制调节有关的适应症的药物。
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明，但本发明并不限于以下实施例。
以下实施例中的某些物料若可通过市售获得，也可以直接以市售替代。
实施例1
本实施例提供一种式I-1表示的化合物：
Figure PCTCN2020131113-appb-000012
步骤1-1：
向3-溴吡啶(30g)的二氧六环溶液(300mL)中加入3-巯基丙酸-2-乙基己酯(43.46g)、三二亚苄基丙酮二钯(5.2g)、4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(4.39g)和N,N-二异丙基乙胺(73.5g)，然后再在氮气保护下于100℃下搅拌2小时。之后，冷却至室温，加入水(300mL)，用乙酸乙酯(150mL*3)萃取。收集合并有机层，用盐水(150mL)洗涤，经无水硫酸钠干燥，过滤并浓缩。浓缩后的残余物通过硅胶柱色谱法纯化，流动相为石油醚/乙酸乙酯(10/1-1/1)，得到呈黄色固体的3-(3-吡啶硫基)丙酸2-乙基己酯(49g，收率87％)。MS(ESI):m/z 296.3(M+H) +。
步骤1-2：
在-78℃下，向3-(3-吡啶硫基)丙酸2-乙基己酯(49g)的四氢呋喃(500mL)溶液中分批加入叔丁基醇钾(37.6g)，并保持温度搅拌1.5小时，然后温热至室温后过滤。将滤液浓缩后通过硅胶柱色谱法纯化，流动相为二氯甲烷/甲醇(30/1-2/1)，得到黄色固体状的3-吡啶硫醇(5.6g，收率30.4％)。MS(ESI):m/z 221.1(2M-H) +。
步骤1-3：
向1H-吡咯-3-羧酸甲酯(9g)的甲苯溶液中加入1-氟-2-碘苯(19g)，碘化亚铜(1.37g)，N 1,N 2-二甲基环己烷-1,2-二胺(1.02g)和碳酸钾(19.9g)，然后在氮气保护下于120℃搅拌反应16小时。之后冷却至室温并过滤。滤液浓缩后通过硅胶柱色谱法纯化，用石油醚/乙酸乙酯(10/1-6/1)洗脱，得到灰白色固体：1-(2-氟苯基)-1H-吡咯-3-甲酸甲酯(5.6g，35.5％收率)，为灰白色固体。MS(ESI):m/z 220.2(M+H) +。
步骤1-4：
向1-(2-氟苯基)-1H-吡咯-3-甲酸甲酯(4.6g)的二甲基甲酰胺(50mL)溶液中滴加N-碘代琥珀酰亚胺(4.73g)，滴加时间15min以上，滴加完毕后室温下搅拌反应72小时。然后加入乙酸乙酯(100mL)，并用盐水(60mL*3)洗涤。收集合并有机层，用无水硫酸钠干燥，然后过滤浓缩。浓缩物通过硅胶柱色谱法纯化，用石油醚/乙酸乙酯(100/1-12/1)洗脱，得到浅黄色油状的5-碘-1-(2-氟苯基)-1H-吡咯-3-甲酸甲酯(3.5g，48.3％产率)。MS(ESI):m/z 346.0(M+H) +。
步骤1-5：
向5-碘-1-(2-氟苯基)-1H-吡咯-3-甲酸甲酯(3.5g)在二氧六环(80mL)的溶液中加入3-吡啶硫醇(1.13g)、碘化亚铜(193mg)和磷酸钾(4.3g)，然后在氮气保护下于110℃搅拌反应16小时。之后冷却至室温并过滤，浓缩滤液。浓缩残余物通过硅胶柱色谱法纯化，用石油醚/乙酸乙酯(20/1-10/1)洗脱，得到无色油状的1-(2-氟苯基)-5-(3-吡啶硫基)-1H-吡咯-3-羧酸甲酯(0.5g，15％收率)。MS(ESI):m/z 329.1(M+H) +。
步骤1-6：
在0℃下，向1-(2-氟苯基)-5-(3-吡啶硫基)-1H-吡咯-3-羧酸甲酯(500mg)的无水四氢呋喃(20mL)溶液中滴加四氢锂铝(290mg)的溶液，滴加时间超过5分钟，然后保温搅拌反应1小时。然后依次加入水(0.29mL)和氢氧化钠溶液(15％，0.29mL)淬灭。淬灭后的溶液在0℃下搅拌5分钟，然后加入水(0.87mL)。在0℃下再搅拌30分钟后过滤，滤液经无水硫酸钠干燥后过滤浓缩，得到无色油状的(1-(2-氟苯基)-5-(吡啶-3-基硫基)-1H-吡咯-3-基)甲醇(320mg，70％收率)。MS(ESI):m/z 301.1(M+H) +。
