WO2021098715A1 - 一种吩噻嗪类铁死亡抑制剂及其制备方法和用途 - Google Patents

一种吩噻嗪类铁死亡抑制剂及其制备方法和用途 Download PDF

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WO2021098715A1
WO2021098715A1 PCT/CN2020/129707 CN2020129707W WO2021098715A1 WO 2021098715 A1 WO2021098715 A1 WO 2021098715A1 CN 2020129707 W CN2020129707 W CN 2020129707W WO 2021098715 A1 WO2021098715 A1 WO 2021098715A1
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alkyl
heterocyclic group
substituted
compound
membered saturated
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French (fr)
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杨胜勇
李琳丽
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成都恒昊投资有限公司
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Priority to CN202080080607.9A priority patent/CN115052867B/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the invention belongs to the technical field of chemically synthesized drugs, and specifically relates to a phenothiazine iron death inhibitor, and a preparation method and application thereof.
  • Ferroptosis is an atypical way of cell death.
  • the morphological characteristics of iron death are mainly manifested as the decrease of mitochondrial volume, the increase of mitochondrial membrane density, the decrease or disappearance of mitochondrial cristae, the rupture of the outer mitochondrial membrane, and the normal size of the nucleus. This is the difference between iron death and apoptosis, necrosis and autophagy
  • the biochemical characteristics of iron death mainly include the accumulation of iron and ROS in cells, the activation of the mitogen-activated protein kinase (MAPK) signaling system, the inhibition of the cystine/glutamate transporter system, and the increased oxidation of NADPH.
  • MAPK mitogen-activated protein kinase
  • iron death is related to degenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as pathological cell death such as tumor, stroke, ischemia-reperfusion injury and renal cell degeneration.
  • Ferrostatin The first generation of Ferrostatin is called Ferrostatin-1, which inhibits the formation of iron ions induced by Erastin- and RSL3 in HT1080 cells.
  • the activity of Ferrostain-1 mainly depends on aromatic amines, which specifically inhibit the accumulation of ROS caused by lipid oxidation.
  • the second generation (called SRS11-92) and the third generation of Ferrostatins (called SRS16-86) have better plasma stability and metabolic stability, and can significantly prevent tissue damage in vivo (E.g. acute kidney injury and ischemia reperfusion injury).
  • Liproxstatin-1 can prevent ROS accumulation and cell death in GPX4-/- cells. In addition, Liproxstatin-1 inhibits iron death induced by FINs. Liproxstatin-1 can also protect mice from liver damage caused by ischemia-reperfusion.
  • Zileuton is a specific inhibitor of 5-LOX oral activity. By inhibiting the production of cytosolic ROS, Zileuton provides significant protection of cells in HT22 cells (mouse hippocampal cell line) from the effects of increased iron ions induced by glutamate and ergotin.
  • the present invention provides a phenothiazine iron death inhibitor, and the present invention also provides its preparation method and application.
  • the present invention provides a compound represented by formula I, or a salt thereof, or a stereoisomer thereof:
  • X and Y are independently selected from CR 1 and N;
  • Z is selected from C, N;
  • the dotted line indicates that there is at least one unsaturated double bond in the A ring
  • R 1 is selected from hydrogen, C 1 ⁇ C 8 alkyl, halogen, hydroxyl, carboxy, nitro, amino, 3-8 membered saturated heterocyclic group;
  • Ring B is selected from 3-8 membered saturated heterocyclic groups and 3-8 membered unsaturated heterocyclic groups independently substituted by n R 2;
  • n is an integer selected from 0, 1, 2, 3 or 4;
  • R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 8 membered saturated heterocyclic group, and substituted 3 to 8 membered unsaturated cycloalkyl;
  • R 5 is selected from hydrogen, C 1 ⁇ C 8 alkyl
  • the substituent of the alkyl group is selected from substituted or unsubstituted 3-8 membered saturated heterocyclic group, 3-8 membered saturated cycloalkyl, -NR 6 R 7 , 3-10 membered unsaturated cycloalkyl, C 1 ⁇ C 8 alkoxy;
  • R 6 and R 7 are each independently selected from C 1 ⁇ C 8 alkyl groups
  • the substituent of the saturated heterocyclic group is selected from C 1 ⁇ C 8 alkyl, -C(O)OR 5 ;
  • the substituents of the unsaturated cycloalkyl group are selected from C 1 ⁇ C 8 alkyl groups, nitro groups, halogens, and hydroxyl groups;
  • the heteroatom of the heterocyclic group is selected from N, O and S.
  • X is selected from CR 1 , N;
  • R 1 is selected from hydrogen, C 1 ⁇ C 8 alkyl, halogen, hydroxyl, carboxy, nitro, amino, 3-8 membered saturated heterocyclic group;
  • Ring B is selected from 3-8 membered saturated heterocyclic groups or 3-8 membered unsaturated heterocyclic groups independently substituted by n R 2;
  • n is an integer selected from 0, 1, 2, 3 or 4;
  • R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1 to C 8 alkyl, 3 to 8 membered saturated heterocyclic group, and substituted 3 to 8 membered unsaturated cycloalkyl;
  • R 5 is independently selected from hydrogen, C 1 ⁇ C 8 alkyl
  • the substituent of the alkyl group is selected from substituted or unsubstituted 3-8 membered saturated heterocyclic group, 3-8 membered saturated cycloalkyl, -NR 6 R 7 , 3-10 membered unsaturated cycloalkyl, C 1 ⁇ C 8 alkoxy;
  • R 6 and R 7 are each independently selected from C 1 ⁇ C 8 alkyl groups
  • the substituent of the saturated heterocyclic group is selected from C 1 ⁇ C 8 alkyl, -C(O)OR 5 ;
  • the substituents of the unsaturated cycloalkyl group are selected from C 1 ⁇ C 8 alkyl groups, nitro groups, halogens, and hydroxyl groups;
  • the heteroatom of the heterocyclic group is selected from N, O and S.
  • X is selected from CR 1 , N;
  • R 1 is selected from hydrogen
  • Ring B is selected from a 5- to 6-membered saturated heterocyclic group or a 5- to 6-membered unsaturated heterocyclic group independently substituted by n R 2;
  • n is an integer from 0 to 3;
  • R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1 -C 2 alkyl, 3 to 6-membered saturated heterocyclic group, and substituted 3 to 6-membered unsaturated cycloalkyl;
  • R 5 is independently selected from hydrogen, C 1 ⁇ C 4 alkyl
  • the substituent of the alkyl group is selected from substituted or unsubstituted 3-6 membered saturated heterocyclic group, 4-5 membered saturated cycloalkyl, -NR 6 R 7 , 3-6 membered unsaturated cycloalkyl, C 1 ⁇ C 4 alkoxy;
  • R 6 and R 7 are each independently selected from C 1 ⁇ C 3 alkyl groups
  • the substituent of the saturated heterocyclic group is selected from C 1 -C 4 alkyl, -C(O)OR 5 ;
  • the substituents of the unsaturated cycloalkyl group are selected from C 1 ⁇ C 4 alkyl groups, nitro groups, halogens, and hydroxyl groups;
  • the heteroatom of the heterocyclic group is selected from N, O or S.
  • Ring B is selected from a 5- to 6-membered saturated heterocyclic group or a 5- to 6-membered unsaturated heterocyclic group independently substituted by n R 2;
  • n is an integer from 0 to 1;
  • Each R 2 is independently selected from substituted or unsubstituted C 1 ⁇ C 2 alkyl, halogen, amino, substituted or unsubstituted 4-6 membered saturated heterocyclic group;
  • the substituents of the alkyl group are selected from substituted or unsubstituted 4- to 6-membered saturated heterocyclic groups, 4- to 5-membered saturated cycloalkyls, and C 1 to C 3 alkoxy groups;
  • the substituent of the saturated heterocyclic group is selected from C 1 ⁇ C 2 alkyl, -C(O)OR 5 ;
  • R 5 is independently selected from hydrogen, C 1 ⁇ C 4 alkyl
  • the heteroatom of the heterocyclic group is selected from N, O or S.
  • Ring B is selected from a 5- to 6-membered saturated heterocyclic group or a 5- to 6-membered unsaturated heterocyclic group substituted by n R 2;
  • n is an integer selected from 0, 1, 2 or 3;
  • R 3 and R 4 are each independently selected from hydrogen, substituted C 1 -C 2 alkyl, and substituted aryl;
  • R 5 is independently selected from hydrogen, C 1 ⁇ C 2 alkyl
  • the substituent of the alkyl group is selected from substituted or unsubstituted 5-6 membered saturated heterocyclic group, 4-6 membered saturated cycloalkyl group, -NR 6 R 7 , aryl, naphthyl, C 1 ⁇ C 3 alkane Oxy;
  • R 6 and R 7 are each independently selected from C 1 ⁇ C 3 alkyl groups
  • the substituent of the saturated heterocyclic group is selected from C 1 ⁇ C 8 alkyl, -C(O)OR 5 ;
  • the substituents of the aryl group are selected from C 1 ⁇ C 2 alkyl groups and nitro groups;
  • the heteroatom of the heterocyclic group is selected from N, O or S.
  • R 1 is selected from hydrogen, 4-6 membered saturated heterocyclic group
  • R 3 and R 4 are each independently selected from hydrogen, substituted or unsubstituted C 1 -C 3 alkyl, 4 to 6-membered saturated heterocyclic group, and substituted 4- to 5-membered unsaturated cycloalkyl;
  • R 5 is selected from hydrogen, C 1 ⁇ C 4 alkyl
  • the substituent of the alkyl group is selected from substituted or unsubstituted 4-6 membered saturated heterocyclic group, 4-6 membered saturated cycloalkyl group, -NR 6 R 7 , aryl group, naphthyl group;
  • R 6 and R 7 are each independently selected from C 1 ⁇ C 2 alkyl groups
  • the substituent of the saturated heterocyclic group is selected from C 1 -C 4 alkyl, -C(O)OR 5 ;
  • the substituents of the unsaturated cycloalkyl group are selected from C 1 ⁇ C 4 alkyl groups, nitro groups, halogens, and hydroxyl groups;
  • the heteroatom of the heterocyclic group is selected from N, O and S.
  • the compound is one of the following compounds:
  • the present invention also provides the use of the aforementioned compound, its salt, or its stereoisomer in the preparation of an iron death inhibitor; the iron death inhibitor can be used as a targeted drug for inhibiting cell iron death.
