WO2021184958A1 - Angiogenesis inhibitor, preparation method therefor and use thereof - Google Patents

Angiogenesis inhibitor, preparation method therefor and use thereof Download PDF

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WO2021184958A1
WO2021184958A1 PCT/CN2021/073616 CN2021073616W WO2021184958A1 WO 2021184958 A1 WO2021184958 A1 WO 2021184958A1 CN 2021073616 W CN2021073616 W CN 2021073616W WO 2021184958 A1 WO2021184958 A1 WO 2021184958A1
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methyl
indol
fluoro
oxy
yloxy
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PCT/CN2021/073616
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French (fr)
Chinese (zh)
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孙效华
杨阳
陈庆广
尹大伟
刘洋
王静
王静然
李玉花
杨红振
胡怀忠
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北京康辰药业股份有限公司
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Priority to CN202180000162.3A priority Critical patent/CN112912373B/en
Publication of WO2021184958A1 publication Critical patent/WO2021184958A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a compound used as an angiogenesis inhibitor and a preparation method and application thereof.
  • Receptor tyrosine kinase is a transmembrane protein with three parts: extracellular domain, transmembrane domain and intracellular domain.
  • the function of the intracellular domain is to act as a kinase to phosphorylate specific amino acid residues in proteins and affect cell proliferation. Variation of tyrosine kinase or abnormal activity changes will lead to the occurrence of the disease.
  • Tyrosine kinases can be classified into growth factor receptors (such as EGFR, VEGFR, PDGFR, FGFR, and erbB2) or non-receptor kinases (such as c-src, bcr-abl). These kinases may be abnormally expressed in human cancers, such as breast cancer, colorectal cancer, gastric cancer, blood cancer, and ovarian cancer.
  • Angiogenesis is an important part of general physiological processes, such as embryo formation and wound healing. However, variant angiogenesis can lead to related diseases, such as psoriasis, rheumatoid arthritis, atheroma, and tumors.
  • Tumor angiogenesis is mainly regulated by vascular endothelial cell growth factor (VEGF) in the tumor, which acts through at least two different receptors (VEGFR1, VEGFR2).
  • VEGF receptor is highly specific to vascular endothelial cells.
  • VEGF combines with its receptor VEGFR to produce a series of physiological and biochemical reactions, and ultimately promote the formation of new blood vessels.
  • angiogenesis factors and angiogenesis inhibitors maintain a relatively balanced level. In the process of tumor growth, the high expression of VEGF and VEGFR disrupts this balance and promotes the formation of tumor new blood vessels.
  • cediranib is a relatively powerful drug.
  • the chemical structure of cediranib is shown below.
  • Cediranib has been used in clinical research for ovarian cancer, gallbladder cancer, renal cell carcinoma, prostate cancer, cervical cancer, etc. However, due to the obvious adverse reactions of cediranib (mainly hypertension, fatigue, diarrhea, hand-foot syndrome, etc.), it was finally not approved for marketing in the EU.
  • the present invention provides a cyclobutyl-containing compound used as a tyrosine kinase inhibitor, the compound having a structure represented by formula (I).
  • the compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, isotopic derivatives and solvates, and pharmaceutical compositions containing the compounds, can be used for the treatment of tyrosine kinases, especially those related to VEGFR Treatment of tumor diseases.
  • the compound of the present invention has the structure shown in formula I:
  • X is selected from -C(H)-, N, -C(F)-, -C(CF 3 )-, -C(CN)-;
  • R is selected from a hydroxyl group, a carboxyl group, an ester group, -N(R 1 R 2 ), or R is selected from an oxygen atom and the oxygen atom forms a ketone carbonyl group with the cyclobutyl group directly connected to it;
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, Ar ;
  • R 1 and R 2 form a 4-10 membered heterocyclic group with the nitrogen atom to which they are connected, and the ring of the heterocyclic group further includes at least one atom of N, O, and S; and the heterocyclic ring
  • the hydrogen atom on the group is optionally substituted with 1-3 R 3 which are the same or different;
  • R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, ester group;
  • Ar is selected from C 6 -C 10 aryl groups, 5-10 membered heteroaryl groups, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O and S; Ar can be the same or 1-3 Different R 4 substitutions; R 4 is selected from hydrogen, hydroxyl, halogen, trifluoromethyl, nitro, amino, nitrile, sulfonic acid, sulfonamide, C 1 -C 6 alkyl, C 1 -C 6 Alkyl acyl, C 3 -C 6 cycloalkyl.
  • the inventors of the present invention analyzed the structure-activity relationship and in vivo pharmacokinetic characteristics of cediranib and found that there are functional groups in the structure that affect metabolism, which makes the half-life longer, exceeding 30 hours, leading to adverse reactions.
  • the present invention performs structure-activity relationship analysis on the basis of the structure of cediranib, and optimizes its structure. On the one hand, it maintains its activity (even higher than that of cediranib), and on the other hand, it improves its pharmacokinetics. Nature, shorten the half-life of the drug, and improve its druggability.
  • the presence of a cyclobutyl group on the molecular branch can increase the rigidity of the branch where the cyclobutyl is located.
  • the presence of a four-membered ring Make the 1,3-position substituents have cis and trans configurations, increase the directionality of the molecule, and make the compound easier to bind to the target, thereby increasing the activity of the drug, reducing the dose of the drug, and reducing the side effects of the drug.
  • the molecular branch of the compound of the present invention contains cyclobutyl, and the cyclobutyl makes the compound of the present invention have obvious advantages.
  • cyclopropyl can also increase the rigidity of molecular branches, but compounds containing cyclopropyl branches have obvious metabolic problems and have a particularly long half-life.
  • cyclopentyl and cyclohexyl have relatively more conformations (for example, cyclohexyl has a chair conformation and a boat conformation), resulting in insufficient rigidity of molecular branches.
  • X is selected from -C(F)-, -C(CF 3 )-, -C(CN)-.
  • Fluorine atoms, trifluoromethyl groups and cyano groups are all strong electron-withdrawing groups. These strong electron-withdrawing groups can form hydrogen bonds with the target protein to enhance the binding force with the target, thereby further enhancing the activity of the drug, reducing the dosage and reducing toxic side effect.
  • the group R and the methylene group (-CH 2 -) connected to R and the methylene group at the meta position of the methylene group can also form a cis group shown in formula II.
  • the formula structure or the trans structure shown in formula III is as follows.
  • the compound of the present invention exhibits a cis or trans structure.
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar; Ar is selected from benzene Group, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl.
  • the molecular structure contains the NR 1 R 2 group attached to the cyclobutyl group.
  • These terminal substituents connected to the cyclobutyl group have a certain degree of freedom, which leads to an increase in the probability of the substituent group contacting the target mutation site, thereby increasing the group selectivity.
  • R 1 and R 2 can form a chain and an aromatic ring separately, and an aromatic ring or an aromatic heterocyclic ring can increase the fat solubility of the entire molecule, so that the molecule can reach the patient's site.
  • R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar;
  • Ar is selected from benzene Group, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl;
  • heterocyclic group is selected from 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 4-methyl-1 -Piperidinyl, 1-cyclobutylamino.
  • the molecular structure contains a -N(R 1 R 2 ) group linked to a cyclobutyl group. These groups can extend the rigidity of the side chain of the cyclobutyl, further increase the rigidity of the branched molecule, so as to increase the directionality of the molecule, and it is easy to better combine with the target.
  • the compound of the present invention is selected from any one of the following compounds:
  • the present invention also provides a method for preparing the compound of formula I according to claim 1, said method comprising the following reaction route:
  • the method includes the following steps:
  • the solvent 1 is selected from at least one of DMSO, DMF, acetonitrile, methanol, ethanol, and tert-butanol;
  • the alkaline reagent is selected from cesium carbonate, potassium carbonate, and sodium carbonate , At least one of sodium methoxide, sodium ethoxide, and sodium tert-butoxide;
  • the solvent 2 is selected from at least one of methanol, ethanol, isopropanol, and tert-butanol.
  • the benzyl group in compound C01 can be removed using methods commonly used in the art. In the method of the present invention, the benzyl group is removed by a hydrogenation reaction, wherein the hydrogenation reduction reaction includes hydrogenation of the compound C01 with hydrogen under the catalysis of a Pd/C catalyst to remove the benzyl group.
  • the Pd/C catalyst can be 5wt% Pd/C or 10wt% Pd/C commonly used in industry (5wt% or 10wt% represents the mass ratio of metal palladium in the Pd/C catalyst mixture). Based on the mass of compound C01, the addition ratio of 5wt% Pd/C or 10wt% Pd/C ranges from 5% to 20%;
  • the solvent 3 is selected from at least one of THF (tetrahydrofuran), DMF (N,N-dimethylformamide), and DCM (dichloromethane).
  • the present invention also provides a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt of the compound or a solvate of the compound, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be made into a variety of dosage forms.
  • the preparation form of the pharmaceutical composition of the present invention may be an oral preparation or an injection.
  • the compound of the present invention is an inhibitor of tyrosine kinase activity.
  • it can be used in the treatment of diseases caused by the abnormal activity of protein kinases VEGFR2, EGFR, FGFR, and RET.
  • diseases can be It is a malignant tumor or cancer.
  • the diseases are tumor angiogenesis.
  • the present invention provides a method for treating cancer or tumor angiogenesis, which method comprises administering an effective dose of the compound of the present invention to a patient in need of treatment.
  • Halogen means F, Cl, Br, I, At.
  • C 1 -C 10 alkyl refers to an alkyl chain having 1-10 carbon atoms, which may be straight or branched. For example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and so on.
  • the hydrogen atom on the C1-10 alkyl carbon may be further substituted with a predetermined substituent.
  • C 3 -C 7 cycloalkyl refers to a cycloalkyl chain having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • the hydrogen atom on the carbon atom in the cycloalkyl group may be substituted with a predetermined substituent.
  • C 2 -C 10 alkenyl refers to an alkene chain with 2-10 carbon atoms containing a carbon-carbon double bond.
  • the carbon-carbon double bond can be on the main chain or on a branch, such as ethylene Group, propenyl, butenyl, isobutenyl, etc.
  • the hydrogen atom on the carbon atom on C2-10 may be further substituted with a predetermined substituent.
  • C 2 -C 10 alkynyl refers to an alkene chain with 2-10 carbon atoms containing a carbon-carbon triple bond.
  • the carbon-carbon triple bond can be on the main chain or on a branch, such as acetylene Group, propynyl, butynyl, isobutynyl, etc.
  • the hydrogen on the carbon atom on C2-10 may be further substituted with a predetermined substituent.
  • Ar can refer to an aromatic monocyclic or bicyclic group having 6-10 carbon atoms, or a 5-10 membered monocyclic/bicyclic heteroaryl group.
  • the carbon atoms on the ring can be substituted by N, O, S atoms, such as phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, furyl, thienyl, pyrrolyl, etc.; ring carbon
  • the hydrogen of the atom may be further substituted with a predetermined substituent.
  • Prodrug refers to a derivative of the compound of the present invention that is converted into a derivative of the compound of the present invention by oxidation, reduction, hydrolysis and other reactions catalyzed by enzymes in the living body under physiological conditions.
  • Metal refers to all molecules derived from the compounds of the present invention produced in cells or organisms (preferably humans).
  • Isotopic derivative refers to the structure constituting the compound of the present invention that contains one or more isotope atoms existing in unnatural proportions. For example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N).
  • Solidvate means that the compound of the present invention and the solvent molecule form a solvent complex in the form of physical bonding. This physical bond includes hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, tetrahydrofuran, ethyl acetate, acetonitrile and the like.
  • Compounds of formula (I) can be prepared in crystalline form and can be in solvate form (including hydrate form).
  • the pharmaceutically acceptable salt of the compound of formula (I) contains one or more basic or acidic groups, especially the pharmaceutically usable salt thereof.
  • alkali metal salt, alkaline earth metal salt, ammonium salt More precisely, it may be sodium salt, potassium salt, calcium salt, magnesium salt or organic amine such as ethylamine, ethanolamine, triethylamine or amino acid salt.
  • the compounds of the present invention can form protonated compounds of formula (I) with inorganic or organic acids. Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, tartaric acid, etc. Other acids known to those skilled in the art.
  • “Pharmaceutical composition” when used as a medicine refers to the composition of the compound of formula (I) of the present invention and its salts, isotope derivatives, metabolites, prodrugs, solvates and other substances with or without biological activity, It can be used to treat or prevent proliferative diseases (including angiogenesis) related to protease tyrosine kinase receptors, such as solid tumors and hematomas.
  • proliferative diseases including angiogenesis
  • Figure 1 is the general structure of the compound of formula I according to the present invention.
  • Figure 2 shows the average tumor volume of the compound of Example 22 applied in an ovarian cancer SK-OV-3 model
  • Figure 3 shows the body weight changes of experimental animals in which the compound of Example 22 is applied in an ovarian cancer SK-OV-3 model
  • Figure 4 shows the average tumor volume of experimental animals in which the compound of Example 26 is applied in an ovarian cancer SK-OV-3 model
  • Figure 5 shows the weight change of experimental animals when the compound of Example 26 is applied in an ovarian cancer SK-OV-3 model
  • Figure 6 shows the average tumor volume of experimental animals in which the compound of Example 26 is applied in the Caki-1 model of renal cancer
  • Figure 7 shows the weight changes of experimental animals in each experimental group in the application of the compound of Example 26 in the Caki-1 model of renal cancer.
  • Example 22 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclohexanone reductive amination reaction to synthesize cis-N-3-(((4-((4-fluoro-2-methyl-1H-indyl) Dol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclohexylamine.
  • Example 32 trans-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yl (Oxy)methyl)cyclobutylamine hydrochloride reacts with 1,4-dibromobutane to synthesize trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)- 6-Methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinazoline.
  • Example 23 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclohexanone reductive amination reaction to synthesize trans-N-3-(((4-((4-fluoro-2-methyl-1H-indyl) Dol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclohexylamine.
  • trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride undergoes reductive amination reaction with cyclobutanone, and is separated and purified by preparative liquid chromatography under formic acid conditions to obtain trans-N,N-dicyclobutyl-3 -(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutylamine .
  • Example 23 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclopentanone undergo reductive amination reaction to synthesize trans-N-3-(((4-((4-fluoro-2-methyl-1H- Indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclopentylamine.
  • Example 26 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinoline-7- (Yl)oxy)methyl)cyclobutylamine hydrochloride and 1,4-dibromobutane to synthesize cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy) )-6-Methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinoline formate.
  • Example 48 1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine salt
  • the acid salt is used as the raw material to undergo reductive amination reaction with paraformaldehyde, which is purified by preparative liquid chromatography under formic acid conditions to synthesize 1-(((4-((1H-indol-5-yl)oxy)-6-methoxy Quinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine.
  • In vitro activity evaluation uses the HTRF KinEASE-TK detection kit produced by Cisbio.
  • HTRF KinEASE-TK detection kit is a universal kit for activity detection of tyrosine kinase.
  • VEGFR2 is a kind of tyrosine kinase.
  • the biotin-labeled substrate will undergo an enzymatic reaction under the catalysis of the kinase VEGFR2 to bring the substrate with a phosphate group.
  • the detection reagent Streptavidin-XL665 can be combined with biotin on the substrate through Streptavidin.
  • Another detection reagent, TK-antibody-Eu3+-Cryptate can bind to phosphorylated substrates. Energy is transferred from the donor Eu to the acceptor XL665, which makes the XL665 emit light.
  • the resulting signal is directly proportional to the level of phosphorylation of the substrate.
  • a small molecule inhibitor of VEGFR2 hinders the phosphorylation reaction of VEGFR2
  • the distance between Eu and XL665 will affect the occurrence of fluorescence energy transfer and the signal will be weakened.
  • the signal intensity change is used to judge the blocking of VEGFR2 kinase activity by small molecule inhibitors.
  • Cisbio's HTRF KinEASE-TK kit manual 62TK0PEB, 62TK0PEC and 62TK0PEJ for specific experimental operation methods. A brief description is as follows. Take a new 384-well ELISA plate, add 4 ⁇ L of enzyme reaction buffer to the positive reaction wells, add 6 ⁇ L of enzyme reaction buffer to the negative reaction wells, and add 4 ⁇ L of enzyme reaction buffer to the test wells. Dilute small molecule compounds of different concentrations to be tested. Then add 2 ⁇ L ATP, 2 ⁇ L substrate, 2 ⁇ L VEGFR2 enzyme to each well, and incubate at room temperature for 40min to 1h.
  • A means the activity range is 0.1-1 nM; B means the activity range is 1-10 nM; C means the activity range is greater than 10 nM.
  • the compounds in Examples 1-19 of the present invention have lower IC50 for the tyrosine kinases VEGFR, EGFR, FGFR, and RET, indicating that the tyrosine kinases VEGFR, EGFR, FGFR, and RET have a lower IC50 for the tyrosine kinases of the present invention.
  • the compound has good sensitivity and can be effectively used in the treatment of diseases related to abnormal tyrosine kinase activity.
  • Examples 48 to 52 are examples of cyclopropyl substitution.
  • the present invention uses cyclobutyl to replace the side chain, which greatly enhances the directionality and selectivity of the molecule, and makes it an order of magnitude improvement in enzymatic activity.
  • the structure of the compound in Example 33 (IC50 of 2.21 nM) is similar to that of the positive control cediranib (IC50 of 3.62 nM), but compared with cediranib, the drug activity has also been improved to a certain extent.
  • Example 22 has a four-membered cyclobutyl substituted side chain.
  • the bioavailability (F%) increased by 2-3 times, while the in vivo exposure (AUC inf ) increased by 4-6 times, the maximum blood concentration (C max ) was also significantly increased, indicating that the four-membered cyclobutyl substitution example has more Superior medicinal properties.
  • Example 22 To evaluate the anti-tumor effects of Example 22 and Example 26 on the CDX model of ovarian cancer SK-OV-3 cell subcutaneous tumor in mice.
  • Subcutaneous tumor transplantation method Inoculate 1 ⁇ 10 7 SK-OV-3 cells subcutaneously on the right back of the tested mouse BALB/c-nude mice (18-22g), and resuspend the cells in PBS suspension, each Inoculate 0.1mL. Regularly observe the tumor growth. When the average tumor volume reaches 100-200mm 3 , the drugs are randomly divided into groups according to the tumor size and the weight of the mice. The grouping day is set to Day 0, and the administration starts on Day 0.
  • the experiment is divided into vehicle control group, low-dose group (1.5mg/kg), medium-dose group (2.5mg/kg) and high-dose group (5mg/kg), vehicle control group 3 mice, Example 22 and Examples 26 low-, medium-, and high-dose groups of 6 mice in each group were administered orally once a day for three weeks.
  • T/C relative tumor proliferation rate
  • TGI% relative tumor inhibition rate
  • the experimental animals are kept in an independent ventilated IVC box with constant temperature and humidity, and adapt to the environment for at least 7 days in advance.
  • the breeding room temperature is 20-26°C
  • humidity is 40-70%
  • ventilation is 10-20 times per hour
  • Light give animals cobalt 60 radiation sterilized complete pellet feed for rats, and unlimited free intake of drinking tap water sterilized by high-pressure steam.
  • Example 22 and Example 26 exhibited significant dose-dependent tumor suppression on the CDX model of ovarian cancer SK-OV-3, and Example 22 at 1.5 mg/kg
  • the TGI% of, 2.5mg/kg and 5mg/kg were 77.53%, 97.67% and 113.82%, respectively.
  • the TGI% of Example 26 at 1.5 mg/kg, 2.5 mg/kg, and 5 mg/kg were 69.59%, 103.05% and 109.13%, respectively.
  • Example 26 showed a dose-dependent tumor suppression on the CDX model of renal cancer Caki-1. It has obvious tumor suppression effects at the doses of 2.5 mg/kg and 5 mg/kg, and the tumor growth inhibition rate (TGI%) is 63.43% and respectively. 77.45%, the tumor weight analysis result was consistent with the relative tumor volume analysis result, and compared with the control group, there was a statistically significant difference (p ⁇ 0.01). In all the treatment groups of Example 26, there were no animal deaths and compound-related toxicity reactions, and the animal weights increased at the end of the administration. The experimental results are shown in Figure 6, Figure 7, Table 6 and Table 7.
  • the present invention provides a compound containing cyclobutyl. Experimental results show that the compound of the present invention can be used in the treatment of tumor diseases caused by abnormal activity of tyrosine kinases such as VEGFR, and has good application prospects.

Abstract

The present invention falls within the field of medical technology, and discloses a compound as shown by formula I or a pharmaceutically acceptable salt, cis- or trans-isomer, prodrug, metabolite, isotope derivative and solvate thereof. The compound of the present invention is a cyclobutyl-containing compound used as a tyrosine kinase inhibitor, and can be used for treating tumor diseases related to tyrosine kinase, especially VEGFR. Due to the presence of the cyclobutyl group, the substituents at 1- and 3-position have cis and trans configurations. The rigidity of a branched chain molecule and the directivity of the molecule can be enhanced, and the compound can easily be better bound to a target, so that the dosage of a drug can be reduced, and side effects of the drug is reduced. The present invention also provides a preparation method, the kinase activity, pharmacokinetic data, and pharmacodynamic data of the compound, and the results show that the compound of the present invention has a wide range of application in the treatment of tumor diseases caused by abnormal activity of tyrosine kinases such as VEGFR.

Description

血管生成抑制剂、其制备方法和应用Angiogenesis inhibitor, its preparation method and application
本申请要求于2020年3月18日提交中国专利局、申请号为202010193508.3、发明名称为“血管生成抑制剂、其制备方法及其应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。This application claims the priority of a Chinese patent application filed with the Chinese Patent Office on March 18, 2020, the application number is 202010193508.3, and the invention title is "angiogenesis inhibitor, its preparation method and its application", the entire content of which is incorporated by reference In this application.
技术领域Technical field
本发明属于医药技术领域，具体涉及一种用作血管生成抑制剂的化合物及其制备方法和应用。The invention belongs to the technical field of medicine, and specifically relates to a compound used as an angiogenesis inhibitor and a preparation method and application thereof.
背景技术Background technique
受体酪氨酸激酶是一种跨膜蛋白，具有胞外区、跨膜区以及胞内区三部分。胞内区的功能是作为激酶将蛋白质中的特定氨基酸残基磷酸化并影响细胞的增殖。酪氨酸激酶的变异或非正常的活性变化将导致病情的发生。酪氨酸激酶可以分为生长因子受体(例如EGFR、VEGFR、PDGFR、FGFR和erbB2)或者非受体激酶(如c-src、bcr-abl)。这些激酶可能在人类癌症中异常表达，比如乳腺癌、结直肠癌、胃癌、血癌和卵巢癌等等。Receptor tyrosine kinase is a transmembrane protein with three parts: extracellular domain, transmembrane domain and intracellular domain. The function of the intracellular domain is to act as a kinase to phosphorylate specific amino acid residues in proteins and affect cell proliferation. Variation of tyrosine kinase or abnormal activity changes will lead to the occurrence of the disease. Tyrosine kinases can be classified into growth factor receptors (such as EGFR, VEGFR, PDGFR, FGFR, and erbB2) or non-receptor kinases (such as c-src, bcr-abl). These kinases may be abnormally expressed in human cancers, such as breast cancer, colorectal cancer, gastric cancer, blood cancer, and ovarian cancer.
血管生成是一般生理过程的重要组成部分，比如胚胎的形成和创伤的愈合。但是，变异的血管生成会导致相关疾病的发生，比如银屑病、风湿性关节炎、动脉粥样化、肿瘤等。肿瘤血管的生成主要是通过肿瘤内血管内皮细胞生长因子(VEGF)来调节，其通过至少两种不同的受体(VEGFR1、VEGFR2)发挥作用。VEGF受体对血管内皮细胞具有高度的特异性，VEGF与其受体VEGFR结合，产生一系列生理和生化反应，最终促进新生血管的生成。在正常血管中，血管生成因子和血管生成抑制因子保持着比较平衡的水平，而在肿瘤的生长过程中，VEGF和VEGFR的高表达破坏了这种平衡，促进了肿瘤新生血管的形成。Angiogenesis is an important part of general physiological processes, such as embryo formation and wound healing. However, variant angiogenesis can lead to related diseases, such as psoriasis, rheumatoid arthritis, atheroma, and tumors. Tumor angiogenesis is mainly regulated by vascular endothelial cell growth factor (VEGF) in the tumor, which acts through at least two different receptors (VEGFR1, VEGFR2). VEGF receptor is highly specific to vascular endothelial cells. VEGF combines with its receptor VEGFR to produce a series of physiological and biochemical reactions, and ultimately promote the formation of new blood vessels. In normal blood vessels, angiogenesis factors and angiogenesis inhibitors maintain a relatively balanced level. In the process of tumor growth, the high expression of VEGF and VEGFR disrupts this balance and promotes the formation of tumor new blood vessels.
目前在血管内皮生长因子抑制剂类药物中，西地尼布是一种药效比较强的药物。西地尼布的化学结构如下所示。At present, among the vascular endothelial growth factor inhibitor drugs, cediranib is a relatively powerful drug. The chemical structure of cediranib is shown below.
Figure PCTCN2021073616-appb-000001
Figure PCTCN2021073616-appb-000001
西地尼布曾用于卵巢癌、胆囊癌、肾细胞癌、前列腺癌、宫颈癌等的临床研究。但是，由于西地尼布不良反应明显(主要是高血压、疲劳、腹泻、手足综合征等)，最终在欧盟未被批准上市。Cediranib has been used in clinical research for ovarian cancer, gallbladder cancer, renal cell carcinoma, prostate cancer, cervical cancer, etc. However, due to the obvious adverse reactions of cediranib (mainly hypertension, fatigue, diarrhea, hand-foot syndrome, etc.), it was finally not approved for marketing in the EU.