步骤1-7：
向(1-(2-氟苯基)-5-(吡啶-3-基硫基)-1H-吡咯-3-基)甲醇(320mg)的二氯甲烷(10mL)溶液中加入二氯亚砜(254mg)，然后在室温下搅拌反应2h，之后浓缩得到浅黄色油状的3-((4-(氯甲基)-1-(2-氟苯基)-1H-吡咯-2-基)硫基)吡啶(280mg，82.5％收率)。MS(ESI):m/z 315.1(M-Cl+MeOH+H) +。
步骤1-8：
在室温下将3-((4-(氯甲基)-1-(2-氟苯基)-1H-吡咯-2-基)硫基)吡啶(280mg)加至甲胺/四氢呋喃(2N，10mL)的混合物中搅拌16小时。然后将混合物浓缩并并通过制备型薄层层析纯化(二氯甲烷/甲醇＝20/1)，得到1-(1-(2-氟苯基)-5-(吡啶-3-基硫基)-1H-吡咯-3-基)-N-甲基甲胺(200mg,72.6％产率)，为黄色固体。MS(ESI):m/z 314.2(M+H) +。
步骤1-9：
向1-(1-(2-氟苯基)-5-(吡啶-3-基硫基)-1H-吡咯-3-基)-N-甲基甲胺(200mg)的MeOH(10mL)和水(0.5mL)溶液中加入过氧化单硫酸钾盐(784mg)，然后在室温下搅拌4小时。之后加入饱和亚硫酸钠溶液(10mL)，并在室温下搅拌10分钟，然后用二氯甲烷/异丙醇(3/1，15mL*3)萃取。收集并合并有机层经无水硫酸钠干燥后，过滤浓缩，最后通过制备型薄层层析(DCM/MeOH＝20/1)纯化，得到1-(1-(2-氟苯基)-5-(吡啶-3-砜基)-1H-吡咯-3-基)-N-甲基甲胺(25mg，11％产率)，为灰白色固体。MS(ESI):m/z346.0(M+H) +。 1H NMR(400mHz,CDCl3)δ8.72(dd,J＝4.0Hz&1.6Hz,1H),8.57(d,J＝5.6Hz,1H),7.77～7.75(m,1H),7.48～7.46(m,1H),7.34(d,J＝1.6Hz,1H),7.34～7.30(m,2H),7.22(t,J＝6.4Hz,1H),7.04(t,J＝6.4Hz,1H),7.00(d,J＝1.6Hz,1H),3.81(s,2H),2.55(s,3H)ppm。
实施例2
本实施例提供一种式(II-1)表示的化合物：
Figure PCTCN2020131113-appb-000013
步骤2-1
向异氰基乙酸甲酯(10.0g)和2-氟苯甲酰氯(16.8g)的四氢呋喃(100mL)溶液中加入三乙胺(22.4g)和4-二甲氨基吡啶(1.23g)。然后将反应混合物在回流下搅拌过夜，之后停止反应并过滤。用乙酸乙酯(200ml)淋洗过滤物，收集合并有机相。用水和盐水洗涤有机相，并用无水硫酸镁干燥，之后过滤并真空浓缩，得到粗产物。通过硅胶柱色谱法(石油醚/乙酸乙酯＝5/1)纯化粗产物，得到为白色固体的化合物5-(2-氟苯基)噁唑-4甲酸甲酯(13g，收率：60％)。
步骤2-2
将5-(2-氟苯基)噁唑-4甲酸甲酯(13g)的浓盐酸/甲醇(26mL/78mL)的混合物 在50℃下搅拌反应4h。之后冷却至室温，然后减压除去甲醇。剩余物用乙醇洗涤并过滤。用乙酸乙酯/甲醇的混合溶液重结晶得到白色固体化合物2-氨基-3-(2-氟苯基)-3-氧代丙酸甲酯的盐酸盐(11g,产率:79％).
步骤2-3
将2-氨基-3-(2-氟苯基)-3-氧代丙酸甲酯的盐酸盐(11g)和硫氰化钾(5.2g)的混合物在水(22mL)中加热至80-90℃过夜。之后置于冰浴中冷却析晶，之后将析出的粗产物过滤收集,然后用乙醇洗涤粗产物得到白色固体化合物5-(2-氟苯基)-2-巯基-1H-咪唑-4甲酸甲酯(10g,产率:94％).