  • the present invention also provides the aforementioned compounds, or salts thereof, or stereoisomers thereof in preparation for the treatment or prevention of neurodegenerative diseases, tumors, tissue ischemia-reperfusion injury, stroke, cardiovascular diseases, renal failure, Use in medicine for diabetic complications; preferably, the neurodegenerative disease is selected from Alzheimer's disease and Parkinson's disease.
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned compound, or a salt thereof, or a stereoisomer thereof as an active ingredient, and optionally a pharmaceutically acceptable auxiliary agent; preferably, the pharmaceutical composition It is in the form of oral preparations or intravenous preparations.
  • pharmaceutically acceptable adjuvant includes a pharmaceutically acceptable carrier or excipient.
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • substitution refers to the replacement of a hydrogen atom in a molecule by a different atom or group of atoms.
  • the structures of the compounds in the present invention all refer to structures that can exist stably.
  • the minimum and maximum content of carbon atoms in a hydrocarbon group are represented by prefixes.
  • the prefix (C a -C b ) alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, a C 1 -C 8 alkyl group refers to a straight or branched chain alkyl group containing 1 to 8 carbon atoms; a C 1 -C 8 alkoxy group refers to an alkoxy group containing 1 to 8 carbon atoms .
  • the alkyl group in the present invention is preferably a C 1 ⁇ C 8 alkyl group, more preferably a C 1 ⁇ C 6 alkyl group, particularly preferably a C 1 ⁇ C 4 alkyl group or a C 1 ⁇ C 2 alkyl group; similarly, the present invention
  • the alkoxy group in the invention is preferably a C 1 to C 8 alkoxy group, more preferably a C 1 to C 6 alkoxy group, and particularly preferably a C 1 to C 4 alkoxy group or a C 1 to C 2 alkoxy group.
  • 3 to 8 membered saturated cycloalkyl refers to a monocyclic or polycyclic cycloalkyl composed of 3 to 8 carbon atoms, wherein the cycloalkyl has no double bond;
  • 3 to 10 membered unsaturated cycloalkyl refers to a monocyclic or polycyclic cycloalkyl group consisting of 3-10 carbon atoms, wherein the cycloalkyl group contains one or more double bonds;
  • a 3- to 8-membered saturated heterocyclic group refers to a saturated heterocyclic group without double bonds A monocyclic heterocyclic group, wherein the heterocyclic group carries at least one nitrogen atom selected from O, S or substituted, and the remaining ring atoms are carbon;
  • a 3- to 8-membered unsaturated heterocyclic group refers to an unsaturated group containing a double bond A monocyclic heterocyclic group, wherein the heterocyclic ring carries at least one nitrogen atom selected from O, S or
  • halogen is fluorine, chlorine, bromine or iodine.
  • the invention synthesizes a new phenothiazine compound, which has a good inhibitory effect on iron death and can be used to prepare iron death inhibitors. It can also be used to prepare and treat neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, etc.; it can also be used to treat strokes, such as hemorrhagic stroke and ischemic stroke; in addition, it can also be used to treat tumors and tissues. Ischemia-reperfusion injury, cardiovascular disease, cerebrovascular disease, renal failure and diabetic complications and other diseases related to iron death; at the same time, the phenothiazine compound synthesized in the present invention has good cardiac safety and has broad market expectation.
  • Figure 1 shows the therapeutic effect of the compound of the present invention on ischemic stroke in SD rats in a rat middle cerebral artery embolism (MCAO) stroke model.
  • Figure A shows the anatomical photos of the rat brain after different treatments
  • Figure B shows the effect of different treatment groups on the volume of cerebral infarction (in Figure B, * means p ⁇ 0.05; *** means p ⁇ 0.001)
  • Figure C shows the neurological function score (Longa five-point neurological score value) under the intravenous injection of 5 mg/kg in different treatment groups.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained by purchasing commercially available products.
  • Ferroptosis screening model mainly uses MTT cell viability detection method. Firstly, the fibrosarcoma cell line is cultured in a dish, and the cells in the logarithmic growth phase are seeded in a 96-well plate (3000-10000 cells/well) in a specific number, 100 ⁇ L per well, and then placed in 37°C, 5% CO 2 Culture in an environmental incubator to allow the cells to adhere to the wall.
  • each compound After 24 hours, add 100 ⁇ L of a certain concentration of the compound prepared in the designated medium and the Ferroptosis inducer Erastin (final concentration 10 ⁇ M), each compound is set to 3 replicate wells to ensure the accuracy of the results, and a negative control group, Positive control group (Ferrostain-1 5 ⁇ M), blank control group and solvent control group. After adding the medicine, put it into the incubator and cultivate for 72h.
  • the EC 50 test was performed on the compound prepared in the example (the EC 50 test is the average of three tests, and Ferrostain-1 is the positive control group), and the results are shown in the following table:
  • the compound prepared by the present invention has a good inhibitory effect on Ferroptosis, especially compound 14 and compound 20.
  • the effect of inhibiting Ferroptosis is very excellent, which is significantly better than the positive drug Ferrostain-1. It can be used to prepare iron death inhibitors and Diseases related to iron death, such as neurodegeneration, tissue ischemia-reperfusion injury, stroke, cardiovascular, renal failure, and diabetic complications.
  • a rat middle cerebral artery occlusion (MCAO) stroke model (also known as a cerebral ischemia model) was established by the thread embolization method, and the compound of the present invention was used to study ischemic stroke in SD rats under multiple administrations The therapeutic effect.
  • MCAO middle cerebral artery occlusion
  • each group received intravenous injection within 30 minutes of plugging the middle cerebral artery with a suture and 2 hours after reperfusion, for a total of 2 administrations; the dosage of each group was 5 mg/kg.
  • middle cerebral artery embolization (middle cerebral artery occlusion, MCAO) stroke model (also known as cerebral ischemia model)
  • MCAO middle cerebral artery occlusion
  • the compound of the present invention was used to study the treatment of SD rats with different doses and single administration for ischemic stroke effect.
  • the test is divided into 6 groups, namely the model control group, the two administration groups of Example Compound 14 (low-dose group 2.5 mg/kg, high-dose group 5 mg/kg), and the two administration groups of comparative compound 1 (low dose group).
  • the dose group is 2.5 mg/kg
  • the high dose group is 5 mg/kg
  • the positive drug administration group butyphthalide, the dose is 5 mg/kg.
  • Each group was assigned 18 model animals, and within 10 minutes of reperfusion, compound 14, comparative compound 1, and positive drugs were administered via tail vein injection. After 24 hours of reperfusion, the animals were subjected to NSS scores to evaluate neurological function, and then the animals were dissected, brains were taken, and TTC stained.
  • the comparative compound 1 is the compound 38 of Example 2 in Chinese Patent Application Publication CN108484527A shown in the following formula,
  • the high and low dose administration groups of compound 14 and the high and low dose administration groups of control compound 1 can reduce the range of brain tissue lesions and necrosis, as shown in Table 2 below:
  • Table 2 The range of cerebral infarction and inhibition rate of cerebral infarction in experimental animals
  • the HEK293 cells stably expressing hERG ion channels were transferred to the perfusion tank and perfused with extracellular fluid at room temperature. Each cell used itself as a control. All test compounds were dissolved and dissolved by shaking with dimethyl sulfoxide, with concentration gradients of 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 10 ⁇ M, and 30 ⁇ M. All tested compounds were perfused with a perfusion system that utilizes its own gravity. At least two cells are tested at each concentration. After the current is stable (or 5 minutes), compare the current changes before and after the compound is used to calculate the blocking effect of the compound. The test electrode is drawn with PC-10. Whole-cell patch clamp recording, noise is filtered at one-fifth of the sampling frequency.
  • the cells were clamped at -80mV, and then depolarized to +60mV for 850ms with a square wave lasting 4 seconds, and then repolarized to -50mV for 1275ms to elicit the hERG tail current. This procedure is repeated every 15 seconds.
  • the hERG tail current is pure hERG current. After the current is stabilized, continuous extracellular perfusion administration is adopted from low concentration to high concentration. Start with a low concentration, continue to perfusion until the efficacy is stable, and then proceed to the next concentration of perfusion.
  • Stimulus delivery and signal acquisition are carried out through Patch Master software; the patch clamp amplifier amplifies the signal and filters it to 10KHz.
  • Use Fit Master, EXCEL, Graph pad Prism and SPSS 21.0 for further data analysis and curve fitting.
  • the peak value of the tail current and its baseline are corrected.
  • the wake inhibition rate is used to express the effect of each compound at different concentrations.
  • Inhibition rate % 100 ⁇ (peak tail current before administration-peak tail current after administration)/peak tail current before administration
  • the SD of the inhibition rate of each concentration of all cells is less than or equal to 15, as the acceptance criterion.
  • the IC 50 value is obtained by fitting the Hill equation:
  • Comparative compound 1 is CN108484527A's compound 38
  • comparative compound 2 is CN111574474A's compound 59
  • Terfenadine was withdrawn from the market by the FDA because of its severe effect on myocardial ion channels and delayed cardiac repolarization and other cardiac toxic side effects.
  • Cardiovascular and cerebrovascular diseases are chronic diseases and usually require life-long management and long-term medication. Therefore, in addition to the definite curative effect, the safety of this type of therapeutic drugs must reach a fairly high level in order to effectively ensure the safety of patients with long-term medication.
  • the main reasons for drug-induced cardiotoxicity include: blocking the heart's rapid delayed rectifier current (IKr), causing the QT interval to be prolonged during the cardiac action potential, and then inducing torsion de pointes (TdP), which can be severe in severe cases. Cause sudden death.
  • IKr rapid delayed rectifier current
  • TdP torsion de pointes
  • the significantly low hERG IC 50 value of a compound means a higher potential risk of cardiotoxicity; compounds with a sufficiently high hERG IC 50 value are considered to have sufficient cardiac safety.
  • the above results indicate that the compound of the present invention represented by compound 14 has no obvious effect on the human hERG ion channel that is stably expressed in HEK293 cells, and has good cardiac safety.
  • the cardiac safety data characterized by the hERG inhibitory concentration IC 50 value shows that compared with other structures, the compound of the present invention represented by compound 14 has significantly improved cardiac safety, for example, compared with the cardiac safety of comparative compound 1 (hERG The detected IC 50 value) is increased by about 100 or more, which is more than 50 times the cardiac safety of CN111574474A compound 59.