在结构上与本发明化合物类似的化合物的实施例在以下文献中公开：WO2008112407，WO2000047212。Examples of compounds structurally similar to the compounds of the present invention are disclosed in the following documents: WO2008112407, WO2000047212.
发明内容Summary of the invention
针对现有技术中存在的问题，本发明提供了一种用作酪氨酸激酶抑制剂的含有环丁基的化合物，该化合物具有式(I)所示的结构。本发明的化合物及其药学上可接受的盐、前药、同位素衍生物和溶剂化物，及其包含所述化合物的药物组合物，可以用于治疗与酪氨酸激酶，尤其是与VEGFR相关的肿瘤疾病的治疗。In view of the problems in the prior art, the present invention provides a cyclobutyl-containing compound used as a tyrosine kinase inhibitor, the compound having a structure represented by formula (I). The compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, isotopic derivatives and solvates, and pharmaceutical compositions containing the compounds, can be used for the treatment of tyrosine kinases, especially those related to VEGFR Treatment of tumor diseases.
本发明的化合物具有式I所示的结构：The compound of the present invention has the structure shown in formula I:
Figure PCTCN2021073616-appb-000002
Figure PCTCN2021073616-appb-000002
其中，X选自-C(H)-、N、-C(F)-、-C(CF 3)-、-C(CN)-； Wherein, X is selected from -C(H)-, N, -C(F)-, -C(CF 3 )-, -C(CN)-;
R选自羟基、羧基、酯基、-N(R 1R 2)，或R选自氧原子且氧原子与与其直接相连的环丁基形成酮羰基； R is selected from a hydroxyl group, a carboxyl group, an ester group, -N(R 1 R 2 ), or R is selected from an oxygen atom and the oxygen atom forms a ketone carbonyl group with the cyclobutyl group directly connected to it;
R 1和R 2相同或不同，分别独立地选自氢、C 1-C 10烷基、C 3-C 7环烷基、C 2-C 10烯基、C 2-C 10炔基、Ar； R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, Ar ；
R 1和R 2与所连接的氮原子形成4-10元杂环基，所述杂环基的环上还 包括任选的N、O、S中的至少一种原子；且所述杂环基上的氢原子任选地被1-3个相同或不同的R 3取代； R 1 and R 2 form a 4-10 membered heterocyclic group with the nitrogen atom to which they are connected, and the ring of the heterocyclic group further includes at least one atom of N, O, and S; and the heterocyclic ring The hydrogen atom on the group is optionally substituted with 1-3 R 3 which are the same or different;
R 3选自氢、C 1-C 4烷基、C 1-C 4烷氧基、卤素、三氟甲基、羟基、氨基、羧基、酯基； R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, ester group;
Ar选自C 6-C 10芳基、5-10元杂芳基，其中，杂芳基含有1-3个选自N、O和S中的杂原子；Ar可以被1-3个相同或不同的R 4取代；R 4选自氢、羟基、卤素、三氟甲基、硝基、氨基、腈基、磺酸基、磺酰胺基、C 1-C 6烷基、C 1-C 6烷基酰基、C 3-C 6环烷基。 Ar is selected from C 6 -C 10 aryl groups, 5-10 membered heteroaryl groups, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O and S; Ar can be the same or 1-3 Different R 4 substitutions; R 4 is selected from hydrogen, hydroxyl, halogen, trifluoromethyl, nitro, amino, nitrile, sulfonic acid, sulfonamide, C 1 -C 6 alkyl, C 1 -C 6 Alkyl acyl, C 3 -C 6 cycloalkyl.
本发明的发明人通过分析西地尼布的构效关系以及体内药代特点，发现其结构中有影响代谢的官能团存在，使得其半衰期较长，超过了30小时，导致不良反应发生。本发明在西地尼布结构基础上，进行构效关系分析，对其进行了结构的优化，一方面保持了其活性(甚至高于西地尼布)，另一方面改善其药代动力学性质，缩短药物的半衰期，提高其成药性。在本发明的化合物中，分子支链(即，R-环丁基甲基-氧基)上环丁基基团的存在能够增加环丁基所在的支链的刚性，同时，四元环的存在，使得1,3位取代基具有順式以及反式构型，增加了分子的方向性，使化合物易于与靶标更好的结合，从而可以增加药物的活性，减少药物的剂量，减轻药物的副作用。The inventors of the present invention analyzed the structure-activity relationship and in vivo pharmacokinetic characteristics of cediranib and found that there are functional groups in the structure that affect metabolism, which makes the half-life longer, exceeding 30 hours, leading to adverse reactions. The present invention performs structure-activity relationship analysis on the basis of the structure of cediranib, and optimizes its structure. On the one hand, it maintains its activity (even higher than that of cediranib), and on the other hand, it improves its pharmacokinetics. Nature, shorten the half-life of the drug, and improve its druggability. In the compound of the present invention, the presence of a cyclobutyl group on the molecular branch (ie, R-cyclobutylmethyl-oxy) can increase the rigidity of the branch where the cyclobutyl is located. At the same time, the presence of a four-membered ring, Make the 1,3-position substituents have cis and trans configurations, increase the directionality of the molecule, and make the compound easier to bind to the target, thereby increasing the activity of the drug, reducing the dose of the drug, and reducing the side effects of the drug.
本发明化合物的分子支链中含有环丁基，环丁基使得本发明化合物具有明显的优势。环丙基与环丁基相比，虽然环丙基也能增加分子支链的刚性，但是，含有环丙基支链的化合物存在明显的代谢问题，半衰期特别长。而环戊基和环己基相对于环丁基而言，环戊基与环己基的构象相对多一些(例如，环己基具有椅式构象和船式构象)，导致分子支链的刚性不够。The molecular branch of the compound of the present invention contains cyclobutyl, and the cyclobutyl makes the compound of the present invention have obvious advantages. Compared with cyclobutyl, cyclopropyl can also increase the rigidity of molecular branches, but compounds containing cyclopropyl branches have obvious metabolic problems and have a particularly long half-life. Compared with cyclobutyl, cyclopentyl and cyclohexyl have relatively more conformations (for example, cyclohexyl has a chair conformation and a boat conformation), resulting in insufficient rigidity of molecular branches.
优选地，在本发明所述化合物的一些实施方式中，X选自-C(F)-、-C(CF 3)-、-C(CN)-。氟原子、三氟甲基和氰基都是强吸电子基团，这些强吸电子基团能够与靶标蛋白形成氢键，增强与靶标的结合力，从而进一步增强药物活性，减少用药剂量，减少毒副作用。 Preferably, in some embodiments of the compound of the present invention, X is selected from -C(F)-, -C(CF 3 )-, -C(CN)-. Fluorine atoms, trifluoromethyl groups and cyano groups are all strong electron-withdrawing groups. These strong electron-withdrawing groups can form hydrogen bonds with the target protein to enhance the binding force with the target, thereby further enhancing the activity of the drug, reducing the dosage and reducing toxic side effect.
在本发明所述化合物中一些实施方式中，基团R与与R连接亚甲基(-CH 2-)以及与处于该亚甲基间位的亚甲基还可以形成式II所示的顺式结构或式III所示的反式结构，如下所示。 In some embodiments of the compound of the present invention, the group R and the methylene group (-CH 2 -) connected to R and the methylene group at the meta position of the methylene group can also form a cis group shown in formula II. The formula structure or the trans structure shown in formula III is as follows.
Figure PCTCN2021073616-appb-000003
Figure PCTCN2021073616-appb-000003
例如，当R选自羟基、羧基、酯基、-N(R 1R 2)时，本发明的化合物表现出顺式或反式结构。 For example, when R is selected from a hydroxyl group, a carboxyl group, an ester group, and -N(R 1 R 2 ), the compound of the present invention exhibits a cis or trans structure.
优选地，在本发明所述化合物中，R 1和R 2相同或不同，分别独立地选自氢、C 1-C 10烷基、C 3-C 7环烷基、Ar；Ar选自苯基、萘基、喹啉基、吡啶基、呋喃基、噻吩基、吡咯基。在这些化合物中，分子结构包含与环丁基连接的NR 1R 2基团。这些与环丁基连接的末端取代基具有一定的自由度，导致取代基团与靶标突变位点接触的几率增加，从而可以增加基团的选择性。例如，R 1和R 2可以单独成链状及芳香环，而芳香环或芳香杂环能够增加整个分子的脂溶性，以利于分子到达病患部位。 Preferably, in the compound of the present invention, R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar; Ar is selected from benzene Group, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl. In these compounds, the molecular structure contains the NR 1 R 2 group attached to the cyclobutyl group. These terminal substituents connected to the cyclobutyl group have a certain degree of freedom, which leads to an increase in the probability of the substituent group contacting the target mutation site, thereby increasing the group selectivity. For example, R 1 and R 2 can form a chain and an aromatic ring separately, and an aromatic ring or an aromatic heterocyclic ring can increase the fat solubility of the entire molecule, so that the molecule can reach the patient's site.
优选地，在本发明所述化合物中，R 1和R 2相同或不同，分别独立地选自氢、C 1-C 10烷基、C 3-C 7环烷基、Ar；Ar选自苯基、萘基、喹啉基、吡啶基、呋喃基、噻吩基、吡咯基；杂环基选自1-哌啶基、4-吗啉基、1-吡咯烷基、4-甲基-1-哌啶基、1-环丁胺基。在这些化合物中，分子结构包含与环丁基连接的-N(R 1R 2)基团。这些基团能够延长环丁基侧链的刚性强度，进一步增加支链分子的刚性，以增加分子的方向性，易于与靶标更好地结合。 Preferably, in the compound of the present invention, R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar; Ar is selected from benzene Group, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl; heterocyclic group is selected from 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 4-methyl-1 -Piperidinyl, 1-cyclobutylamino. In these compounds, the molecular structure contains a -N(R 1 R 2 ) group linked to a cyclobutyl group. These groups can extend the rigidity of the side chain of the cyclobutyl, further increase the rigidity of the branched molecule, so as to increase the directionality of the molecule, and it is easy to better combine with the target.
本发明所述的化合物选自以下化合物中的任意一种：The compound of the present invention is selected from any one of the following compounds:
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁醇3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutanol
Figure PCTCN2021073616-appb-000004
Figure PCTCN2021073616-appb-000004
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutylamine
Figure PCTCN2021073616-appb-000005
Figure PCTCN2021073616-appb-000005
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁酸3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyric acid
Figure PCTCN2021073616-appb-000006
Figure PCTCN2021073616-appb-000006
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)-N,N-二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)-N,N -Dimethylcyclobutylamine
Figure PCTCN2021073616-appb-000007
Figure PCTCN2021073616-appb-000007
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啉环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morpholinocyclobutyl)methoxy)quinazoline
Figure PCTCN2021073616-appb-000008
Figure PCTCN2021073616-appb-000008
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-3-(三氟甲基)苯胺N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-3-(trifluoromethyl)aniline
Figure PCTCN2021073616-appb-000009
Figure PCTCN2021073616-appb-000009
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-3-(三氟甲基)2,3-二甲基苯胺N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-3-(trifluoromethyl)2,3-dimethylaniline
Figure PCTCN2021073616-appb-000010
Figure PCTCN2021073616-appb-000010
4-氟-氮-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-氮-甲基苯胺4-Fluoro-nitrogen-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy) (Methyl)cyclobutyl)-nitrogen-methylaniline
Figure PCTCN2021073616-appb-000011
Figure PCTCN2021073616-appb-000011
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy ) Quinazoline
Figure PCTCN2021073616-appb-000012
Figure PCTCN2021073616-appb-000012
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy) Quinazoline
Figure PCTCN2021073616-appb-000013
Figure PCTCN2021073616-appb-000013
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-氮杂环丁烷-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-azetidin-1-yl)cyclobutyl) (Methoxy)quinazoline
Figure PCTCN2021073616-appb-000014
Figure PCTCN2021073616-appb-000014
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutylamine
Figure PCTCN2021073616-appb-000015
Figure PCTCN2021073616-appb-000015
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)-氮,氮二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)-nitrogen, nitrogen Methylcyclobutylamine
Figure PCTCN2021073616-appb-000016
Figure PCTCN2021073616-appb-000016
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutanol
Figure PCTCN2021073616-appb-000017
Figure PCTCN2021073616-appb-000017
7-((3-(二甲基胺)环丁基)甲氧基)-4-(4-氟-2甲基-1H-吲哚-5-基氧基)-3-腈基-6-甲氧基喹啉7-((3-(Dimethylamine)cyclobutyl)methoxy)-4-(4-fluoro-2methyl-1H-indol-5-yloxy)-3-cyano-6 -Methoxyquinoline
Figure PCTCN2021073616-appb-000018
Figure PCTCN2021073616-appb-000018
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-(哌啶-1基)环丁基)甲氧基)-3-腈基喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-(piperidin-1-yl)cyclobutyl)methoxy )-3-cyanoquinoline
Figure PCTCN2021073616-appb-000019
Figure PCTCN2021073616-appb-000019
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啡环丁基)甲氧基)-3-腈基喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morphinecyclobutyl)methoxy)-3-nitrile quinoline
Figure PCTCN2021073616-appb-000020
Figure PCTCN2021073616-appb-000020
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-7-((3-羟基环丁基)甲氧基)-3-腈基-6-甲氧基喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-7-((3-hydroxycyclobutyl)methoxy)-3-cyano-6-methoxy quinoline
Figure PCTCN2021073616-appb-000021
Figure PCTCN2021073616-appb-000021
3-((3-氟-4(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇3-((3-Fluoro-4(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutane alcohol
Figure PCTCN2021073616-appb-000022
Figure PCTCN2021073616-appb-000022
7-((3-氨基环丁基)甲氧基)-4-(4-氟-2-甲基-1H-5-基氧基)-3-腈基-6甲氧基喹啉7-((3-Aminocyclobutyl)methoxy)-4-(4-fluoro-2-methyl-1H-5-yloxy)-3-cyano-6methoxyquinoline
Figure PCTCN2021073616-appb-000023
Figure PCTCN2021073616-appb-000023
4-氟-氮-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)苯胺4-Fluoro-nitrogen-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy) (Methyl)cyclobutyl)aniline
Figure PCTCN2021073616-appb-000024
Figure PCTCN2021073616-appb-000024
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-3-(三氟甲基)喹啉-7-基氧基)甲基)-氮,氮二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-3-(trifluoromethyl)quinolin-7-yloxy )Methyl)-nitrogen, azadimethylcyclobutylamine
Figure PCTCN2021073616-appb-000025
Figure PCTCN2021073616-appb-000025
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)环己)环丁基)环己胺N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)cyclohexyl) ring Butyl) cyclohexylamine
Figure PCTCN2021073616-appb-000026
Figure PCTCN2021073616-appb-000026
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)环己)环丁基)环戊胺N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)cyclohexyl) ring Butyl) cyclopentylamine
Figure PCTCN2021073616-appb-000027
Figure PCTCN2021073616-appb-000027
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)环己)环丁基)环丁胺N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)cyclohexyl) ring Butyl) cyclobutylamine
Figure PCTCN2021073616-appb-000028
Figure PCTCN2021073616-appb-000028
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )Cyclobutylamine
Figure PCTCN2021073616-appb-000029
Figure PCTCN2021073616-appb-000029
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )Cyclobutylamine
Figure PCTCN2021073616-appb-000030
Figure PCTCN2021073616-appb-000030
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine
Figure PCTCN2021073616-appb-000031
Figure PCTCN2021073616-appb-000031
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine
Figure PCTCN2021073616-appb-000032
Figure PCTCN2021073616-appb-000032
顺式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉Cis-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine
Figure PCTCN2021073616-appb-000033
Figure PCTCN2021073616-appb-000033
反式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉Trans-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine
Figure PCTCN2021073616-appb-000034
Figure PCTCN2021073616-appb-000034
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinazoline
Figure PCTCN2021073616-appb-000035
Figure PCTCN2021073616-appb-000035
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinazoline
Figure PCTCN2021073616-appb-000036
Figure PCTCN2021073616-appb-000036
顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclohexylamine
Figure PCTCN2021073616-appb-000037
Figure PCTCN2021073616-appb-000037
顺式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑 啉-7-基)氧)甲基)环丁胺Cis-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- (Yl)oxy)methyl)cyclobutylamine
Figure PCTCN2021073616-appb-000038
Figure PCTCN2021073616-appb-000038
顺式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Cis-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutylamine
Figure PCTCN2021073616-appb-000039
Figure PCTCN2021073616-appb-000039
顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclopentylamine
Figure PCTCN2021073616-appb-000040
Figure PCTCN2021073616-appb-000040
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinazoline
Figure PCTCN2021073616-appb-000041
Figure PCTCN2021073616-appb-000041
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环 丁基)甲氧基)喹唑啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl (Oxy)quinazoline
Figure PCTCN2021073616-appb-000042
Figure PCTCN2021073616-appb-000042
反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclohexylamine
Figure PCTCN2021073616-appb-000043
Figure PCTCN2021073616-appb-000043
反式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Trans-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- (Yl)oxy)methyl)cyclobutylamine
Figure PCTCN2021073616-appb-000044
Figure PCTCN2021073616-appb-000044
反式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Trans-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutylamine
Figure PCTCN2021073616-appb-000045
Figure PCTCN2021073616-appb-000045
反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基) 氧)甲基)环丁基)环戊胺Trans-N-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclopentylamine
Figure PCTCN2021073616-appb-000046
Figure PCTCN2021073616-appb-000046
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine
Figure PCTCN2021073616-appb-000047
Figure PCTCN2021073616-appb-000047
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine
Figure PCTCN2021073616-appb-000048
Figure PCTCN2021073616-appb-000048
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Cyclobutylamine
Figure PCTCN2021073616-appb-000049
Figure PCTCN2021073616-appb-000049
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Cyclobutylamine
Figure PCTCN2021073616-appb-000050
Figure PCTCN2021073616-appb-000050
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine
Figure PCTCN2021073616-appb-000051
Figure PCTCN2021073616-appb-000051
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine
Figure PCTCN2021073616-appb-000052
Figure PCTCN2021073616-appb-000052
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinoline
Figure PCTCN2021073616-appb-000053
Figure PCTCN2021073616-appb-000053
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinoline
Figure PCTCN2021073616-appb-000054
Figure PCTCN2021073616-appb-000054
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinoline
Figure PCTCN2021073616-appb-000055
Figure PCTCN2021073616-appb-000055
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl (Oxy)quinoline
Figure PCTCN2021073616-appb-000056
Figure PCTCN2021073616-appb-000056
1-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N, N-Dimethylcyclopropylamine
Figure PCTCN2021073616-appb-000057
Figure PCTCN2021073616-appb-000057
1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine
Figure PCTCN2021073616-appb-000058
Figure PCTCN2021073616-appb-000058
1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine
Figure PCTCN2021073616-appb-000059
Figure PCTCN2021073616-appb-000059
1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine
Figure PCTCN2021073616-appb-000060
Figure PCTCN2021073616-appb-000060
1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethyl Cyclopropylamine
Figure PCTCN2021073616-appb-000061
Figure PCTCN2021073616-appb-000061
本发明还提供了一种制备权利要求1所述的式I化合物的方法，所述方法包括以下反应路线：The present invention also provides a method for preparing the compound of formula I according to claim 1, said method comprising the following reaction route:
Figure PCTCN2021073616-appb-000062
Figure PCTCN2021073616-appb-000062
在本发明的制备方法中，所述方法包括以下步骤：In the preparation method of the present invention, the method includes the following steps:
(1)将sm1与sm2溶解于溶剂1中，加入碱性试剂，在50-100℃的温度范围内进行反应，得到化合物C01；(1) Dissolve sm1 and sm2 in solvent 1, add alkaline reagents, and react in the temperature range of 50-100°C to obtain compound C01;
(2)将化合物C01溶解于溶剂2中，通过氢化反应脱去苄基，得到化合物C02；(2) The compound C01 is dissolved in solvent 2, and the benzyl group is removed by hydrogenation reaction to obtain compound C02;
(3)将化合物C02溶解于溶剂3中，加入sm3、DIAD和PPh 3，在20℃温至50℃的温度范围内反应，得到化合物C03； (3) Compound 3 C02 dissolved in the solvent, is added sm3, DIAD and PPh3 3, the reaction was warmed to 50 deg.] C in the temperature range of 20 ℃, to give Compound C03;
优选地，在步骤(1)中，所述溶剂1选自DMSO、DMF、乙腈、甲醇、乙醇、叔丁醇中的至少一种；所述碱性试剂选自碳酸铯、碳酸钾、碳酸钠、甲醇钠、乙醇钠、叔丁醇钠中的至少一种；Preferably, in step (1), the solvent 1 is selected from at least one of DMSO, DMF, acetonitrile, methanol, ethanol, and tert-butanol; the alkaline reagent is selected from cesium carbonate, potassium carbonate, and sodium carbonate , At least one of sodium methoxide, sodium ethoxide, and sodium tert-butoxide;
优选地，在步骤(2)中，所述溶剂2选自甲醇、乙醇、异丙醇、叔丁醇中的至少一种。化合物C01中的苄基可以采用本领域常用的方法来脱去。在本发明的方法中，通过氢化反应将苄基脱去，其中，所述氢化还原反应包括在Pd/C催化剂的催化下，用氢气对化合物C01进行氢化，以脱去苄基。Pd/C催化剂可以采用工业上常用的5wt％Pd/C或10wt％Pd/C(5wt％或10wt％表示Pd/C催化剂混合物中金属钯的质量比)。以化合物C01的质量计，5wt％Pd/C或10wt％Pd/C的添加比例范围为5％～20％；Preferably, in step (2), the solvent 2 is selected from at least one of methanol, ethanol, isopropanol, and tert-butanol. The benzyl group in compound C01 can be removed using methods commonly used in the art. In the method of the present invention, the benzyl group is removed by a hydrogenation reaction, wherein the hydrogenation reduction reaction includes hydrogenation of the compound C01 with hydrogen under the catalysis of a Pd/C catalyst to remove the benzyl group. The Pd/C catalyst can be 5wt% Pd/C or 10wt% Pd/C commonly used in industry (5wt% or 10wt% represents the mass ratio of metal palladium in the Pd/C catalyst mixture). Based on the mass of compound C01, the addition ratio of 5wt% Pd/C or 10wt% Pd/C ranges from 5% to 20%;
优选地，在步骤(3)中，所述溶剂3选自THF(四氢呋喃)、DMF(N,N-二甲基甲酰胺)、DCM(二氯甲烷)中的至少一种。Preferably, in step (3), the solvent 3 is selected from at least one of THF (tetrahydrofuran), DMF (N,N-dimethylformamide), and DCM (dichloromethane).
本发明还提供了一种药物组合物，其包含本发明所述的化合物或化合物的药学上可接受的盐或化合物的溶剂化物，以及药学上可接受的载体。The present invention also provides a pharmaceutical composition, which comprises the compound or a pharmaceutically acceptable salt of the compound or a solvate of the compound, and a pharmaceutically acceptable carrier.
为了适应不同的给药方式，本发明的药物组合物可以制成多种剂型。具体地，本发明所述药物组合物的制剂形式可以是口服制剂或注射剂。In order to adapt to different modes of administration, the pharmaceutical composition of the present invention can be made into a variety of dosage forms. Specifically, the preparation form of the pharmaceutical composition of the present invention may be an oral preparation or an injection.
本发明的化合物是一种酪氨酸激酶活性抑制剂，当其制备成各种制剂 后，可以应用在治疗因蛋白激酶VEGFR2、EGFR、FGFR、RET的异常活性所引起的疾病中，这些疾病可以是恶性肿瘤或癌症。例如，卵巢癌、肾癌、甲状腺髓样癌、肝癌、胃癌、食管癌、肺癌、胆管癌、胆道癌、结直肠癌、乳腺癌、前列腺癌、胰腺癌、黑色素瘤等。The compound of the present invention is an inhibitor of tyrosine kinase activity. When it is prepared into various preparations, it can be used in the treatment of diseases caused by the abnormal activity of protein kinases VEGFR2, EGFR, FGFR, and RET. These diseases can be It is a malignant tumor or cancer. For example, ovarian cancer, kidney cancer, medullary thyroid cancer, liver cancer, stomach cancer, esophageal cancer, lung cancer, cholangiocarcinoma, biliary tract cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, melanoma, etc.
在本发明所述的化合物所治疗的疾病中，所述疾病为肿瘤血管形成。Among the diseases treated by the compounds of the present invention, the diseases are tumor angiogenesis.
本发明提供了一种治疗癌症或肿瘤血管形成的方法，所述方法包括对需要治疗的患者给予有效剂量的本发明所述的化合物。The present invention provides a method for treating cancer or tumor angiogenesis, which method comprises administering an effective dose of the compound of the present invention to a patient in need of treatment.
本发明的含义内，有如下使用术语：Within the meaning of the present invention, the following terms are used:
“卤素”是指F、Cl、Br、I、At。"Halogen" means F, Cl, Br, I, At.
“C 1-C 10烷基”是指具有1-10个碳原子的烷基链，可以是直链，也可以带支链。例如：甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等等。C1-10烷基碳可上的氢原子可以进一步被规定的取代基取代。 "C 1 -C 10 alkyl" refers to an alkyl chain having 1-10 carbon atoms, which may be straight or branched. For example: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl and so on. The hydrogen atom on the C1-10 alkyl carbon may be further substituted with a predetermined substituent.
