2, 8-disubstituted quinoline macrocyclic compound and application thereof

Abstract

The invention provides a 2, 8-disubstituted quinoline macrocyclic compound with a structure as shown in a formula I or a pharmaceutically acceptable salt or a stereoisomer thereof, and a preparation method and application of the 2, 8-disubstituted quinoline macrocyclic compound. Compared with a 2, 8-disubstituted quinazoline lead compound, the 2, 8-disubstituted quinoline macrocyclic compound disclosed by the invention has better PDGFR alphaD842V kinase inhibition activity and anti-tumor effect, also has better inhibition effect on PDGFR alphaD842V / G680R mutant kinase and PDGFR alphaG680R mutant kinase, shows very strong anti-proliferative activity in corresponding Ba / F3-PDGFR alpha stable strain cells, and can be used for preparing anti-tumor drugs. The compound can play a good role in inhibiting tumor cells, and can be used for preparing drugs for preventing or treating PDGFRalpha kinase mediated diseases (such as tumors). # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry and relates to anti-tumor drug compounds, in particular to 2,8-disubstituted quinoline macrocyclic compounds and uses thereof. Background Art

[0002] As an important member of the type III receptor tyrosine kinase family, PDGFRα kinase is widely expressed in mesenchymal cells such as fibroblasts, peripheral cells, and vascular smooth muscle cells, and drives the migration and proliferation of these cells. Studies have shown that PDGFR and its ligands may be involved in the occurrence and development of tumors, and related gene mutations have been detected in hematological tumors, gliomas, and soft tissue tumors. Under normal circumstances, after PDGFRα binds to the PDGF ligand, it will trigger receptor dimerization and phosphorylation, thereby initiating downstream signaling pathways and regulating cell growth. However, in patients with gastrointestinal stromal tumors (GISTs), PDGFRα gene mutations allow the receptor to be continuously phosphorylated without the need for ligands, thereby activating multiple signaling pathways including SRC / RAC1 / JNK, PI3K / AKT / mTOR, and RAS / RAF / MEK / MAPK, ultimately leading to abnormal proliferation of tumor cells.

[0003] In the clinical treatment of gastrointestinal stromal tumors, four lines of drugs have been developed. Among them, imatinib, sunitinib and regorafenib are the first three lines of drugs, which are multi-target kinase inhibitors, but they are not effective for tumors carrying PDGFRα. D842V Patients with mutated GISTs show drug resistance. Ripretinib, as a fourth-line drug, has alleviated the clinical drug resistance problem of some GISTs patients to a certain extent. Afatinib is currently the only drug targeting PDGFRα D842V However, its clinical application is limited by neurocognitive side effects and acquired resistance mutations in solvent front and gatekeeper residues in some patients after medication, resulting in limited treatment options for patients. Summary of the invention

[0004] Based on this, the present invention provides a 2,8-disubstituted quinoline macrocyclic compound, which has a D842V Mutated PDGFRα kinases have strong inhibitory activity and can be used to prepare drugs for preventing or treating diseases (such as tumors) mediated by PDGFRα kinase.

[0005] The present invention includes the following technical solutions.

[0006] In the first aspect, the present invention provides a 2,8-disubstituted quinoline macrocyclic compound having a structure as shown in Formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0007]

[0008] Among them, R is selected from: 5- to 8-membered heterocyclic groups;

[0009] n is selected from: 1, 2, 3, 4, 5, 6.

[0010] Further preferably, R is selected from: 5- to 8-membered saturated heterocyclic groups.

[0011] Further preferably, R is selected from: 5- to 8-membered heterocyclic groups with heteroatoms being N.

[0012] Further preferably, R is selected from: 5- to 8-membered heterocyclic groups with 2 heteroatoms being N.

[0013] Further preferably, R is selected from: 6-membered heterocyclic groups with 2 heteroatoms being N, 7-membered heterocyclic groups with 2 heteroatoms being N.

[0014] Further preferably, R is selected from the following groups:

[0015]

[0016] Further preferably, the 2,8-disubstituted quinoline macrocyclic compounds are selected from the following compounds:

[0017]

[0018] In a second aspect, the present invention provides the use of the 2,8-disubstituted quinoline macrocyclic compounds or their pharmaceutically acceptable salts or their stereoisomers, including the following:

[0019] The present invention provides the use of the 2,8-disubstituted quinoline macrocyclic compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of PDGFRα kinase inhibitors; wherein, the PDGFRα kinase can be wild-type PDGFRα kinase or mutant PDGFRα kinase, preferably PDGFRα kinase with D842V mutation and / or G680R mutation.

[0020] Further preferably, the present invention provides the use of the 2,8-disubstituted quinoline macrocyclic compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of PDGFRα G680R kinase inhibitors.

[0021] Further preferably, the present invention provides the use of the 2,8-disubstituted quinoline macrocyclic compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of PDGFRα D842V / G680R kinase inhibitors.

[0022] The present invention also provides the use of the 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a drug for treating and / or preventing a disease caused by abnormal expression of PDGFRα kinase, preferably PDGFRα D842V mutation, PDGFRα G680R mutation or PDGFRα D842V / G680R mutation-mediated diseases.