  • the present invention synthesizes a new phenothiazine compound, which has a good inhibitory effect on iron death and can be used to prepare iron death inhibitors. It can also be used to prepare medicines for the treatment of cardiovascular and cerebrovascular diseases represented by stroke, as well as neurodegenerative diseases, tumors, tissue ischemia-reperfusion injury, renal failure, diabetic complications and other diseases related to iron death; at the same time;
  • the compound of the present invention represented by compound 14 has very good druggability, such as better cardiac safety, solubility, and no hemolytic reaction, can be prepared as an injection, and has a broad market prospect.

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Abstract

一种吩噻嗪类铁死亡抑制剂及其制备方法和用途。具体提供了式I所示的化合物、或其盐、或其立体异构体。该合成的吩噻嗪类化合物对铁死亡有良好的抑制作用并且具有良好的用药安全性，可用于制备铁死亡抑制剂，也可以用于制备治疗神经退行性疾病、肿瘤、组织缺血再灌注损伤、脑卒中、心血管疾病、肾衰竭以及糖尿病并发症等与铁死亡相关的疾病的药物。

Description

一种吩噻嗪类铁死亡抑制剂及其制备方法和用途 技术领域
本发明属于化学合成药物技术领域，具体涉及一种吩噻嗪类铁死亡抑制剂及其制备方法和用途。
背景技术
铁死亡(Ferroptosis)是一种非典型的细胞死亡方式。铁死亡在形态学上的特征主要表现为线粒体体积变小，线粒体膜密度增加，线粒体嵴减少或消失，线粒体外膜破裂，而细胞核大小正常，这是铁死亡区别于凋亡、坏死和自噬的主要形态学特征。铁死亡的生化特点主要表现为细胞内铁和ROS的积累、丝裂原活化蛋白激酶(MAPK)信号传导系统的激活、胱氨酸/谷氨酸转运蛋白系统的抑制以及NADPH氧化增加等。
目前认为铁死亡与阿尔茨海默症、帕金森病等退行性疾病以及肿瘤、中风、缺血再灌注损伤和肾细胞变性等病理性细胞死亡相关。
目前，铁死亡小分子抑制剂大多数是抗氧化剂或铁螯合剂。现有技术中主要存在三种具有特定抗铁死亡活性的化合物：
Ferrostatin：第一代Ferrostatin被称为Ferrostatin-1，在HT1080细胞中起抑制Erastin-和RSL3诱导的铁离子形成的作用。Ferrostain-1的活性主要取决于芳香胺，其特异性抑制脂质氧化引起的ROS的积累。与Ferrostatin-1相比，第二代(称为SRS11-92)和第三代Ferrostatins(称为SRS16-86)具有更好的血浆稳定性和代谢稳定性，并且，在体内能够显著防止组织损伤(例如急性肾损伤和缺血再灌注损伤)。
Liproxstatin-1：Liproxstatin-1可以阻止GPX4-/-细胞中的ROS积累和细胞死亡。此外，Liproxstatin-1抑制FINs诱导的铁死亡。Liproxstatin-1也能保护小鼠免受缺血再灌注引起的肝损伤。
Zileuton：Zileuton是5-LOX的口服活性特异性抑制剂。Zileuton通过抑制细胞溶质ROS的产生，在HT22细胞(小鼠海马细胞系)中提供了显著的保护细胞免受谷氨酸盐和麦角菌素诱导的铁离子增多的影响的作用。
Figure PCTCN2020129707-appb-000001
尽管现有技术中已经报道了一些铁死亡抑制剂，但其活性并不高，成药性差。因此，现有技术中迫切需要一种具备更好活性且成药性良好的铁死亡抑制剂。如何制备得到一种活性较高，成药性好且能够作为治疗神经退行性、组织缺血再灌注损伤、脑卒中、心血管、肾衰竭以及糖尿病并发症等疾病药物的铁死亡抑制剂，是亟待解决的难题。
发明内容
为了解决上述问题，本发明提供了一种吩噻嗪类铁死亡抑制剂，本发明还提供了其制备方法和用途。
在第一个方面，本发明提供了式I所示的化合物、或其盐、或其立体异构体：
Figure PCTCN2020129707-appb-000002
其中，
X、Y分别独立选自CR 1、N；
Z选自C、N；
虚线表示A环中至少存在一个不饱和双键；
R 1选自氢、C 1～C 8烷基、卤素、羟基、羧基、硝基、氨基、3～8元饱和杂环基；
B环选自被n个R 2独立地取代的3～8元饱和杂环基和3～8元不饱和杂环基；
n为选自0、1、2、3或4的整数；
每个R 2分别独立选自取代或未取代的C 1～C 8烷基、卤素、羟基、羧基、氨基、硝基、取代或未取代的3～8元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
R 3、R 4分别独立选自氢、取代或未取代的C 1～C 8烷基、3～8元饱和杂环基、取代的3～8元不饱和环烷基；
R 5选自氢、C 1～C 8烷基；
所述烷基的取代基选自取代或未取代的3～8元饱和杂环基、3～8元饱和环烷基、-NR 6R 7、3～10元不饱和环烷基、C 1～C 8烷氧基；
R 6、R 7分别独立选自C 1～C 8烷基；
所述饱和杂环基的取代基选自C 1～C 8烷基、-C(O)OR 5；
所述不饱和环烷基的取代基选自C 1～C 8烷基、硝基、卤素、羟基；
所述杂环基的杂原子选自N、O和S。
进一步地，所述化合物为式II所示化合物：
Figure PCTCN2020129707-appb-000003
其中，
X选自CR 1、N；
R 1选自氢、C 1～C 8烷基、卤素、羟基、羧基、硝基、氨基、3～8元饱和杂环基；
B环选自被n个R 2独立地取代的3～8元饱和杂环基或3～8元不饱和杂环基；
n为选自0、1、2、3或4的整数；
每个R 2分别独立选自取代或未取代的C 1～C 8烷基、卤素、羟基、羧基、氨基、硝基、取代或未取代的3～8元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
R 3、R 4分别独立选自氢、取代或未取代的C 1～C 8烷基、3～8元饱和杂环基、取代的3～8元不饱和环烷基；
R 5独立选自氢、C 1～C 8烷基；
所述烷基的取代基选自取代或未取代的3～8元饱和杂环基、3～8元饱和环烷基、-NR 6R 7、3～10元不饱和环烷基、C 1～C 8烷氧基；
R 6、R 7分别独立选自C 1～C 8烷基；
所述饱和杂环基的取代基选自C 1～C 8烷基、-C(O)OR 5；
所述不饱和环烷基的取代基选自C 1～C 8烷基、硝基、卤素、羟基；
所述杂环基的杂原子选自N、O和S。
进一步地，
X选自CR 1、N；
R 1选自氢；
B环选自被n个R 2独立地取代的5～6元饱和杂环基或5～6元不饱和杂环基；
n为0～3的整数；
每个R 2分别独立选自取代或未取代的C 1～C 3烷基、卤素、氨基、取代或未取代的4～6元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
R 3、R 4分别独立选自氢、取代或未取代的C 1～C 2烷基、3～6元饱和杂环基、取代的3～6元不饱和环烷基；
R 5独立选自氢、C 1～C 4烷基；
所述烷基的取代基选自取代或未取代的3～6元饱和杂环基、4～5元饱和环烷基、-NR 6R 7、3～6元不饱和环烷基、C 1～C 4烷氧基；
R 6、R 7分别独立选自C 1～C 3烷基；
所述饱和杂环基的取代基选自C 1～C 4烷基、-C(O)OR 5；
所述不饱和环烷基的取代基选自C 1～C 4烷基、硝基、卤素、羟基；
所述杂环基的杂原子选自N、O或S。
进一步地，所述化合物为式III所示化合物：
Figure PCTCN2020129707-appb-000004
其中，
B环选自被n个R 2独立地取代的5～6元饱和杂环基或5～6元不饱和杂环基；
n为0～1的整数；
每个R 2分别独立选自取代或未取代的C 1～C 2烷基、卤素、氨基、取代或未取代的4～6元饱和杂环基；
所述烷基的取代基选自取代或未取代的4～6元饱和杂环基、4～5元饱和环烷基、C 1～C 3烷氧基；
所述饱和杂环基的取代基选自C 1～C 2烷基、-C(O)OR 5；
R 5独立选自氢、C 1～C 4烷基；
所述杂环基的杂原子选自N、O或S。
进一步地，所述化合物为式IV所示化合物：
Figure PCTCN2020129707-appb-000005
其中，
B环选自被n个R 2取代的5～6元饱和杂环基或5～6元不饱和杂环基；
n为选自0、1、2或3的整数；
每个R 2分别独立选自取代或未取代的C 1～C 3烷基、卤素、氨基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
R 3、R 4分别独立选自氢、取代的C 1～C 2烷基、取代的芳基；
R 5独立选自氢、C 1～C 2烷基；
所述烷基的取代基选自取代或未取代的5～6元饱和杂环基、4～6元饱和环烷基、-NR 6R 7、芳基、萘基、C 1～C 3烷氧基；
R 6、R 7分别独立选自C 1～C 3烷基；
所述饱和杂环基的取代基选自C 1～C 8烷基、-C(O)OR 5；
所述芳基的取代基选自C 1～C 2烷基、硝基；
所述杂环基的杂原子选自N、O或S。
进一步地，所述化合物为式V所示化合物：
Figure PCTCN2020129707-appb-000006
其中，
R 1选自氢、4～6元饱和杂环基；
R 2为无，或R 2选自取代或未取代的C 1～C 3烷基、卤素、取代或未取代的4～6元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
R 3、R 4分别独立选自氢、取代或未取代的C 1～C 3烷基、4～6元饱和杂环基、取代的4～5元不饱和环烷基；
R 5选自氢、C 1～C 4烷基；
所述烷基的取代基选自取代或未取代的4～6元饱和杂环基、4～6元饱和环烷基、-NR 6R 7、芳基、萘基；
R 6、R 7分别独立选自C 1～C 2烷基；
所述饱和杂环基的取代基选自C 1～C 4烷基、-C(O)OR 5；
所述不饱和环烷基的取代基选自C 1～C 4烷基、硝基、卤素、羟基；
所述杂环基的杂原子选自N、O和S。
进一步地，所述化合物为如下化合物之一：
Figure PCTCN2020129707-appb-000007
Figure PCTCN2020129707-appb-000008
本发明还提供了前述的化合物、或其盐、或其立体异构体在制备铁死亡 抑制剂中的用途；所述铁死亡抑制剂可以作为用于抑制细胞铁死亡的靶向药物。