“C 3-C 7环烷基”是指具有3-7个碳原子的环烷基链，例如环丙基、环丁基、环戊基、环己基、环庚基。环烷基中的碳原子上的氢原子可被规定的取代基取代。 "C 3 -C 7 cycloalkyl" refers to a cycloalkyl chain having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The hydrogen atom on the carbon atom in the cycloalkyl group may be substituted with a predetermined substituent.
“C 2-C 10烯基”是指具有2-10个碳原子的含碳-碳双键的烯链，碳-碳双键可以在主链上，也可以在支链上，例如：乙烯基、丙烯基、丁烯基、异丁烯基等等。C2-10上的碳原子上的氢原子可以进一步被规定的取代基取代。 "C 2 -C 10 alkenyl" refers to an alkene chain with 2-10 carbon atoms containing a carbon-carbon double bond. The carbon-carbon double bond can be on the main chain or on a branch, such as ethylene Group, propenyl, butenyl, isobutenyl, etc. The hydrogen atom on the carbon atom on C2-10 may be further substituted with a predetermined substituent.
“C 2-C 10炔基”是指具有2-10个碳原子的含碳-碳三键的烯链，碳-碳三键可以在主链上，也可以在支链上，例如：乙炔基、丙炔基、丁炔基、异丁炔基等等。C2-10上的碳原子上的氢可以进一步被规定的取代基取代。 "C 2 -C 10 alkynyl" refers to an alkene chain with 2-10 carbon atoms containing a carbon-carbon triple bond. The carbon-carbon triple bond can be on the main chain or on a branch, such as acetylene Group, propynyl, butynyl, isobutynyl, etc. The hydrogen on the carbon atom on C2-10 may be further substituted with a predetermined substituent.
“Ar”可以是指具有6-10个碳原子的芳香单环基、双环基，也可以是5-10元单环/双环杂芳基。同时，环上的碳原子可以被N、O、S原子取代，例如苯基、萘基、喹啉基、异喹啉基、吡啶基、呋喃基、噻吩基、吡咯基等等；环上碳原子的氢可以进一步被规定的取代基取代。"Ar" can refer to an aromatic monocyclic or bicyclic group having 6-10 carbon atoms, or a 5-10 membered monocyclic/bicyclic heteroaryl group. At the same time, the carbon atoms on the ring can be substituted by N, O, S atoms, such as phenyl, naphthyl, quinolyl, isoquinolyl, pyridyl, furyl, thienyl, pyrrolyl, etc.; ring carbon The hydrogen of the atom may be further substituted with a predetermined substituent.
“前药”是指在生理条件下，在活体内通过酶催化进行的氧化、还原、水解等反应而转化为本发明化合物的衍生物。"Prodrug" refers to a derivative of the compound of the present invention that is converted into a derivative of the compound of the present invention by oxidation, reduction, hydrolysis and other reactions catalyzed by enzymes in the living body under physiological conditions.
“代谢物”是指在细胞或有机体(优选人)中，产生的源自于本发明化合物的所有分子。"Metabolite" refers to all molecules derived from the compounds of the present invention produced in cells or organisms (preferably humans).
“同位素衍生物”是指构成本发明化合物的结构中，含有一个或多个以非天然比例存在的同位素原子。例如氘(2H或D)，碳-13(13C)，氮-15 (15N)。"Isotopic derivative" refers to the structure constituting the compound of the present invention that contains one or more isotope atoms existing in unnatural proportions. For example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N).
“溶剂化物”是指本发明化合物与溶剂分子通过物理结合的形式形成溶剂络合物。该物理结合包含氢键结合。常规溶剂包含水、甲醇、乙醇、乙酸、四氢呋喃、乙酸乙酯、乙腈等。式(I)化合物可以结晶形式制备且可呈溶剂化物形式(包括水合物形式)。"Solvate" means that the compound of the present invention and the solvent molecule form a solvent complex in the form of physical bonding. This physical bond includes hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, tetrahydrofuran, ethyl acetate, acetonitrile and the like. Compounds of formula (I) can be prepared in crystalline form and can be in solvate form (including hydrate form).
式(I)化合物的药学上可接受的盐，包含一个或多个碱性或酸性基团，特别是其药学上可以利用的盐。例如碱金属盐、碱土金属盐、铵盐。更精确的可以是钠盐、钾盐、钙盐、镁盐或有机胺如乙胺、乙醇胺、三乙胺或氨基酸盐。本发明化合物可以与无机酸或有机酸形成被质子化的式(I)化合物，酸的实例包括盐酸、硫酸、磷酸、硝酸、甲磺酸、乳酸、苹果酸、马来酸、酒石酸等以及本领域人员已知的其他酸。The pharmaceutically acceptable salt of the compound of formula (I) contains one or more basic or acidic groups, especially the pharmaceutically usable salt thereof. For example, alkali metal salt, alkaline earth metal salt, ammonium salt. More precisely, it may be sodium salt, potassium salt, calcium salt, magnesium salt or organic amine such as ethylamine, ethanolamine, triethylamine or amino acid salt. The compounds of the present invention can form protonated compounds of formula (I) with inorganic or organic acids. Examples of acids include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, lactic acid, malic acid, maleic acid, tartaric acid, etc. Other acids known to those skilled in the art.
“药物组合物”在用作药物时，是指本发明式(I)化合物以及其盐、同位素衍生物、代谢物、前药、溶剂化物与其他具有或不具有生物活性物质组成的组合物，可以用于治疗或预防与蛋白酶酪氨酸激酶受体相关的疾病为增殖性疾病(包括血管生成)，如实体瘤、血液瘤等。"Pharmaceutical composition" when used as a medicine refers to the composition of the compound of formula (I) of the present invention and its salts, isotope derivatives, metabolites, prodrugs, solvates and other substances with or without biological activity, It can be used to treat or prevent proliferative diseases (including angiogenesis) related to protease tyrosine kinase receptors, such as solid tumors and hematomas.
附图说明Description of the drawings
图1是本发明所述的式I化合物的通式结构；Figure 1 is the general structure of the compound of formula I according to the present invention;
图2示出了实施例22的化合物应用在卵巢癌SK-OV-3模型中的平均肿瘤体积；Figure 2 shows the average tumor volume of the compound of Example 22 applied in an ovarian cancer SK-OV-3 model;
图3示出了实施例22的化合物应用在卵巢癌SK-OV-3模型中的实验动物的体重变化；Figure 3 shows the body weight changes of experimental animals in which the compound of Example 22 is applied in an ovarian cancer SK-OV-3 model;
图4示出了实施例26的化合物应用在卵巢癌SK-OV-3模型中的实验动物的平均肿瘤体积；Figure 4 shows the average tumor volume of experimental animals in which the compound of Example 26 is applied in an ovarian cancer SK-OV-3 model;
图5示出了实施例26的化合物应用在卵巢癌SK-OV-3模型中的实验动物体重变化；Figure 5 shows the weight change of experimental animals when the compound of Example 26 is applied in an ovarian cancer SK-OV-3 model;
图6示出了实施例26的化合物应用在肾癌Caki-1模型中的实验动物的平均肿瘤体积；Figure 6 shows the average tumor volume of experimental animals in which the compound of Example 26 is applied in the Caki-1 model of renal cancer;
图7示出了实施例26的化合物应用在肾癌Caki-1模型中各实验组的实验动物的体重变化。Figure 7 shows the weight changes of experimental animals in each experimental group in the application of the compound of Example 26 in the Caki-1 model of renal cancer.
具体实施方式Detailed ways
下面通过具体实施例对本发明进行详细的说明。The present invention will be described in detail below through specific embodiments.
实施例1Example 1
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutylamine
化合物结构：Compound structure:
Figure PCTCN2021073616-appb-000063
Figure PCTCN2021073616-appb-000063
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000064
Figure PCTCN2021073616-appb-000064
合成方法：resolve resolution:
7-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉的制备：Preparation of 7-(benzyloxy)-4-((4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazoline:
向反应瓶中加入4-氟-5-羟基-2-甲基吲哚(1.65g,1eq)，7-苄氧基-4-氯-6-甲氧基喹唑啉(3.0g,1eq)，N,N-二甲基甲酰胺(60mL)和碳酸铯(9.75g,3eq)，室温搅拌5min后升温100℃氮气保护下反应16小时。LCMS检测反应完全，停止反应，降温至室温后，加水(500mL)，乙酸乙酯(200mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品硅胶柱层析得到7-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉(2.3g,收率53％)。MS:[M+1]+:430.1.Add 4-fluoro-5-hydroxy-2-methylindole (1.65g, 1eq), 7-benzyloxy-4-chloro-6-methoxyquinazoline (3.0g, 1eq) to the reaction flask , N,N-dimethylformamide (60mL) and cesium carbonate (9.75g, 3eq) were stirred at room temperature for 5min, and then heated at 100°C to react for 16 hours under nitrogen protection. LCMS detects that the reaction is complete. Stop the reaction. After cooling to room temperature, add water (500mL), extract with ethyl acetate (200mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, crude silica gel Column chromatography gave 7-(benzyloxy)-4-((4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazoline (2.3g, yield 53%) MS: [M+1]+: 430.1.
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-醇的制备：Preparation of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-ol:
向反应瓶中加入7-(苄氧基)-4-((4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉(2.3g,1eq)，甲醇(100mL)和钯碳(5wt％Pd/C,460mg,投料比20％)，氢气置换三次。在2atm的氢气环境下室温反应20min，LCMS表征反应完全，停止反应，抽滤掉固体，浓缩得到4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-醇(1.9g)粗品。MS:[M+1]+:340.1.该粗品直接用于下一步反应，不进行任何提纯处理。Add 7-(benzyloxy)-4-((4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazoline (2.3g, 1eq), methanol (100mL) and palladium on carbon (5wt%Pd/C, 460mg, feed ratio 20%), hydrogen replacement three times. Reaction at room temperature under 2atm hydrogen environment for 20min, LCMS characterizes the reaction to be complete, stop the reaction, and filter it off with suction The solid was concentrated to give crude 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolin-7-ol (1.9g). MS: [M +1]+:340.1. The crude product was directly used in the next reaction without any purification treatment.
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮的制备：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyl ketone Preparation:
将4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-醇(200.0mg,1eq)，3-(羟甲基)环丁烷-1-酮(SM1，118.0mg,2eq)和三苯基膦(PPh 3，386.4mg,2.5eq)溶于新蒸的四氢呋喃(5mL)中，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(DIAD)(357.5mg,3eq)，室温搅拌过夜，LCMS检测反应完全，停止反应，加水(25mL)淬灭体系，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品硅胶柱层析得到3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮(150mg,收率：60％)。MS:[M+1]+:422.1. The 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolin-7-ol (200.0mg, 1eq), 3-(hydroxymethyl ) Cyclobutan-1-one (SM1, 118.0mg, 2eq) and triphenylphosphine (PPh 3 , 386.4mg, 2.5eq) were dissolved in freshly distilled tetrahydrofuran (5mL), stirred at room temperature for 10 minutes, and added to the reaction system Add diisopropyl azodicarboxylate (DIAD) (357.5mg, 3eq) dropwise at room temperature, stir overnight at room temperature, LCMS detects that the reaction is complete, stop the reaction, add water (25mL) to quench the system, ethyl acetate (20mL*3 ) Extraction, combined the organic phases and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, concentrated, and purified by silica gel column chromatography to obtain 3-((4-(4-fluoro-2-methyl-1H-indole- 5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyl ketone (150 mg, yield: 60%). MS:[M+1]+:422.1.
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺的制备：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutylamine preparation:
将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮(80.0mg,1eq)，甲酸铵(119.7mg,10eq)溶于超干的甲醇(2mL)，在室温搅拌下添加氰基硼氢化钠(59.7mg,5eq)。在氮气保护下室温反应过夜。LCMS检测反应完毕，停止反应。加水(10mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺(8.6mg,收率10.7％)。MS:[M+1]+:423.1.The 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyl Ketone (80.0 mg, 1 eq), ammonium formate (119.7 mg, 10 eq) were dissolved in ultra-dry methanol (2 mL), and sodium cyanoborohydride (59.7 mg, 5 eq) was added with stirring at room temperature. React overnight at room temperature under nitrogen protection. LCMS detects the completion of the reaction and stops the reaction. Add water (10mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain 3-((4-(4) -Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutylamine (8.6mg, yield 10.7%) . MS:[M+1]+:423.1.
1H NMR(400MHz,d 6-DMSO,HCl salt)δ11.44(s,1H),8.67(d,J＝5.6Hz,1H),8.42-8.15(m,3H),7.66(d,J＝11.6Hz,1H),7.48(p,J＝8.4Hz, 1H),7.18(d,J＝8.7Hz,1H),7.08-6.94(m,1H),6.22(d,J＝19.0Hz,1H),4.30(d,J＝6.8Hz,1H),4.25(d,J＝6.8Hz,1H),4.02/4.01(s,3H),3.91-3.85(m,0.65H)/3.69-3.64(m,0.51H),2.92-2.85(m,0.64H)/2.70-2.63(m,0.55H),2.46-2.32(m,5H),2.27-2.22(m,1.33H)/2.11-2.04(m,1.12H)。 1 H NMR (400MHz, d 6 -DMSO, HCl salt) δ 11.44 (s, 1H), 8.67 (d, J = 5.6 Hz, 1H), 8.42-8.15 (m, 3H), 7.66 (d, J = 11.6Hz, 1H), 7.48 (p, J = 8.4 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.08-6.94 (m, 1H), 6.22 (d, J = 19.0 Hz, 1H) , 4.30(d,J=6.8Hz,1H), 4.25(d,J=6.8Hz,1H),4.02/4.01(s,3H),3.91-3.85(m,0.65H)/3.69-3.64(m, 0.51H), 2.92-2.85(m, 0.64H)/2.70-2.63(m, 0.55H), 2.46-2.32(m, 5H), 2.27-2.22(m, 1.33H)/2.11-2.04(m, 1.12 H).
实施例2Example 2
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁醇3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutanol
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000065
Figure PCTCN2021073616-appb-000065
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000066
Figure PCTCN2021073616-appb-000066
合成方法：resolve resolution:
将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮(30.0mg,1eq)溶于超干的甲醇(2mL)，在室温搅拌下添加硼氢化钠(11mg,4eq)。在氮气保护下室温反应1小时。LCMS检测反应完毕，停止反应。加水(10mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到33-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁醇(29mg,收率96％)。MS:[M+1]+:424.1.The 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyl The ketone (30.0 mg, 1 eq) was dissolved in ultra-dry methanol (2 mL), and sodium borohydride (11 mg, 4 eq) was added with stirring at room temperature. React at room temperature for 1 hour under the protection of nitrogen. LCMS detects the completion of the reaction and stops the reaction. Add water (10mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain 33-((4-(4 -Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutanol (29 mg, yield 96%). MS:[M+1]+:424.1.
1H NMR(400MHz,d 6-DMSO)δ11.34(s,1H),8.88(s,1H),8.49(s,1H),7.60(s,1H),7.37(s,1H),7.16(d,J＝8.6Hz,1H),7.05-6.95(m,1H),6.24(s,1H),5.06(s,1H),4.80-4.74(m,1H),4.20(d,J＝7.2Hz,0.55Hz)/4.16(d,J＝7.2Hz,1.38H),3.99(s,3H),2.44-2.31(m,4H),2.30-1.94(m,3H),1.74-1.66(m.1.66H)/1.48-1.42(m,0.57H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.34 (s, 1H), 8.88 (s, 1H), 8.49 (s, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 7.16 ( d,J=8.6Hz,1H),7.05-6.95(m,1H), 6.24(s,1H), 5.06(s,1H), 4.80-4.74(m,1H), 4.20(d,J=7.2Hz ,0.55Hz)/4.16(d,J=7.2Hz,1.38H),3.99(s,3H),2.44-2.31(m,4H),2.30-1.94(m,3H),1.74-1.66(m.1.66 H)/1.48-1.42 (m, 0.57H).
实施例3Example 3
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)-N,N-二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)-N,N -Dimethylcyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000067
Figure PCTCN2021073616-appb-000067
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000068
Figure PCTCN2021073616-appb-000068
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)-N,N-二甲基环丁胺的制备：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)-N,N -Preparation of dimethylcyclobutylamine:
将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮(80.0mg,1eq)，二甲胺盐酸盐(75mg,5eq)溶于超干的甲醇(2mL)，在室温搅拌下添加氰基硼氢化钠(59.7mg,5eq)。在氮气保护下室温反应过夜。LCMS检测反应完毕，停止反应。加水(10mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)-N,N-二甲基环丁胺(13.8mg,收率16.2％)。MS:[M+1]+:451.2.The 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyl Ketone (80.0 mg, 1 eq), dimethylamine hydrochloride (75 mg, 5 eq) were dissolved in ultra-dry methanol (2 mL), and sodium cyanoborohydride (59.7 mg, 5 eq) was added with stirring at room temperature. React overnight at room temperature under nitrogen protection. LCMS detects the completion of the reaction and stops the reaction. Add water (10mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain 3-((4-(4) -Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)-N,N-dimethylcyclobutylamine ( 13.8mg, yield 16.2%). MS:[M+1]+:451.2
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.50(s,1H),7.62(s,1H),7.43-7.39(m,1H),7.17-7.15(m,1H),6.99(t,J＝6.4Hz,1H),6.24(s,1H),4.81-4.74(m,1H),4.28-4.19(m,2H),4.00-3.99(m,3H),3.06-3.14(m,1H),2.71-2.66(m,0.66H)/2.46-2.21(m,10.54H),2.15-2.08(m,1H),1.99-1.95(m,1H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 8.50 (s, 1H), 7.62 (s, 1H), 7.43-7.39 (m, 1H), 7.17-7.15 (m, 1H) ), 6.99 (t, J = 6.4 Hz, 1H), 6.24 (s, 1H), 4.81-4.74 (m, 1H), 4.28-4.19 (m, 2H), 4.00-3.99 (m, 3H), 3.06- 3.14(m,1H),2.71-2.66(m,0.66H)/2.46-2.21(m,10.54H),2.15-2.08(m,1H),1.99-1.95(m,1H).
实施例4Example 4
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲 基)-N-甲基环丁胺：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)-N-methyl Cyclobutylamine:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000069
Figure PCTCN2021073616-appb-000069
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000070
Figure PCTCN2021073616-appb-000070
参照实施例3的合成方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮与甲胺盐酸盐反应合成3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)-N-甲基环丁胺。MS:[M+1]+:437.2.Referring to the synthesis method of Example 3, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy Synthesis of 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquine by reaction of methyl) cyclobutyl ketone and methylamine hydrochloride Oxazolinyl-7-yloxy)methyl)-N-methylcyclobutylamine. MS:[M+1]+:437.2.
实施例5Example 5
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啉环丁基)甲氧基)喹唑啉：4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morpholinocyclobutyl)methoxy)quinazoline:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000071
Figure PCTCN2021073616-appb-000071
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000072
Figure PCTCN2021073616-appb-000072
参照实施例3的合成方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧 基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮与吗啉反应合成4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啉环丁基)甲氧基)喹唑啉(收率15％)。MS:[M+1]+:493.2.Referring to the synthesis method of Example 3, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3- Morpholine (cyclobutyl)methoxy)quinazoline (yield 15%). MS:[M+1]+:493.2.
1H NMR(400MHz,d 6-DMSO)δ11.34(s,1H),8.50(s,1H),7.60(s,1H),7.37(s,1H),7.16(d,J＝8.6Hz,1H),7.03-6.95(m,1H),6.24(s,1H),4.26(d,J＝7.3Hz,0.4H)/4.17(d,J＝6.4Hz,1.7H),3.98(s,3H),3.59-3.54(m,4H),2.41(s,3H),2.27(s,4H),2.21-2.17(m,2H),1.74-1.65(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.34 (s, 1H), 8.50 (s, 1H), 7.60 (s, 1H), 7.37 (s, 1H), 7.16 (d, J = 8.6 Hz, 1H),7.03-6.95(m,1H),6.24(s,1H),4.26(d,J=7.3Hz,0.4H)/4.17(d,J=6.4Hz,1.7H),3.98(s,3H ), 3.59-3.54 (m, 4H), 2.41 (s, 3H), 2.27 (s, 4H), 2.21-2.17 (m, 2H), 1.74-1.65 (m, 2H).
实施例6Example 6
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-2,3-二甲基苯胺：N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-2,3-dimethylaniline:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000073
Figure PCTCN2021073616-appb-000073
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000074
Figure PCTCN2021073616-appb-000074
参照实施例3的合成方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮与2,3-二甲基苯胺反应合成N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-2,3-二甲基苯胺(收率：20％)。MS:[M+1]+:527.2.Referring to the synthesis method of Example 3, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy Synthesis of N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy) by the reaction of cyclobutyl ketone with 2,3-dimethylaniline -6-Methoxyquinazolinyl-7-yloxy)methyl)cyclobutyl)-2,3-dimethylaniline (yield: 20%). MS:[M+1]+:527.2.
1H NMR(400MHz,d 6-DMSO)δ11.34(s,1H),8.51(d,J＝6.4Hz,1H),7.61(d,J＝6.0Hz,1H),7.51-7.33(m,1H),7.16(d,J＝8.6Hz,1H),6.99(td,J＝8.0,3.4Hz,1H),6.88(t,J＝7.7Hz,1H),6.45(d,J＝7.4Hz,1H),6.34(dd,J＝12.3,8.1Hz,1H),6.24(s,1H),4.91(d,J＝6.8Hz,0.37H)/4.82(d,J＝9.8Hz,0.70H),4.34(d,J＝7.2Hz,0.73H)/4.23(d,J＝5.2Hz,1.34H),4.00(d,J＝4.4Hz,3H),3.86-3.76(m,1H),2.64-2.59(m,2H),2.42(s,3H), 2.36-2.32(m,1H),2.17(s,4H),2.01(d,J＝6.8Hz,3H),1.90-1.75(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ11.34 (s, 1H), 8.51 (d, J = 6.4 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.51-7.33 (m, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.99 (td, J = 8.0, 3.4 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.45 (d, J = 7.4 Hz, 1H), 6.34(dd,J＝12.3,8.1Hz,1H), 6.24(s,1H), 4.91(d,J＝6.8Hz,0.37H)/4.82(d,J＝9.8Hz,0.70H), 4.34(d,J=7.2Hz,0.73H)/4.23(d,J=5.2Hz,1.34H), 4.00(d,J=4.4Hz,3H),3.86-3.76(m,1H),2.64-2.59 (m, 2H), 2.42 (s, 3H), 2.36-2.32 (m, 1H), 2.17 (s, 4H), 2.01 (d, J=6.8 Hz, 3H), 1.90-1.75 (m, 2H).
实施例7Example 7
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-苯胺：N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-aniline:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000075
Figure PCTCN2021073616-appb-000075
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000076
Figure PCTCN2021073616-appb-000076
参照实施例3的合成方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮与苯胺反应合成N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-苯胺。MS:[M+1]+:499.2.Referring to the synthesis method of Example 3, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy Synthesis of N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazole by reaction of phenyl)methyl)cyclobutyl ketone and aniline (Alkolinyl-7-yloxy)methyl)cyclobutyl)-aniline. MS:[M+1]+:499.2.
实施例8Example 8
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-3-(三氟甲基)-苯胺：N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-3-(trifluoromethyl)-aniline:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000077
Figure PCTCN2021073616-appb-000077
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000078
Figure PCTCN2021073616-appb-000078
参照实施例3的合成方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基酮与3-(三氟甲基)-苯胺反应合成N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-基氧基)甲基)环丁基)-3-(三氟甲基)-苯胺。MS:[M+1]+:567.2.Referring to the synthesis method of Example 3, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy (Yl)-6-methoxyquinazolin-7-yloxy)methyl)cyclobutyl)-3-(trifluoromethyl)-aniline. MS:[M+1]+:567.2.
实施例9Example 9
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy ) Quinazoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000079
Figure PCTCN2021073616-appb-000079
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000080
Figure PCTCN2021073616-appb-000080
合成方法：resolve resolution:
向反应瓶中加入3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺(100.0mg,1eq)，1,5-二溴戊烷(60.6mg,1.2eq)，碳酸钾(90.4mg,3eq)和N,N-二甲基甲酰胺(5mL)。在氮气保护下80℃搅拌反应3小时。LCMS检测反应完毕，停止反应。加水(30mL)，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉(17mg,收率16％)。MS:[M+1]+:491.1.Add 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl to the reaction flask ) Cyclobutylamine (100.0mg, 1eq), 1,5-dibromopentane (60.6mg, 1.2eq), potassium carbonate (90.4mg, 3eq) and N,N-dimethylformamide (5mL). The reaction was stirred at 80°C for 3 hours under the protection of nitrogen. LCMS detects the completion of the reaction and stops the reaction. Add water (30mL), extract with ethyl acetate (20mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain 4-(4-fluoro-2) -Methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy)quinazoline (17mg, yield Rate 16%). MS:[M+1]+:491.1.
实施例10Example 10
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy) Quinazoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000081
Figure PCTCN2021073616-appb-000081
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000082
Figure PCTCN2021073616-appb-000082
参照实施例9的方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺与1,4-二溴丁烷反应得到4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉。MS:[M+1]+:477.1.Referring to the method of Example 9, the 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy )Methyl)cyclobutylamine reacts with 1,4-dibromobutane to obtain 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7- ((3-pyrrol-1-yl)cyclobutyl)methoxy)quinazoline. MS:[M+1]+:477.1.