[0023] The present invention also provides the use of the 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a drug for treating and / or preventing tumors.

[0024] Further preferably, the tumor is a tumor caused by abnormal expression of PDGFRα kinase.

[0025] Further preferably, the tumor is a tumor carrying PDGFRα D842V mutation, PDGFRα G680R mutation or PDGFRα D842V / G680R mutation.

[0026] Further preferably, the tumor is gastric cancer, preferably gastric cancer caused by abnormal expression of PDGFRα kinase, more preferably gastric cancer carrying PDGFRα D842V mutation, PDGFRα G680R mutation or PDGFRα D842V / G680R mutation.

[0027] Further preferably, the tumor is gastrointestinal stromal tumor, preferably gastrointestinal stromal tumor caused by abnormal expression of PDGFRα kinase, more preferably gastrointestinal stromal tumor carrying PDGFRα D842V mutation, PDGFRα G680R mutation or PDGFRα D842V / G680R mutation.

[0028] In a third aspect, the present invention provides an anti-tumor pharmaceutical composition prepared from an active ingredient and a pharmaceutically acceptable excipient, wherein the active ingredient comprises the 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the present invention.

[0029] Based on the 2,8-disubstituted quinazoline lead compound (i.e., compound 5 in the examples), through the transition of the parent nucleus and the replacement of the substituted part of the piperidine ring, the present invention finally optimizes to obtain a new 2,8-disubstituted quinoline macrocyclic compound that can more effectively target PDGFRα D842V protein and the downstream signaling pathway, and can overcome PDGFRα D842V mutation resistance.

[0030] The 2,8-disubstituted quinoline macrocyclic compounds of the present invention have better PDGFRα D842V kinase inhibitory activity and anti-tumor effect than the 2,8-disubstituted quinazoline lead compounds, and also have good inhibitory effects on PDGFRα D842V / G680R mutant kinases and PDGFRα G680R mutant kinases. They show strong anti-proliferative activity in the corresponding Ba / F3-PDGFRα stable cell lines, can exert a good inhibitory effect on tumor cells, and can be used to prepare drugs for preventing or treating diseases (such as tumors) mediated by PDGFRα kinase, and can be used to treat tumors (especially gastrointestinal stromal tumors) of humans and other mammals. Detailed implementation manners

[0031] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, these embodiments are provided to make the understanding of the disclosed content of the present invention more thorough and comprehensive.

[0032] For the experimental methods without specific conditions noted in the following examples, they are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. All kinds of commonly used chemical reagents used in the examples are commercially available products.

[0033] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not used to limit the present invention. The term "and / or" used in the present invention includes any and all combinations of one or more of the related listed items.

[0034] In addition, as used in the present invention, the term "or" is the inclusive "or" symbol and is equivalent to the term "and / or", unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for other factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meanings of "a", "an" and "the" include plural referents. The meaning of "in..." includes "in..." and "on...".

[0035] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, wherein one or more ring atoms are heteroatoms selected from N, O or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Examples include morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and their N-oxides. The heterocyclic substituent can be linked through a carbon atom or through a heteroatom.

[0036] The present invention includes the free form of the compound of formula I, as well as its pharmaceutically acceptable salts and stereoisomers. The term "free form" refers to an amine compound in non-salt form. The pharmaceutically acceptable salts included not only include the exemplary salts of the specific compounds described herein, but also include the typical pharmaceutically acceptable salts of all free forms of the compounds of formula I. The free form of the specific salt of the compound can be separated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free form differs somewhat from its respective salt form in certain physical properties such as solubility in polar solvents, but for the purposes of the invention, such acid salts and base salts are equivalent to their respective free forms in other pharmaceutical aspects.

[0037] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric or excess amount of the desired salt form of an inorganic or organic acid in a suitable solvent or a combination of solvents.

[0038] Therefore, the pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by reacting the basic compounds of the present invention with inorganic or organic acids. For example, the conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and also include salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, 2-hydroxyethanesulfonic acid, trifluoroacetic acid, etc.

[0039] The present invention also provides a pharmaceutical composition which comprises an active ingredient in a safe and effective amount range, and a pharmaceutically acceptable excipient.

[0040] The "active ingredient" as described in the present invention refers to the compound of formula I as described in the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a prodrug molecule thereof.

[0041] The "active ingredient" and the pharmaceutical composition as described in the present invention can be used as PDGFRα (especially PDGFRα D842V ) inhibitors and can be used to prepare drugs for preventing and / or treating tumors and the like.

[0042] "Safe and effective amount" means that the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.

[0043] "Pharmaceutically acceptable excipients" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity.

[0044] "Compatibility" herein means that the components in the composition can be mixed with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.

[0045] Some examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0046] In another preferred embodiment, the compound of formula I of the present invention can form a complex with a macromolecular compound or a polymer through non-bonding interactions. In another preferred embodiment, the compound of formula I of the present invention, as a small molecule, can also be connected to a macromolecular compound or a polymer through a chemical bond. The macromolecular compound can be a biological macromolecule such as a polysaccharide, a protein, a nucleic acid, a polypeptide, etc.