本发明还提供了前述的化合物、或其盐、或其立体异构体在制备用于治疗或预防神经退行性疾病、肿瘤、组织缺血再灌注损伤、脑卒中、心血管疾病、肾衰竭、糖尿病并发症的药物中的用途；优选地，所述神经退行性疾病选自阿尔茨海默症和帕金森病。
本发明还提供了一种药物组合物，它包含前述的化合物、或其盐、或其立体异构作为活性成分，以及任选地药学上可接受的辅助剂；优选地，所述药物组合物为口服制剂或静脉注射制剂的形式。所述“药学上可接受的辅助剂”包括药学上可接受的载体或赋形剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或原子团所替换。
本发明中所述化合物的结构均是指能够稳定存在的结构。
本发明取代基“-C(O)NR 3R 4”的结构式为
Figure PCTCN2020129707-appb-000009
本发明取代基“-C(O)R 5”的结构式为
Figure PCTCN2020129707-appb-000010
本发明取代基“-C(O)OR 5”的结构式为
Figure PCTCN2020129707-appb-000011
本发明中碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(C a～C b)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C 1～C 8烷基是指包含1～8个碳原子的直链或支链烷基；C 1～C 8烷氧基是指包含1～8个碳原子的烷氧基。本发明中的烷基优选为C 1～C 8烷基，更优选为C 1～C 6烷基，特别优选为C 1～C 4烷基或C 1～C 2烷基；类似地，本发明中的烷氧基优 选为C 1～C 8烷氧基，更优选为C 1～C 6烷氧基，特别优选为C 1～C 4烷氧基或C 1～C 2烷氧基。
本发明中，3～8元饱和环烷基是指由3～8个碳原子组成的单环或多环环烷基，其中该环烷基中无双键；3～10元不饱和环烷基是指由3～10个碳原子组成的单环或多环环烷基，其中该环烷基中含有一个或多个双键；3～8元饱和杂环基是指没有双键的饱和的单环杂环基，其中该杂环基中携带至少一个选自O、S或取代的氮原子，其余环原子为碳；3～8元不饱和杂环基是指含有双键的不饱和的单环杂环基，其中该杂环中携带至少一个选自O、S或取代的氮原子，其余环原子为碳。
本发明中，卤素为氟、氯、溴或碘。
本发明合成了一种新的吩噻嗪类化合物，该类化合物对铁死亡有良好的抑制作用，可用于制备铁死亡抑制剂。也可以用于制备治疗神经退行性疾病,如阿尔兹海默症、帕金森病等；同时可用于治疗脑卒中，如出血性脑卒中、缺血性脑卒中；此外还可用于治疗肿瘤、组织缺血再灌注损伤、心血管疾病、脑血管疾病、肾衰竭以及糖尿病并发症等与铁死亡相关的疾病的药物；同时，本发明合成的吩噻嗪类化合物具备良好心脏安全性，具有广阔的市场前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
附图说明
图1显示本发明化合物在大鼠脑中动脉栓塞(MCAO)脑卒中模型中对SD大鼠缺血性脑卒中的治疗效果。其中，图A显示的是不同处理后的大鼠大脑解剖照片，图B是表明不同处理组对脑梗塞体积的影响(在图B中,*表示p<0.05；***表示p<0.001)，图C是表明不同处理组静脉注射5mg/kg剂量下的神经功能性评分(Longa五分法神经学评分值)。
以下通过实施例形式体现的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售 产品获得。
实施例1、2-(1-(1-(杂氮环丁烷-3-氨基)-1H吡唑[3,4-b]吡啶-5-基)乙烯基)-10H吩噻嗪(化合物1)的合成
1、(E)-N'-(1-(10H-吩噻嗪-2-基)亚乙基)-4-甲基苯磺酰肼(中间体I)的合成
中间体I的合成路线如下：
Figure PCTCN2020129707-appb-000012
2-乙酰基吩噻嗪(10.0g，41.44mmol，1.0eq)和4-甲基苯磺酰肼(7.72g，41.44mmol，1.0eq)用100mL MeOH溶解，加入1mL HOAc，移至60℃反应，TLC监控反应，约4h后反应完毕。冷却至室温，黄色固体出现，减压抽滤，用MeOH和乙醚洗至滤液无色，真空干燥即得中间体I(15g)，产率为88.4％。
2、中间体II的合成
中间体II的合成路线如下：
Figure PCTCN2020129707-appb-000013
中间体I(120mg，0.293mmol，1.2eq)，3-(5-溴-1H-吡唑啉[3,4-B]吡啶-1-基)壬二酸叔丁酯(86mg，0.244mmol，1.0eq),三(二亚苄-BASE丙酮)二钯(0)Pd 2(dpa) 3(24mg，0.03mmol，0.1eq)，2-二环己基磷-2,4,6-三异丙基联苯X-phos(25mg，0.03mmol，0.2eq)和无水t-BuOLi(43mg，0.537mmol，2.2eq)用10mL1,4-二氧六环溶解，置换氩气3次，移至70℃反应，TLC监控反应，约4h后反应完毕。冷却至室温，用硅藻土过滤，反应液减压浓缩，残余物用饱和NaHCO 3水溶液/DCM萃取，有机层浓缩后经柱层析分离得到中间体Ⅱ(91mg)，收率为55.3％。
3、化合物1的合成
化合物1的合成路线如下：
Figure PCTCN2020129707-appb-000014
91mg中间体Ⅱ加入2mL二氯甲烷，3mL三氟乙酸，常温下反应半小时后旋干，DCM溶解，以PE:EA＝1:1为展开剂，TLC纯化。分离得到目标产物化合物1(67mg)，收率为91.2％。
化合物1的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.61(s,1H),8.55(d,J＝1.8Hz,1H),8.38(s,1H),8.19(d,J＝1.8Hz,1H),6.95(dt,J＝15.5,7.4Hz,3H),6.79–6.71(m,2H),6.63(d,J＝7.7Hz,2H),6.04–5.97(m,1H),5.60(s,1H),5.51(s,1H),4.53(dd,J＝13.8,6.9Hz,4H),4.49–4.42(m,1H).
HRMS m/z(ESI)calcd for C 23H 19N 5S[M+H] + 398.1361 found:398.1363。
实施例2、化合物2的合成
Figure PCTCN2020129707-appb-000015
采用实施例1相似的合成方法，制备得到化合物2，收率为36.4％。
化合物2的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.54(t,J＝5.4Hz,2H),8.16(s,1H),8.11(s,1H),7.03–6.88(m,3H),6.86–6.69(m,2H),6.60(d,J＝9.1Hz,2H),5.57(s,1H),5.50(s,1H),4.38(d,J＝7.0Hz,2H),3.82(d,J＝9.1Hz,2H),3.25(t,J＝10.7Hz,2H),2.23(ddd,J＝10.9,7.6,3.9Hz,1H),1.38–1.20(m,4H).
HRMS m/z(ESI)calcd for C 26H 24N 4OS[M+H] + 441.1671 found:441.1673。
实施例3、化合物3的合成
Figure PCTCN2020129707-appb-000016
采用实施例1相似的合成方法，制备得到化合物3，收率为45.1％。
化合物3的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.58–8.47(m,2H),8.15(s,1H),8.10(d,J＝2.0Hz,1H),6.95(dt,J＝17.5,5.4Hz,3H),6.81(dd,J＝8.0,1.7Hz,1H),6.75(td,J＝7.6,1.1Hz,1H),6.60(dd,J＝10.4,1.4Hz,2H),5.57(s,1H),5.50(s,1H),4.39(d,J＝7.5Hz,2H),1.63–1.60(m,2H),1.51(td,J＝7.9,2.8Hz,2H),1.37–1.29(m,2H),1.24(d,J＝6.9Hz,2H),1.16(d,J＝6.7Hz,1H).
HRMS m/z(ESI)calcd for C 26H 24N 4S[M+H] + 425.1722 found:425.1725。
实施例4、化合物4的合成
Figure PCTCN2020129707-appb-000017
采用实施例1相似的合成方法，制备得到化合物4，收率为39.5％。
化合物4的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.57–8.49(m,2H),8.16(s,1H),8.11(d,J＝2.1Hz,1H),6.94(ddd,J＝10.4,8.2,1.1Hz,3H),6.83–6.72(m,2H),6.60(dd,J＝9.6,1.4Hz,2H),5.57(s,1H),5.50(s,1H),4.38(d,J＝7.0Hz,2H),3.91(d,J＝12.4Hz,2H),2.74–2.57(m,2H),2.17(ddd,J＝14.9,9.5,3.9Hz,1H),1.54–1.44(m,2H),1.39(d,J＝6.8Hz,9H),1.20–1.10(m,2H).
HRMS m/z(ESI)calcd for C 31H 33N 5O 2S[M+H] + 540.2355 found:540.2357。
实施例5、化合物5的合成
Figure PCTCN2020129707-appb-000018
采用实施例1相似的合成方法，制备得到化合物5，收率为52.1％。
化合物5的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ11.33(s,1H),8.55(s,1H),7.86(s,1H),7.47(s,1H),7.38(d,J＝8.5Hz,2H),7.11(dd,J＝19.7,11.2Hz,2H),6.97(d,J＝7.8 Hz,1H),6.91(d,J＝7.7Hz,2H),6.84–6.70(m,3H),6.61(d,J＝5.6Hz,2H),5.33(s,1H),5.32(s,1H),1.23(s,6H).
HRMS m/z(ESI)calcd for C31H24N4O3S[M+H]+ 533.1569 found:533.1571。
实施例6、化合物6的合成
Figure PCTCN2020129707-appb-000019
采用实施例1相似的合成方法，制备得到化合物6，收率为53.5％。
化合物6的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ11.61(s,1H),8.52(s,1H),8.41(t,J＝5.7Hz,1H),7.53(s,1H),7.40(t,J＝6.0Hz,1H),7.13(dd,J＝8.5,1.5Hz,1H),7.08(d,J＝1.2Hz,1H),6.99–6.88(m,3H),6.81–6.71(m,2H),6.63–6.56(m,2H),5.36(s,1H),5.35(s,1H),3.63–3.53(m,5H),3.44–3.39(m,2H),2.43(s,5H).