步骤2-4
在氩气氛围下，向5-(2-氟苯基)-2-巯基-1H-咪唑-4甲酸甲酯(10.0g),3-碘吡啶(12.2g)和磷酸钾(12.6g)的二甲基亚砜(80mL)溶液中加入碘化亚铜(377mg)，然后在100℃下反应4h。向反应液中加入乙酸乙酯(100mL)和水(50mL)。水相用乙酸乙酯多次萃取(100mL*3)，将有机相合并后用无水硫酸钠干燥浓缩。浓缩物用硅胶柱色谱纯化(PE:EA＝1:1)得到黄色油状化合物5-(2-氟苯基)-2-(吡啶-3-巯基)-1H-咪唑-4甲酸甲酯(7.0g,产率：54％)。
步骤2-5
0℃下，向5-(2-氟苯基)-2-(吡啶-3-巯基)-1H-咪唑-4甲酸甲酯(7.0g)的四氢呋喃(100mL)中加入氢化锂铝(4.04g)，并在室温下反应4h。反应物在0℃用十水硫酸钠淬灭，之后过滤浓缩得到黄色油状化合物5-(2-氟苯基)-2-(吡啶-3-巯基)-1H-咪唑-4-基甲醇(5.0g，产率:78％).
步骤2-6
在室温下向化合物5-(2-氟苯基)-2-(吡啶-3-巯基)-1H-咪唑-4-基甲醇(5.0g)的二氯甲烷(60mL)溶液中添加二氧化锰(14.5g)。将反应混合物在室温下搅拌反应16小时。过滤反应混合物，浓缩滤液，得到黄色固体状的5-(2-氟苯基)-2-(吡啶-3-巯基)-1H-咪唑-4-甲醛(3.5g，收率：70％)。
步骤2-7
在室温下，向5-(2-氟苯基)-2-(吡啶-3-巯基)-1H-咪唑-4-甲醛(3.5g)的甲醇(40mL)溶液中加入甲胺盐酸盐(1.19g)。将该反应液在室温下搅拌2小时，然后冷却至0℃，分批加入氰基硼氢化钠(1.47g)(缓慢加入)并在该温度下搅拌30分钟。向所得混合物 中加入水(5.00mL)并浓缩。浓缩残余物用乙酸乙酯(50×3mL)萃取。干燥有机层，并通过减压浓缩将其除去，并将残余物通过制备薄层色谱纯化(PE：EA＝1：1)，得到1-(5-(2-氟苯基)-2-(吡啶-3-基硫基)-1H-咪唑-4-基)-N-甲基甲胺，为黄色油状物(1.0g，收率：27％)。
步骤2-8
在室温下向化合物1-(5-(2-氟苯基)-2-(吡啶-3-基硫基)-1H-咪唑-4-基)-N-甲基甲胺(1.0g)在甲醇/水(10mL)的溶液中加入过氧单磺酸钾(3.26g)。将该溶液在室温搅拌过夜。向所得混合物中加入水(10mL)，并用二氯甲烷(50×3mL)萃取。将有机层干燥并在减压下除去，并将残余物通过制备型高效液相色谱纯化，得到1-(5-(2-氟苯基)-2-(吡啶-3-基砜基)-1H-咪唑-4-基)-N-甲基甲胺，为白色固体(21.24mg，产率：2％)。 1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.76(d,J＝3.6Hz,1H),8.24(d,J＝7.6Hz,1H),7.62-7.59(m,1H),7.52(t,J＝7.6Hz,1H),7.32(s,1H),7.25-7.20(m,2H),3.97(s,2H),2.52(s,3H).
实施例3
本实施例提供一种式(II-2)表示的化合物：
Figure PCTCN2020131113-appb-000014
参照实施例2的方法，将2-氟苯甲酰氯更换为2-甲氧基苯甲酰氯，得到化合物1-(5-(2-甲氧基苯基)-2-(吡啶-3-基砜基)-1H-咪唑-4-基)-N-甲基甲胺，为白色固体(21.24mg，产率：2％)。 1H NMR(400MHz,DMSO-d 6)δ9.03(d,J＝2.0Hz,1H),8.76(t,J＝1.2Hz,1H),8.26-8.23(m,1H),7.62-7.59(m,1H),7.37-7.27(m,2H),7.04(d,J＝8.0Hz,1H),6.96(t,J＝7.6Hz,1H),3.87(s,2H),3.74(s,3H),3.55-3.25(m,2H),2.50(s,3H).