[0047] There is no particular limitation on the administration mode of the active ingredient or the pharmaceutical composition of the present invention. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

[0048] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

[0049] In these solid dosage forms, the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or is mixed with the following components:

[0050] (a) Filling agents or plasticizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid;

[0051] (b) Binders, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic;

[0052] (c) Humectants, such as glycerol;

[0053] (d) Disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;

[0054] (e) Sustained-release agents, such as paraffin wax;

[0055] (f) Absorption accelerators, such as quaternary ammonium compounds;

[0056] (g) Wetting agents, such as cetyl alcohol and glyceryl monostearate;

[0057] (h) Adsorbents, such as kaolin; and

[0058] (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0059] The solid dosage forms described above can also be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed and released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances.

[0060] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers, and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants, such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and fragrances.

[0061] In addition to the active ingredient, the suspension may contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar, or mixtures of these substances.

[0062] Compositions for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and sterile powders for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0063] The compounds of the present invention can be administered alone or in combination with other therapeutic drugs.

[0064] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage during administration is an effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 20 - 500 mg. Of course, the specific dosage should also consider factors such as the route of administration and the health status of the patient, which are within the scope of the skills of a skilled physician.

[0065] The following are specific examples.

[0066] Synthesis of Compound 1 in Example 1

[0067] Compound 1 was synthesized according to the following reaction formula:

[0068]

[0069] 1. Synthesis method of Intermediate 1 - Intermediate 6

[0070] Dissolve 3 - amino - 4 - nitrophenol (986 mg, 6.4 mmol) in 20 mL of N,N - dimethylformamide solvent, add potassium carbonate (1.77 g, 12.8 mmol) and benzyl bromide (0.79 mL, 19.44 mmol), stir at 100 °C for 2 hours, monitor by TLC. After the reaction is complete, cool to room temperature, add 20 mL of water to dilute the reaction solution, then add 20 mL of ethyl acetate for extraction. The organic phase is washed twice with saturated brine, and then dried with anhydrous Na 2 SO 4 After drying, concentrate and purify by silica gel column chromatography, with the mobile phase being petroleum ether:ethyl acetate = 8:1, to obtain Intermediate 1 (625 mg, yield: 40%).

[0071] Intermediate 1 (773 mg, 3.17 mmol) and 2,8-dichloroquinoline (0.52 g, 2.64 mmol) were dissolved in a two-necked flask containing 15 mL of ultra-dry tert-butanol (t-BuOH) solvent. Then, palladium acetate (35.9 mg, 0.16 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (91.7 mg, 0.16 mmol), and cesium carbonate (2.07 g, 6.34 mmol) were added. The reaction system was repeatedly purged with argon three times and the reaction system was sealed. The mixture was stirred at 80 °C for 4 hours. Monitored by TLC, after the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed repeatedly with ethyl acetate. Then, 15 mL of water was added for extraction three times, the organic phase was collected, washed with saturated brine, and then with anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with the mobile phase of petroleum ether:ethyl acetate = 5:1 to obtain Intermediate 2 (321 mg, yield: 25%).

[0072] Intermediate 2 (352 mg, 0.87 mmol) was dissolved in 15 mL of acetic acid, and trimethyl orthoformate (0.57 mL, 5.2 mmol) and iron powder (0.20 g, 3.5 mmol) were added. The reaction solution was stirred at 70 °C for 3 hours. Monitored by TLC, after the reaction was complete, the reaction solution was filtered through diatomaceous earth, the reaction solution was concentrated, and purified by silica gel column chromatography with the mobile phase of dichloromethane:methanol = 100:1 to obtain Intermediate 3 (214 mg, yield: 64%).

[0073] Intermediate 3 (193 mg, 0.5 mmol) and tert-butyl piperazine-1-carboxylate acetate (147.6 mg, 0.6 mmol) were dissolved in a two-necked flask containing 10 mL of ultra-dry 1,4-dioxane solvent. Then, Pd 2 (dba) 3 palladium (45 mg, 0.05 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl (20 mg, 0.05 mmol), and sodium tert-butoxide (72 mg, 0.75 mmol) were added. The reaction system was repeatedly purged with argon three times and the reaction system was sealed. The reaction was carried out overnight at 100 °C. Monitored by TLC, after the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed repeatedly with dichloromethane. Then, 15 mL of water was added for extraction three times, the organic phase was collected, washed with saturated brine, and then with anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with the mobile phase of dichloromethane:methanol = 100:1 to obtain Intermediate 4 (236 mg, yield 88%).

[0074] Intermediate 4 (150 mg, 0.28 mmol) was dissolved in 10 mL of methanol solvent, and 10% palladium on carbon (containing 55% water) (29.8 mg, 0.028 mmol) was added. The mixture was evacuated and the system was replaced with hydrogen, and it was stirred at room temperature overnight under a hydrogen atmosphere. Monitored by TLC, after the reaction was complete, the reaction solution was filtered through diatomaceous earth and washed with methanol. The filtrate was dried with anhydrous Na 2 SO 4 After drying, it was concentrated and purified by silica gel column chromatography. The mobile phase was dichloromethane:methanol = 50:1 to obtain Intermediate 5 (103.5 mg, yield: 83%).