实施例11Example 11
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-氮杂环丁烷-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-azetidin-1-yl)cyclobutyl) (Methoxy)quinazoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000083
Figure PCTCN2021073616-appb-000083
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000084
Figure PCTCN2021073616-appb-000084
参照实施例9的方法，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺与1,3-二溴丙烷反应得到4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-氮杂环丁烷-1-基)环丁基)甲氧基)喹唑啉。MS:[M+1]+:463.1.Referring to the method of Example 9, the 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy )Methyl)cyclobutylamine reacts with 1,3-dibromopropane to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-( (3-Azetidine-1-yl)cyclobutyl)methoxy)quinazoline. MS:[M+1]+:463.1.
实施例12Example 12
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutanol
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000085
Figure PCTCN2021073616-appb-000085
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000086
Figure PCTCN2021073616-appb-000086
合成方法：resolve resolution:
7-(苄氧基)-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉的制备：Preparation of 7-(benzyloxy)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinoline:
向反应瓶中加入4-氟-5-羟基-2-甲基吲哚(1.65g,1eq)，7-苄氧基-4-氯-6-甲氧基喹啉(3.0g,1eq)，N,N-二甲基甲酰胺(60mL)和碳酸钾(3.67g,3eq)，室温搅拌5min后升温100℃氮气保护下反应16小时。LCMS检测反应完全，停止反应，降温至室温后，加水(500mL)，乙酸乙酯(200mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽 滤，浓缩，粗品硅胶柱层析得到7-(苄氧基)-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉(1.2g,收率27％)。MS:[M+1]+:429.1.Add 4-fluoro-5-hydroxy-2-methylindole (1.65g, 1eq), 7-benzyloxy-4-chloro-6-methoxyquinoline (3.0g, 1eq) to the reaction flask, N,N-dimethylformamide (60mL) and potassium carbonate (3.67g, 3eq) were stirred at room temperature for 5 minutes, and then heated at 100°C to react for 16 hours under nitrogen protection. LCMS detects that the reaction is complete. Stop the reaction. After cooling to room temperature, add water (500mL), extract with ethyl acetate (200mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and crude silica gel Column chromatography gave 7-(benzyloxy)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinoline (1.2g, yield 27 %). MS:[M+1]+:429.1.
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-醇的制备：Preparation of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-ol:
向反应瓶中加入7-(苄氧基)-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉(1.21g,1eq)，甲醇(100mL)和钯碳(含量5wt％,0.46g,投料比30％)，氢气置换三次。在2atm的氢气环境下室温反应4小时，LCMS检测反应完全，停止反应，抽滤掉固体，浓缩得到4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-醇(0.82g，收率：80％)。MS:[M+1]+:339.1.该产品直接用于下部反应，不进行任何提纯处理。Add 7-(benzyloxy)-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinoline (1.21g, 1eq) to the reaction flask , Methanol (100mL) and palladium on carbon (content 5wt%, 0.46g, feed ratio 30%), hydrogen replacement three times. The reaction was carried out at room temperature under 2atm hydrogen atmosphere for 4 hours. LCMS detected that the reaction was complete. The reaction was stopped. The solid was filtered off with suction and concentrated to obtain 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)- 6-Methoxyquinolinyl-7-ol (0.82 g, yield: 80%). MS:[M+1]+:339.1. The product is directly used in the lower reaction without any purification treatment.
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮的制备：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutyl ketone preparation:
将4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-醇(100.0mg,1eq)，3-(羟甲基)环丁烷-1-酮(59.0mg,2eq)和三苯基膦(192.4mg,2.5eq)溶于新蒸的四氢呋喃(5mL)中，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(180mg,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(25mL)淬灭体系，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品硅胶柱层析得到3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮(20mg,收率：16％)。MS:[M+1]+:421.1.The 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-ol (100.0mg, 1eq), 3-(hydroxymethyl) Cyclobutan-1-one (59.0mg, 2eq) and triphenylphosphine (192.4mg, 2.5eq) were dissolved in freshly steamed tetrahydrofuran (5mL), stirred at room temperature for 10 minutes, and then added dropwise to the reaction system at room temperature. Diisopropyl azodicarboxylate (180mg, 3eq), stirred overnight at room temperature, LCMS characterizes that the reaction is complete, stop the reaction, add water (25mL) to quench the system, extract with ethyl acetate (20mL*3), combine the organic phases and wash with saturated brine One time, drying with anhydrous sodium sulfate, suction filtration, concentration, and crude silica gel column chromatography to obtain 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methyl Oxoquinolinyl-7-yloxy)methyl)cyclobutyl ketone (20 mg, yield: 16%). MS:[M+1]+:421.1.
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇的制备：Preparation of 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutanol :
将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮(20.0mg,1eq)溶于超干的甲醇(2mL)，在室温搅拌下添加硼氢化钠(8mg,4eq)。在氮气保护下室温反应1小时。LCMS检测反应完毕，停止反应。加水(10mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经反相制备液相色谱提纯得到3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇(6mg,收率30％)。MS:[M+1]+:423.1.3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutyl ketone (20.0mg, 1eq) was dissolved in ultra-dry methanol (2mL), and sodium borohydride (8mg, 4eq) was added with stirring at room temperature. React at room temperature for 1 hour under the protection of nitrogen. LCMS detects the completion of the reaction and stops the reaction. Add water (10mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is purified by reverse phase preparative liquid chromatography to obtain 3-((4 -(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutanol (6mg, yield 30% ). MS:[M+1]+:423.1.
1H NMR(400MHz,d 6-DMSO)δ11.44(s,1H),8.41(d,J＝5.2Hz,1H), 7.58(s,1H),7.37(s,1H),7.22(d,J＝8.5Hz,1H),6.99(t,J＝8.0Hz,1H),6.35-6.21(m,2H),5.06(d,J＝5.6Hz,1H),4.13(dd,J＝14.9,6.6Hz,2H),4.06-3.89(m,4H),2.44-2.30(m,4H),2.29-2.12(m,2H),1.78-1.62(m,2H). 1 H NMR (400MHz, d 6 -DMSO) δ 11.44 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.58 (s, 1H), 7.37 (s, 1H), 7.22 (d, J = 8.5Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.35-6.21 (m, 2H), 5.06 (d, J = 5.6 Hz, 1H), 4.13 (dd, J = 14.9, 6.6 Hz, 2H), 4.06-3.89 (m, 4H), 2.44-2.30 (m, 4H), 2.29-2.12 (m, 2H), 1.78-1.62 (m, 2H).
实施例13Example 13
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁胺：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutylamine:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000087
Figure PCTCN2021073616-appb-000087
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000088
Figure PCTCN2021073616-appb-000088
合成方法：resolve resolution:
将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮(80.0mg,1eq)，甲酸铵(119.7mg,10eq)溶于超干的甲醇(2mL)，在室温搅拌下添加氰基硼氢化钠(59.7mg,5eq)。在氮气保护下室温反应过夜。LCMS检测反应完毕，停止反应。加水(10mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺(8.6mg,收率10.7％)。MS:[M+1]+:422.1.3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutyl ketone (80.0mg, 1eq), ammonium formate (119.7mg, 10eq) was dissolved in ultra-dry methanol (2mL), and sodium cyanoborohydride (59.7mg, 5eq) was added with stirring at room temperature. React overnight at room temperature under nitrogen protection. LCMS detects the completion of the reaction and stops the reaction. Add water (10mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain 3-((4-(4) -Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutylamine (8.6mg, yield 10.7%) . MS:[M+1]+:422.1.
实施例14Example 14
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)-N,N-二甲基环丁胺：3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)-N,N- Dimethylcyclobutylamine:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000089
Figure PCTCN2021073616-appb-000089
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000090
Figure PCTCN2021073616-appb-000090
合成方法：resolve resolution:
参照实施例13，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮与二甲胺盐酸盐反应合成3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)-N,N-二甲基环丁胺。MS:[M+1]+:450.2.Referring to Example 13, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl ) Cyclobutyl ketone reacts with dimethylamine hydrochloride to synthesize 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl- 7-yloxy)methyl)-N,N-dimethylcyclobutylamine. MS:[M+1]+:450.2.
实施例15Example 15
3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)-N-甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)-N-methyl Cyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000091
Figure PCTCN2021073616-appb-000091
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000092
Figure PCTCN2021073616-appb-000092
合成方法：resolve resolution:
参照实施例13，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮与甲胺盐酸盐反应合成3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)-N-甲基环丁胺。MS: [M+1]+:436.2.Referring to Example 13, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl ) Cyclobutyl ketone reacts with methylamine hydrochloride to synthesize 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7 -Yloxy)methyl)-N-methylcyclobutylamine. MS: [M+1]+:436.2.
实施例16Example 16
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啉环丁基)甲氧基)喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morpholinocyclobutyl)methoxy)quinoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000093
Figure PCTCN2021073616-appb-000093
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000094
Figure PCTCN2021073616-appb-000094
合成方法：resolve resolution:
参照实施例13，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮与吗啉反应合成4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啉环丁基)甲氧基)喹啉。MS:[M+1]+:492.2.Referring to Example 13, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl ) Cyclobutyl ketone reacts with morpholine to synthesize 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morpholine cyclobutyl Group) methoxy) quinoline. MS:[M+1]+:492.2.
实施例17Example 17
N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基)-2,3-二甲基苯胺N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutane Yl)-2,3-dimethylaniline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000095
Figure PCTCN2021073616-appb-000095
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000096
Figure PCTCN2021073616-appb-000096
参照实施例13，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮与2,3-二甲基苯胺反应合成N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧唑啉基-7-基氧基)甲基)环丁基)-2,3-二甲基苯胺。MS:[M+1]+:526.2.Referring to Example 13, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl ) Cyclobutyl ketone reacts with 2,3-dimethylaniline to synthesize N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methyl Oxazolinyl-7-yloxy)methyl)cyclobutyl)-2,3-dimethylaniline. MS:[M+1]+:526.2.
实施例18Example 18
4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉：4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy )quinoline:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000097
Figure PCTCN2021073616-appb-000097
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000098
Figure PCTCN2021073616-appb-000098
参照实施例13，将3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基酮与1,5-二溴戊烷反应合成4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉。MS:[M+1]+:490.1.Referring to Example 13, 3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl ) Cyclobutyl ketone reacts with 1,5-dibromopentane to synthesize 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-(( 3-piperidin-1-yl)cyclobutyl)methoxy)quinoline. MS:[M+1]+:490.1.
实施例19Example 19
7-((3-氨基环丁基)甲氧基)-4-(4-氟-2-甲基-1H-5-基氧基)-3-腈基-6-甲氧基喹啉7-((3-Aminocyclobutyl)methoxy)-4-(4-fluoro-2-methyl-1H-5-yloxy)-3-cyano-6-methoxyquinoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000099
Figure PCTCN2021073616-appb-000099
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000100
Figure PCTCN2021073616-appb-000100
合成方法：resolve resolution:
叔丁基-(3-((4-氯-3-氰基-6-甲氧喹啉基-7-基氧基)甲基)环丁基)氨基甲酸酯的制备：Preparation of tert-butyl-(3-((4-chloro-3-cyano-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutyl)carbamate:
将4-氯-7-羟基-6-甲氧喹啉基-3-甲腈(300mg,1eq)，3-(Boc-氨基)环丁基甲醇(515mg,2eq)和三苯基膦(840mg,2.5eq)溶于新蒸的四氢呋喃(15mL)中，室温搅拌10min后，向反应体系中添加偶氮二羧酸二异丙酯(775mg,3eq)。室温搅拌过夜，LCMS检测反应完全，停止反应。加水淬灭，乙酸乙酯萃取，饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，浓缩，经柱层析提纯得到叔丁基-(3-((4-氯-3-氰基-6-甲氧喹啉基-7-基氧基)甲基)环丁基)氨基甲酸酯(300mg,收率59％)。MS:[M+1]+:418.1.Combine 4-chloro-7-hydroxy-6-methoxyquinolinyl-3-carbonitrile (300mg, 1eq), 3-(Boc-amino) cyclobutyl carbinol (515mg, 2eq) and triphenylphosphine (840mg , 2.5eq) was dissolved in freshly distilled tetrahydrofuran (15mL), stirred at room temperature for 10min, and then diisopropyl azodicarboxylate (775mg, 3eq) was added to the reaction system. Stir at room temperature overnight. LCMS detects that the reaction is complete and stops the reaction. Quench with water, extract with ethyl acetate, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain tert-butyl-(3-((4-chloro-3-cyano- 6-Methoxyquinolinyl-7-yloxy)methyl)cyclobutyl)carbamate (300mg, yield 59%). MS:[M+1]+:418.1.
叔丁基-(3-((3-氰基-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基)氨基甲酸酯的制备：Tert-Butyl-(3-((3-cyano-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy Preparation of (methyl)cyclobutyl)carbamate:
向反应瓶中加入叔丁基-(3-((4-氯-3-氰基-6-甲氧喹啉基-7-基氧基)甲基)环丁基)氨基甲酸酯(300mg,1eq),4-氟-5-羟基-2-甲基吲哚(142mg,1.2eq)，碳酸铯(466mg,2eq)和N,N-二甲基甲酰胺(10mL)，100℃反应过夜，LCMS检测反应完毕，停止反应。加水淬灭，乙酸乙酯萃取， 饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，浓缩，经柱层析和薄层色谱提纯得到叔丁基-(3-((3-氰基-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基)氨基甲酸酯(300mg,收率76％)。MS:[M+1]+:547.1.Add tert-butyl-(3-((4-chloro-3-cyano-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutyl)carbamate (300mg ,1eq), 4-fluoro-5-hydroxy-2-methylindole (142mg, 1.2eq), cesium carbonate (466mg, 2eq) and N,N-dimethylformamide (10mL), react at 100℃ overnight , LCMS detects that the reaction is complete, stop the reaction. Quenched with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography and thin layer chromatography to obtain tert-butyl-(3-((3-cyano- 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)cyclobutyl)carbamate ( 300mg, yield 76%). MS:[M+1]+:547.1.
7-((3-氨基环丁基)甲氧基)-4-(4-氟-2-甲基-1H-5-基氧基)-3-腈基-6-甲氧基喹啉盐酸盐的制备：7-((3-Aminocyclobutyl)methoxy)-4-(4-fluoro-2-methyl-1H-5-yloxy)-3-cyano-6-methoxyquinoline salt Preparation of acid salt:
向反应瓶中加入叔丁基-(3-((3-氰基-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁基)氨基甲酸酯(100mg,1eq)和氯化氢-二氧六环溶液(4M,10mL)，室温搅拌3小时，LCMS检测反应完毕，停止反应。直接浓缩后的到7-((3-氨基环丁基)甲氧基)-4-(4-氟-2-甲基-1H-5基氧基)-3-腈基-6-甲氧基喹啉盐酸盐(78mg,收率：70％)。MS:[M+1-HCl]+:447.3.Add tert-butyl-(3-((3-cyano-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyloxy) to the reaction flask -7-yloxy)methyl)cyclobutyl)carbamate (100mg, 1eq) and hydrogen chloride-dioxane solution (4M, 10mL) were stirred at room temperature for 3 hours. LCMS detected that the reaction was completed and the reaction was stopped. Directly concentrated to 7-((3-aminocyclobutyl)methoxy)-4-(4-fluoro-2-methyl-1H-5 yloxy)-3-cyano-6-methoxy Quinoline hydrochloride (78mg, yield: 70%). MS:[M+1-HCl]+:447.3.
1H NMR(400MHz,d 6-DMSO)δ11.39(s,1H),8.73(s,1H),7.60-7.43(m,2H),7.13(d,J＝8.8Hz,1H),6.97(t,J＝8.0Hz,1H),6.27(s,1H),4.24-4.16(m,2H),3.90(s,3H),3.62-3.55(m,1H),2.67-2.58(m,1H),2.44-2.31(m,5H),2.12(d,J＝7.6Hz,2H),1.93(dd,J＝19.1,9.2Hz,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.39 (s, 1H), 8.73 (s, 1H), 7.60-7.43 (m, 2H), 7.13 (d, J = 8.8 Hz, 1H), 6.97 ( t,J=8.0Hz,1H),6.27(s,1H),4.24-4.16(m,2H),3.90(s,3H),3.62-3.55(m,1H),2.67-2.58(m,1H) , 2.44-2.31 (m, 5H), 2.12 (d, J = 7.6 Hz, 2H), 1.93 (dd, J = 19.1, 9.2 Hz, 2H).
实施例20Example 20
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐的制备Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl ) Preparation of cyclobutylamine hydrochloride
化合物的结构式:The structural formula of the compound:
Figure PCTCN2021073616-appb-000101
Figure PCTCN2021073616-appb-000101
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000102
Figure PCTCN2021073616-appb-000102
合成方法：resolve resolution:
顺式-3-(Boc-氨基)环丁基甲醇的制备Preparation of cis-3-(Boc-amino)cyclobutyl carbinol
在室温下，向顺-3-(叔-丁氧羰基氨基)环丁羧酸(500.0mg,1eq)的四氢呋喃(10mL)溶液中滴加硼烷四氢呋喃络合物(1mol/L in THF,9.3mL,4eq)，室温搅拌2小时，LCMS表针反应完毕，停止反应。加水(50mL)淬灭反应，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩得到粗品顺-3-(Boc-氨基)环丁基甲醇(400mg,收率:82％)。MS:[M+1]+:202.2.At room temperature, add borane tetrahydrofuran complex (1mol/L in THF, 9.3 mL, 4eq), stirring at room temperature for 2 hours, the reaction of the LCMS gauge needle is complete, and the reaction is stopped. The reaction was quenched by adding water (50mL), extracted with ethyl acetate (20mL*3), the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain crude cis-3-(Boc-amino)cyclobutane Methanol (400mg, yield: 82%). MS:[M+1]+:202.2.
叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯的制备Tert-Butyl-cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl) (Oxygen) methyl) cyclobutanyl) carbamate preparation
向反应瓶中加入粗品顺-3-(Boc-氨基)环丁基甲醇(400mg,2eq)，4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-醇(337.3mg,1eq)，三苯基膦(651mg,2.5eq)和新蒸的四氢呋喃(20mL)，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(600mg,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(150mL)淬灭体系，乙酸乙酯(40mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经硅胶柱层析和反向制备液相得到叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(210mg,收率：40％)。MS:[M+1]+:523.2.Add crude cis-3-(Boc-amino)cyclobutylmethanol (400mg, 2eq), 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6 to the reaction flask -Methoxyquinazoline-7-ol (337.3mg, 1eq), triphenylphosphine (651mg, 2.5eq) and freshly distilled tetrahydrofuran (20mL), after stirring at room temperature for 10 min, add dropwise to the reaction system at room temperature Diisopropyl azodicarboxylate (600mg, 3eq), stirred overnight at room temperature, LCMS characterizes that the reaction is complete, stop the reaction, add water (150mL) to quench the system, extract with ethyl acetate (40mL*3), combine the organic phases and use saturated salt Wash once with water, dry with anhydrous sodium sulfate, filter by suction and concentrate. The crude product is subjected to silica gel column chromatography and reversed phase preparation to obtain tert-butyl-cis-3-(((4-((4-fluoro-2-methyl) -1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutanyl)carbamate (210mg, yield: 40%) . MS:[M+1]+:523.2.
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐的制备Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl ) Preparation of cyclobutylamine hydrochloride
在反应瓶中向叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(210mg,1eq)添加盐酸二氧六环(4M,10mL)，室温搅拌2小时，LCMS表征反应完毕，停止反应，浓缩后得到顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐(110mg,收率：65％)。MS:[M+1-HCl] +:423.2. In the reaction flask, add tert-butyl-cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutanyl)carbamate (210mg, 1eq) was added with dioxane hydrochloride (4M, 10mL), stirred at room temperature for 2 hours, LCMS characterizes that the reaction is complete, stop the reaction, and concentrate After obtaining cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) Methyl)cyclobutylamine hydrochloride (110 mg, yield: 65%). MS:[M+1-HCl] + :423.2.
1H NMR(400MHz,d 6-DMSO,HCl salt)δ11.48(s,1H),8.74(s,1H),8.34(s,3H,-NH 2HCl),7.69(s,1H),7.50(d,J＝10.8Hz,1H),7.18(d,J＝8.6Hz,1H),7.09–6.93(m,1H),6.25(s,1H),4.24(d,J＝6.8Hz,2H),4.02(s,3H),3.69–3.63(m,1H),2.75–2.58(m,1H),2.48–2.33(m,5H),2.16–2.04(m,2H)。 1 H NMR (400MHz, d 6 -DMSO, HCl salt) δ 11.48 (s, 1H), 8.74 (s, 1H), 8.34 (s, 3H, -NH 2 HCl), 7.69 (s, 1H), 7.50 (d,J=10.8Hz,1H), 7.18(d,J=8.6Hz,1H), 7.09–6.93(m,1H), 6.25(s,1H), 4.24(d,J=6.8Hz,2H) ,4.02(s,3H), 3.69–3.63(m,1H), 2.75–2.58(m,1H), 2.48–2.33(m,5H), 2.16–2.04(m,2H).
实施例21Example 21
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )Cyclobutylamine hydrochloride
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000103
Figure PCTCN2021073616-appb-000103
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000104
Figure PCTCN2021073616-appb-000104
合成方法：resolve resolution:
反式-3-(Boc-氨基)环丁基甲醇的制备Preparation of trans-3-(Boc-amino)cyclobutyl carbinol
在室温下，向反式-3-(叔-丁氧羰基氨基)环丁羧酸(1.0g,1eq)的四氢呋喃(10mL)溶液中滴加硼烷四氢呋喃络合物(1mol/L in THF,18.6mL,4eq)，室温搅拌2小时，LCMS表针反应完毕，停止反应。加水(100mL)淬灭反应，乙酸乙酯(50mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩得到粗品反式-3-(Boc-氨基)环丁基甲醇(900mg,收率:96％)。MS:[M+1] +:202.2. At room temperature, add borane tetrahydrofuran complex (1mol/L in THF, 18.6mL, 4eq), stirred at room temperature for 2 hours, the reaction of the LCMS gauge needle is completed, and the reaction is stopped. The reaction was quenched by adding water (100mL), extracted with ethyl acetate (50mL*3), the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain the crude trans-3-(Boc-amino) ring Butyl methanol (900 mg, yield: 96%). MS:[M+1] + :202.2.
叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯的制备Tert-Butyl-trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl) (Oxygen) methyl) cyclobutanyl) carbamate preparation
向反应瓶中加入粗品反式-3-(Boc-氨基)环丁基甲醇(237mg,2eq)，4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-醇(200mg,1eq)，三苯基膦(386mg,2.5eq)和新蒸的四氢呋喃(10mL)，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(357mg,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(50mL)淬灭体系，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经硅胶柱层析和反向制备液相得到叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(180mg,收率：58％)。MS:[M+1] +:523.2. Add crude trans-3-(Boc-amino)cyclobutylmethanol (237mg, 2eq), 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)- to the reaction flask 6-Methoxyquinazolin-7-ol (200mg, 1eq), triphenylphosphine (386mg, 2.5eq) and freshly distilled tetrahydrofuran (10mL) were stirred at room temperature for 10 minutes, and then added dropwise to the reaction system at room temperature Diisopropyl azodicarboxylate (357mg, 3eq), stirred overnight at room temperature, LCMS characterizes that the reaction is complete, stop the reaction, add water (50mL) to quench the system, extract with ethyl acetate (20mL*3), combine the organic phases and use saturated salt Wash once with water, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is subjected to silica gel column chromatography and reversed phase preparation to obtain tert-butyl-trans-3-(((4-((4-fluoro-2-methyl) -1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutanyl)carbamate (180mg, yield: 58%) . MS:[M+1] + :523.2.
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐的制备Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl ) Preparation of cyclobutylamine hydrochloride
在反应瓶中向叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(180mg,1eq)添加盐酸二氧六环(4M,10mL)，室温搅拌2小时，LCMS表征反应完毕，停止反应，浓缩后得到反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐(106mg,收率：73％)。MS:[M+1-HCl] +:423.2. In the reaction flask, add tert-butyl-trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutanyl)carbamate (180mg, 1eq) was added with dioxane hydrochloride (4M, 10mL), stirred at room temperature for 2 hours, LCMS characterizes that the reaction is complete, stop the reaction, and concentrate After obtaining trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) Methyl)cyclobutylamine hydrochloride (106 mg, yield: 73%). MS:[M+1-HCl] + :423.2.
1H NMR(400MHz,d 6-DMSO)δ11.45(s,1H),8.66(s,1H),8.35(s,3H,-N H 2H Cl),7.68(s,1H),7.50(s,1H),7.18(d,J＝8.6Hz,1H),7.01(t,J＝8.0Hz,1H),6.25(s,1H),4.31(d,J＝6.4Hz,2H),4.02(s,3H),3.94–3.86(m,1H),2.93–2.87(m,1H),2.42–2.35(m,5H),2.27–2.21(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.45 (s, 1H), 8.66 (s, 1H), 8.35 (s, 3H, -N H 2 H Cl), 7.68 (s, 1H), 7.50 ( s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.25 (s, 1H), 4.31 (d, J = 6.4 Hz, 2H), 4.02 ( s,3H), 3.94–3.86(m,1H), 2.93–2.87(m,1H), 2.42–2.35(m,5H), 2.27–2.21(m,2H).