实施例4
本实施例提供一种式(III-1)表示的化合物：
Figure PCTCN2020131113-appb-000015
步骤4-1
向2-甲基-3-硝基苯胺(3.04g)的二甲基甲酰胺(50mL)溶液中加入碘化钾(2.84g)和碳酸钾(5.52g)。将混合物在室温下搅拌12h，在氮气氛围下于60℃反应4小时。将混合物倒入水中，用乙酸乙酯萃取并真空浓缩，通过石油醚：乙酸乙酯＝70：30过柱纯化得到黄色固体N,2-二甲基-3-硝基苯胺(1.82g，55％)。
步骤4-2
向N,2-二甲基-3-硝基苯胺(2.16g)的四氢呋喃(100mL)溶液中加入二碳酸二叔丁酯(5.68g)，4-二甲氨基吡啶(3.18g)和三乙胺(3.95g)。将混合物在氮气下于65℃搅拌60小时。将混合物浓缩并通过通过石油醚：乙酸乙酯＝72∶28过柱纯化，得到黄色油状(2-甲基-3-硝基苯基)氨基甲酸叔丁酯(2.32g，67％)。
步骤4-3
向(2-甲基-3-硝基苯基)氨基甲酸叔丁酯(2.0g)在二甲基亚砜(15mL)中的溶液中添加2-氟苯甲醛(2.79g)和1,8-二氮杂二环十一碳-7-烯(10.27g)。将混合物在氮气气氛下于40℃搅拌3天。将混合物倒入水中，用乙酸乙酯萃取，经无水Na2SO4干燥，浓缩并通过柱纯化(石油醚：乙酸乙酯＝73：27)，得到黄色固体(2-(2-(2-(2-氟苯基)-2-羟乙基)-3-硝基苯基)(甲基)氨基甲酸叔丁酯(1.19g，40％)。
步骤4-4
向(2-(2-(2-(2-氟苯基)-2-羟乙基)-3-硝基苯基)(甲基)氨基甲酸叔丁酯(1.09g)在二氯甲烷(25mL)中的溶液中添加氯铬酸吡啶盐(1.81g)。将混合物在30℃下搅拌过夜。将反应混合物过滤并在减压下浓缩，通过过柱纯化(石油醚：乙酸乙酯＝65：35)，得到黄色油状(2-(2-(2-(2-氟苯基)-2-氧乙基)-3-硝基苯基)(甲基)氨基甲酸叔丁酯(1.08g， 97％)。
步骤4-5
向(2-(2-(2-(2-氟苯基)-2-氧乙基)-3-硝基苯基)(甲基)氨基甲酸叔丁酯(621mg)在甲酸(15mL)中的溶液中添加锌(1.05g)。将混合物在氮气气氛下于室温搅拌4h。将混合物过滤并减压浓缩，通过过柱纯化(石油醚：乙酸乙酯＝69：31)，得到灰色固体状(2-(2-氟苯基)-1H-吲哚-4-基)(甲基)氨基甲酸叔丁酯(470mg，86％)。
步骤4-6
将氢化钠(99mg)的无水二甲基甲酰胺(10mL)溶液预冷至0℃。然后加入(2-(2-氟苯基)-1H-吲哚-4-基)(甲基)氨基甲酸叔丁酯(470mg)和吡啶-3-磺酰氯(295mg)。将混合物在室温在氮气气氛下搅拌3小时。将水添加至粗混合物中，并用乙酸乙酯萃取，经无水硫酸钠干燥，浓缩并通过过柱纯化(石油醚：乙酸乙酯＝53：47)以得到黄色油状的(2-(2-氟苯基)-1-(吡啶-3-基砜基)-1H-吲哚-4-基)(甲基)氨基甲酸叔丁酯(358mg)。
步骤4-7
向(2-(2-氟苯基)-1-(吡啶-3-基磺酰基)-1H-吲哚-4-基)(甲基)氨基甲酸叔丁酯(350mg)的二氯甲烷(8mL)溶液中加入三氟乙酸(2mL)。将混合物在室温搅拌1小时。反应混合物用饱和碳酸钠水溶液、盐水洗涤，经无水硫酸钠干燥，浓缩并通过中压色谱纯化(75％)，得到黄色固体状2-(2-氟苯基)-N-甲基-1-(吡啶-3-基砜基)-1H-吲哚-4-胺(185mg，66％)。MS(ESI):m/z 381.9(M+H) +。 1H NMR(400MHz,MeOD)δ8.57(t,1H),8.48(d,1H),7.77-7.74(m,1H),7.50(d,J＝8.4hz 1H),7.30-7.41(m,3H),7.15-7.20(m,2H),7.12-7.07(m,1H),6.78(s,1H),6.44(d,J＝8hz 1H),2.76(s,3H)。
实施例5
本实施例提供一种式(III-2)表示的化合物：
Figure PCTCN2020131113-appb-000016
步骤5-1
向4-甲基-3-硝基苯胺(2.28g)的二氯甲烷(100mL)溶液中加入碳酸酐二叔丁酯(3.93g)和三乙胺(4.56g)。将混合物在45℃下搅拌过夜。将反应混合物在减压下浓缩并通过过柱纯化(石油醚：乙酸乙酯＝70：30)，得到黄色油状(4-甲基-3-硝基苯基)氨基甲酸叔丁酯(870mg，23％)。
步骤5-2