[0075] Intermediate 5 (62 mg, 0.14 mmol) was dissolved in 10 mL of N,N-dimethylformamide (DMF) solvent, 1,3-dibromopropane (42 mg, 0.21 mmol) and cesium carbonate (90.9 mg, 0.28 mmol) were added, and it was stirred at 80 °C overnight. Monitored by TLC, after the reaction was complete, it was cooled to room temperature, 10 mL of water was added to dilute the reaction solution, and then 10 mL of ethyl acetate was added for extraction. The organic phase was washed twice with saturated brine and then with anhydrous Na 2 SO 4 After drying, it was concentrated and purified by silica gel column chromatography. The mobile phase was dichloromethane:methanol = 100:1 to obtain Intermediate 6 (55.4 mg, yield: 70%).

[0076] 2. Synthesis method of Compound 1

[0077] Intermediate 6 (82 mg, 0.14 mmol) was dissolved in 5 mL of dichloromethane solvent, 0.5 mL of trifluoroacetic acid was slowly added dropwise, and it was stirred at room temperature for 3 hours. Monitored by TLC, after the reaction was complete, dichloromethane was added to dilute the reaction solution, and saturated sodium bicarbonate solution was added to adjust the pH to 9. The organic phase was washed twice with saturated brine and then with anhydrous Na 2 SO 4 After drying, the solvent was evaporated to obtain a light green oily liquid. The obtained crude product was dissolved in 60 mL of ultra-dry N,N-dimethylformamide solvent, potassium carbonate (60 mg, 0.42 mmol) was added, and it was stirred at 80 °C for 6 hours. Monitored by TLC, after the reaction was complete, it was cooled to room temperature, 15 mL of water was added to dilute the reaction solution, and then 15 mL of dichloromethane was added for extraction. The organic phase was washed twice with saturated brine and then with anhydrous Na 2 SO 4 After drying, it was concentrated and purified by silica gel column chromatography. The mobile phase was dichloromethane:methanol = 25:1 to obtain Compound 1 (35 mg, total two-step yield: 62.8%).

[0078] Compound 1, a light green solid, yield 62.8%; 11H NMR (400 MHz, CDCl 3 ) δ 9.37 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.33 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 7.0, 2.5 Hz, 1H), 7.52 - 7.48 (m, 1H), 7.48 (s, 1H), 7.09 (dd, J = 8.7, 2.4 Hz, 1H), 4.39 (t, J = 5.7 Hz, 2H), 4.27 - 4.21 (m, 2H), 3.38 - 3.33 (m, 2H), 3.09 - 3.04 (m, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.72 - 2.66 (m, 2H), 2.10 - 2.04 (m, 2H).

[0079] Synthesis of Compound 2 in Example 2

[0080] Replace 1,3 - dibromopropane in Example 1 with 1,4 - dibromobutane, and synthesize the following Compound 2 in the same method as in Example 1.

[0081]

[0082] Compound 2, light green solid (yield: 64%). 1 1H NMR (400 MHz, DMSO - d 6 ) δ 9.10 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.57 (d, J = 8.9 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 2.7 Hz, 1H), 7.68 (s, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 4.36 (t, J = 5.7 Hz, 2H), 3.89 (d, J = 11.0 Hz, 2H), 3.21 (d, J = 9.4 Hz, 2H), 2.89 - 2.80 (m, 4H), 2.69 - 2.58 (m, 2H), 1.85 - 1.75 (m, 4H).

[0083] Synthesis of Compound 3 in Example 3

[0084] Replace 1,3 - dibromopropane in Example 1 with 1,2 - dibromoethane, and replace piperazine - 1 - carboxylate tert - butyl acetate in Example 1 with 1,4 - diazepane - 1 - carboxylate tert - butyl, and synthesize the following Compound 3 in the same method as in Example 1.

[0085]

[0086] Compound 3, light green solid (yield: 64%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.07 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 7.8, 1.9 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 7.3, 1.9 Hz, 1H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 4.49 (q, J = 11.4, 10.9 Hz, 1H), 4.44 - 4.28 (m, 2H), 3.71 - 3.59 (m, 2H), 3.46 (t, J = 11.8 Hz, 1H), 3.21 (d, J = 13.5 Hz, 2H), 3.05 (q, J = 5.5, 4.3 Hz, 1H), 2.96 - 2.86 (m, 2H), 2.84 - 2.78 (m, 1H), 2.38 - 2.28 (m, 1H), 1.80 (d, J = 14.4 Hz, 1H).

[0087] Synthesis of Compound 4 in Example 4

[0088] Compound 4 was synthesized according to the following reaction formula:

[0089]

[0090] 1. Synthesis methods of Intermediate 4-1 to Intermediate 4-7

[0091] Take 2,4,5-trichloropyrimidine (2 g, 10.9 mmol) and dissolve it in 30 mL of isopropanol solvent. Add 1,4-dioxo-8-azaspiro[4.5]decane (1.68 mL, 13.0 mmol) and N,N-diisopropylethylamine (2.16 mL, 13.0 mmol), and stir the reaction solution at 80 °C for 6 hours. Monitor by TLC. After the reaction is complete, cool to room temperature, add 20 mL of water to dilute the reaction solution, then add 20 mL of ethyl acetate for extraction. Wash the organic phase twice with saturated brine, and then use anhydrous Na 2 SO 4 After drying, concentrate and purify by silica gel column chromatography. The mobile phase is petroleum ether:ethyl acetate = 5:1 to obtain Intermediate 4-1 (2.34 g, yield: 74%).