实施例22Example 22
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000105
Figure PCTCN2021073616-appb-000105
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000106
Figure PCTCN2021073616-appb-000106
合成方法：resolve resolution:
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺的制备Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine preparation
在反应瓶中向顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐(80mg,1eq)的甲醇(3mL)溶液中，添加多聚甲醛(52.4mg,10eq)和1滴醋酸，室温搅拌10min后，相反应体系添加三乙酰氧基硼氢化钠(185.1mg,5eq)。室温反应过夜，LCMS表征反应完毕，停止反应。将未反应的多聚甲醛固体抽滤掉，母液直接经制备液相提纯得到顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺甲酸盐(20mg,收率：24％)。MS:[M+1-HCl] +:451.2 In the reaction flask, add cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl )Oxy)methyl)cyclobutylamine hydrochloride (80mg, 1eq) in methanol (3mL), add paraformaldehyde (52.4mg, 10eq) and 1 drop of acetic acid. After stirring at room temperature for 10min, the phase reaction system is added Sodium triacetoxyborohydride (185.1 mg, 5 eq). React at room temperature overnight, the LCMS characterization of the reaction is complete, and the reaction is stopped. The unreacted paraformaldehyde solid is filtered off with suction, and the mother liquor is directly purified by the preparation liquid phase to obtain cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl) Oxygen)-6-methoxyquinazolin-7-yl)oxy)methyl)-N,N-dimethylcyclobutylcarbamate (20 mg, yield: 24%). MS:[M+1-HCl] + :451.2
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),9.65(s,1H,-N H + ),8.52(s,1H),7.63(s,1H),7.42(s,1H),7.16(d,J＝8.4Hz,1H),7.01–6.96(m,1H),6.24(s,1H),4.21(d,J＝6.4Hz,2H),3.99(s,3H),3.70–3.60(m,1H),2.71(d,J＝4.8Hz,6H),2.61–2.56(m,1H),2.47–2.41(m,5H),2.11–2.05(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 9.65 (s, 1H, -N H + ), 8.52 (s, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 7.16(d,J=8.4Hz,1H),7.01-6.96(m,1H),6.24(s,1H),4.21(d,J=6.4Hz,2H),3.99(s,3H), 3.70–3.60(m,1H), 2.71(d,J=4.8Hz,6H), 2.61–2.56(m,1H), 2.47–2.41(m,5H), 2.11–2.05(m,2H).
实施例23Example 23
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000107
Figure PCTCN2021073616-appb-000107
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000108
Figure PCTCN2021073616-appb-000108
合成方法：resolve resolution:
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺的制备：Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl ) Preparation of -N,N-Dimethylcyclobutylamine:
在反应瓶中向反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐(80mg,1eq)的甲醇(3mL)溶液中，添加多聚甲醛(52.4mg,10eq)和1滴醋酸，室温搅拌10min后，相反应体系添加三乙酰氧基硼氢化钠(185.1mg,5eq)。室温反应过夜，LCMS表征反应完毕，停止反应。将未反应的多聚甲醛固体抽滤掉，母液直接经制备薄层色谱提纯得到反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺(32mg,收率：35％)。MS:[M+1] +:451.2 In the reaction flask to trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl )Oxy)methyl)cyclobutylamine hydrochloride (80mg, 1eq) in methanol (3mL), add paraformaldehyde (52.4mg, 10eq) and 1 drop of acetic acid. After stirring at room temperature for 10min, the phase reaction system is added Sodium triacetoxyborohydride (185.1 mg, 5 eq). React at room temperature overnight, the LCMS characterization of the reaction is complete, and the reaction is stopped. The unreacted paraformaldehyde solid was filtered off with suction, and the mother liquor was directly purified by preparative thin layer chromatography to obtain trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl) )Oxygen)-6-methoxyquinazolin-7-yl)oxy)methyl)-N,N-dimethylcyclobutylamine (32mg, yield: 35%). MS:[M+1] + :451.2
1H NMR(400MHz,d 6-DMSO)δ11.37(s,1H),8.51(s,1H),7.61(s,1H),7.42(s,1H),7.16(d,J＝8.6Hz,1H),6.99(t,J＝7.9Hz,1H),6.24(s,1H),4.27(d,J＝6.8Hz,2H),4.00(s,3H),3.23–3.14(m,1H),2.68–2.61(m,1H),2.42(s,3H),2.27–2.18(m,8H),2.09–2.03(m,2H)。 1 H NMR(400MHz,d 6 -DMSO)δ11.37(s,1H),8.51(s,1H),7.61(s,1H),7.42(s,1H),7.16(d,J=8.6Hz, 1H), 6.99(t,J=7.9Hz,1H), 6.24(s,1H), 4.27(d,J=6.8Hz,2H), 4.00(s,3H), 3.23–3.14(m,1H), 2.68–2.61(m,1H), 2.42(s,3H), 2.27–2.18(m,8H), 2.09–2.03(m,2H).
实施例24Example 24
顺式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉Cis-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000109
Figure PCTCN2021073616-appb-000109
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000110
Figure PCTCN2021073616-appb-000110
合成方法：resolve resolution:
顺式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉的制备：Cis-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine preparation:
向顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐(60mg,1eq)的N,N-二甲基甲酰胺(4mL)溶液中，添加2,2'-二溴二乙谜(49mg,1.5eq)和碳酸钾(59mg,3eq)，90℃搅拌9小时后，LCMS表征反应完毕，停止反应。加水(20mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到顺式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉(30mg,收率：43％)。MS:[M+1] +:493.2. To cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl Yl)cyclobutylamine hydrochloride (60mg, 1eq) in N,N-dimethylformamide (4mL) solution, add 2,2'-dibromodiethyl ether (49mg, 1.5eq) and potassium carbonate (59mg, 3eq), stirred at 90°C for 9 hours, LCMS characterizes that the reaction is complete, and the reaction is stopped. Add water (20mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain cis-4-(3- (((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl) Morpholine (30 mg, yield: 43%). MS:[M+1] + :493.2.
1H NMR(400MHz,d 6-DMSO)δ11.34(s,1H),8.50(s,1H),7.60(s,1H),7.38(s,1H),7.16(d,J＝8.4Hz,1H),6.98(t,J＝8.0Hz,1H),6.24(s,1H),4.17(d,J＝6.4Hz,2H),3.99(s,3H),3.58(s,4H),2.73–2.64(m,2H),2.41(s,3H),2.27–2.18(m,6H),1.77–1.64(m,2H). 1 H NMR (400MHz, d 6 -DMSO) δ 11.34 (s, 1H), 8.50 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.17 (d, J = 6.4 Hz, 2H), 3.99 (s, 3H), 3.58 (s, 4H), 2.73- 2.64(m, 2H), 2.41(s, 3H), 2.27-2.18(m, 6H), 1.77-1.64(m, 2H).
实施例25Example 25
反式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉的合成Trans-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine synthesis
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000111
Figure PCTCN2021073616-appb-000111
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000112
Figure PCTCN2021073616-appb-000112
合成方法：resolve resolution:
反式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉的制备：Trans-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine preparation:
向反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐(60mg,1eq)的N,N-二甲基甲酰胺(4mL)溶液中，添加2,2'-二溴二乙谜(49mg,1.5eq)和碳酸钾(59mg,3eq)，90℃搅拌9小时后，LCMS表征反应完毕，停止反应。加水(20mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品制备薄层色谱提纯得到反式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉(30mg,收率：43％)。MS:[M+1] +:493.2. To trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl Yl)cyclobutylamine hydrochloride (60mg, 1eq) in N,N-dimethylformamide (4mL) solution, add 2,2'-dibromodiethyl ether (49mg, 1.5eq) and potassium carbonate (59mg, 3eq), stirred at 90°C for 9 hours, LCMS characterizes that the reaction is complete, and the reaction is stopped. Add water (20mL), extract with ethyl acetate (10mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, concentrate, and purify the crude product by preparative thin-layer chromatography to obtain trans-4-(3- (((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl) Morpholine (30 mg, yield: 43%). MS:[M+1] + :493.2.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.51(s,1H),7.61(s,1H),7.38(s,1H),7.16(d,J＝8.4Hz,1H),6.98(t,J＝8.0Hz,1H),6.24(s,1H),4.24(d,J＝6.8Hz,2H),4.00(s,3H),3.59(s,4H),2.74–2.63(m,2H),2.42(s,3H),2.29–2.18(m,6H),1.78–1.64(m,2H)。 1 H NMR(400MHz,d 6 -DMSO)δ11.35(s,1H),8.51(s,1H),7.61(s,1H),7.38(s,1H),7.16(d,J=8.4Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.24 (d, J = 6.8 Hz, 2H), 4.00 (s, 3H), 3.59 (s, 4H), 2.74- 2.63(m, 2H), 2.42(s, 3H), 2.29–2.18(m, 6H), 1.78–1.64(m, 2H).
实施例26Example 26
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉、Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) Methoxy) quinazoline,
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000113
Figure PCTCN2021073616-appb-000113
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000114
Figure PCTCN2021073616-appb-000114
合成方法：resolve resolution:
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉的制备：Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy) quinazoline preparation:
向反应瓶中加入顺式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺(100.0mg,1eq)，1,5-二溴戊烷(60.6mg,1.2eq)，碳酸钾(90.4mg,3eq)和N,N-二甲基甲酰胺(5mL)。在氮气保护下80℃搅拌反应3小时。LCMS表征反应完毕，停止反应。加水(30mL)，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经制备液相色谱在甲酸条件下提纯得到顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉甲酸盐(60mg,收率60％)。MS:[M+1] +:491.3. Add cis-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy to the reaction flask )Methyl)cyclobutylamine (100.0mg, 1eq), 1,5-dibromopentane (60.6mg, 1.2eq), potassium carbonate (90.4mg, 3eq) and N,N-dimethylformamide (5mL ). The reaction was stirred at 80°C for 3 hours under the protection of nitrogen. The LCMS characterization reaction is complete, and the reaction is stopped. Add water (30mL), extract with ethyl acetate (20mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is purified by preparative liquid chromatography under formic acid conditions to obtain cis- 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy ) Quinazoline formate (60 mg, yield 60%). MS:[M+1] + :491.3.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.49(s,1H),8.32(s,0.5H, HCOOH),7.60(s,1H),7.37(s,1H),7.16(d,J＝8.4Hz,1H),7.04–6.91(m,1H),6.24(s,1H),4.16(d,J＝6.4Hz,2H),3.98(s,3H),2.65–2.56(m,1H),2.47–2.41(m,4H),2.27–2.12(m,5H),1.74–1.60(m,2H),1.56–1.43(m,4H),1.41–1.34(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 8.49 (s, 1H), 8.32 (s, 0.5H, H COOH), 7.60 (s, 1H), 7.37 (s, 1H) ), 7.16(d,J=8.4Hz,1H),7.04-6.91(m,1H),6.24(s,1H),4.16(d,J=6.4Hz,2H),3.98(s,3H),2.65 --2.56 (m, 1H), 2.47 - 2.41 (m, 4H), 2.27 - 2.12 (m, 5H), 1.74 - 1.60 (m, 2H), 1.56 - 1.43 (m, 4H), 1.41 - 1.34 (m, 2H).
实施例27Example 27
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环 丁基)甲氧基)喹唑啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinazoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000115
Figure PCTCN2021073616-appb-000115
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000116
Figure PCTCN2021073616-appb-000116
合成方法：resolve resolution:
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉的制备：Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy) quinazoline preparation:
按照实施例26的合成方法顺式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺与1,4-二溴丁烷反应合成顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉。MS:[M+1] +:477.3. According to the synthesis method of Example 26 cis-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yl (Oxy)methyl)cyclobutylamine reacts with 1,4-dibromobutane to synthesize cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methyl Oxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinazoline. MS:[M+1] + :477.3.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),9.97(s,1H),8.51(s,1H),7.63(s,1H),7.42(s,1H),7.16(d,J＝8.6Hz,1H),7.05–6.94(m,1H),6.24(s,1H),4.24(d,J＝6.4Hz,2H),4.00(s,3H),3.81–3.73(m,1H),3.51–3.41(m,2H),3.04–2.94(m,2H),2.87–2.60(m,1H),2.47–2.42(m,4H),2.18–2.11(m,2H),2.04–1.87(m,4H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 9.97 (s, 1H), 8.51 (s, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 7.16 ( d,J=8.6Hz,1H), 7.05–6.94(m,1H), 6.24(s,1H), 4.24(d,J=6.4Hz,2H), 4.00(s,3H), 3.81–3.73(m ,1H),3.51–3.41(m,2H),3.04–2.94(m,2H), 2.87–2.60(m,1H), 2.47–2.42(m,4H), 2.18–2.11(m,2H), 2.04 –1.87(m,4H).
实施例28Example 28
顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclohexylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000117
Figure PCTCN2021073616-appb-000117
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000118
Figure PCTCN2021073616-appb-000118
合成方法：resolve resolution:
顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺的制备：Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl) cyclobutyl) cyclohexyl amine preparation:
按照实施例22的合成方法顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环己酮还原胺化反应合成顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺。MS:[M+1] +:505.3. According to the synthesis method of Example 22 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclohexanone reductive amination reaction to synthesize cis-N-3-(((4-((4-fluoro-2-methyl-1H-indyl) Dol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclohexylamine. MS:[M+1] + :505.3.
1H NMR(400MHz,d 6-DMSO)δ11.37(s,1H),9.21–8.88(m,1H),8.51(s,1H),7.62(s,1H),7.40(s,1H),7.16(d,J＝7.8Hz,1H),7.05–6.90(m,1H),6.24(s,1H),4.24(d,J＝2.8Hz,2H),3.99(s,3H),3.78–3.70(m,1H),3.03–2.82(m,1H),2.76–2.61(m,1H),2.46–2.35(m,5H),2.17–2.07(m,2H),2.01–1.95(m,2H),1.81–1.70(m,2H),1.61–1.58(m,1H),1.32–1.24(m,3H),1.14–1.07(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.37 (s, 1H), 9.21-8.88 (m, 1H), 8.51 (s, 1H), 7.62 (s, 1H), 7.40 (s, 1H), 7.16(d,J=7.8Hz,1H), 7.05–6.90(m,1H), 6.24(s,1H), 4.24(d,J=2.8Hz,2H), 3.99(s,3H), 3.78–3.70 (m,1H),3.03-2.82(m,1H),2.76-2.61(m,1H),2.46-2.35(m,5H),2.17-2.07(m,2H),2.01-1.95(m,2H) ,1.81–1.70(m,2H),1.61–1.58(m,1H),1.32–1.24(m,3H),1.14–1.07(m,2H).
实施例29Example 29
顺式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Cis-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- (Yl)oxy)methyl)cyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000119
Figure PCTCN2021073616-appb-000119
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000120
Figure PCTCN2021073616-appb-000120
合成方法：resolve resolution:
顺式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺的制备：Cis-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- Preparation of (oxy)methyl)cyclobutylamine:
按照实施例22的合成方法顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环丁酮发生还原胺化反应，经制备液相色谱在甲酸条件下分离提纯得到顺式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺。MS:[M+1] +:477.3. According to the synthesis method of Example 22 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride undergoes reductive amination reaction with cyclobutanone, and is separated and purified by preparative liquid chromatography under formic acid conditions to obtain cis-N-cyclobutyl-3-(( (4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutylamine. MS:[M+1] + :477.3.
1H NMR(400MHz,d 6-DMSO)δ11.36(s,1H),8.50(s,1H),7.61(s,1H),7.38(s,1H),7.16(d,J＝8.4Hz,1H),6.99(t,J＝8.0Hz,1H),6.24(s,1H),4.18(d,J＝5.6Hz,2H),3.99(s,3H),3.34–3.30(m,2H),2.41–2.30(m,5H),2.15–2.09(m,2H),2.03–1.77(m,5H),1.72–1.58(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.36 (s, 1H), 8.50 (s, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.18 (d, J = 5.6 Hz, 2H), 3.99 (s, 3H), 3.34–3.30 (m, 2H), 2.41–2.30(m,5H), 2.15–2.09(m,2H), 2.03–1.77(m,5H), 1.72–1.58(m,2H).
实施例30Example 30
顺式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Cis-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000121
Figure PCTCN2021073616-appb-000121
合成方法：resolve resolution:
Figure PCTCN2021073616-appb-000122
Figure PCTCN2021073616-appb-000122
合成方法：resolve resolution:
顺式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺甲酸盐的制备：Cis-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline Preparation of -7-yl)oxy)methyl)cyclobutylamine formate:
按照实施例29的合成方法顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环丁酮发生还原胺化反应，经制备液相色谱在甲酸条件下分离提纯得到顺式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺甲酸盐。MS:[M+1] +:531.3. According to the synthesis method of Example 29 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride undergoes reductive amination reaction with cyclobutanone, and is separated and purified by preparative liquid chromatography under formic acid conditions to obtain cis-N,N-dicyclobutyl-3 -(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutylamine Formate. MS:[M+1] + :531.3.
1H NMR(400MHz,d 6-DMSO)δ11.36(s,1H),10.69(s,1H),8.51(s,1H),7.62(s,1H),7.39(s,1H),7.16(d,J＝8.4Hz,1H),6.99(t,J＝8.0Hz,1H),6.24(s,1H),4.18(d,J＝4.4Hz,2H),3.99(s,3H),3.70–3.60(m,2H),3.28–3.24(m,1H),2.41–2.25(m,9H),2.19–1.96(m,6H),1.77–1.57(m,4H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.36 (s, 1H), 10.69 (s, 1H), 8.51 (s, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 7.16 ( d,J=8.4Hz,1H), 6.99(t,J=8.0Hz,1H), 6.24(s,1H), 4.18(d,J=4.4Hz,2H), 3.99(s,3H), 3.70– 3.60(m,2H), 3.28–3.24(m,1H), 2.41–2.25(m,9H), 2.19–1.96(m,6H), 1.77–1.57(m,4H).
实施例31Example 31
顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclopentylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000123
Figure PCTCN2021073616-appb-000123
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000124
Figure PCTCN2021073616-appb-000124
合成方法：resolve resolution:
顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺的制备：Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) Preparation of (methyl)cyclobutyl)cyclopentylamine:
按照实施例22的合成方法顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环戊酮发生还原胺化反应合成顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺。MS:[M+1] +:491.3. According to the synthesis method of Example 22 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclopentanone undergo reductive amination reaction to synthesize cis-N-3-(((4-((4-fluoro-2-methyl-1H- Indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclopentylamine. MS:[M+1] + :491.3.
1H NMR(400MHz,d 6-DMSO)δ11.36(s,1H),8.51(s,1H),7.61(s,1H),7.40(s,1H),7.16(d,J＝8.8Hz,1H),6.98(t,J＝8.0Hz,1H),6.24(s,1H),4.21(d,J＝5.6Hz,2H),3.99(s,3H),3.57–3.51(m,1H),3.26–3.24(m,1H),2.61–2.57(m,1H),2.46–2.41(m,5H),1.97–1.84(m,4H),1.72–1.63(m,2H),1.56–1.43(m,4H),1.29–1.27(m,1H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.36 (s, 1H), 8.51 (s, 1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.16 (d, J = 8.8Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.21 (d, J = 5.6 Hz, 2H), 3.99 (s, 3H), 3.57–3.51 (m, 1H), 3.26–3.24(m,1H), 2.61–2.57(m,1H), 2.46–2.41(m,5H), 1.97–1.84(m,4H), 1.72–1.63(m,2H), 1.56–1.43(m ,4H),1.29–1.27(m,1H).
实施例32Example 32
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinazoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000125
Figure PCTCN2021073616-appb-000125
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000126
Figure PCTCN2021073616-appb-000126
合成方法：resolve resolution:
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉的制备：Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy) quinazoline preparation:
向反应瓶中加入反式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺盐酸盐(100.0mg,1eq)，1,5-二溴戊烷(60.6mg,1.2eq)，碳酸钾(90.4mg,3eq)和N,N-二甲基甲酰胺(5mL)。在氮气保护下80℃搅拌反应3小时。LCMS表征反应完毕，停止反应。加水(30mL)，乙酸乙酯(20mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经制备薄层色谱在提纯得到反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉甲酸盐(60mg,收率60％)。MS:[M+1] +:491.3. Add trans-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy to the reaction flask ) Methyl) cyclobutylamine hydrochloride (100.0mg, 1eq), 1,5-dibromopentane (60.6mg, 1.2eq), potassium carbonate (90.4mg, 3eq) and N,N-dimethylformaldehyde Amide (5 mL). The reaction was stirred at 80°C for 3 hours under the protection of nitrogen. The LCMS characterization reaction is complete, and the reaction is stopped. Add water (30mL), extract with ethyl acetate (20mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is purified by preparative thin-layer chromatography to obtain trans-4-( 4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy)quinazole Morinoformate (60mg, yield 60%). MS:[M+1] + :491.3.
1H NMR(400MHz,d 6-DMSO)δ11.36(s,1H),8.50(s,1H),7.61(s,1H),7.37(s,1H),7.16(d,J＝8.4Hz,1H),7.00(t,J＝8.0Hz,1H),6.24(s,1H),4.26(d,J＝6.8Hz,2H),4.00(s,3H),3.09–2.61(m,2H),2.45–2.14(m,8H),1.89–1.70(m,2H),1.55(s,4H),1.43(d,J＝1.8Hz,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.36 (s, 1H), 8.50 (s, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.26 (d, J = 6.8 Hz, 2H), 4.00 (s, 3H), 3.09–2.61 (m, 2H), 2.45–2.14 (m, 8H), 1.89–1.70 (m, 2H), 1.55 (s, 4H), 1.43 (d, J = 1.8 Hz, 2H).
实施例33Example 33
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl (Oxy)quinazoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000127
Figure PCTCN2021073616-appb-000127
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000128
Figure PCTCN2021073616-appb-000128
合成方法：resolve resolution:
按照实施例32的合成方法反式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺盐酸盐与1,4-二溴丁烷反应合成反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉。MS:[M+1] +:477.3. According to the synthesis method of Example 32 trans-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yl (Oxy)methyl)cyclobutylamine hydrochloride reacts with 1,4-dibromobutane to synthesize trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)- 6-Methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinazoline. MS:[M+1] + :477.3.
1H NMR(400MHz,d 6-DMSO)δ11.36(s,1H),8.51(s,1H),7.60(s,1H),7.41(s,1H),7.16(d,J＝8.4Hz,1H),7.05–6.94(m,1H),6.24(s,1H),4.31(d,J＝6.8Hz,2H),3.99(s,3H),3.79–3.72(m,1H),3.51–3.43(m,2H),3.05–2.92(m,2H),2.88–2.61(m,1H),2.47–2.42(m,4H),2.16–2.11(m,2H),1.99–1.87(m,4H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.36 (s, 1H), 8.51 (s, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.05–6.94(m,1H), 6.24(s,1H), 4.31(d,J=6.8Hz,2H), 3.99(s,3H), 3.79–3.72(m,1H), 3.51–3.43 (m,2H),3.05–2.92(m,2H), 2.88–2.61(m,1H), 2.47–2.42(m,4H), 2.16–2.11(m,2H),1.99–1.87(m,4H) .
实施例34Example 34
反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclohexylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000129
Figure PCTCN2021073616-appb-000129
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000130
Figure PCTCN2021073616-appb-000130
合成方法：resolve resolution:
反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺的制备：Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl) cyclobutyl) cyclohexyl amine preparation:
按照实施例23的合成方法反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环己酮还原胺化反应合成反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺。MS:[M+1] +:505.3. According to the synthesis method of Example 23 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclohexanone reductive amination reaction to synthesize trans-N-3-(((4-((4-fluoro-2-methyl-1H-indyl) Dol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclohexylamine. MS:[M+1] + :505.3.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.51(s,1H),7.61(s,1H),7.41(s,1H),7.16(d,J＝7.8Hz,1H),7.07–6.91(m,1H),6.24(s,1H),4.29(d,J＝5.6Hz,2H),4.00(s,3H),3.79–3.70(m,1H),3.04–2.82(m,1H),2.78–2.63(m,1H),2.44–2.31(m,5H),2.19–2.07(m,2H),2.02–1.95(m,2H),1.83–1.70(m,2H),1.62–1.58(m,1H),1.34–1.24(m,3H),1.15–1.09(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 8.51 (s, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.07–6.91(m,1H), 6.24(s,1H), 4.29(d,J=5.6Hz,2H), 4.00(s,3H), 3.79–3.70(m,1H),3.04–2.82 (m,1H), 2.78-2.63(m,1H), 2.44-2.31(m,5H), 2.19-2.07(m,2H), 2.02-1.95(m,2H), 1.83--1.70(m,2H) ,1.62–1.58(m,1H),1.34–1.24(m,3H),1.15–1.09(m,2H).
实施例35Example 35
反式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Trans-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- (Yl)oxy)methyl)cyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000131
Figure PCTCN2021073616-appb-000131
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000132
Figure PCTCN2021073616-appb-000132
合成方法：resolve resolution:
反式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺的制备：Trans-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- Preparation of (oxy)methyl)cyclobutylamine:
按照实施例4的合成方法反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环丁酮发生还原胺化反应，经制备液相色谱在甲酸条件下分离提纯得到反式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺。MS:[M+1] +:477.3. According to the synthesis method of Example 4 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride undergoes reductive amination reaction with cyclobutanone. Trans-N-cyclobutyl-3-(( (4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutylamine. MS:[M+1] + :477.3.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.51(s,1H),7.61(s,1H),7.37(s,1H),7.16(d,J＝8.4Hz,1H),7.00(t,J＝8.0Hz,1H),6.26(s,1H),4.24(d,J＝6.4Hz,2H),3.99(s,3H),3.33–3.19(m,2H),2.39–2.30(m,5H),2.15–2.09(m,2H),2.02–1.79(m,5H),1.74–1.61(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 8.51 (s, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.26 (s, 1H), 4.24 (d, J = 6.4 Hz, 2H), 3.99 (s, 3H), 3.33-3.19 (m, 2H), 2.39–2.30(m,5H), 2.15–2.09(m,2H), 2.02–1.79(m,5H), 1.74–1.61(m,2H).