将氢化钠(300mg)的无水二甲基甲酰胺(15mL)溶液预冷至0℃，然后加入(4-甲基-3-硝基苯基)氨基甲酸叔丁酯(2.09g)和碘化钾(1.18mg)。将混合物在氮气气氛下在室温搅拌2h。将水添加到粗混合物中，并用乙酸乙酯萃取，用无水硫酸钠干燥，浓缩并通过过柱纯化(石油醚：乙酸乙酯＝75：25)以产生黄色油状甲基(4-甲基-3-硝基苯基)氨基甲酸叔丁酯(1.95g，88％)。
其余步骤参考实施例4中的步骤4-3至4-7，最终得到黄色固体状2-(2-氟苯基)-N-甲基-1-(吡啶-3-基砜基)-1H-吲哚-6-胺(110mg,87％)。MS(ESI):m/z 381.9(M+H) +。 1H NMR(400MHz,MeOD)δ8.63(t,1H),8.50(d,1H),7.82(d,J＝1.6Hz,1H),7.72-7.75(m,1H),7.42-7.39(m,2H),7.37-7.30(m,2H),7.20-7.16(m,1H),7.12-7.07(m,1H),6.98-6.95(m,1H),6.65(s,1H),2.94(s,3H)。
实施例6
本实施例提供一种式(III-3)表示的化合物：
Figure PCTCN2020131113-appb-000017
步骤6-1
向4-氟-2-甲基-1-硝基苯(5.0g)和甲胺盐酸盐(3.2g)的二甲基亚砜(10mL)溶液中添加碳酸钾(12g)。加完后，将反应混合物加热至100℃并搅拌过夜。然后将混合物冷却至室温，并用乙酸乙酯萃取，分离有机层，先后用水和盐水洗涤，用无水硫酸钠干 燥，浓缩，得到黄色油状的N,3-二甲基-4-硝基苯胺(4.8g，89.7％)。
接下来参照实施例4中的步骤4-2至4-6，并将步骤4-2中的溶剂更换为乙腈，得到黄色固体状化合物(2-(2-氟苯基)-1-(吡啶-3-基砜基)-1H-吲哚-5-基)(甲基)氨基甲酸叔丁酯(221mg,20.1％)。
步骤6-7
将(2-(2-氟苯基)-1-(吡啶-3-基砜基)-1H-吲哚-5-基)(甲基)氨基甲酸叔丁酯(100mg)和盐酸在乙醇中搅拌过夜。用碳酸钠将溶液的pH值调节至7，过滤后得到黄色固体2-(2-氟苯基)-N-甲基-1-(吡啶-3-基磺酰基)-1H-吲哚-5-胺(60mg，76.0％)。MS(ESI):m/z 382.1(M+H) +。 1H NMR(400MHz,MeOD)δ8.75(t,1H),8.52(d,1H),7.83(d,J＝9.2Hz,1H),7.75-7.72(m,1H),7.56-7.48(m,3H),7.35-7.31(m,2H),6.79(s,1H),6.73-6.70(m,1H),6.53(d,J＝2.4Hz,1H),5.77(d,J＝5.2Hz,1H),2.66(d,J＝5.2Hz,3H)。
实施例7
本实施例提供一种式(III-4)表示的化合物：
Figure PCTCN2020131113-appb-000018
使用实施例5的中间体(2-(2-氟苯基)-1H-吲哚-6-基)(甲基)氨基甲酸叔丁酯作为原料，参照实施例4中4-6与4-7的步骤，并将吡啶-3-磺酰氯更换为6-氯吡啶-3-磺酰氯，最终得到1-((6-氯吡啶-3-基)砜基)-2-(2-氟苯基)-N-甲基-1H-吲哚-6-胺(90mg,80％)，为黄绿色固体。MS(ESI):m/z 415.8(M+H) +。 1H NMR(400MHz,MeOD)δ8.31(d,J＝2.8Hz,1H),7.81(d,J＝1.6Hz,1H),7.67-7.65(m,1H),7.45-7.39(m,3H),7.36-7.32(m,1H),7.21-7.17(m,1H),7.13-7.08(m,1H),7.00-6.98(m,1H),6.69(s,1H),2.94(s,3H)。
药效试验
实验例1、H +/K +-ATPase生物学评价
使用猪胃H+/K+-ATPase。将测试化合物与0.25μg/mL酶在改良的Bis-Tris-Acteate缓冲液pH 5.5中于37℃预孵育15分钟。通过添加0.1mM ATP进行60分钟的孵育来引发反应。取样以测定通过biomol绿色试剂在630nm处分光光度法形成的无机磷酸盐的量。IC50值是使用MathIQTM(英国ID Business Solutions Ltd.)通过非线性最小二乘回归分析确定的。
表1：各化合物的IC50值
化合物 IC50(H+/K+-ATPase)(uM)
3010 ＞1.0
3011 ＞1.0
3012 ＞1.0
3013 ＞1.0
3024 ＞1.0
3025 ＞1.0
3033实施例1 0.064
本发明化合物对H+/K+-ATPase具有明显的抑制活性。
实验例2、胃溃疡小鼠溃疡指数及溃疡抑制率的影响