HRMS m/z(ESI)calcd for C 29H 28N 4O 2S[M+H] + 497.1933 found:497.1935。
实施例7、化合物7的合成
Figure PCTCN2020129707-appb-000020
采用实施例1相似的合成方法，制备得到化合物7，收率为54.2％。
化合物7的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.61(s,1H),7.97(d,J＝0.8Hz,1H),7.77(s,1H),7.52(d,J＝0.8Hz,1H),6.97(ddd,J＝19.1,11.7,4.0Hz,3H),6.85–6.73(m,2H),6.71(d,J＝1.6Hz,1H),6.66(d,J＝7.9Hz,1H),6.01(d,J＝2.0Hz,1H),5.32(d,J＝2.0Hz,1H),4.32–4.14(m,4H),3.85–3.68(m,4H).
HRMS m/z(ESI)calcd for C 24H 21N 5OS[M+H] + 428.1467 found:428.1469。
实施例8、化合物8的合成
Figure PCTCN2020129707-appb-000021
采用实施例1相似的合成方法，制备得到化合物8，收率为58.4％。
化合物8的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.52(d,J＝2.0Hz,2H),8.30(s,1H),8.16(d,J＝2.1Hz,1H),6.95(ddd,J＝17.8,8.8,1.2Hz,3H),6.80(dd,J＝8.0,1.8Hz,1H),6.75(td,J＝7.6,1.2Hz,1H),6.62–6.54(m,2H),5.82(tt,J＝8.1,5.5Hz,1H),5.60(s,1H),5.49(s,1H),4.39(dd,J＝30.0,21.9Hz,4H),1.43(s,9H).
HRMS m/z(ESI)calcd for C 28H 27N 5O 2S[M+H] + 498.1885 found:498.1887。
实施例9、化合物9的合成
Figure PCTCN2020129707-appb-000022
采用实施例1相似的合成方法，制备得到化合物9，收率为52.8％。
化合物9的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ11.48(s,1H),8.53(s,1H),8.10(d,J＝7.8Hz,1H),7.99(s,1H),7.79(s,1H),7.29(s,1H),7.13(d,J＝7.8Hz,1H),7.05–6.85(m,3H),6.85–6.70(m,2H),6.61(s,2H),5.42(s,1H),5.38(s,1H),3.58(s,4H),3.39(d,J＝5.2Hz,2H),2.45(d,J＝15.9Hz,6H).
HRMS m/z(ESI)calcd for C29H28N4O2S[M+H]+ 497.1933 found:497.1933。
实施例10、化合物10的合成
Figure PCTCN2020129707-appb-000023
采用实施例1相似的合成方法，制备得到化合物10，收率为55.1％。
化合物10的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ12.07(s,1H),9.95(s,1H),8.53(s,1H),8.31(s,1H),8.05(dd,J＝20.0,8.3Hz,1H),7.42–7.34(m,1H),7.24(d,J＝8.2Hz,1H),7.09–6.87(m,3H),6.81(dd,J＝7.9,1.4Hz,1H),6.75(t,J＝7.4Hz,1H),6.60(d,J＝7.4Hz,2H),5.44(s,2H).
HRMS m/z(ESI)calcd for C 23H 16N 2OS[M+H] + 369.0983 found:369.0985。
实施例11、化合物11的合成
Figure PCTCN2020129707-appb-000024
采用实施例1相似的合成方法，制备得到化合物11，收率为46.3％。
化合物11的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ10.64(s,1H),8.56(s,1H),7.23(d,J＝1.9Hz,1H),7.10(dd,J＝8.3,2.0Hz,1H),6.97(ddd,J＝7.9,4.2,1.4Hz,2H),6.91(d,J＝7.9Hz,2H),6.78–6.71(m,2H),6.62(dd,J＝7.9,0.8Hz,1H),6.57(d,J＝1.7Hz,1H),5.37(s,2H),3.48(s,2H).
HRMS m/z(ESI)calcd for C 22H 16N 2OS 2[M+H] + 389.0704 found:389.0706。
实施例12、化合物12的合成
Figure PCTCN2020129707-appb-000025
采用实施例1相似的合成方法，制备得到化合物12，收率为48.6％。
化合物12的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.56(s,1H),8.29(d,J＝8.7Hz,1H),7.80(s,2H),7.56(d,J＝1.6Hz,1H),7.40(dd,J＝8.6,1.7Hz,1H),7.04–6.88(m,3H),6.86–6.70(m,2H),6.61(dd,J＝9.6,1.2Hz,2H),5.63(s,1H),5.57(s,1H),4.36(q,J＝7.1Hz,2H),2.62(s,3H),1.36(t,J＝7.1Hz,3H).
HRMS m/z(ESI)calcd for C 27H 23N 3O 2S[M+H] + 454.1511 found:454.1513。
实施例13、化合物13的合成
Figure PCTCN2020129707-appb-000026
采用实施例1相似的合成方法，制备得到化合物13，收率为49.6％。
化合物13的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.56(s,1H),6.97(td,J＝7.8,1.4Hz,1H),6.94–6.88(m,2H),6.88–6.82(m,1H),6.77(d,J＝1.8Hz,2H),6.75(d,J＝2.0Hz,1H),6.72(d,J＝1.7Hz,1H),6.63(dd,J＝7.9,0.9Hz,1H),6.59(d,J＝1.7Hz,1H),5.31(s,2H),4.25(s,4H).
HRMS m/z(ESI)calcd for C 22H 17NO 2S[M+H] + 360.0980 found:360.0982。
实施例14、化合物14的合成
Figure PCTCN2020129707-appb-000027
采用实施例1相似的合成方法，制备得到化合物14，收率为52.6％。
化合物14的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.90(dd,J＝4.2,1.6Hz,1H),8.54(s,1H),8.40(d,J＝7.7Hz,1H),8.02(d,J＝8.7Hz,1H),7.90(d,J＝1.8Hz,1H),7.72(dd,J＝8.7,2.0Hz,1H),7.54(dd,J＝8.3,4.2Hz,1H),7.02–6.88(m,3H),6.83(dd,J＝7.9,1.8Hz,1H),6.75(td,J＝7.6,1.1Hz,1H),6.60(dd,J＝4.2,2.5Hz,2H),5.60(s,1H),5.58(s,1H).
HRMS m/z(ESI)calcd for C 23H 16N 2S[M+H] + 353.1034 found:353.1036。
实施例15、化合物15的合成
Figure PCTCN2020129707-appb-000028
采用实施例1相似的合成方法，制备得到化合物15，收率为51.3％。
化合物15的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.56(s,1H),7.39(dd,J＝12.2,5.0Hz,2H),7.11(dd,J＝8.3,1.5Hz,1H),6.97(dd,J＝10.9,4.3Hz,1H),6.92(dd,J＝7.4,3.7Hz,2H),6.78–6.72(m,2H),6.63(d,J＝7.8Hz,1H),6.56(d,J＝1.7Hz,1H),5.48(s,1H),5.43(s,1H).
HRMS m/z(ESI)calcd for C 21H 13F 2NO 2S[M+H] + 382.0635 found:382.0637。
实施例16、化合物16的合成
Figure PCTCN2020129707-appb-000029
采用实施例1相似的合成方法，制备得到化合物16，收率为49.4％。
化合物16的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.55(s,1H),8.01(d,J＝8.3Hz,1H),7.15(s,1H),7.09(d,J＝8.3Hz,1H),6.97(td,J＝7.7,1.4Hz,1H),6.93–6.87(m,2H),6.79–6.70(m,2H),6.63(dd,J＝7.9,0.9Hz,1H),6.58(d,J＝1.7Hz,1H),5.33(s,1H),5.33(s,1H),4.09(dd,J＝14.2,5.7Hz,2H),3.19–3.06(m,2H),2.16(s,3H).
HRMS m/z(ESI)calcd for C 24H 20N 2OS[M+H] + 385.1296 found:385.1298。
实施例17、化合物17的合成
Figure PCTCN2020129707-appb-000030
采用实施例1相似的合成方法，制备得到化合物17，收率为48.5％。
化合物17的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.56(s,1H),7.62(d,J＝1.5Hz,1H),7.16(s,1H),6.97(dd,J＝11.0,4.3Hz,1H),6.90(dd,J＝7.4,3.9Hz,2H),6.80–6.71(m,2H),6.61(dd,J＝12.1,4.5Hz,2H),6.53(s,1H),5.24(s,1H),5.19(s,1H),3.49(t,J＝8.4Hz,2H),2.96(t,J＝8.3Hz,2H).
HRMS m/z(ESI)calcd for C 21H 17N 3S[M+H] + 344.1143 found:344.1145。
实施例18、化合物18的合成
Figure PCTCN2020129707-appb-000031
采用实施例1相似的合成方法，制备得到化合物18，收率为50.9％。
化合物18的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.55(s,1H),8.29(s,1H),7.82(s,2H),7.68(d,J＝8.6Hz,1H),7.52(dd,J＝8.6,1.5Hz,1H),7.03–6.87(m,3H),6.78(ddd,J＝15.0,11.0,4.5Hz,2H),6.61(d,J＝8.5Hz,2H),5.56(s,1H),5.52(s,1H),4.36(q,J＝7.1Hz,2H),2.64(s,3H),1.35(t,J＝7.1Hz,3H).
HRMS m/z(ESI)calcd for C27H23N3O2S[M+H]+ 454.1511 found:454.1513。
实施例19、化合物19的合成
Figure PCTCN2020129707-appb-000032
采用实施例1相似的合成方法，制备得到化合物19，收率为49.9％。
化合物19的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.55–8.50(m,2H),8.20(s,1H),8.13(d,J＝2.0Hz,1H),7.00–6.89(m,3H),6.82(dd,J＝8.0,1.8Hz,1H),6.75(td,J＝7.6,1.0Hz,1H),6.64–6.55(m,2H),5.71–5.61(m,1H),5.59(s,1H),5.49(s,1H),4.13(ddd,J＝22.8,12.1,7.2Hz,2H),3.94(ddd,J＝14.3,6.2,3.9Hz,2H),2.49–2.38(m,2H).
HRMS m/z(ESI)calcd for C24H20N4OS[M+H]+ 413.1358 found:413.1360。
实施例20、化合物20的合成
Figure PCTCN2020129707-appb-000033
采用实施例1相似的合成方法，制备得到化合物20，收率为41.2％。
化合物20的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.60–8.41(m,2H),8.17(s,1H),8.11(d,J＝1.9Hz,1H),6.94(dt,J＝18.3,9.1Hz,3H),6.83(dd,J＝7.9,1.6Hz,1H),6.75(t,J＝7.5Hz,1H),6.58(dd,J＝7.3,4.8Hz,2H),5.58(s,1H),5.48(s,1H),4.80(ddd,J＝15.1,9.6,3.9Hz,1H),2.93(d,J＝10.8Hz,2H),2.25(s,3H),2.23–1.98(m,4H),1.90(d,J＝10.8Hz,2H).