实施例36Example 36
反式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Trans-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000133
Figure PCTCN2021073616-appb-000133
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000134
Figure PCTCN2021073616-appb-000134
合成方法：resolve resolution:
反式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺甲酸盐的制备：Trans-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline Preparation of -7-yl)oxy)methyl)cyclobutylamine formate:
按照实施例29的合成方法反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环丁酮发生还原胺化反应，经制备液相色谱在甲酸条件下分离提纯得到反式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺。MS:[M+1] +:531.3. According to the synthesis method of Example 29 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride undergoes reductive amination reaction with cyclobutanone, and is separated and purified by preparative liquid chromatography under formic acid conditions to obtain trans-N,N-dicyclobutyl-3 -(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutylamine . MS:[M+1] + :531.3.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.51(s,1H),7.61(s,1H),7.40(s,1H),7.16(d,J＝8.4Hz,1H),6.99(t,J＝8.0Hz,1H),6.24(s,1H),4.24(d,J＝5.6Hz,2H),3.99(s,3H),3.71–3.61(m,2H),3.28–3.24(m,1H),2.41–2.24(m,9H),2.21–1.96(m,6H),1.77–1.57(m,4H)。 1 H NMR(400MHz,d 6 -DMSO)δ11.35(s,1H),8.51(s,1H),7.61(s,1H),7.40(s,1H),7.16(d,J=8.4Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.24 (d, J = 5.6 Hz, 2H), 3.99 (s, 3H), 3.71–3.61 (m, 2H), 3.28–3.24(m,1H), 2.41–2.24(m,9H), 2.21–1.96(m,6H), 1.77–1.57(m,4H).
实施例37Example 37
反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclopentylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000135
Figure PCTCN2021073616-appb-000135
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000136
Figure PCTCN2021073616-appb-000136
合成方法：resolve resolution:
反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺的制备：Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) Preparation of (methyl)cyclobutyl)cyclopentylamine:
按照实施例23的合成方法反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺盐酸盐与环戊酮发生还原胺化反应合成反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺。MS:[M+1] +:491.3. According to the synthesis method of Example 23 trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7 -Yl)oxy)methyl)cyclobutylamine hydrochloride and cyclopentanone undergo reductive amination reaction to synthesize trans-N-3-(((4-((4-fluoro-2-methyl-1H- Indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutyl)cyclopentylamine. MS:[M+1] + :491.3.
1H NMR(400MHz,d 6-DMSO)δ11.35(s,1H),8.51(s,1H),7.60(s,1H),7.39(s,1H),7.16(d,J＝8.4Hz,1H),6.98(t,J＝8.0Hz,1H),6.24(s,1H),4.29(d,J＝6.4Hz,2H),3.99(s,3H),3.58–3.51(m,1H),3.30–3.26(m,1H),2.62–2.57(m,1H),2.47–2.41(m,5H),1.97–1.84(m,4H),1.72–1.63(m,2H),1.56–1.43(m,4H),1.29–1.27(m,1H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.35 (s, 1H), 8.51 (s, 1H), 7.60 (s, 1H), 7.39 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.24 (s, 1H), 4.29 (d, J = 6.4 Hz, 2H), 3.99 (s, 3H), 3.58–3.51 (m, 1H), 3.30–3.26(m,1H), 2.62–2.57(m,1H), 2.47–2.41(m,5H), 1.97–1.84(m,4H), 1.72–1.63(m,2H), 1.56–1.43(m ,4H),1.29–1.27(m,1H).
实施例38Example 38
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine
化合物的结构式:The structural formula of the compound:
Figure PCTCN2021073616-appb-000137
Figure PCTCN2021073616-appb-000137
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000138
Figure PCTCN2021073616-appb-000138
合成方法：resolve resolution:
叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)(甲基)氨基甲酸酯的制备Tert-Butyl-cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl) Preparation of (oxy)methyl)cyclobutanyl)(methyl)carbamate
向反应瓶中加入顺式-叔丁基-3-(羟甲基)环丁基)(甲基)氨基甲酸酯(860mg,2eq)，4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-醇(674.6mg,1eq)，三苯基膦(1.31g,2.5eq)和新蒸的四氢呋喃(40mL)，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(1.21g,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(250mL)淬灭体系，乙酸乙酯(100mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经硅胶柱层析和反向制备液相得到叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)(甲基)氨基甲酸酯(503mg,收率：59％)。MS:[M+1]+:536.3.Add cis-tert-butyl-3-(hydroxymethyl)cyclobutyl)(methyl)carbamate (860mg, 2eq), 4-(4-fluoro-2-methyl-1H) to the reaction flask -Indol-5-yloxy)-6-methoxyquinazolin-7-ol (674.6mg, 1eq), triphenylphosphine (1.31g, 2.5eq) and freshly distilled tetrahydrofuran (40mL), After stirring for 10 min at room temperature, add diisopropyl azodicarboxylate (1.21g, 3eq) dropwise to the reaction system at room temperature. Stir at room temperature overnight. LCMS characterizes that the reaction is complete. The reaction is stopped. Water (250mL) is added to quench the system. Ester (100mL*3) was extracted, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated. The crude product was subjected to silica gel column chromatography and reversed to prepare the liquid phase to obtain tert-butyl-cis-3- (((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutanyl ) (Methyl) carbamate (503 mg, yield: 59%). MS:[M+1]+:536.3.
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺盐酸盐的制备Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine hydrochloride preparation
在反应瓶中向叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)(甲基)氨基甲酸酯(503mg,1eq)添加盐酸-乙酸乙酯溶液(2M,25mL)，室温搅拌16小时，LCMS表征反应完毕，停止反应，抽滤，固体用乙酸乙酯洗两次后得到顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁 基胺盐酸盐(320mg,收率：75％)。MS:[M+1-HCl]+:436.2.In the reaction flask, add tert-butyl-cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutanyl)(methyl)carbamate (503mg, 1eq) was added with hydrochloric acid-ethyl acetate solution (2M, 25mL), stirred at room temperature for 16 hours, LCMS characterization reaction was completed , The reaction was stopped, filtered with suction, and the solid was washed twice with ethyl acetate to obtain cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)- 6-Methoxyquinazolin-7-yl)oxy)methyl)-N-methylcyclobutylamine hydrochloride (320mg, yield: 75%). MS: [M+1-HCl]+: 436.2
1H NMR(400MHz,CDCl 3)δ11.38(s,1H),8.99(s,2H),8.55(s,1H),7.64(s,1H),7.42(s,1H),7.16(d,J＝8.8Hz,1H),6.99(t,J＝8.4Hz 1H),6.24(s,1H),4.24(d,J＝6.8Hz,2H),4.00(s,3H),3.68–3.54(m,1H),2.73–2.60(m,1H),2.48–2.35(m,7H),2.25–2.20(m,1H),2.11–2.07(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 11.38 (s, 1H), 8.99 (s, 2H), 8.55 (s, 1H), 7.64 (s, 1H), 7.42 (s, 1H), 7.16 (d, J = 8.8Hz, 1H), 6.99 (t, J = 8.4Hz 1H), 6.24 (s, 1H), 4.24 (d, J = 6.8 Hz, 2H), 4.00 (s, 3H), 3.68–3.54 (m ,1H), 2.73–2.60(m,1H), 2.48–2.35(m,7H), 2.25–2.20(m,1H), 2.11–2.07(m,2H).
实施例39Example 39
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine
化合物的结构式:The structural formula of the compound:
Figure PCTCN2021073616-appb-000139
Figure PCTCN2021073616-appb-000139
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000140
Figure PCTCN2021073616-appb-000140
合成方法：resolve resolution:
叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)(甲基)氨基甲酸酯的制备Tert-Butyl-trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl) Preparation of (oxy)methyl)cyclobutanyl)(methyl)carbamate
向反应瓶中加入反式-叔丁基-3-(羟甲基)环丁基)(甲基)氨基甲酸酯(860mg,2eq)，4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹唑啉-7-醇(674.6mg,1eq)，三苯基膦(1.31g,2.5eq)和新蒸的四氢呋喃(40mL)，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(1.21g,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(250mL)淬灭体系，乙酸乙酯(100mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经硅胶柱层析和反向制备液相 得到叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)(甲基)氨基甲酸酯(503mg,收率：59％)。MS:[M+1]+:536.3.Add trans-tert-butyl-3-(hydroxymethyl)cyclobutyl)(methyl)carbamate (860mg, 2eq), 4-(4-fluoro-2-methyl-1H) to the reaction flask -Indol-5-yloxy)-6-methoxyquinazolin-7-ol (674.6mg, 1eq), triphenylphosphine (1.31g, 2.5eq) and freshly distilled tetrahydrofuran (40mL), After stirring for 10 min at room temperature, add diisopropyl azodicarboxylate (1.21g, 3eq) dropwise to the reaction system at room temperature. Stir at room temperature overnight. LCMS characterizes that the reaction is complete. The reaction is stopped. Water (250mL) is added to quench the system. Ester (100mL*3) was extracted, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, and concentrated. The crude product was subjected to silica gel column chromatography and reversed phase preparation to obtain tert-butyl-trans-3- (((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl)cyclobutanyl ) (Methyl) carbamate (503 mg, yield: 59%). MS:[M+1]+:536.3.
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺盐酸盐的制备Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine hydrochloride preparation
在反应瓶中向叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁烷基)(甲基)氨基甲酸酯(503mg,1eq)添加盐酸-乙酸乙酯溶液(2M,25mL)，室温搅拌16小时，LCMS表征反应完毕，停止反应，抽滤，固体用乙酸乙酯洗两次后得到反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺盐酸盐(311mg,收率：71％)。MS:[M+1-HCl]+:436.2.In the reaction flask, add tert-butyl-trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutanyl)(methyl)carbamate (503mg, 1eq) was added with hydrochloric acid-ethyl acetate solution (2M, 25mL), stirred at room temperature for 16 hours, LCMS characterization reaction was completed , Stop the reaction, filter with suction, and wash the solid twice with ethyl acetate to obtain trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)- 6-Methoxyquinazolin-7-yl)oxy)methyl)-N-methylcyclobutylamine hydrochloride (311 mg, yield: 71%). MS: [M+1-HCl]+: 436.2
1H NMR(400MHz,CDCl 3)δ11.38(s,1H),9.06(s,2H),8.55(s,1H),7.64(s,1H),7.44(s,1H),7.16(d,J＝8.8Hz,1H),6.99(t,J＝8.4Hz 1H),6.24(s,1H),4.29(d,J＝6.4Hz,2H),4.01(s,3H),3.68–3.54(m,1H),2.73–2.60(m,1H),2.48–2.35(m,7H),2.25–2.17(m,1H),2.13–2.07(m,2H)。 1 H NMR (400MHz, CDCl 3 ) δ 11.38 (s, 1H), 9.06 (s, 2H), 8.55 (s, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.16 (d, J = 8.8Hz, 1H), 6.99 (t, J = 8.4Hz 1H), 6.24 (s, 1H), 4.29 (d, J = 6.4 Hz, 2H), 4.01 (s, 3H), 3.68–3.54 (m ,1H), 2.73–2.60(m,1H), 2.48–2.35(m,7H), 2.25–2.17(m,1H), 2.13–2.07(m,2H).
实施例40Example 40
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Cyclobutylamine
化合物的结构式:The structural formula of the compound:
Figure PCTCN2021073616-appb-000141
Figure PCTCN2021073616-appb-000141
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000142
Figure PCTCN2021073616-appb-000142
合成方法：resolve resolution:
叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯的制备Tert-Butyl-cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy )Methyl)cyclobutanyl)carbamate preparation
向反应瓶中加入粗品顺-3-(Boc-氨基)环丁基甲醇(800mg,2eq)，4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-醇(674.6mg,1eq)，三苯基膦(1.31g,2.5eq)和新蒸的四氢呋喃(40mL)，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(1.21g,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(250mL)淬灭体系，乙酸乙酯(100mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经硅胶柱层析和反向制备液相得到叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(525mg,收率：50％)。MS:[M+1]+:522.2.Add crude cis-3-(Boc-amino)cyclobutylmethanol (800mg, 2eq), 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6 to the reaction flask -Methoxyquinoline-7-ol (674.6mg, 1eq), triphenylphosphine (1.31g, 2.5eq) and freshly distilled tetrahydrofuran (40mL), after stirring at room temperature for 10 minutes, add dropwise to the reaction system at room temperature Diisopropyl azodicarboxylate (1.21g, 3eq), stirred overnight at room temperature, LCMS characterizes that the reaction is complete, the reaction is stopped, the system is quenched by adding water (250mL), extracted with ethyl acetate (100mL*3), the organic phases are combined and saturated Wash with brine once, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is subjected to silica gel column chromatography and reversed phase preparation to obtain tert-butyl-cis-3-(((4-((4-fluoro-2- Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclobutanyl)carbamate (525mg, yield: 50%) . MS:[M+1]+:522.2.
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐的制备Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Preparation of cyclobutylamine hydrochloride
在反应瓶中向叔丁基-顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(525mg,1eq)添加盐酸-乙酸乙酯溶液(2M,25mL)，室温搅拌16小时，LCMS表征反应完毕，停止反应，抽滤，固体用乙酸乙酯洗两次后得到顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐(380mg,收率：83％)。MS:[M+1-HCl]+:422.2.Add tert-butyl-cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyoxazoline- 7-yl)oxy)methyl)cyclobutanyl)carbamate (525mg, 1eq) was added with hydrochloric acid-ethyl acetate solution (2M, 25mL), stirred at room temperature for 16 hours, LCMS characterization of the reaction was completed, stop the reaction, pump After filtration, the solid was washed twice with ethyl acetate to obtain cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy Quinolin-7-yl)oxy)methyl)cyclobutylamine hydrochloride (380 mg, yield: 83%). MS:[M+1-HCl]+:422.2.
1H NMR(400MHz,d 6-DMSO)δ11.64(s,1H),8.76(d,J＝6.5Hz,1H),8.27(s,3H,NH 2HCl),7.81(s,1H),7.76(s,1H),7.30(d,J＝8.6Hz,1H),7.15–7.06(m,1H),6.81(d,J＝6.5Hz,1H),6.33(s,1H),4.26(d,J＝6.4Hz,2H),4.06(s,3H),3.69(dd,J＝12.9,7.6Hz,1H),2.73–2.63(m,1H),2.48–2.34(m,5H),2.11(dd,J＝20.1,9.5Hz,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.64 (s, 1H), 8.76 (d, J = 6.5 Hz, 1H), 8.27 (s, 3H, NH 2 HCl), 7.81 (s, 1H), 7.76(s,1H),7.30(d,J=8.6Hz,1H),7.15-7.06(m,1H),6.81(d,J=6.5Hz,1H),6.33(s,1H), 4.26(d ,J=6.4Hz,2H),4.06(s,3H), 3.69(dd,J=12.9,7.6Hz,1H), 2.73–2.63(m,1H), 2.48–2.34(m,5H), 2.11( dd, J=20.1, 9.5 Hz, 2H).
实施例41Example 41
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Cyclobutylamine
化合物的结构式:The structural formula of the compound:
Figure PCTCN2021073616-appb-000143
Figure PCTCN2021073616-appb-000143
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000144
Figure PCTCN2021073616-appb-000144
合成方法：resolve resolution:
叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯的制备Tert-Butyl-trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy )Methyl)cyclobutanyl)carbamate preparation
向反应瓶中加入粗品反式-3-(Boc-氨基)环丁基甲醇(800mg,2eq)，4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-醇(674.6mg,1eq)，三苯基膦(1.31g,2.5eq)和新蒸的四氢呋喃(40mL)，室温搅拌10min后，向反应体系在室温下滴加偶氮二甲酸二异丙酯(1.21g,3eq)，室温搅拌过夜，LCMS表征反应完全，停止反应，加水(250mL)淬灭体系，乙酸乙酯(100mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经硅胶柱层析和反向制备液相得到叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(470mg,收率：45％)。MS:[M+1]+:522.2.Add crude trans-3-(Boc-amino)cyclobutylmethanol (800mg, 2eq), 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)- to the reaction flask 6-Methoxyquinoline-7-ol (674.6mg, 1eq), triphenylphosphine (1.31g, 2.5eq) and freshly distilled tetrahydrofuran (40mL) were stirred at room temperature for 10 minutes, and then dropped into the reaction system at room temperature Add diisopropyl azodicarboxylate (1.21g, 3eq), stir overnight at room temperature, LCMS characterizes that the reaction is complete, stop the reaction, add water (250mL) to quench the system, extract with ethyl acetate (100mL*3), combine the organic phases and use Wash with saturated brine once, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is subjected to silica gel column chromatography and reversed phase preparation to obtain tert-butyl-trans-3-(((4-((4-fluoro-2 -Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclobutanyl)carbamate (470mg, yield: 45% ). MS:[M+1]+:522.2.
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐的制备Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Preparation of cyclobutylamine hydrochloride
在反应瓶中向叔丁基-反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基唑啉-7-基)氧)甲基)环丁烷基)氨基甲酸酯(470mg,1eq)添加盐酸-乙酸乙酯溶液(2M,15mL)，室温搅拌16小时，LCMS表征反应完毕，停止反应，抽滤，固体用乙酸乙酯洗两次后得到反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐(305mg,收率：74％)。MS:[M+1-HCl]+:422.2.Add tert-butyl-trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyoxazoline- 7-yl)oxy)methyl)cyclobutanyl)carbamate (470mg, 1eq) was added with hydrochloric acid-ethyl acetate solution (2M, 15mL), stirred at room temperature for 16 hours, LCMS characterizes that the reaction is complete, stop the reaction, pump After filtration, the solid was washed twice with ethyl acetate to obtain trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxy Quinolin-7-yl)oxy)methyl)cyclobutylamine hydrochloride (305mg, yield: 74%). MS:[M+1-HCl]+:422.2.
1H NMR(400MHz,d 6-DMSO)δ11.66(s,1H),8.77(d,J＝6.8Hz,1H),8.34(d,J＝4.4Hz,3H),7.82(s,1H),7.77(s,1H),7.31(d,J＝8.8Hz,1H),7.12(t,J＝8.0Hz,1H),6.83(d,J＝6.0Hz,1H),6.33(s,1H),4.32(d,J＝6.4Hz,2H),4.07(s,3H),3.96–3.88(m,1H),2.98–2.91(m,1H),2.44–2.36(m,5H),2.30–2.23(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.66 (s, 1H), 8.77 (d, J = 6.8 Hz, 1H), 8.34 (d, J = 4.4 Hz, 3H), 7.82 (s, 1H) ,7.77(s,1H),7.31(d,J=8.8Hz,1H),7.12(t,J=8.0Hz,1H),6.83(d,J=6.0Hz,1H),6.33(s,1H) , 4.32(d,J=6.4Hz,2H),4.07(s,3H),3.96–3.88(m,1H),2.98–2.91(m,1H),2.44–2.36(m,5H),2.30–2.23 (m, 2H).
实施例42Example 42
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000145
Figure PCTCN2021073616-appb-000145
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000146
Figure PCTCN2021073616-appb-000146
合成方法：resolve resolution:
顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺的制备Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine preparation
在反应瓶中向顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐(80mg,1eq)的甲醇(3mL)溶液中，添加多聚甲醛(52.4mg,10eq)和1滴醋酸，室温搅拌10min后，相反应体系添加三乙酰氧基硼氢化钠(185.1mg,5eq)。室温反应过夜，LCMS表征反应完毕，停止反应。将未反应的多聚甲醛固体抽滤掉，母液直接经制备液相提纯得到顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基 喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺甲酸盐(30mg,收率：36％)。MS:[M+1-HCl] +:450.2 To cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl) in the reaction flask (Oxy) methyl) cyclobutylamine hydrochloride (80mg, 1eq) in methanol (3mL) solution, add paraformaldehyde (52.4mg, 10eq) and 1 drop of acetic acid, after stirring at room temperature for 10min, the phase reaction system is added three Sodium acetoxyborohydride (185.1 mg, 5 eq). React at room temperature overnight, the LCMS characterization of the reaction is complete, and the reaction is stopped. The unreacted paraformaldehyde solid is filtered off with suction, and the mother liquor is directly purified by the preparation liquid phase to obtain cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl) (Oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclobutylcarbamate (30 mg, yield: 36%). MS:[M+1-HCl] + :450.2
1H NMR(400MHz,d 6-DMSO)δ11.47(s,1H),8.41(d,J＝5.2Hz,1H),8.26(s,1H),7.59(s,1H),7.41(s,1H),7.22(d,J＝8.4Hz,1H),7.04–6.96(m,1H),6.33(dd,J＝5.2,0.8Hz,1H),6.28(s,1H),4.25(d,J＝6.8Hz,2H),3.99(s,3H),3.05–2.95(m,1H),2.61–2.53(m,1H),2.42(s,3H),2.23–2.01(m,8H),2.02–1.97(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.47 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.26 (s, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.04-6.96 (m, 1H), 6.33 (dd, J = 5.2, 0.8 Hz, 1H), 6.28 (s, 1H), 4.25 (d, J ＝6.8Hz,2H),3.99(s,3H),3.05–2.95(m,1H),2.61–2.53(m,1H),2.42(s,3H),2.23–2.01(m,8H),2.02– 1.97 (m, 2H).
实施例43Example 43
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000147
Figure PCTCN2021073616-appb-000147
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000148
Figure PCTCN2021073616-appb-000148
合成方法：resolve resolution:
反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺的制备：Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Preparation of -N,N-Dimethylcyclobutylamine:
在反应瓶中向反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐(80mg,1eq)的甲醇(3mL)溶液中，添加多聚甲醛(52.4mg,10eq)和1滴醋酸，室温搅拌10min后，相反应体系添加三乙酰氧基硼氢化钠(185.1mg,5eq)。室温反应过夜，LCMS 表征反应完毕，停止反应。将未反应的多聚甲醛固体抽滤掉，母液直接经制备薄层色谱提纯得到反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺甲酸盐(25mg,收率：23％)。MS:[M+1] +:450.2. In the reaction flask to trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl) (Oxy) methyl) cyclobutylamine hydrochloride (80mg, 1eq) in methanol (3mL) solution, add paraformaldehyde (52.4mg, 10eq) and 1 drop of acetic acid, after stirring at room temperature for 10min, the phase reaction system is added three Sodium acetoxyborohydride (185.1 mg, 5 eq). React at room temperature overnight. LCMS characterizes that the reaction is complete, and the reaction is stopped. The unreacted paraformaldehyde solid was filtered off with suction, and the mother liquor was directly purified by preparative thin layer chromatography to obtain trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl )Oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclobutylcarbamate (25mg, yield: 23%). MS:[M+1] + :450.2.
1H NMR(400MHz,d 6-DMSO)δ11.46(s,1H),8.42(d,J＝5.2Hz,1H),8.25(s,1H),7.59(s,1H),7.42(s,1H),7.22(d,J＝8.6Hz,1H),7.04–6.96(m,1H),6.33(dd,J＝5.2,0.8Hz,1H),6.28(s,1H),4.20(d,J＝7.2Hz,2H),3.97(s,3H),3.04–2.95(m,1H),2.66–2.56(m,1H),2.42(s,3H),2.20–2.05(m,8H),2.05–1.94(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.46 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 7.22(d,J=8.6Hz,1H), 7.04–6.96(m,1H), 6.33(dd,J=5.2,0.8Hz,1H), 6.28(s,1H), 4.20(d,J =7.2Hz,2H),3.97(s,3H),3.04–2.95(m,1H),2.66–2.56(m,1H),2.42(s,3H),2.20–2.05(m,8H),2.05– 1.94 (m, 2H).
实施例44Example 44
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000149
Figure PCTCN2021073616-appb-000149
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000150
Figure PCTCN2021073616-appb-000150
合成方法：resolve resolution:
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉甲酸盐的制备：Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy) quinoline formate preparation:
向反应瓶中加入顺式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁胺(198mg,1eq)，1,5-二溴戊烷(121.2mg,1.2 eq)，碳酸钾(180.8mg,3eq)和N,N-二甲基甲酰胺(10mL)。在氮气保护下80℃搅拌反应3小时。LCMS表征反应完毕，停止反应。加水(70mL)，乙酸乙酯(30mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经制备液相色谱在甲酸条件下提纯得到顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉甲酸盐(65mg,收率32％)。MS:[M+1] +:490.3. Add cis-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) to the reaction flask Methyl)cyclobutylamine (198 mg, 1 eq), 1,5-dibromopentane (121.2 mg, 1.2 eq), potassium carbonate (180.8 mg, 3 eq) and N,N-dimethylformamide (10 mL). The reaction was stirred at 80°C for 3 hours under the protection of nitrogen. The LCMS characterization reaction is complete, and the reaction is stopped. Add water (70mL), extract with ethyl acetate (30mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is purified by preparative liquid chromatography under formic acid conditions to obtain cis- 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy ) Quinoline formate (65mg, yield 32%). MS:[M+1] + :490.3.
1H NMR(400MHz,d 6-DMSO)δ11.42(s,1H),8.41(d,J＝5.2Hz,1H),8.20(s,1H, HCOOH),7.58(s,1H),7.38(s,1H),7.22(d,J＝8.8Hz,1H),6.99(t,J＝8.0Hz,1H),6.32(d,J＝5.2Hz,1H),6.28(s,1H),4.11(d,J＝6.4Hz,2H),3.96(s,3H),2.75–2.67(m,1H),2.47–2.36(m,4H),2.31–2.20(m,6H),1.76–1.68(m,2H),1.52–1.45(m,4H),1.40–1.39(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.42 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H, H COOH), 7.58 (s, 1H), 7.38 (s, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.32 (d, J = 5.2 Hz, 1H), 6.28 (s, 1H), 4.11 (d,J=6.4Hz,2H), 3.96(s,3H), 2.75–2.67(m,1H), 2.47–2.36(m,4H), 2.31–2.20(m,6H), 1.76–1.68(m ,2H),1.52–1.45(m,4H),1.40–1.39(m,2H).