[0092] Dissolve intermediate 4-1 (2.34 g, 8.06 mmol) and 5-methoxy-2-nitroaniline (1.62 g, 9.67 mmol) in a two-necked flask containing 30 mL of anhydrous dioxane solvent, and then add Pd 2 (dba) 3 (738.5 mg, 0.8 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (Davephos) (466.6 mg, 0.8 mmol) and cesium carbonate (5.25 g, 16.1 mmol). Replace the reaction system with argon three times repeatedly and seal the reaction system. Stir at 100 °C overnight. Monitor by TLC. After the reaction is complete, filter the reaction solution through diatomaceous earth and wash the filter cake repeatedly with dichloromethane. Then add 15 mL of water and extract three times. Collect the organic phase, wash it with saturated brine, and then use anhydrous Na 2 SO 4 dry, filter, concentrate under reduced pressure and purify by silica gel column chromatography. The mobile phase is dichloromethane:methanol = 200:1 to obtain intermediate 4-2 (1.12 g, yield: 33%).

[0093] Dissolve intermediate 4-2 (1.47 g, 3.48 mmol) in 15 mL of acetic acid, add trimethyl orthoformate (2.28 mL, 20.9 mmol) and iron powder (0.78 g, 13.9 mmol). Stir the reaction solution at 70 °C for 3 hours. Monitor by TLC. After the reaction is complete, filter the reaction solution through diatomaceous earth, concentrate the reaction solution and purify by silica gel column chromatography. The mobile phase is dichloromethane:methanol = 100:1 to obtain intermediate 4-3 (852 mg, yield: 61%).

[0094] Dissolve intermediate 4-3 (852 mg, 2.12 mmol) in 10 mL of tetrahydrofuran solvent, slowly dropwise add 10 mL of 2N HCl solution, and react the reaction solution at 50 °C for 24 hours. Monitor by TLC. After the reaction is complete, concentrate the reaction solution, adjust the pH to 7 with saturated sodium bicarbonate solution, then add dichloromethane for extraction. Collect the organic phase, and use anhydrous Na 2 SO 4 dry, filter, concentrate under reduced pressure to obtain intermediate 4-4 (660 mg, yield: 87%).

[0095] Dissolve intermediate 4-4 (300 mg, 0.83 mmol) in 15 mL of anhydrous dichloromethane solvent, add a small amount of 4A molecular sieve and 2 drops of glacial acetic acid. After stirring at room temperature for 20 minutes, add 3-aminopropanol (75.7 mg, 0.99 mmol) and sodium cyanoborohydride (210 mg, 3.32 mmol), and continue stirring at room temperature for 6 hours. Monitor by TLC. After the reaction is complete, adjust the pH to 7 with saturated sodium bicarbonate solution, separate the organic phase, wash the organic phase twice with saturated brine, and then use anhydrous Na 2 SO 4 Dry and concentrate, purify by silica gel column chromatography, and the mobile phase is dichloromethane:methanol = 20:1 to obtain intermediate 4-5 (111 mg, yield: 32%).

[0096] Dissolve intermediate 4-5 (111 mg, 0.26 mmol) in 10 mL of anhydrous dichloromethane solvent, displace the system with argon, and then cool to -78 °C. Slowly add boron tribromide (0.15 mL, 1.59 mmol) to this solution with stirring. After the addition is complete, continue stirring at room temperature for 5 hours. Monitor by TLC. After the reaction is complete, cool the system to 0 °C and slowly add saturated aqueous sodium bicarbonate solution until the pH reaches 7. Filter the solid and wash it with methanol, and dry the filter cake under vacuum to obtain intermediate 4-6 (38.6 mg, yield: 36%).

[0097] Dissolve intermediate 4-6 (100 mg, 0.25 mmol) in 10 mL of ultra-dry methanol solvent, slowly add triethylamine (50 mg, 0.5 mmol) and di-tert-butyl dicarbonate (59.5 mg, 0.27 mmol) dropwise in an ice bath environment. After the addition is complete, place the system at room temperature and continue stirring for 6 hours. Monitor by TLC. After the reaction is complete, add dichloromethane to the system, and then wash it with water three times repeatedly. Separate the organic phase and use anhydrous Na 2 SO 4 Dry and concentrate, purify by silica gel column chromatography, and the mobile phase is dichloromethane:methanol = 30:1 to obtain intermediate 4-7 (62.4 mg, yield: 51%).