HRMS m/z(ESI)calcd for C 26H 25N 5S[M+H] + 440.1831 found:440.1833。
实施例21、化合物21的合成
Figure PCTCN2020129707-appb-000034
采用实施例1相似的合成方法，制备得到化合物21，收率为46.5％。
化合物21的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.60–8.45(m,2H),8.14(s,1H),8.10(d,J＝2.0Hz,1H),7.01–6.89(m,3H),6.81(dd,J＝8.0,1.8Hz,1H),6.75(td,J＝7.6,1.1Hz,1H),6.65–6.53(m,2H),5.57(s,1H),5.49(s,1H),4.50(d,J＝7.2Hz,2H),2.89(dt,J＝15.1,7.5Hz,1H),1.97(dd,J＝8.2,6.5Hz,2H),1.90–1.78(m,4H).
HRMS m/z(ESI)calcd for C 25H 22N 4S[M+H] + 411.1565 found:411.1567。
实施例22、化合物22的合成
Figure PCTCN2020129707-appb-000035
采用实施例1相似的合成方法，制备得到化合物22，收率为47.5％。
化合物22的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ9.17(s,1H),8.64(s,1H),8.52(d,J＝1.4Hz,1H),8.48(s,1H),8.30(t,J＝5.7Hz,1H),6.97(ddd,J＝16.5,8.6,3.9Hz,3H),6.83(dd,J＝7.9,1.7Hz,1H),6.77(td,J＝7.5,1.1Hz,1H),6.70(d,J＝1.7Hz,1H),6.66(dd,J＝7.9,0.9Hz,1H),6.04(d,J＝1.3Hz,1H),5.51(d,J＝1.3Hz,1H),2.51(d,J＝1.6Hz,2H),2.42(t,J＝6.5Hz,2H),2.18(s,6H).
HRMS m/z(ESI)calcd for C 25H 24N 6OS[M+H] + 457.1732 found:457.1734。
实施例23、化合物23的合成
Figure PCTCN2020129707-appb-000036
采用实施例1相似的合成方法，制备得到化合物23，收率为50.4％。
化合物23的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.64(s,1H),8.53(d,J＝1.3Hz,1H),8.49(s,1H),8.44(d,J＝8.3Hz,1H),6.96(dd,J＝17.0,7.8Hz,3H),6.83(dd,J＝7.9,1.7Hz,1H),6.77(td,J＝7.6,1.1Hz,1H),6.70(d,J＝1.7Hz,1H),6.66(d,J＝7.9Hz,1H),6.04(d,J＝1.2Hz,1H),5.51(s,1H),4.08–3.97(m,1H),3.90–3.82(m,2H),3.43–3.36(m,2H),1.70(dd,J＝9.9,6.6Hz,4H).
HRMS m/z(ESI)calcd for C 26H 23N 5O 2S[M+H] + 470.1572 found:470.1574。
实施例24、化合物24的合成
Figure PCTCN2020129707-appb-000037
采用实施例1相似的合成方法，制备得到化合物24，收率为49.6％。
化合物24的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.58(dd,J＝12.7,6.5Hz,2H),8.53(d,J＝1.1Hz,1H),8.48(s,1H),7.06–6.90(m,3H),6.83(dd,J＝7.9,1.6Hz,1H),6.76(t,J＝7.5Hz,1H),6.67(dd,J＝16.2,4.7Hz,2H),6.04(s,1H),5.52(s,1H),3.83(dd,J＝11.3,2.4Hz,2H),3.30–3.13(m,4H),1.93–1.73(m,1H),1.57(d,J＝12.8Hz,2H),1.23(dd,J＝11.0,4.8Hz,2H).
HRMS m/z(ESI)calcd for C 27H 25N 5O 2S[M+H] + 484.1729 found:484.1731。
实施例25、化合物25的合成
Figure PCTCN2020129707-appb-000038
采用实施例1相似的合成方法，制备得到化合物25，收率为38.7％。
化合物25的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ9.16(s,1H),9.01(d,J＝8.4Hz,1H),8.64(s,1H),8.57–8.43(m,2H),8.24(d,J＝8.3Hz,1H),7.95(d,J＝7.9Hz,1H),7.83(d,J＝8.2Hz,1H),7.70(d,J＝7.0Hz,1H),7.61–7.46(m,3H),7.02–6.90(m,3H),6.82(dd,J＝7.9,1.7Hz,1H),6.76(td,J＝7.6,1.1Hz,1H),6.70(d,J＝1.7Hz,1H),6.66(d,J＝7.9Hz,1H),6.04(d,J＝1.3Hz,1H),5.98(dd,J＝14.9,7.2Hz,1H),5.51(d,J＝1.2Hz,1H),1.67(d,J＝6.9Hz,3H).
HRMS m/z(ESI)calcd for C33H25N5OS[M+H]+ 540.1780 found:540.1782。
实施例26、化合物26的合成
Figure PCTCN2020129707-appb-000039
采用实施例1相似的合成方法，制备得到化合物26，收率为57.9％。
化合物26的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ9.17(s,1H),8.85(d,J＝8.5Hz,1H),8.62(s,1H),8.52(d,J＝1.3Hz,1H),8.48(s,1H),7.43(d,J＝7.2Hz,2H),7.32(t,J＝7.5Hz,2H),7.22(t,J＝7.3Hz,1H),6.99(dd,J＝13.0,4.7Hz,2H),6.93(dd,J＝5.8,1.8Hz,1H),6.83(dd,J＝7.9,1.7Hz,1H),6.76(td,J＝7.6,1.1Hz,1H),6.69(d,J＝1.7Hz,1H),6.65(dd,J＝7.9,0.9Hz,1H),6.04(d,J＝1.3Hz,1H),5.51(d,J＝1.3Hz,1H),5.23–5.12(m,1H),1.52(d,J＝7.0Hz,3H).
HRMS m/z(ESI)calcd for C 29H 23N 5OS[M+H] + 490.1623 found:490.1625。
实施例27、化合物27的合成
Figure PCTCN2020129707-appb-000040
采用实施例1相似的合成方法，制备得到化合物27，收率为50.7％。
化合物27的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.59(s,1H),8.52(d,J＝1.9Hz,1H),8.17(s,1H),8.11(d,J＝1.9Hz,1H),7.02–6.88(m,3H),6.82(dd,J＝8.0,1.5Hz,1H),6.75(t,J＝7.5Hz,1H),6.67–6.52(m,2H),5.58(s,1H),5.49(s,1H),4.64(t,J＝5.4Hz,2H),3.86(t,J＝5.4Hz,2H),3.23(s,3H).
HRMS m/z(ESI)calcd for C 23H 20N 4OS[M+H] + 401.1358 found:401.1360。
实施例28、化合物28的合成
Figure PCTCN2020129707-appb-000041
采用实施例1相似的合成方法，制备得到化合物28，收率为53.8％。
化合物28的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.57(s,1H),8.52(d,J＝1.8Hz,1H),8.15(s,1H),8.12(d,J＝1.7Hz,1H),7.00–6.89(m,3H),6.80(d,J＝8.0Hz,1H),6.75(t,J＝7.5Hz,1H),6.60(dd,J＝10.3,4.7Hz,2H),5.58(s,1H),5.49(s,1H),4.09(s,3H).
HRMS m/z(ESI)calcd for C 21H 16N 4S[M+H] + 357.1096 found:357.1098。
实施例29、化合物29的合成
Figure PCTCN2020129707-appb-000042
采用实施例1相似的合成方法，制备得到化合物29，收率为36.9％。
化合物29的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.52(d,J＝12.1Hz,2H),8.18(s,1H),8.12(s,1H),6.99–6.89(m,3H),6.82(d,J＝7.9Hz,1H),6.75(t,J＝7.5Hz,1H),6.59(d,J＝11.5Hz,2H),5.59(s,1H),5.48(s,1H),5.07(td,J＝11.0,5.4Hz,1H),4.11(d,J＝11.5Hz,2H),3.04(s,2H),2.11–1.99(m,2H),1.95(d,J＝10.6Hz,2H),1.44(s,9H).
HRMS m/z(ESI)calcd for C30H31N5O2S[M+H]+ 526.2198 found:526.2200。
实施例30、化合物30的合成
Figure PCTCN2020129707-appb-000043
采用实施例1相似的合成方法，制备得到化合物30，收率为39.8％。
化合物30的 1H NMR和HRMS数据如下：
1H NMR(400MHz,MeOD)δ8.50(s,1H),8.17(s,1H),8.11(s,1H),6.94(t,J＝7.6Hz,1H),6.86(d,J＝7.8Hz,2H),6.78–6.68(m,2H),6.61–6.52(m,2H),5.88–5.78(m,1H),5.58(s,1H),5.46(s,1H),4.48(d,J＝6.5Hz,4H),1.50(s,9H).
HRMS m/z(ESI)calcd for C 28H 27N 5O 2S[M+H] + 498.1885 found:498.1887。
实施例31、化合物31的合成
Figure PCTCN2020129707-appb-000044
采用实施例1相似的合成方法，制备得到化合物31，收率为53.4％。
化合物31的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ13.71(s,1H),8.58–8.44(m,2H),8.13(dd,J＝16.0,1.4Hz,2H),7.00–6.89(m,3H),6.81(dd,J＝8.0,1.8Hz,1H),6.75(td,J＝7.6,1.1Hz,1H),6.59(dd,J＝9.0,4.8Hz,2H),5.56(s,1H),5.49(s,1H).
HRMS m/z(ESI)calcd for C 20H 14N 4S[M+H] + 343.0939 found:343.0941。
实施例32、化合物32的合成
Figure PCTCN2020129707-appb-000045
采用实施例1相似的合成方法，制备得到化合物32，收率为54.3％。
化合物32的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.52(d,J＝2.0Hz,2H),8.32(s,1H),8.16(d,J＝2.0Hz,1H),7.00–6.88(m,3H),6.82–6.71(m,2H),6.58(dd,J＝11.0,4.4 Hz,2H),6.22–6.13(m,1H),5.59(s,1H),5.49(s,1H),5.10(t,J＝6.4Hz,2H),5.07–5.02(m,2H),3.38(q,J＝7.0Hz,2H).