DMSO：二甲亚砜
Solutol HS15：15-羟基硬脂酸聚乙二醇酯
HP-β-CD：羟丙基-β-环糊精
1、药物配制：
溶剂配制：DMSO、Solutol HS15、20％HP-β-CD按重量体积比5：10：85混合配制。
实施例1化合物20mg/kg的配制；取8mg溶于4mL溶剂中得到2mg/mL的溶液。
实施例1化合物10mg/kg的配制：取1mL已配制的2mg/mL溶液加入1mL溶剂，得到1mg/mL的溶液。
2、分组、造模与治疗
雄性ICR小鼠适应性喂养后，随机分为4组，即：空白对照组、模型组、实施例1化合物(10mg/kg)静脉给药组、实施例1化合物(20mg/kg)口服给药组；除空白对照组为5只动物外，其它各组均为10只。所有动物禁食不禁水24h，各组动物单次给予相对应药液。给药30min后，小鼠经口灌胃给予0.15mL的无水乙醇，1h后CO 2过量吸入处死动物，结扎幽门，经食道向胃体内注入1％甲醛溶液1mL，结扎贲门，取出胃后即放入1％甲醛溶液中固定15min。沿胃大弯剪开，生理盐水清洗干净胃内容物，平铺后计算溃疡指数和溃疡 抑制率。
溃疡指数：条索状损伤长度大于1mm者，测量其长度，每毫米计1分；若其宽度大于1mm，将计分按宽度的毫米数加倍；长度小于1mm计0.5分，将计分相加得出该动物的溃疡指数。
溃疡抑制率％＝(模型组溃疡指数-给药组溃疡指数)/模型组溃疡指数×100％
3、试验结果
模型组小鼠在给予0.15ml无水乙醇1h后胃内出现明显的损伤，溃疡指数较高(P<0.01vs.空白对照组)，表明小鼠胃溃疡模型成功。
与模型组相比，尾静脉注射给予10mg/kg的实施例1化合物可明显降低小鼠胃溃疡指数(P<0.01)，其溃疡抑制率为约67％；经口灌胃给予20mg/kg的实施例1化合物亦可显著降低小鼠胃溃疡指数(P<0.01)，其溃疡抑制率高达85％。
表2.受试物对胃溃疡小鼠溃疡指数及溃疡抑制率的影响
Figure PCTCN2020131113-appb-000019
Figure PCTCN2020131113-appb-000020
*P<0.01vs模型组
实验例3、药物动力学实验
1、实验方法：
实验动物：CD1小鼠，体重21-25g，雄性，共18只；口服与静注每组各9只，每 个采集点共3只。
供试品配制：将实施例1化合物配制成2.5mg/mL(为静脉给药用)和2.0mg/mL(为口服给药用)，待用。
给药途径：口服/静脉注射。
给药：1mL/kg(尾静脉注射)或5mL/kg(口服)，单次给药。
样品采集：按照下列时间点采集血液，给药后5min、15min、30min、1hr、2hr、4hr、8hr和24hr取血。
2、样品分析及结果
样品分析：使用LC-MS/MS方法对采集样品进行检测。使用仪器型号为UPLC-MS/MS-02(Triple QuadTM 4000)。
药物动力学数据分析：使用WinNolin按照非房室模型法对所得血药浓度数据进行拟合和计算，部分结果总结在表3中。
表3 按照非房室模型法计算出的目标化合物药物动力学参数
Figure PCTCN2020131113-appb-000021
试验结果表明本发明化合物具有良好的药物动力学特征。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (12)

  1. 一种具有通式I、II或III所示结构的杂环衍生物，
    Figure PCTCN2020131113-appb-100001
    其中：
    M选自N原子或C原子；
    A选自砜基或亚砜基；
    X选自氢或卤素；
    R 1选自被0、1或2个R a取代的吡啶基；
    R 2选自被0、1或2个R b取代的吡啶基或苯基；
    R 3选自C1-3的烷基；
    R a任选自卤素、C1-3的烷基或甲氧基；
    R b任选自卤素、C1-3的烷基或甲氧基。
  2. 如权利要求1所述的杂环衍生物，其特征在于，具有式I所示结构，
    Figure PCTCN2020131113-appb-100002
    其中：
    M选自N原子或C原子；
    A选自砜基或亚砜基；
    X选自氢或卤素；
    R 1选自被0、1或2个R a取代的吡啶基；
    R 2选自被0、1或2个R b取代的吡啶基或苯基；
    R 3选自C1-3的烷基；
    R a任选自卤素、C1-3的烷基或甲氧基；
    R b任选自卤素、C1-3的烷基或甲氧基。
  3. 如权利要求2所述的杂环衍生物，其特征在于，