[0098] 2. Synthetic method of compound 4

[0099] Dissolve intermediate 4-7 (60 mg, 0.12 mmol) and triphenylphosphine (312 mg, 1.2 mmol) in 60 mL of dry dichloromethane solvent, and displace the gas in the reaction system with argon. Place the reaction system in an environment of 0 °C, and slowly add diisopropyl azodicarboxylate (0.2 mL, 1.2 mmol) thereto. Continue to react the reaction system at room temperature for 3 hours. Monitor by TLC. After the reaction is complete, concentrate the reaction system under reduced pressure to obtain a yellow oily liquid. Continue to dissolve the obtained crude product in 10 mL of dichloromethane solvent, add 0.5 mL of trifluoroacetic acid, and continue to stir at room temperature for 3 hours. Monitor by TLC. After the reaction is complete, dilute the reaction solution with dichloromethane, and add saturated sodium bicarbonate solution to adjust the pH to 9. Wash the organic phase twice with saturated brine, and then use anhydrous Na 2 SO 4 dry, purify by silica gel column chromatography, and the mobile phase is dichloromethane:methanol = 30:1 to obtain white solid compound 4 (33 mg, total yield in two steps: 71.7%).

[0100] Compound 4, white solid (yield: 71.7%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.56 (s, 1H), 7.82 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.28 (t, J = 8.0 Hz, 2H), 4.16 (d, J = 13.4 Hz, 2H), 3.20 (d, J = 10.7 Hz, 2H), 3.04 (t, J = 6.8 Hz, 1H), 2.69 (t, J = 5.9 Hz, 2H), 1.94 - 1.75 (m, 6H).

[0101] Synthesis of Compound 5 in Example 5

[0102] Compound 5 is synthesized according to the following reaction formula:

[0103]

[0104] 1. Synthesis method of intermediates 5-1 to 5-4

[0105] 3-Nitrophenol (100 mg, 0.28 mmol) was dissolved in 10 mL of N,N-dimethylformamide (DMF) solvent. tert-Butyl 3-bromopropylcarbamate (99.6 mg, 0.42 mmol) and cesium carbonate (181.8 mg, 0.55 mmol) were added, and the mixture was stirred overnight at 80 °C. Monitored by TLC, after the reaction was complete, it was cooled to room temperature, and 10 mL of water was added to dilute the reaction solution. Then 10 mL of ethyl acetate was added for extraction. The organic phase was washed twice with saturated brine, and then with anhydrous Na 2 SO 4 After drying and concentration, it was purified by silica gel column chromatography with the mobile phase of dichloromethane:methanol = 100:1 to obtain intermediate 5-1 (75.2 mg, yield: 90.7%).

[0106] Intermediate 5-1 (1.5 g, 5.06 mmol) was dissolved in 20 mL of methanol solvent, and 10% palladium on carbon (containing 55% water) (269 mg, 0.25 mmol) was added. The mixture was evacuated and the system was replaced with hydrogen, and it was stirred at room temperature for 2 hours under a hydrogen atmosphere. Monitored by TLC, after the reaction was complete, the reaction solution was filtered through diatomaceous earth and washed with methanol. The filtrate was dried with anhydrous Na 2 SO 4 After drying and concentration, it was purified by silica gel column chromatography with the mobile phase of dichloromethane:methanol = 100:1 to obtain intermediate 5-2 (1.21 g, yield: 89.9%).

[0107] Intermediate 5-2 (1.21 g, 4.54 mmol) was dissolved in 10 mL of sec-butanol solvent, and 8-bromo-2-chloroquinazoline (0.92 g, 3.78 mmol) and trifluoroacetic acid (144 μL, 1.88 mmol) were added. The mixture was heated to 110 °C in an argon atmosphere and stirred at this temperature for 12 hours. Monitored by TLC, after the reaction was complete, the system was cooled to room temperature, and 10 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was extracted with 15 mL of dichloromethane solvent, and the organic phase was dried with anhydrous Na 2 SO 4 After drying and concentration, it was purified by silica gel column chromatography with the mobile phase of dichloromethane:methanol = 100:1 to obtain intermediate 5-3 (471.5 mg, yield: 22%).

[0108] Intermediate 5-3 (1.23 g, 3.0 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.46 mL, 3.6 mmol) were dissolved in a two-necked flask containing 10 mL of ultra-dry 1,4-dioxane solvent, and then Pd 2 (dba) 3Palladium (0.27 g, 0.3 mmol), 2 - dicyclohexylphosphino - 2'-(N,N - dimethylamino) - biphenyl (0.12 g, 0.3 mmol) and sodium tert - butoxide (0.43 g, 4.5 mmol). The reaction system was purged with argon three times repeatedly and the reaction system was sealed. The reaction was carried out overnight at 100 °C. Monitored by TLC, after the reaction was complete, the reaction solution was filtered through diatomaceous earth and the filter cake was washed repeatedly with dichloromethane. Then 15 mL of water was added for extraction three times, the organic phase was collected, washed with saturated brine, and then with anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure and purified by silica gel column chromatography. The mobile phase was dichloromethane:methanol = 100:1 to obtain intermediate 5 - 4 (698.5 mg, yield 43.5%).