HRMS m/z(ESI)calcd for C 24H 20N 4OS[M+H] + 413.1358 found:413.1360。
实施例33、化合物33的合成
Figure PCTCN2020129707-appb-000046
采用实施例1相似的合成方法，制备得到化合物33，收率为53.6％。
化合物33的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.57–8.47(m,2H),8.15(s,1H),8.11(d,J＝2.1Hz,1H),6.99–6.90(m,3H),6.82(dd,J＝8.0,1.8Hz,1H),6.75(td,J＝7.6,1.0Hz,1H),6.62–6.54(m,2H),5.58(s,1H),5.49(s,1H),4.51(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H).
HRMS m/z(ESI)calcd for C 22H 18N 4S[M+H] + 371.1252 found:371.1255。
实施例34、化合物34的合成
Figure PCTCN2020129707-appb-000047
采用实施例1相似的合成方法，制备得到化合物34，收率为55.5％。
化合物34的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.51(s,1H),7.46(d,J＝1.2Hz,1H),7.42(d,J＝8.5Hz,1H),7.33(d,J＝3.1Hz,1H),7.10(dd,J＝8.5,1.6Hz,1H),6.96(td,J＝7.8,1.4Hz,1H),6.93–6.88(m,2H),6.81–6.71(m,2H),6.61(dd,J＝5.6,1.4Hz,2H),6.42(d,J＝2.5Hz,1H),5.34(s,2H),3.80(s,3H).
HRMS m/z(ESI)calcd for C 22H 17N 3S[M+H] + 356.1143 found:356.1145。
实施例35、化合物35的合成
Figure PCTCN2020129707-appb-000048
采用实施例1相似的合成方法，制备得到化合物35，收率为45.4％。
化合物35的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.00(d,J＝8.4Hz,1H),7.78(d,J＝5.5Hz,2H),7.47(dd,J＝7.5,3.6Hz,2H),7.34–7.30(m,1H),6.99–6.90(m,3H),6.82(dd,J＝7.9,1.8Hz,1H),6.74(td,J＝7.6,1.1Hz,1H),6.62–6.57(m,2H),5.49(s,1H),5.45(s,1H).
HRMS m/z(ESI)calcd for C 21H 14N 2S 2[M+H] + 359.0598 found:359.0600。
实施例36、化合物36的合成
Figure PCTCN2020129707-appb-000049
采用实施例1相似的合成方法，制备得到化合物36，收率为36.7％。
化合物36的 1H NMR和HRMS数据如下：
1H NMR(400MHz,DMSO)δ8.59(s,1H),8.51(d,J＝1.8Hz,1H),8.22(s,1H),8.15(s,1H),7.03–6.88(m,3H),6.83–6.71(m,2H),6.67–6.57(m,2H),5.59(s,1H),5.49(s,1H),5.30–5.13(m,1H),3.28–3.15(m,4H),2.38(ddd,J＝15.1,13.6,3.6Hz,2H),2.14(d,J＝12.0Hz,2H).
HRMS m/z(ESI)calcd for C 25H 23N 5S[M+H] + 426.1674 found:426.1676。
以下通过具体的试验例证明本发明的有益效果。
生物活性试验例1、本发明化合物对铁死亡的抑制率的研究
本实施例为了研究铁死亡的抑制剂，自主构建了铁死亡的筛选模型，具体如下：
Ferroptosis筛选模型主要是采用MTT细胞活力检测法。首先在皿中培养纤维肉瘤细胞株，将处于对数生长期的细胞按特定数量接种于96孔板中(3000-10000个/孔)，每孔100μL，然后放入37℃、5％CO 2环境的孵箱中培养，让细胞贴壁。24h后，加入100μL使用指定的培养基配制好的一定浓度的化合物和Ferroptosis诱导剂Erastin(终浓度10μM)，每个化合物设置3个复孔，以保证结果的准确性，并且设置阴性对照组、阳性对照组(Ferrostain-1 5μM)、空白对照组和溶剂对照组。加药之后放入孵箱，培养72h。并在MTT实验当 天预先配好MTT测试液(溶于生理盐水的5mg/mLMTT溶液，4℃避光保存)，每孔加入20μL MTT溶液，放入孵箱继续培养2-4h，然后，每孔加入50μL 20％SDS溶液(溶于MiliiQ水，加入1％的浓盐酸)，放入孵箱中过夜，第二天用酶标仪检测570nm处吸光度值，以计算药物对Ferroptosis的抑制率。一般对照组的吸光度值应在0.8-1.2之间为正常值。取得吸光度值数据之后，计算3个复孔的平均值，采用如下公式计算抑制率：
抑制率％(inhibition rate，IR)＝[1-(A 实验组-A 空白)/(A 溶剂-A 空白)]*100％
使用Graph Pad Prism 5软件拟合抑制率变化曲线并算出EC 50。
对实施例制备的化合物进行EC 50的测试(EC 50的测试取得是三次测试的平均值，Ferrostain-1为阳性对照组)，结果如下表所示：
表1 本发明化合物的EC 50值
化合物 EC 50(μM) 化合物 EC 50(μM)
2 0.038 4 0.076
6 0.015 7 0.024
8 0.055 9 0.012
10 0.015 11 0.033
13 0.037 14 0.006
15 0.010 16 0.010
17 0.089 19 0.013
20 0.0002 22 0.014
23 0.067 24 0.056
25 0.055 26 0.076
27 0.073 28 0.058
29 0.029 30 0.092
31 0.011 32 0.050
33 0.067 34 0.042
35 0.074 36 0.016
Ferrostain-1 0.060    
由表1可知：本发明制备的化合物对Ferroptosis具有良好的抑制作用，特别是化合物14和化合物20，抑制Ferroptosis的效果十分优异，显著优于 阳性药物Ferrostain-1，可用于制备铁死亡抑制剂以及和铁死亡相关的疾病，如神经退行性、组织缺血再灌注损伤、脑卒中、心血管、肾衰竭以及糖尿病并发症等。
生物活性试验例2
通过线栓法建立大鼠脑中动脉栓塞(middle cerebral artery occlusion，MCAO)脑卒中模型(也称脑缺血模型)，研究本发明化合物在多次给药下对SD大鼠缺血性脑卒中的治疗效果。
选择30只雄性SD大鼠，用体积分数4％-5％的恩氟烷诱导麻醉，1％-2％恩氟烷混合70％N2O和30％O2维持麻醉，通过线栓法堵塞大脑中动脉，造成大鼠缺血模型；缺血大鼠置于室温使其体温保持37℃；1.5h后拉出线栓进行再灌注。试验分3个组(每个随机分得10只SD大鼠)：分别为模型对照组(Vehicle)、样品组(给药本发明化合物14)、阳性药物组(给药Fer-1)。各组动物均用线栓堵塞大脑中动脉1.5h后拉出线栓进行再灌注，并于再灌注24h后对动物进行解剖。各组在用线栓堵塞大脑中动脉30min内和再灌注2h后分别进行1次静脉注射给药，共给药2次；各组给药剂量均为5mg/kg。术后1天解剖后TTC染色计算各组脑梗塞体积。脑梗塞体积＝脑梗塞面积％*脑体积。实验结果如附图1所示。
生物活性试验例3 本发明化合物在大鼠MCAO脑卒中模型的活性试验
1、试验方法
通过大鼠脑中动脉栓塞(middle cerebral artery occlusion，MCAO)脑卒中模型(也称脑缺血模型)，研究本发明化合物在不同剂量、单次给药对SD大鼠缺血性脑卒中的治疗效果。
选择雄性SD大鼠，经2～3.0％异氟烷麻醉诱导后，通过线栓法堵塞大脑中动脉，造成大鼠缺血模型；缺血大鼠置于室温使其体温保持37℃；90min后拉出线栓进行再灌注。
试验分6个组，分别为模型对照组、实施例化合物14的两个给药组(低剂量组2.5mg/kg、高剂量组5mg/kg)、对比化合物1的两个给药组(低剂量组2.5mg/kg、高剂量组5mg/kg)以及阳性药给药组(丁苯酞，给药剂量5mg/kg)。每组分配18只模型动物，于再灌注10min内，通过尾静脉注射 给予化合物14、对比化合物1及阳性药。再灌注24h后对动物进行NSS评分以评价神经功能，随后对动物解剖、取脑、进行TTC染色，通过测定脑梗死范围、计算抑制率，综合分析评估测试化合物对大鼠缺血性脑卒中的治疗效果。其中，所述对比化合物1为如下式所示的中国专利申请公开CN108484527A中的实施例2化合物38，
Figure PCTCN2020129707-appb-000050
(CN108484527A中化合物38)。
以梗塞组织重量占全脑重量的百分比作为梗塞范围(％)，并以梗塞范围计算各药物治疗组的抑制率(％)，抑制率计算公式如下：
Figure PCTCN2020129707-appb-000051
2、试验结果：
(1)脑梗塞范围和脑梗塞抑制率：
化合物14的高、低剂量给药组，以及对照化合物1的高、低剂量给药组均可减少脑组织病变坏死范围，详见下表2：
表2 实验动物脑梗塞范围和脑梗塞抑制率
Figure PCTCN2020129707-appb-000052
备注：“--”表示该项没有数据，*表示与模型对照组动物相比P<0.05。
生物活性试验例4 利用膜片钳测定本发明化合物对稳态表达于HEK293细 胞的人类hERG离子通道的作用
将hERG离子通道稳态表达HEK293细胞转移到灌流槽中，于室温下用细胞外液进行灌流，每个细胞以自身为对照。所有测试化合物均用二甲基亚砜振荡溶解溶解，配置为0.3μM、1μM、3μM、10μM、30μM的浓度梯度。受试化合物均采用利用自身重力的灌流系统进行灌流。每个浓度至少测试两个细胞。在电流稳定(或5分钟)后，再比较化合物使用前后的电流大小变化来计算化合物的阻断作用。测试电极用PC-10拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。将细胞钳制在–80mV，然后用持续4秒方波去极化到+60mV持续850ms，然后复极化至-50mV维持1275ms，引出hERG尾电流。这一程序每15秒重复一次。hERG尾电流是纯hERG电流。电流稳定后采用从低浓度到高浓度胞外连续灌流给药的方式。从低浓度开始，持续灌流至药效稳定，然后进行下一浓度的灌流。