实施例45Example 45
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000151
Figure PCTCN2021073616-appb-000151
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000152
Figure PCTCN2021073616-appb-000152
合成方法：resolve resolution:
顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉的制备：Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinoline preparation:
按照实施例26的合成方法顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺盐酸盐与1,4-二溴丁烷反应合成顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉甲酸盐。MS:[M+1] +:476.3. According to the synthesis method of Example 26 cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinoline-7- (Yl)oxy)methyl)cyclobutylamine hydrochloride and 1,4-dibromobutane to synthesize cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy) )-6-Methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinoline formate. MS:[M+1] + :476.3.
1H NMR(400MHz,d 6-DMSO)δ11.43(s,1H),8.42(d,J＝5.2Hz,1H),8.17(s,1H),7.59(s,1H),7.39(s,1H),7.22(d,J＝8.4Hz,1H),6.99(t,J＝8.0Hz,1H),6.33(d,J＝5.2Hz,1H),6.28(s,1H),4.16(d,J＝6.4Hz,2H),3.96(s,3H),3.20–3.15(m,1H),3.03–2.99(m,1H),2.92–2.83(m,3H),2.62–2.55(m,1H),2.42–2.30(m,5H),2.12–1.99(m,3H),1.88–1.80(m,3H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.43 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 7.39 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.33 (d, J = 5.2 Hz, 1H), 6.28 (s, 1H), 4.16 (d, J=6.4Hz,2H),3.96(s,3H), 3.20–3.15(m,1H),3.03–2.99(m,1H), 2.92–2.83(m,3H), 2.62–2.55(m,1H) ,2.42–2.30(m,5H), 2.12–1.99(m,3H), 1.88–1.80(m,3H).
实施例46Example 46
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000153
Figure PCTCN2021073616-appb-000153
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000154
Figure PCTCN2021073616-appb-000154
合成方法：resolve resolution:
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉甲酸盐的制备：Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy) quinoline formate preparation:
向反应瓶中加入反式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹 啉基-7-基氧基)甲基)环丁胺盐酸盐(198mg,1eq)，1,5-二溴戊烷(131.2mg,1.2eq)，碳酸钾(180.8mg,3eq)和N,N-二甲基甲酰胺(10mL)。在氮气保护下80℃搅拌反应3小时。LCMS表征反应完毕，停止反应。加水(70mL)，乙酸乙酯(30mL*3)萃取，合并有机相并用饱和食盐水洗一次，无水硫酸钠干燥，抽滤，浓缩，粗品经制备液相色谱在甲酸条件下提纯得到反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉甲酸盐(25mg,收率25％)。MS:[M+1] +:490.3. Add trans-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy) to the reaction flask Methyl) cyclobutylamine hydrochloride (198mg, 1eq), 1,5-dibromopentane (131.2mg, 1.2eq), potassium carbonate (180.8mg, 3eq) and N,N-dimethylformamide ( 10mL). The reaction was stirred at 80°C for 3 hours under the protection of nitrogen. The LCMS characterization reaction is complete, and the reaction is stopped. Add water (70mL), extract with ethyl acetate (30mL*3), combine the organic phases and wash once with saturated brine, dry with anhydrous sodium sulfate, filter with suction, and concentrate. The crude product is purified by preparative liquid chromatography under formic acid conditions to obtain trans- 4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy ) Quinoline formate (25mg, yield 25%). MS:[M+1] + :490.3.
1H NMR(400MHz,d 6-DMSO)δ11.43(s,1H),8.42(d,J＝5.2Hz,1H),8.22(s,1H),7.59(s,1H),7.42(s,1H),7.22(d,J＝8.8Hz,1H),7.04–6.94(m,1H),6.32(d,J＝5.2Hz,1H),6.28(s,1H),4.21(d,J＝7.2Hz,2H),3.96(s,3H),3.04–2.97(m,1H),2.64–2.60(m,1H),2.42(s,3H),2.33–2.26(m,4H),2.13–2.06(m,2H),2.01–1.97(m,2H),1.54–1.50(m,4H),1.44–1.39(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.43 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H),7.22(d,J=8.8Hz,1H),7.04-6.94(m,1H),6.32(d,J=5.2Hz,1H),6.28(s,1H),4.21(d,J=7.2 Hz, 2H), 3.96 (s, 3H), 3.04-2.97 (m, 1H), 2.64-2.60 (m, 1H), 2.42 (s, 3H), 2.33-2.26 (m, 4H), 2.13-2.06 ( m, 2H), 2.01–1.97 (m, 2H), 1.54–1.50 (m, 4H), 1.44–1.39 (m, 2H).
实施例47Example 47
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl (Oxy)quinoline
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000155
Figure PCTCN2021073616-appb-000155
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000156
Figure PCTCN2021073616-appb-000156
合成方法：resolve resolution:
反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环 丁基)甲氧基)喹啉甲酸盐的制备：Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl ((Oxy)quinoline formate preparation:
按照实施例13的合成方法反式-3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁胺盐酸盐与1,4-二溴丁烷反应，经制备液相色谱在甲酸条件下提纯合成反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉甲酸盐。MS:[M+1] +:476.3. According to the synthesis method of Example 13 trans-3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy (4) Methyl) cyclobutylamine hydrochloride reacts with 1,4-dibromobutane, and purified by preparative liquid chromatography under formic acid conditions to synthesize trans-4-(4-fluoro-2-methyl-1H- Indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy)quinoline formate. MS:[M+1] + :476.3.
1H NMR(400MHz,d 6-DMSO)δ11.43(s,1H),8.43(d,J＝5.2Hz,1H),8.14(s,1H),7.60(s,1H),7.43(s,1H),7.22(d,J＝8.2Hz,1H),6.99(t,J＝8.0Hz,1H),6.33(d,J＝5.2Hz,1H),6.28(s,1H),4.31(d,J＝7.2Hz,2H),3.97(s,3H),3.80–3.71(m,1H),3.21–3.17(s,1H),3.05–2.97(m,3H),2.83–2.75(m,2H),2.57–2.54(m,1H),2.42(s,3H),2.39–2.28(m,2H),2.27–2.14(m,2H),1.95–1.82(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.43 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.60 (s, 1H), 7.43 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.33 (d, J = 5.2 Hz, 1H), 6.28 (s, 1H), 4.31 (d, J=7.2Hz,2H),3.97(s,3H),3.80–3.71(m,1H),3.21–3.17(s,1H),3.05–2.97(m,3H),2.83-2.75(m,2H) , 2.57–2.54(m,1H), 2.42(s,3H), 2.39–2.28(m,2H), 2.27–2.14(m,2H), 1.95–1.82(m,2H).
实施例48Example 48
1-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N, N-Dimethylcyclopropylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000157
Figure PCTCN2021073616-appb-000157
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000158
Figure PCTCN2021073616-appb-000158
合成方法：resolve resolution:
室温下，向1-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐(133mg,1eq)的甲醇(6mL)溶液中，添加多聚 甲醛(270mg,10eq)和1滴醋酸，室温搅拌10min后，相反应体系添加氰基硼氢化钠(92.8mg,5eq)。室温反应过夜，LCMS表征反应完毕，停止反应。将未反应的多聚甲醛固体抽滤掉，母液直接经制备液相色谱提纯得到1-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺(45mg,收率：35％)。MS:[M+1] +:436.2. At room temperature, to 1-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl ) To the methanol (6mL) solution of cyclopropylamine hydrochloride (133mg, 1eq), add paraformaldehyde (270mg, 10eq) and 1 drop of acetic acid, stir at room temperature for 10min, then add sodium cyanoborohydride (92.8mg ,5eq). React at room temperature overnight, the LCMS characterization of the reaction is complete, and the reaction is stopped. The unreacted paraformaldehyde solid was filtered off with suction, and the mother liquor was directly purified by preparative liquid chromatography to obtain 1-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy) -6-Methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine (45mg, yield: 35%). MS:[M+1] + :436.2.
1H NMR(400MHz,d 6-DMSO)δ11.46(s,1H),8.44(d,J＝5.2Hz,1H),7.63(s,1H),7.45(s,1H),7.22(d,J＝8.8Hz,1H),7.00(t,J＝7.2Hz 1H),6.36(d,J＝5.2Hz,1H),6.28(s,1H),4.42(s,2H),3.99(s,3H),2.87(s,6H),2.42(s,3H),1.56–0.88(m,4H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.46 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 8.8Hz, 1H), 7.00 (t, J = 7.2Hz 1H), 6.36 (d, J = 5.2Hz, 1H), 6.28 (s, 1H), 4.42 (s, 2H), 3.99 (s, 3H) ), 2.87 (s, 6H), 2.42 (s, 3H), 1.56-0.88 (m, 4H).
实施例49Example 49
1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000159
Figure PCTCN2021073616-appb-000159
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000160
Figure PCTCN2021073616-appb-000160
合成方法：resolve resolution:
1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐的制备Preparation of 1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine hydrochloride
按照实施例12的合成方法，以5-羟基吲哚为原料与7-苄氧基-4-氯-6-甲氧基喹啉经烷基化反应催化加氢反应合成4-(1H-吲哚-5-基氧基)-6-甲 氧基喹啉-7-醇，然后与1-(叔丁氧羰基氨基)环丙基甲醇发生Mitsunobu反应，并经盐酸-乙酸乙酯溶液脱保护反应生成1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐。MS:[M+1-HCl] +:376.2. According to the synthesis method of Example 12, 5-hydroxyindole was used as the raw material and 7-benzyloxy-4-chloro-6-methoxyquinoline to undergo alkylation reaction to catalyze the hydrogenation reaction to synthesize 4-(1H-indole). Dole-5-yloxy)-6-methoxyquinoline-7-ol, then Mitsunobu reaction with 1-(tert-butoxycarbonylamino)cyclopropylmethanol, and deprotection by hydrochloric acid-ethyl acetate solution The reaction produces 1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine hydrochloride. MS:[M+1-HCl] + :376.2.
1H NMR(400MHz,d 6-DMSO)δ11.33(s,1H),9.00(s,3H,-N H3Cl),8.71(d,J＝6.4Hz,1H),7.82(s,1H),7.77(s,1H),7.59(d,J＝2.0Hz,1H),7.51–(d,J＝8.4Hz,1H),7.33(d,J＝1.6Hz,1H),7.00(dd,J＝8.4,2.0Hz,1H),6.60(d,J＝6.4Hz,1H),4.45(s,2H),4.04(s,3H),1.28–1.25(m,2H),1.11–1.08(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.33 (s, 1H), 9.00 (s, 3H, -N H3 Cl), 8.71 (d, J = 6.4 Hz, 1H), 7.82 (s, 1H) ,7.77(s,1H),7.59(d,J=2.0Hz,1H),7.51-(d,J=8.4Hz,1H),7.33(d,J=1.6Hz,1H),7.00(dd,J =8.4,2.0Hz,1H),6.60(d,J=6.4Hz,1H),4.45(s,2H),4.04(s,3H),1.28–1.25(m,2H),1.11–1.08(m, 2H).
实施例50Example 50
1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000161
Figure PCTCN2021073616-appb-000161
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000162
Figure PCTCN2021073616-appb-000162
合成方法：resolve resolution:
1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺的制备Preparation of 1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine
按照实施例48的合成方法，以1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐为原料与多聚甲醛发生还原胺化反应，经制备液相色谱在甲酸条件下提纯合成1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺。MS:[M+1] +:404.2. According to the synthesis method of Example 48, 1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine salt The acid salt is used as the raw material to undergo reductive amination reaction with paraformaldehyde, which is purified by preparative liquid chromatography under formic acid conditions to synthesize 1-(((4-((1H-indol-5-yl)oxy)-6-methoxy Quinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine. MS:[M+1] + :404.2.
1H NMR(400MHz,d 6-DMSO)δ11.40(s,1H),8.59(s,1H),7.74(s,1H), 7.57(d,J＝7.6Hz,2H),7.49(s,2H),7.03(d,J＝8.4Hz,1H),6.59(s,1H),6.50(s,1H),4.54(s,2H),4.03(s,3H),2.94(s,6H),1.55–1.43(m,2H),1.22–1.08(m,2H)。 1 H NMR(400MHz,d 6 -DMSO)δ11.40(s,1H),8.59(s,1H),7.74(s,1H), 7.57(d,J=7.6Hz,2H),7.49(s, 2H), 7.03 (d, J = 8.4Hz, 1H), 6.59 (s, 1H), 6.50 (s, 1H), 4.54 (s, 2H), 4.03 (s, 3H), 2.94 (s, 6H), 1.55–1.43 (m, 2H), 1.22–1.08 (m, 2H).
实施例51Example 51
1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000163
Figure PCTCN2021073616-appb-000163
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000164
Figure PCTCN2021073616-appb-000164
合成方法：resolve resolution:
1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐的制备Preparation of 1-(((4-((2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine hydrochloride
按照实施例12的合成方法，以5-羟基-2-甲基吲哚为原料与7-苄氧基-4-氯-6-甲氧基喹啉经烷基化反应催化加氢反应合成4-(2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-醇，然后与1-(叔丁氧羰基氨基)环丙基甲醇发生Mitsunobu反应，并经盐酸-乙酸乙酯溶液脱保护反应合成1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐。MS:[M+1-HCl] +:390.2. According to the synthesis method of Example 12, 5-hydroxy-2-methylindole was used as a raw material and 7-benzyloxy-4-chloro-6-methoxyquinoline to be synthesized by alkylation reaction and catalytic hydrogenation reaction. -(2-Methyl-1H-indol-5-yloxy)-6-methoxyquinoline-7-ol, then Mitsunobu reaction with 1-(tert-butoxycarbonylamino)cyclopropyl methanol, And through the hydrochloric acid-ethyl acetate solution deprotection reaction to synthesize 1-(((4-((2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl) (Oxy)methyl)cyclopropylamine hydrochloride. MS:[M+1-HCl] + :390.2.
1H NMR(400MHz,d 6-DMSO)δ11.38(s,1H),8.94(s,3H,-N H3Cl),8.75(d,J＝6.8Hz,1H),7.82(d,J＝2.8Hz,1H),7.80(d,J＝8.4Hz,1H), 7.46(d,J＝8.8Hz,1H),7.41(d,J＝2.4Hz,1H),7.37(s,1H),6.98(d,J＝8.8,2.4Hz,1H),6.74(d,J＝8.8Hz,1H),6.22(s,1H),4.42(s,2H),4.07(s,3H),2.40(s,3H),1.27–1.24(m,2H),1.11–1.07(m,2H)。 1 H NMR (400MHz, d 6 -DMSO) δ 11.38 (s, 1H), 8.94 (s, 3H, -N H3 Cl), 8.75 (d, J = 6.8 Hz, 1H), 7.82 (d, J = 2.8Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.37 (s, 1H), 6.98 (d, J = 8.8, 2.4 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.22 (s, 1H), 4.42 (s, 2H), 4.07 (s, 3H), 2.40 (s, 3H), 1.27–1.24 (m, 2H), 1.11–1.07 (m, 2H).
实施例52Example 52
1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺:1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethyl Cyclopropylamine:
化合物的结构式：The structural formula of the compound:
Figure PCTCN2021073616-appb-000165
Figure PCTCN2021073616-appb-000165
合成路线：synthetic route:
Figure PCTCN2021073616-appb-000166
Figure PCTCN2021073616-appb-000166
合成方法：resolve resolution:
1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺的制备1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethyl Preparation of Cyclopropylamine
按照实施例48的合成方法，以1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺盐酸盐为原料与多聚甲醛发生还原胺化反应，经制备液相色谱在甲酸条件下提纯合成1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺。MS:[M+1] +:418.2. According to the synthesis method of Example 48, 1-(((4-((2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl Cyclopropylamine hydrochloride as a raw material undergoes reductive amination reaction with paraformaldehyde. It is purified by preparative liquid chromatography under formic acid conditions to synthesize 1-(((4-((2-methyl-1H-indole-5) -Yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine. MS:[M+1] + :418.2.
1H NMR(400MHz,d 6-DMSO)δ11.25(s,1H),8.64(s,1H),7.76(s,1H),7.59(s,1H),7.43(d,J＝8.4Hz,1H),7.36(s,1H),6.94(dd,J＝8.8,2.0Hz,1H),6.63(s,1H),6.20(s,1H),4.55(s,2H),4.04(s,3H),2.94(s,6H),2.42(s,3H),1.55–1.48(m,2H),1.20–1.10(m,2H)。 1 H NMR(400MHz,d 6 -DMSO)δ11.25(s,1H),8.64(s,1H),7.76(s,1H),7.59(s,1H),7.43(d,J=8.4Hz, 1H), 7.36 (s, 1H), 6.94 (dd, J = 8.8, 2.0 Hz, 1H), 6.63 (s, 1H), 6.20 (s, 1H), 4.55 (s, 2H), 4.04 (s, 3H) ), 2.94 (s, 6H), 2.42 (s, 3H), 1.55-1.48 (m, 2H), 1.20-1.10 (m, 2H).
1、酪氨酸激酶活性抑制体外筛选试验1. In vitro screening test for inhibition of tyrosine kinase activity
体外活性评价：体外激酶水平的检测采用Cisbio公司生产的HTRF KinEASE-TK检测试剂盒。In vitro activity evaluation: In vitro kinase level detection uses the HTRF KinEASE-TK detection kit produced by Cisbio.
VEGFR2小分子抑制剂的筛选原理和方法：The screening principles and methods of VEGFR2 small molecule inhibitors:
1)原理：HTRF KinEASE-TK检测试剂盒为针对酪氨酸激酶进行活性检测的通用试剂盒。VEGFR2为酪氨酸激酶的一种。带有生物素(biotin)标记的底物将在激酶VEGFR2的催化作用下发生酶反应，使底物带上磷酸基团。检测试剂Streptavidin-XL665可通过链和亲霉素(Streptavidin)与底物上的生物素(biotin)相结合。另外一种检测试剂TK-antibody-Eu3+-Cryptate能够与磷酸化的底物相结合。能量从供体Eu转移到受体XL665上，使XL665发光。所得信号与底物发生磷酸化的水平呈正比。当有VEGFR2的小分子抑制剂阻碍VEGFR2发生磷酸化反应时，Eu与XL665距离较远，将会影响荧光能量转移的发生，信号将会减弱。通过信号的强度变化来判断小分子抑制剂对于VEGFR2激酶活性的阻断情况。、1) Principle: HTRF KinEASE-TK detection kit is a universal kit for activity detection of tyrosine kinase. VEGFR2 is a kind of tyrosine kinase. The biotin-labeled substrate will undergo an enzymatic reaction under the catalysis of the kinase VEGFR2 to bring the substrate with a phosphate group. The detection reagent Streptavidin-XL665 can be combined with biotin on the substrate through Streptavidin. Another detection reagent, TK-antibody-Eu3+-Cryptate, can bind to phosphorylated substrates. Energy is transferred from the donor Eu to the acceptor XL665, which makes the XL665 emit light. The resulting signal is directly proportional to the level of phosphorylation of the substrate. When a small molecule inhibitor of VEGFR2 hinders the phosphorylation reaction of VEGFR2, the distance between Eu and XL665 will affect the occurrence of fluorescence energy transfer and the signal will be weakened. The signal intensity change is used to judge the blocking of VEGFR2 kinase activity by small molecule inhibitors. ,
2)方法：具体实验操作方法可参照Cisbio公司的HTRF KinEASE-TK试剂盒说明书62TK0PEB,62TK0PEC和62TK0PEJ。简单描述如下，取一张新的384孔酶标板，在阳性反应孔中加入4μL酶反应缓冲液，在阴性反应孔中加入6μL酶反应缓冲液，在测试孔中加入4μL由酶反应缓冲液稀释的浓度不同的待测小分子化合物。然后再向各孔中加入2μL ATP，2μL底物，2μL VEGFR2酶，常温下孵育40min到1h。反应结束后，向每孔中加入10μL Streptavidin-XL665和TK-antibody-Eu3+-Cryptate的混合液，室温下静置2h以上，用酶标仪检测620nM和665nM的荧光信号。信号比例的计算公式为：(665nM处信号值)/(620nM处信号值)*10 4。每个化合物选用8-10个浓度梯度，每个浓度设三个复孔，所得结果通过GraphPad Prism软件进行非线性拟合得出化合物的IC50值。其他激酶如EGFR、FGFR、RET的活性检测，采取与VEGFR2相同原理的测试方法。 2) Method: Refer to Cisbio's HTRF KinEASE-TK kit manual 62TK0PEB, 62TK0PEC and 62TK0PEJ for specific experimental operation methods. A brief description is as follows. Take a new 384-well ELISA plate, add 4μL of enzyme reaction buffer to the positive reaction wells, add 6μL of enzyme reaction buffer to the negative reaction wells, and add 4μL of enzyme reaction buffer to the test wells. Dilute small molecule compounds of different concentrations to be tested. Then add 2μL ATP, 2μL substrate, 2μL VEGFR2 enzyme to each well, and incubate at room temperature for 40min to 1h. After the reaction is over, add 10μL of Streptavidin-XL665 and TK-antibody-Eu3+-Cryptate mixture to each well, let it stand at room temperature for more than 2h, and detect the fluorescence signals of 620nM and 665nM with a microplate reader. The calculation formula of the signal ratio is: (signal value at 665nM)/(signal value at 620nM)*10 4 . Each compound uses 8-10 concentration gradients, and each concentration has three replicate wells. The obtained results are nonlinearly fitted with GraphPad Prism software to obtain the compound's IC50 value. The activity detection of other kinases such as EGFR, FGFR, and RET adopts the same principle test method as VEGFR2.
在酪氨酸激酶活性抑制体外筛选试验中，发明人还采用了药物——西地尼布进行对比。In the in vitro screening test for tyrosine kinase activity inhibition, the inventors also used the drug-cediranib for comparison.
表1 酪氨酸激酶活性抑制IC50(nM)Table 1 Inhibition of tyrosine kinase activity IC50 (nM)
化合物Compound VEGFR1VEGFR1 VEGFR2VEGFR2 VEGFR3VEGFR3 EGFREGFR FGFR1FGFR1 FGRR2FGRR2 FGFR3FGFR3 RETRET
实施例1Example 1 AA BB AA AA AA AA AA AA
实施例2Example 2 AA AA AA AA AA AA AA AA
实施例3Example 3 AA BB AA AA BB AA BB CC
实施例4Example 4 AA BB AA AA BB BB CC AA
实施例5Example 5 AA BB BB AA AA BB AA AA
实施例6Example 6 AA BB AA AA AA AA BB AA
实施例7Example 7 AA BB AA AA AA AA AA AA
实施例8Example 8 BB BB CC AA BB AA BB AA
实施例9Example 9 AA BB AA AA AA AA AA AA
实施例10Example 10 AA AA AA AA AA AA AA AA
实施例11Example 11 AA AA AA AA BB BB BB CC
实施例12Example 12 AA AA AA AA AA AA BB BB
实施例13Example 13 AA AA BB BB BB BB BB BB
实施例14Example 14 AA AA AA AA AA AA AA AA
实施例15Example 15 AA BB AA AA AA AA AA AA
实施例16Example 16 BB AA AA AA BB AA BB AA
实施例17Example 17 BB BB BB BB BB BB CC BB
实施例18Example 18 AA AA AA AA AA AA AA AA
实施例19Example 19 BB BB CC BB BB BB BB BB
西地尼布Sidiranib BB BB BB BB BB CC CC CC
注：A表示活性范围在0.1-1nM；B表示活性范围在1-10nM；C表示活性范围大于10nM。Note: A means the activity range is 0.1-1 nM; B means the activity range is 1-10 nM; C means the activity range is greater than 10 nM.
由表1的数据可知，本发明实施例1-19中的化合物对酪氨酸激酶VEGFR、EGFR、FGFR、RET具有较低的IC50，说明酪氨酸激酶VEGFR、EGFR、FGFR、RET对本发明的化合物具有良好的敏感性，可以有效地用于这些酪氨酸激酶活性异常相关疾病的治疗。It can be seen from the data in Table 1 that the compounds in Examples 1-19 of the present invention have lower IC50 for the tyrosine kinases VEGFR, EGFR, FGFR, and RET, indicating that the tyrosine kinases VEGFR, EGFR, FGFR, and RET have a lower IC50 for the tyrosine kinases of the present invention. The compound has good sensitivity and can be effectively used in the treatment of diseases related to abnormal tyrosine kinase activity.
表2 实施例20至实施例52以及西地尼布对VEGFR2的活性抑制IC50(nM)数据Table 2 Example 20 to Example 52 and the activity of cediranib on VEGFR2 inhibition IC50 (nM) data
化合物Compound VEGFR2VEGFR2 化合物Compound VEGFR2VEGFR2
实施例20Example 20 3.423.42 实施例38Example 38 2.532.53
实施例21Example 21 4.294.29 实施例39Example 39 2.962.96
实施例22Example 22 1.631.63 实施例40Example 40 0.210.21
实施例23Example 23 7.067.06 实施例41Example 41 0.340.34
实施例24Example 24 4.044.04 实施例42Example 42 0.370.37
实施例25Example 25 6.066.06 实施例43Example 43 0.520.52
实施例26Example 26 1.531.53 实施例44Example 44 0.720.72
实施例27Example 27 3.033.03 实施例45Example 45 1.031.03
实施例28Example 28 3.743.74 实施例46Example 46 1.731.73
实施例29Example 29 1.561.56 实施例47Example 47 1.111.11
实施例30Example 30 2.072.07 实施例48Example 48 5.535.53
实施例31Example 31 2.062.06 实施例49Example 49 16.2816.28
实施例32Example 32 1.841.84 实施例50Example 50 22.8222.82
实施例33Example 33 2.212.21 实施例51Example 51 7.377.37
实施例34Example 34 1.961.96 实施例52Example 52 7.977.97
实施例35Example 35 3.023.02 西地尼布Sidiranib 3.623.62
实施例36Example 36 2.672.67  To  To
实施例37Example 37 2.802.80  To  To
注：实施例48至实施例52为环丙基取代的实施例。Note: Examples 48 to 52 are examples of cyclopropyl substitution.