    所述R 1选自被0、1或2个R a取代的1-吡啶基、2-吡啶基或3-吡啶基；
    所述R 2选自被0、1或2个R a取代的1-吡啶基、2-吡啶基、3-吡啶基或苯基。
  4. 如权利要求3所述的杂环衍生物，其特征在于，
    R 3选自甲基或乙基；
    R a任选自氟、氯、甲基或甲氧基；
    R b任选自氟、氯、甲基或甲氧基。
  5. 如权利要求4所述的杂环衍生物，其特征在于，
    所述R 1选自
    Figure PCTCN2020131113-appb-100003
    所述R 2选自:
    Figure PCTCN2020131113-appb-100004
  6. 如权利要求5所述的杂环衍生物，其特征在于，
    所述R 1选自
    Figure PCTCN2020131113-appb-100005
    所述R 2选自:
    Figure PCTCN2020131113-appb-100006
  7. 如权利要求1所述的杂环衍生物，其特征在于，具有式II所示结构，
    Figure PCTCN2020131113-appb-100007
    其中：
    M是N原子；
    A是砜基；
    R 1选自被0、1或2个R a取代的吡啶基；
    R 2选自被0、1或2个R b取代的吡啶基或苯基；
    R 3选自C1-3的烷基；
    R a任选自卤素、C1-3的烷基或甲氧基；
    R b任选自卤素、C1-3的烷基或甲氧基。
  8. 如权利要求1所述的杂环衍生物，其特征在于，具有式III所示结构，
    Figure PCTCN2020131113-appb-100008
    其中：
    A选自砜基；
    R 1选自被0、1或2个R a取代的吡啶基；
    R 2选自被0、1或2个R b取代的吡啶基或苯基；
    R 3选自C1-3的烷基；
    R a任选自卤素、C1-3的烷基或甲氧基；
    R b任选自卤素、C1-3的烷基或甲氧基。
  9. 如权利要求1所述的杂环衍生物，其特征在于，包括：
    Figure PCTCN2020131113-appb-100009
    Figure PCTCN2020131113-appb-100010
    Figure PCTCN2020131113-appb-100011
  10. 一种药物组合物，含有如权利要求1～9任一所述杂环衍生物及药物上可接受的载体。
  11. 一种如权利要求1～9任一所述杂环衍生物或如权利要求10所述的药物组合物在制备预防和/或治疗与具有质子泵抑制作用调节有关的病症或疾病的药物中的用途。
  12. 根据权利要求11所述的用途，其特征在于：所述与具有质子泵抑制作用调节有关的病症或疾病包括溃疡、食管炎、胃炎、胃食管反流、幽门螺杆菌感染和胃癌。
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Publication number Priority date Publication date Assignee Title
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008108380A2 (en) * 2007-02-28 2008-09-12 Takeda Pharmaceutical Company Limited Pyrrole compounds
CN101300229A (zh) * 2005-08-30 2008-11-05 武田药品工业株式会社 作为胃酸分泌抑制剂的1-杂环基磺酰基、2-氨基甲基、5-(杂)芳基取代的1-h-吡咯衍生物
WO2009041705A2 (en) * 2007-09-28 2009-04-02 Takeda Pharmaceutical Company Limited 5-membered heterocyclic compounds as proton pump inhibitors
CN105330647A (zh) * 2014-08-14 2016-02-17 江苏柯菲平医药股份有限公司 吡咯磺酰类衍生物、其制备方法及其在医药上的应用
CN105367550A (zh) * 2014-08-11 2016-03-02 江苏柯菲平医药股份有限公司 四氢环戊二烯并[c]吡咯类衍生物、其制备方法及其在医药上的应用