通过Patch Master软件进行刺激发放及信号采集；膜片钳放大器放大信号，滤波为10KHz。使用Fit Master，EXCEL，Graph pad Prism和SPSS 21.0等进行进一步数据分析和曲线拟合。在数据处理中，判断对hERG的阻断效应时，将尾电流的峰值和其基线进行校正。用尾流的抑制率表示不同浓度下各化合物的作用。
抑制率％＝100×(给药前尾电流峰值-给药后尾电流峰值)/给药前尾电流峰值
所有细胞各个浓度的抑制率的SD≤15，作为可接受标准。
IC 50数值由Hill方程进行拟合所得：
Figure PCTCN2020129707-appb-000053
测试结果
Figure PCTCN2020129707-appb-000054
Figure PCTCN2020129707-appb-000055
注：对比化合物1为CN108484527A的化合物38，对比化合物2为CN111574474A的化合物59；Terfenadine(特非那丁)因严重影响心肌离子通道导致的延迟心脏复极等心脏毒副作用而被FDA撤市。
心脑血管疾病属于慢性病，通常需要终生管理，长期用药，因此除了疗效确切之外，这一类的治疗药物的安全性必须达到相当高的水平，才能有效保障患者长期用药的安全。
药物引起心脏毒性的主要原因包括:阻断心脏的快速延迟整流电流(IKr),造成心脏动作电位时程中QT间期延长,进而诱发尖端扭转性室性心动过速(TdP),严重时可引起突然死亡。
在药物开发领域，化合物的明显低的hERG IC 50值意味着具有较高的心脏毒性的潜在风险；具有足够高的hERG IC 50值的化合物才被认为有足够的心脏安全性。
上述结果表明，以化合物14代表的本发明化合物对稳态表达于HEK293细胞的人类hERG离子通道无明显作用，具有良好的心脏安全性。以hERG抑制浓度IC 50值为表征的心脏安全性数据说明，与其他结构相比，以化合物14为代表的本发明化合物具有显著提高的心脏安全性，如较对比化合物1的心脏安全性(hERG检测的IC 50值)提高约100以上，较CN111574474A化合物59的心脏安全性提高约50倍以上。
综上，本发明合成了一种新的吩噻嗪类化合物，该类化合物对铁死亡有良好的抑制作用，可用于制备铁死亡抑制剂。也可以用于制备治疗以脑卒中为代表的心脑血管疾病，以及神经退行性疾病、肿瘤、组织缺血再灌注损伤、、肾衰竭以及糖尿病并发症等与铁死亡相关的疾病的药物；同时，以化合物14为代表的本发明化合物具有非常好的成药性，如具有更好的心脏安全性、溶解性，以及无溶血反应，可制备为注射剂，具有广阔的市场前景。

Claims (10)

  1. 式I所示的化合物、或其盐、或其立体异构体：
    Figure PCTCN2020129707-appb-100001
    其中，
    X、Y分别独立选自CR 1、N；
    Z选自C、N；
    虚线表示A环中至少存在一个不饱和双键；
    R 1选自氢、C 1～C 8烷基、卤素、羟基、羧基、硝基、氨基、3～8元饱和杂环基；
    B环选自被n个R 2独立地取代的3～8元饱和杂环基或3～8元不饱和杂环基；
    n为0～4的整数；
    每个R 2分别独立选自取代或未取代的C 1～C 8烷基、卤素、羟基、羧基、氨基、硝基、取代或未取代的3～8元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
    R 3、R 4分别独立选自氢、取代或未取代的C 1～C 8烷基、3～8元饱和杂环基、取代的3～8元不饱和环烷基；
    R 5选自氢、C 1～C 8烷基；
    所述烷基的取代基选自取代或未取代的3～8元饱和杂环基、3～8元饱和环烷基、-NR 6R 7、3～10元不饱和环烷基、C 1～C 8烷氧基；
    R 6、R 7分别独立选自C 1～C 8烷基；
    所述饱和杂环基的取代基选自C 1～C 8烷基、-C(O)OR 5；
    所述不饱和环烷基的取代基选自C 1～C 8烷基、硝基、卤素、羟基；
    所述杂环基的杂原子选自N、O和S。
  2. 根据权利要求1所述的化合物、或其盐、或其立体异构体，其特征在于：所述化合物为式II所示的化合物、或其盐、或其立体异构体：
    Figure PCTCN2020129707-appb-100002
    其中，
    X选自CR 1、N；
    R 1选自氢、C 1～C 8烷基、卤素、羟基、羧基、硝基、氨基、3～8元饱和杂环基；
    B环选自被n个R 2取代的3～8元饱和杂环基或3～8元不饱和杂环基；
    n为0～4的整数；
    每个R 2分别独立选自取代或未取代的C 1～C 8烷基、卤素、羟基、羧基、氨基、硝基、取代或未取代的3～8元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
    R 3、R 4分别独立选自氢、取代或未取代的C 1～C 8烷基、3～8元饱和杂环基、取代的3～8元不饱和环烷基；
    R 5独立选自氢、C 1～C 8烷基；
    所述烷基的取代基选自取代或未取代的3～8元饱和杂环基、3～8元饱和环烷基、-NR 6R 7、3～10元不饱和环烷基、C 1～C 8烷氧基；
    R 6、R 7分别独立选自C 1～C 8烷基；
    所述饱和杂环基的取代基选自C 1～C 8烷基、-C(O)OR 5；
    所述不饱和环烷基的取代基选自C 1～C 8烷基、硝基、卤素、羟基；
    所述杂环基的杂原子选自N、O和S。
  3. 根据权利要求1或2所述的化合物、或其盐、或其立体异构体，其特征在于：
    X选自CR 1、N；
    R 1选自氢；
    B环选自被n个R 2独立地取代的5～6元饱和杂环基或5～6元不饱和杂环基；
    n为0～3的整数；
    每个R 2分别独立选自取代或未取代的C 1～C 3烷基、卤素、氨基、取代或未取代的4～6元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
    R 3、R 4分别独立选自氢、取代或未取代的C 1～C 2烷基、3～6元饱和杂环基、取代的3～6元不饱和环烷基；
    R 5独立选自氢、C 1～C 4烷基；
    所述烷基的取代基选自取代或未取代的3～6元饱和杂环基、4～5元饱和环烷基、-NR 6R 7、3～6元不饱和环烷基、C 1～C 4烷氧基；
    R 6、R 7分别独立选自C 1～C 3烷基；
    所述饱和杂环基的取代基选自C 1～C 4烷基、-C(O)OR 5；
    所述不饱和环烷基的取代基选自C 1～C 4烷基、硝基、卤素、羟基；
    所述杂环基的杂原子选自N、O或S。
  4. 根据权利要求1至3中任一项所述的化合物、或其盐、或其立体异构体，其特征在于：所述化合物为式III所示的化合物、或其盐、或其立体异构体：
    Figure PCTCN2020129707-appb-100003
    其中，
    B环选自被n个R 2取代的5～6元饱和杂环基或5～6元不饱和杂环基；
    n为0～1的整数；
    每个R 2分别独立选自取代或未取代的C 1～C 2烷基、卤素、氨基、取代或未取代的4～6元饱和杂环基；
    所述烷基的取代基选自取代或未取代的4～6元饱和杂环基、4～5元饱和环烷基、C 1～C 3烷氧基；
    所述饱和杂环基的取代基选自C 1～C 2烷基、-C(O)OR 5；
    R 5独立选自氢、C 1～C 4烷基；
    所述杂环基的杂原子选自N、O和S。
  5. 根据权利要求1至3中任一项所述的化合物、或其盐、或其立体异构体，其特征在于：所述化合物为式IV所示的化合物、或其盐、或其立体异构体：
    Figure PCTCN2020129707-appb-100004
    其中，
    B环选自被n个R 2独立地取代的5～6元饱和杂环基或5～6元不饱和杂环基；
    n为0～3的整数；
    每个R 2分别独立选自取代或未取代的C 1～C 3烷基、卤素、氨基、 -C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
    R 3、R 4分别独立选自氢、取代的C 1～C 2烷基、取代的芳基；
    R 5独立选自氢、C 1～C 2烷基；
    所述烷基的取代基选自取代或未取代的5～6元饱和杂环基、4～6元饱和环烷基、-NR 6R 7、芳基、萘基、C 1～C 3烷氧基；
    R 6、R 7分别独立选自C 1～C 3烷基；
    所述饱和杂环基的取代基选自C 1～C 8烷基、-C(O)OR 5；
    所述芳基的取代基选自C 1～C 2烷基、硝基；
    所述杂环基的杂原子选自N、O和S。
  6. 根据权利要求1所述的化合物、或其盐、或其立体异构体，其特征在于：所述化合物为式V所示：
    Figure PCTCN2020129707-appb-100005
    其中，
    R 1选自氢、4～6元饱和杂环基；
    R 2为无，或R 2选自取代或未取代的C 1～C 3烷基、卤素、取代或未取代的4～6元饱和杂环基、-C(O)NR 3R 4、-C(O)R 5或-C(O)OR 5；或同一个碳原子上的两个R 2组成＝O；
    R 3、R 4分别独立选自氢、取代或未取代的C 1～C 3烷基、4～6元饱和杂环基、取代的4～5元不饱和环烷基；
    R 5选自氢、C 1～C 4烷基；
    所述烷基的取代基选自取代或未取代的4～6元饱和杂环基、4～6元饱和环烷基、-NR 6R 7、芳基、萘基；
    R 6、R 7分别独立选自C 1～C 2烷基；
    所述饱和杂环基的取代基选自C 1～C 4烷基、-C(O)OR 5；
    所述不饱和环烷基的取代基选自C 1～C 4烷基、硝基、卤素、羟基；
    所述杂环基的杂原子选自N、O或S。
  7. 根据权利要求1～6任一项所述的化合物、或其盐、或其立体异构体，其特征在于：所述化合物为如下化合物之一、或其盐、或其立体异构体：
    Figure PCTCN2020129707-appb-100006
    Figure PCTCN2020129707-appb-100007
  8. 权利要求1～7任一项所述的化合物、或其盐、或其立体异构体在制备铁死亡抑制剂中的用途。
  9. 权利要求1～7任一项所述的化合物、或其盐、或其立体异构体在制备治疗或预防神经退行性疾病、肿瘤、组织缺血再灌注损伤、脑卒中、心血管疾病、脑血管疾病、肾衰竭、糖尿病并发症的药物中的用途；优选地，所述神经退行性疾病为阿尔茨海默症、帕金森病。
  10. 一种药物组合物，其包含权利要求1～7任一项所述的化合物、或其盐、或其立体异构作为活性成分，以及任选的药学上可接受的辅助剂；优选地，所述药物组合物为口服制剂或静脉注射制剂的形式。
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