[0109] 2. Synthesis method of compound 5

[0110] Intermediate 5 - 4 (112 mg, 0.2 mmol) was dissolved in 5 mL of tetrahydrofuran solvent, 5 mL of 2N HCl solution was slowly added dropwise, and the reaction solution was reacted at 50 °C for 24 hours. Monitored by TLC, after the reaction was complete, the reaction solution was concentrated, saturated sodium bicarbonate solution was added to adjust the pH to 7, then dichloromethane was added for extraction, the organic phase was collected, and anhydrous Na 2 SO 4 dried, filtered, concentrated under reduced pressure to obtain a light green oily liquid. The crude product was then dissolved in 80 mL of anhydrous dichloromethane solvent, a small amount of 4A molecular sieve was added, 2 drops of glacial acetic acid were added, and the mixture was stirred at room temperature for 20 minutes, then sodium triacetoxyborohydride (177.2 mg, 0.83 mmol) was added, and the stirring was continued at room temperature for 6 hours. Monitored by TLC, after the reaction was complete, saturated sodium bicarbonate solution was added, the organic phase was separated, the organic phase was washed twice with saturated brine, and then with anhydrous Na 2 SO 4 dried and concentrated, and purified by silica gel column chromatography. The mobile phase was dichloromethane:methanol = 20:1 to obtain light green solid compound 5 (15.7 mg, total two - step yield: 20%).

[0111] Compound 5, light green solid, yield 20%; 11H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 9.25 (d, J = 4.3 Hz, 1H), 8.46 (s, 1H), 7.55–7.46 (m, 1H), 7.31–7.19 (m, 3H), 6.88 (t, J = 6.1 Hz, 1H), 6.77 (t, J = 6.3 Hz, 1H), 4.22–4.11 (m, 2H), 3.75 (s, 2H), 3.57–3.49 (m, 2H), 3.18 (s, 1H), 2.70 (s, 2H), 2.31 - 2.16 (m, 2H), 2.07 (s, 2H), 1.90 (d, J = 11.5 Hz, 2H).

[0112] Example 6 Compound against PDGFRα D842V Kinase IC 50 Test

[0113] Using a FRET (Fluorescence Resonance Energy Transfer)-based Z’-Lyte assay system (detected by fluorescence, enzyme-coupled form, based on the difference in sensitivity of proteolytic cleavage between phosphorylated and non-phosphorylated polypeptides), according to the manufacturer's instructions (Life Technologies, Carlsbad, CA, USA), the inhibitory activity of the compound against PDGFRα D842V Kinase was tested.

[0114] Enzymatic reaction: Add 5 μL of enzyme-substrate system to a 384-well plate: 30 nM kinase, 5 mM magnesium chloride (MgCl 2 2), 50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) pH 7.5, 2 mM manganese chloride (MnCl 2 2), 1 mM ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), 0.01% Brij-35, 2 μM Tyr04 peptide substrate. Then transfer 5 μM concentration of ATP and different concentration gradients of the test compound using an echo520 ultra-micro liquid pipetting system, mix by shaking and centrifuge, and incubate at room temperature for 1 hour.

[0115] Detection reaction: Add 2.5 μL of developer to each well, incubate at room temperature for 1 hour, and then add 2.5 μL of termination solution.

[0116] Plate reading and calculation: A multimode microplate reader (Perkin Elmer EnVision Multimode Plate Reader) was used to detect the fluorescence signal (the fluorescence signal ratio of 445 nm (coumarin) / 520 nm (fluorescein)), and the phosphorylation ratio was calculated. Then, the inhibition rate of each well was calculated through the fully active wells and the control signal wells. Inhibition rate = 100×(1 - phosphorylation ratio of the compound / phosphorylation ratio of the negative control). Graphpad Prism 5.0 (Graphpad Software, Inc) was used to analyze the experimental data and calculate the IC50 value.

[0117] The results of the kinase activity test are shown in Table 1.

[0118] Table 1 Inhibitory activity test results of compounds against PDGFRα D842V kinase (IC 50 : nM)

[0119] Compound Number <![CDATA[PDGFRα D842V > Compound 1 70.0 Compound 2 103.5 Compound 3 911.5 Compound 4 ＞10000 Compound 5 1497

[0120] As can be seen from the data in Table 1, the 2,8-disubstituted quinoline macrocyclic compounds of the present invention have strong inhibitory activity against PDGFRα D842V kinase, and compound 1 exhibits the optimal activity.

[0121] Example 7 Study on the cell proliferation inhibitory activity based on the Ba / F3-PDGFRα D842V stable cell line

[0122] The Ba / F3-PDGFRα D842V cell line used in this experiment, the Ba / F3-PDGFRα D842V / G680R cell line can be obtained commercially or constructed by the following method. Among them, the mouse Ba / F3 cell line was purchased from the German Collection of Microorganisms and Cell Cultures (DSMZ).

[0123] Establish a Ba / F3 cell line stably expressing PDGFRα D842V , Ba / F3-PDGFRα D842V / G680R : Synthesize the wild-type PDGFRα fusion gene FIP1L1-PDGFRα and clone it into the pCDNA3.1(+) vector (Invitrogen, Carlsbad, CA). Use the QuickChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA) to introduce point mutations into the wild-type construct. Use Cell Line Kit V kit (VCA-1003) electrotransfected the pcDNA3.1 plasmid containing the PDGFRα fusion gene into Ba / F3 cells; two weeks after transfection, geneticin (G418) (Merck, Whitehouse Station, NJ) with a final concentration of 800 mg / mL was added for cell screening, and interleukin-3 (IL-3) was withdrawn within the next two weeks to establish a stable polyclonal cell line, and then a stable monoclonal cell line was obtained by limiting dilution. All Ba / F3 stable cell lines were verified by DNA sequencing, protein expression, and anti-proliferative effects on positive drugs. Parental Ba / F3 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 10 ng / mL IL-3, while the PDGFRα fusion-transformed Ba / F3 stable cell line was cultured in the same medium without IL-3. Monoclonal cells with completely correct identification were used for the cell proliferation inhibition activity test of the inhibitor.