CN105492423A (zh) * 2013-08-29 2016-04-13 株式会社大熊制药 四氢环戊并吡咯衍生物及用于制备其的方法
CN107875387A (zh) * 2016-09-29 2018-04-06 江苏柯菲平医药股份有限公司 一种含有吡咯磺酰类衍生物的复方药物及其用途
CN111943932A (zh) * 2020-08-06 2020-11-17 四川国康药业有限公司 一种可以治疗消化性溃疡的3-吡啶磺酰-1-n-杂吡咯衍生物及其制备方法和用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101300229A (zh) * 2005-08-30 2008-11-05 武田药品工业株式会社 作为胃酸分泌抑制剂的1-杂环基磺酰基、2-氨基甲基、5-(杂)芳基取代的1-h-吡咯衍生物
WO2008108380A2 (en) * 2007-02-28 2008-09-12 Takeda Pharmaceutical Company Limited Pyrrole compounds
WO2009041705A2 (en) * 2007-09-28 2009-04-02 Takeda Pharmaceutical Company Limited 5-membered heterocyclic compounds as proton pump inhibitors
CN105492423A (zh) * 2013-08-29 2016-04-13 株式会社大熊制药 四氢环戊并吡咯衍生物及用于制备其的方法
CN105367550A (zh) * 2014-08-11 2016-03-02 江苏柯菲平医药股份有限公司 四氢环戊二烯并[c]吡咯类衍生物、其制备方法及其在医药上的应用
CN105330647A (zh) * 2014-08-14 2016-02-17 江苏柯菲平医药股份有限公司 吡咯磺酰类衍生物、其制备方法及其在医药上的应用
CN107875387A (zh) * 2016-09-29 2018-04-06 江苏柯菲平医药股份有限公司 一种含有吡咯磺酰类衍生物的复方药物及其用途
CN111943932A (zh) * 2020-08-06 2020-11-17 四川国康药业有限公司 一种可以治疗消化性溃疡的3-吡啶磺酰-1-n-杂吡咯衍生物及其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NISHIDA HARUYUKI; FUJIMORI IKUO; ARIKAWA YASUYOSHI; HIRASE KEIZO; ONO KOJI; NAKAI KAZUO; INATOMI NOBUHIRO; HORI YASUNOBU; MATSUKAW: "Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 13, 27 April 2017 (2017-04-27), AMSTERDAM, NL, pages 3447 - 3460, XP085037327, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2017.04.034 *
YASUYOSHI ARIKAWA, NISHIDA HARUYUKI, KURASAWA OSAMU, HASUOKA ATSUSHI, HIRASE KEIZO, INATOMI NOBUHIRO, HORI YASUNOBU, MATSUKAWA JUN: "Discovery of a Novel Pyrrole Derivative 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1 H -pyrrol-3-yl]- N -methylmethanamine Fumarate (TAK-438) as a Potassium-Competitive Acid Blocker (P-CAB)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 55, no. 9, 10 May 2012 (2012-05-10), US, pages 4446 - 4456, XP055260738, ISSN: 0022-2623, DOI: 10.1021/jm300318t *

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