[0124] Cell proliferation inhibition activity test: Cells in the logarithmic growth phase were seeded into 96-well plates at 5000 - 8000 cells per well. After 24 hours of seeding, the cells were treated with the medium containing the test compound and incubated for an additional 72 hours. After the treatment, 10 μL of Cell Counting Kit-8 cell counting reagent (CCK-8, CK04, Dojindo Laboratories, Kumamoto, Japan) was added to each well and incubated with the cells for 3 hours. Then, the absorbance values at 450 nm and 650 nm were measured using a microplate reader. The absorbance value (A) of each well was calculated as OD450 - OD650, and the cell survival rate of each well was calculated as V% = (As - Ac) / (Ab - Ac) × 100%. The data are the average of at least three independent experiments. The half-maximal inhibitory concentration (IC 50 ) was calculated using the log(inhibitor) vs. response - variable slope (four parameters) with the medical plotting software (GraphPad Prism 8.0). As is the absorbance value of the well with the test compound, Ac is the absorbance value of the well without cells and the test compound, and Ab is the absorbance value of the well with cells and the vehicle control. The test results are shown in Table 2.

[0125] Table 2 Inhibitory activity test results of compounds on the proliferation of Ba / F3 cells stably expressing PDGFRα D842V (IC 50 : nM)

[0126]

[0127]

[0128] As can be seen from the data in Table 2, the 2,8-disubstituted quinoline macrocyclic compounds of the present invention have strong inhibitory activity against the cell proliferation of Ba / F3-PDGFRα D842V stable strains, among which Compound 1 exhibits the optimal activity and also has strong inhibitory activity against the cell proliferation of Ba / F3-PDGFRα D842V / G680R stable strains.

[0129] Through a series of experiments, the present invention obtained an inhibitor capable of targeting PDGFRα D842V This inhibitor shows strong inhibitory ability against the mutant kinase of PDGFRα D842V and also shows a significant inhibitory effect in Ba / F3-PDGFRα D842V stable strain cells, and can effectively inhibit the growth of tumor cells. Such an inhibitor can be used for preventing or treating diseases mediated by PDGFRα kinase (such as tumors), and has significant potential especially in the treatment of gastrointestinal stromal tumors.

[0130] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0131] The above-described embodiments only represent several implementation manners of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the appended claims.

Claims

1. A 2,8-disubstituted quinoline macrocyclic compound having a structure as shown in formula I or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, R is selected from: 5-8 membered heterocyclic group; n is selected from: 1, 2, 3, 4, 5, 6.

2. The 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R is selected from: 5-8 membered saturated heterocyclic group.

3. The 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R is selected from: a 5-8 membered heterocyclic group wherein the heteroatom is N, preferably a 5-8 membered heterocyclic group wherein the heteroatom is 2 N, more preferably a 6 membered heterocyclic group wherein the heteroatom is 2 N, or a 7 membered heterocyclic group wherein the heteroatom is 2 N.

4. The 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: R is selected from the following groups:

5. The 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, characterized in that: The 2,8-disubstituted quinoline macrocyclic compound is selected from the following compounds:

6. Use of the 2,8-disubstituted quinoline macrocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a PDGFRα kinase inhibitor; the PDGFRα kinase is preferably a PDGFRα kinase with a D842V mutation and / or a G680R mutation.

7. Use of the 2,8-disubstituted quinoline macrocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of a drug for treating and / or preventing a disease, wherein the disease is caused by abnormal expression of PDGFRα kinase, preferably PDGFRα D842V Mutation, PDGFRα G680R Mutation or PDGFRα D842V / G680R Mutation-mediated diseases.

8. Use of the 2,8-disubstituted quinoline macrocyclic compound or a pharmaceutically acceptable salt or a stereoisomer thereof according to any one of claims 1 to 5 in the preparation of a drug for treating and / or preventing tumors; Preferably, the tumor is a tumor caused by abnormal expression of PDGFRα kinase; Preferably, the tumor carries PDGFRα D842V Mutation, PDGFRα G680R Mutation or PDGFRα D842V / G680R Mutated tumors.

9. The use according to claim 8, characterized in that: The tumor is gastric cancer or gastrointestinal stromal tumor, preferably gastric cancer or gastrointestinal stromal tumor caused by abnormal expression of PDGFRα kinase, more preferably a tumor carrying PDGFRα D842V Mutation, PDGFRα G680R Mutation or PDGFRα D842V / G680R Mutation in gastric cancer or gastrointestinal stromal tumor.

10. An anti-tumor pharmaceutical composition, characterized in that: The invention is prepared from active ingredients and pharmaceutically acceptable excipients, wherein the active ingredients include the 2,8-disubstituted quinoline macrocyclic compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

Images