由表2中的活性数据可以看出，由于环丁基的1位与3位的取代基具有顺式以及反式的构型，使其选择性显著增加，相对于取代基为环丙基的结构(实施例48-52)，环丁基取代的化合物实施例活性显著提升。例如，实施例42(顺式)、实施例43(反式)(IC50分别为0.37nM，0.52nM)，与实施例48(IC50为5.53nM)相比，活性分别提高了15倍和10.6倍。由上可见，本发明使用环丁基取代侧链，极大地增强了分子的方向性和选择性，使其在酶学活性方面上有了一个数量级的提升。实施例33(IC50为2.21nM)中的化合物的结构与阳性对照西地尼布(IC50为3.62nM)结构类似，但是相对于西地尼布，药物活性也有了一定程度的提高。From the activity data in Table 2, it can be seen that the substituents at positions 1 and 3 of cyclobutyl have cis and trans configurations, which significantly increase their selectivity. Compared with the substituents of cyclopropyl The structure (Examples 48-52), the activity of the cyclobutyl-substituted compound example was significantly improved. For example, Example 42 (cis) and Example 43 (trans) (IC50 are 0.37nM, 0.52nM, respectively), compared with Example 48 (IC50 is 5.53nM), the activity is increased by 15 times and 10.6 times, respectively . It can be seen from the above that the present invention uses cyclobutyl to replace the side chain, which greatly enhances the directionality and selectivity of the molecule, and makes it an order of magnitude improvement in enzymatic activity. The structure of the compound in Example 33 (IC50 of 2.21 nM) is similar to that of the positive control cediranib (IC50 of 3.62 nM), but compared with cediranib, the drug activity has also been improved to a certain extent.
2、体内药代动力学实验2. In vivo pharmacokinetic experiment
体内药代动力学实验使用雄性Balb/c小鼠进行，每组3或4只动物。表中所列实施例在小鼠经静脉给药剂量为1mg/kg，经口灌胃给药剂量为4mg/kg，给药前均禁食，给药后2小时给予饲料。经口灌胃给药的动物在给药后0.25，0.5，1，2，4，6，8，12，24h采集全血，分离血浆后使用LC-MS/MS方法进行血浆样品中药物浓度检测。使用软件Phoenix TM WinNonlin 6.1版中非房室模型对药代动力学参数进行计算。 In vivo pharmacokinetic experiments were performed using male Balb/c mice, with 3 or 4 animals in each group. In the examples listed in the table, the intravenous dose of 1 mg/kg in mice, and the dose of 4 mg/kg via oral gavage, were all fasted before administration, and feed was given 2 hours after administration. Oral gavage animals will collect whole blood at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 hours after administration, and use LC-MS/MS method to detect the drug concentration in plasma samples after separating the plasma. . The non-compartmental model in the software Phoenix TM WinNonlin version 6.1 was used to calculate the pharmacokinetic parameters.
表3 实施例22、26、43、48的药代动力学参数Table 3 Pharmacokinetic parameters of Examples 22, 26, 43, 48
Figure PCTCN2021073616-appb-000167
Figure PCTCN2021073616-appb-000167
由表3可见，实施例22、实施例26和实施例43的化合物具有四元环丁基取代的侧链，与实施例48(环丙基取代的侧链)的化合物相比，生物利用度(F％)增加了2-3倍，而体内暴露量(AUC inf)增加了4-6倍，最大血药浓度(C max)也显著提高，说明四元环丁基取代的实施例具有更优越的成药性。 It can be seen from Table 3 that the compounds of Example 22, Example 26 and Example 43 have a four-membered cyclobutyl substituted side chain. Compared with the compound of Example 48 (cyclopropyl substituted side chain), the bioavailability (F%) increased by 2-3 times, while the in vivo exposure (AUC inf ) increased by 4-6 times, the maximum blood concentration (C max ) was also significantly increased, indicating that the four-membered cyclobutyl substitution example has more Superior medicinal properties.
3、体内药效学实验3. In vivo pharmacodynamic experiment
1)评价实施例22及实施例26在卵巢癌SK-OV-3细胞小鼠皮下瘤CDX模型上的抗肿瘤作用。1) To evaluate the anti-tumor effects of Example 22 and Example 26 on the CDX model of ovarian cancer SK-OV-3 cell subcutaneous tumor in mice.
皮下移植瘤方法：在受试小鼠BALB/c-nude小鼠(18-22g)右侧背部皮下接种1×10 7的SK-OV-3细胞，细胞重悬在PBS悬液中，每只接种0.1mL。定期观察肿瘤生长情况，当平均肿瘤体积达100-200mm 3时，根据肿瘤大小和小鼠体重随机分组给药。分组当天设定为Day 0，给药开始于Day 0。实验分为溶媒对照组，低剂量组(1.5mg/kg)，中剂量组(2.5mg/kg)和高剂量组(5mg/kg)，溶媒对照组3只小鼠，实施例22及实施例26低、中、高剂量组每组6只小鼠，每天一次经口灌胃给药，共给药三周。根据相对肿瘤增殖率(T/C)及相对肿瘤抑制率(TGI％)进行疗效评价，根据动物体重变化和死亡情况进行初步安全性评价。 Subcutaneous tumor transplantation method: Inoculate 1×10 7 SK-OV-3 cells subcutaneously on the right back of the tested mouse BALB/c-nude mice (18-22g), and resuspend the cells in PBS suspension, each Inoculate 0.1mL. Regularly observe the tumor growth. When the average tumor volume reaches 100-200mm 3 , the drugs are randomly divided into groups according to the tumor size and the weight of the mice. The grouping day is set to Day 0, and the administration starts on Day 0. The experiment is divided into vehicle control group, low-dose group (1.5mg/kg), medium-dose group (2.5mg/kg) and high-dose group (5mg/kg), vehicle control group 3 mice, Example 22 and Examples 26 low-, medium-, and high-dose groups of 6 mice in each group were administered orally once a day for three weeks. According to the relative tumor proliferation rate (T/C) and relative tumor inhibition rate (TGI%), the curative effect was evaluated, and the preliminary safety evaluation was conducted according to the change of animal weight and death.
实验动物均饲养于恒温恒湿的独立通风IVC盒内，并且提前适应环境至少7天，饲养室温度20-26℃，湿度40-70％，10-20次/小时换气，昼夜明暗交替循环光照，给予动物钴60放射灭菌鼠全价颗粒饲料，不限量自由摄取经高压蒸汽灭菌的饮用自来水。The experimental animals are kept in an independent ventilated IVC box with constant temperature and humidity, and adapt to the environment for at least 7 days in advance. The breeding room temperature is 20-26℃, humidity is 40-70%, ventilation is 10-20 times per hour, and light and dark alternately cycle day and night. Light, give animals cobalt 60 radiation sterilized complete pellet feed for rats, and unlimited free intake of drinking tap water sterilized by high-pressure steam.
实施例22、26在卵巢癌SK-OV-3模型中的药效结果及体重变化分别见图2、图3、图4和图5；药效分析表见表4，瘤重分析见表5。The pharmacodynamic results and body weight changes of Examples 22 and 26 in the SK-OV-3 model of ovarian cancer are shown in Figure 2, Figure 3, Figure 4 and Figure 5, respectively; the pharmacodynamic analysis table is shown in Table 4, and the tumor weight analysis is shown in Table 5. .
表4 实施例22和实施例26在卵巢癌SK-OV-3模型各组药效分析表Table 4 Pharmacodynamic analysis table of Example 22 and Example 26 in each group of ovarian cancer SK-OV-3 model
Figure PCTCN2021073616-appb-000168
Figure PCTCN2021073616-appb-000168
图2至图5以及表4的结果显示，实施例22和实施例26的化合物在卵巢癌SK-OV-3的CDX模型上呈现明显的剂量依赖性肿瘤抑制，实施例22在1.5mg/kg、2.5mg/kg、5mg/kg的TGI％分别为77.53％，97.67％和113.82％。实施例26在1.5mg/kg、2.5mg/kg、5mg/kg的TGI％分别为69.59％，103.05％和109.13％。The results of Figures 2 to 5 and Table 4 show that the compounds of Example 22 and Example 26 exhibited significant dose-dependent tumor suppression on the CDX model of ovarian cancer SK-OV-3, and Example 22 at 1.5 mg/kg The TGI% of, 2.5mg/kg and 5mg/kg were 77.53%, 97.67% and 113.82%, respectively. The TGI% of Example 26 at 1.5 mg/kg, 2.5 mg/kg, and 5 mg/kg were 69.59%, 103.05% and 109.13%, respectively.
表5 采用实施例22和实施例26的化合物的各组实验中实验动物的瘤重分析表Table 5 Tumor weight analysis table of experimental animals in each group of experiments using the compounds of Example 22 and Example 26
Figure PCTCN2021073616-appb-000169
Figure PCTCN2021073616-appb-000169
注：数据以“平均值±标准误差”表示。Note: The data are expressed as "mean ± standard error".
瘤重分析结果与相对瘤体积分析结果一致，且与对照组比较具有统计学上的显著性差异(p<0.01)。The results of tumor weight analysis were consistent with the results of relative tumor volume analysis, and compared with the control group, there was a statistically significant difference (p<0.01).
在采用实施例22和26的化合物的实验中，所有治疗组没有出现动物死亡和与化合物相关的毒性反应，给药结束时动物体重均增加，说明化合物的毒性较小。In the experiments using the compounds of Examples 22 and 26, no animal deaths and compound-related toxic reactions occurred in all treatment groups, and the weight of the animals increased at the end of the administration, indicating that the compounds were less toxic.
2)实施例26在肾癌Caki-1的CDX模型上的抗肿瘤作用2) The anti-tumor effect of Example 26 on the CDX model of renal cancer Caki-1
实施例26在肾癌Caki-1的CDX模型上呈现剂量依赖性肿瘤抑制，在2.5mg/kg和5mg/kg剂量具有明显的肿瘤抑制作用，肿瘤生长抑制率(TGI％)分别为63.43％和77.45％，瘤重分析结果与相对瘤体积分析结果一致，且与对照组比较具有统计学上的显著性差异(p<0.01)。在所有实施例26治疗组没有出现动物死亡和与化合物相关的毒性反应，给药结束时动物体重均增加。实验结果如图6、图7、表6和表7所示。Example 26 showed a dose-dependent tumor suppression on the CDX model of renal cancer Caki-1. It has obvious tumor suppression effects at the doses of 2.5 mg/kg and 5 mg/kg, and the tumor growth inhibition rate (TGI%) is 63.43% and respectively. 77.45%, the tumor weight analysis result was consistent with the relative tumor volume analysis result, and compared with the control group, there was a statistically significant difference (p<0.01). In all the treatment groups of Example 26, there were no animal deaths and compound-related toxicity reactions, and the animal weights increased at the end of the administration. The experimental results are shown in Figure 6, Figure 7, Table 6 and Table 7.
表6 实施例26在肾癌Caki-1模型各组药效分析表Table 6 The drug effect analysis table of Example 26 in each group of the renal cancer Caki-1 model
Figure PCTCN2021073616-appb-000170
Figure PCTCN2021073616-appb-000170
表7 采用实施例26的化合物的实验组合在肾癌Caki-1模型各组瘤重分析表Table 7 The experimental combination of the compound of Example 26 was used to analyze the tumor weight in each group of the renal cancer Caki-1 model
Figure PCTCN2021073616-appb-000171
Figure PCTCN2021073616-appb-000171
注：数据以“平均值±标准误差”表示。Note: The data are expressed as "mean ± standard error".
图6、图7以及表6和表7的结果显示，实施例26的化合物在肾癌Caki-1模型上呈现明显的剂量依赖性肿瘤抑制。在采用实施例26的化合物的实验中，所有治疗组没有出现动物死亡和与化合物相关的毒性反应，给药结束时动物体重均增加，说明本发明的化合物毒性小。The results of Figure 6, Figure 7, and Table 6 and Table 7 show that the compound of Example 26 exhibited significant dose-dependent tumor suppression on the Caki-1 model of renal cancer. In the experiment using the compound of Example 26, no animal deaths and compound-related toxic reactions occurred in all treatment groups, and the body weight of the animals increased at the end of the administration, indicating that the compound of the present invention has low toxicity.
本发明提供一种含有环丁基的化合物，实验结果显示，本发明的化合物可以用在治疗与VEGFR等酪氨酸激酶的活性异常引发的肿瘤疾病中，具有良好的应用前景。The present invention provides a compound containing cyclobutyl. Experimental results show that the compound of the present invention can be used in the treatment of tumor diseases caused by abnormal activity of tyrosine kinases such as VEGFR, and has good application prospects.

Claims (10)

  1. 式I所示的化合物或其药学上可接受的盐、前药、代谢物、同位素衍生物、溶剂化物：The compound represented by formula I or a pharmaceutically acceptable salt, prodrug, metabolite, isotope derivative, or solvate thereof:
    Figure PCTCN2021073616-appb-100001
    Figure PCTCN2021073616-appb-100001
    其中，X选自-C(H)-、N、-C(F)-、C-CF 3、-C(CN)-； Wherein, X is selected from -C(H)-, N, -C(F)-, C-CF 3 , -C(CN)-;
    R选自羟基、羧基、酯基、-N(R 1R 2)，或R选自氧原子且氧原子与与其直接相连的环丁基形成酮羰基； R is selected from a hydroxyl group, a carboxyl group, an ester group, -N(R 1 R 2 ), or R is selected from an oxygen atom and the oxygen atom forms a ketone carbonyl group with the cyclobutyl group directly connected to it;
    R 1和R 2相同或不同，分别独立地选自氢、C 1-C 10烷基、C 3-C 7环烷基、C 2-C 10烯基、C 2-C 10炔基、Ar； R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, Ar ；
    R 1和R 2与所连接的氮原子形成4-10元杂环基，所述杂环基的环上还包括任选的N、O、S中的至少一种原子；且所述杂环基上的氢原子任选地被1-3个相同或不同的R 3取代； R 1 and R 2 form a 4-10 membered heterocyclic group with the nitrogen atom to which they are connected, and the ring of the heterocyclic group further includes at least one atom of N, O, and S; and the heterocyclic ring The hydrogen atom on the group is optionally substituted with 1-3 R 3 which are the same or different;
    R 3选自氢、C 1-C 4烷基、C 1-C 4烷氧基、卤素、三氟甲基、羟基、氨基、羧基、酯基； R 3 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, trifluoromethyl, hydroxyl, amino, carboxyl, ester group;
    Ar选自C 6-C 10芳基、5-10元杂芳基，其中，杂芳基含有1-3个选自N、O和S中的杂原子；Ar可以被1-3个相同或不同的R 4取代；R 4选自氢、羟基、卤素、三氟甲基、硝基、氨基、腈基、磺酸基、磺酰胺基、C 1-C 6烷基、C 1-C 6烷基酰基、C 3-C 6环烷基。 Ar is selected from C 6 -C 10 aryl groups, 5-10 membered heteroaryl groups, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O and S; Ar can be the same or 1-3 Different R 4 substitutions; R 4 is selected from hydrogen, hydroxyl, halogen, trifluoromethyl, nitro, amino, nitrile, sulfonic acid, sulfonamide, C 1 -C 6 alkyl, C 1 -C 6 Alkyl acyl, C 3 -C 6 cycloalkyl.
  2. 根据权利要求1的化合物或其药学上可接受的盐、前药、代谢物、同位素衍生物、溶剂化物，其中，基团R与所述环丁基上的亚甲基形成式II所示的顺式结构或式III所示的反式结构：The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, metabolite, isotope derivative, or solvate thereof, wherein the group R and the methylene group on the cyclobutyl form the formula II The cis structure or the trans structure shown in formula III:
    Figure PCTCN2021073616-appb-100002
    Figure PCTCN2021073616-appb-100002
    其中，R选自羟基、羧基、酯基、-N(R 1R 2)。 Wherein, R is selected from a hydroxyl group, a carboxyl group, an ester group, and -N(R 1 R 2 ).
  3. 根据权利要求1或2的化合物或其药学上可接受的盐、前药、代谢物、同位素衍生物、溶剂化物，The compound according to claim 1 or 2 or a pharmaceutically acceptable salt, prodrug, metabolite, isotope derivative, solvate thereof,
    其中，R 1和R 2相同或不同，分别独立地选自氢、C 1-C 10烷基、C 3-C 7环烷基、Ar； Wherein, R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar;
    Ar选自苯基、萘基、喹啉基、吡啶基、呋喃基、噻吩基、吡咯基。Ar is selected from phenyl, naphthyl, quinolinyl, pyridyl, furyl, thienyl, and pyrrolyl.
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐、前药、代谢物、同位素衍生物、溶剂化物，The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, metabolite, isotope derivative, or solvate thereof,
    其中，R 1和R 2相同或不同，分别独立地选自氢、C 1-C 10烷基、C 3-C 7环烷基、Ar； Wherein, R 1 and R 2 are the same or different, and are independently selected from hydrogen, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, Ar;
    Ar选自苯基、萘基、喹啉基、吡啶基、呋喃基、噻吩基、吡咯基；Ar is selected from phenyl, naphthyl, quinolinyl, pyridyl, furyl, thienyl, pyrrolyl;
    所述杂环基选自1-哌啶基、4-吗啉基、1-吡咯烷基、4-甲基-1-哌啶基、1-环丁胺基。The heterocyclic group is selected from 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 4-methyl-1-piperidinyl, and 1-cyclobutylamino.
  5. 根据权利要求1或2所述的化合物或药学上可接受的盐，其中，所述化合物选自以下化合物中的任意一种：The compound or pharmaceutically acceptable salt according to claim 1 or 2, wherein the compound is selected from any one of the following compounds:
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁醇3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutanol
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutylamine
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁酸3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)cyclobutyric acid
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)-N,N-二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl)-N,N -Dimethylcyclobutylamine
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啉环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morpholinocyclobutyl)methoxy)quinazoline
    N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-3-(三氟甲基)苯胺N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-3-(trifluoromethyl)aniline
    N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-3-(三氟甲基)2,3-二甲基苯胺N-(3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)methyl) ring Butyl)-3-(trifluoromethyl)2,3-dimethylaniline
    4-氟-氮-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)-氮-甲基苯胺4-Fluoro-nitrogen-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy) (Methyl)cyclobutyl)-nitrogen-methylaniline
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl)methoxy ) Quinazoline
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methoxy) Quinazoline
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-氮杂环丁烷-1-基)环丁基)甲氧基)喹唑啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-azetidin-1-yl)cyclobutyl) (Methoxy)quinazoline
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutylamine
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)-氮,氮二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolinyl-7-yloxy)methyl)-nitrogen, nitrogen Methylcyclobutylamine
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutanol
    7-((3-(二甲基胺)环丁基)甲氧基)-4-(4-氟-2甲基-1H-吲哚-5-基氧基)-3-腈基-6-甲氧基喹啉7-((3-(Dimethylamine)cyclobutyl)methoxy)-4-(4-fluoro-2methyl-1H-indol-5-yloxy)-3-cyano-6 -Methoxyquinoline
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-(哌啶-1基)环丁基)甲氧基)-3-腈基喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-(piperidin-1-yl)cyclobutyl)methoxy )-3-cyanoquinoline
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吗啡环丁基)甲氧基)-3-腈基喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-morphinecyclobutyl)methoxy)-3-nitrile quinoline
    4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-7-((3-羟基环丁基)甲氧基)-3-腈基-6-甲氧基喹啉4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-7-((3-hydroxycyclobutyl)methoxy)-3-cyano-6-methoxy quinoline
    3-((3-氟-4(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹啉基-7-基氧基)甲基)环丁醇3-((3-Fluoro-4(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)methyl)cyclobutane alcohol
    7-((3-氨基环丁基)甲氧基)-4-(4-氟-2-甲基-1H-5-基氧基)-3-腈基-6甲氧基喹啉7-((3-Aminocyclobutyl)methoxy)-4-(4-fluoro-2-methyl-1H-5-yloxy)-3-cyano-6methoxyquinoline
    4-氟-氮-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)甲基)环丁基)苯胺4-Fluoro-nitrogen-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy) (Methyl)cyclobutyl)aniline
    3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-3-(三氟甲基)喹啉-7-基氧基)甲基)-氮,氮二甲基环丁胺3-((4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-3-(trifluoromethyl)quinolin-7-yloxy )Methyl)-nitrogen, azadimethylcyclobutylamine
    N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)环己)环丁基)环己胺N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)cyclohexyl) ring Butyl) cyclohexylamine
    N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)环己)环丁基)环戊胺N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)cyclohexyl) ring Butyl) cyclopentylamine
    N-(3-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧喹唑啉基-7-基氧基)环己)环丁基)环丁胺N-(3-((4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinazolinyl-7-yloxy)cyclohexyl) ring Butyl) cyclobutylamine
    顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )Cyclobutylamine
    反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )Cyclobutylamine
    顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine
    反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N,N-Dimethylcyclobutylamine
    顺式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉Cis-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine
    反式-4-(3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)吗啡啉Trans-4-(3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy )Methyl)cyclobutyl)morpholine
    顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinazoline
    顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinazoline
    顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclohexylamine
    顺式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Cis-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- (Yl)oxy)methyl)cyclobutylamine
    顺式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Cis-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutylamine
    顺式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺Cis-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclopentylamine
    反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹唑啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinazoline
    反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹唑啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl (Oxy)quinazoline
    反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环己基胺Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclohexylamine
    反式-N-环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Trans-N-cyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline-7- (Yl)oxy)methyl)cyclobutylamine
    反式-N,N-二环丁基-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁胺Trans-N,N-Dicyclobutyl-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazoline -7-yl)oxy)methyl)cyclobutylamine
    反式-N-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)环丁基)环戊胺Trans-N-3-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy) (Methyl)cyclobutyl)cyclopentylamine
    顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine
    反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹唑啉-7-基)氧)甲基)-N-甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)methyl )-N-Methylcyclobutylamine
    顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Cyclobutylamine
    反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) Cyclobutylamine
    顺式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Cis-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine
    反式-3-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丁基胺Trans-3-(((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl) -N,N-Dimethylcyclobutylamine
    顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinoline
    顺式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环 丁基)甲氧基)喹啉Cis-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methan (Oxy)quinoline
    反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-哌啶-1-基)环丁基)甲氧基)喹啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-piperidin-1-yl)cyclobutyl) (Methoxy)quinoline
    反式-4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-((3-吡咯-1-基)环丁基)甲氧基)喹啉Trans-4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-((3-pyrrol-1-yl)cyclobutyl)methyl (Oxy)quinoline
    1-(((4-((4-氟-2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((4-Fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N, N-Dimethylcyclopropylamine
    1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine
    1-(((4-((1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺1-(((4-((1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethylcyclopropylamine
    1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)环丙胺1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)cyclopropylamine
    1-(((4-((2-甲基-1H-吲哚-5-基)氧)-6-甲氧基喹啉-7-基)氧)甲基)-N,N-二甲基环丙胺。1-(((4-((2-Methyl-1H-indol-5-yl)oxy)-6-methoxyquinolin-7-yl)oxy)methyl)-N,N-dimethyl Cyclopropylamine.
  6. 一种制备权利要求1所述的化合物的方法，其中，所述方法包括以下反应路线：A method for preparing the compound of claim 1, wherein the method comprises the following reaction route:
    Figure PCTCN2021073616-appb-100003
    Figure PCTCN2021073616-appb-100003
    所述方法包括以下步骤：The method includes the following steps:
    (1)将sm1与sm2溶解于溶剂1中，加入碱性试剂，在50-100℃的温度范围内进行反应，得到化合物C01；(1) Dissolve sm1 and sm2 in solvent 1, add alkaline reagents, and react in the temperature range of 50-100°C to obtain compound C01;
    (2)将化合物C01溶解于溶剂2中，通过氢化反应脱去苄基，得到化合物C02；(2) The compound C01 is dissolved in solvent 2, and the benzyl group is removed by hydrogenation reaction to obtain compound C02;
    (3)将化合物C02溶解于溶剂3中，加入sm3、DIAD和PPh 3，在20℃至50℃的温度范围内反应，得到化合物C03； (3) Compound 3 C02 dissolved in the solvent, is added sm3, DIAD and PPh3 3, the reaction in the temperature range 50 to 20 ℃ deg.] C to give compound C03;
    优选地，在步骤(1)中，所述溶剂1选自DMSO、DMF、乙腈、甲醇、乙醇、叔丁醇中的至少一种；所述碱性试剂选自碳酸铯、碳酸钾、碳酸钠、 甲醇钠、乙醇钠、叔丁醇钠中的至少一种；Preferably, in step (1), the solvent 1 is selected from at least one of DMSO, DMF, acetonitrile, methanol, ethanol, and tert-butanol; the alkaline reagent is selected from cesium carbonate, potassium carbonate, and sodium carbonate , At least one of sodium methoxide, sodium ethoxide, and sodium tert-butoxide;
    优选地，在步骤(2)中，所述溶剂2选自甲醇、乙醇、异丙醇、叔丁醇中的至少一种；Preferably, in step (2), the solvent 2 is selected from at least one of methanol, ethanol, isopropanol, and tert-butanol;
    优选地，在步骤(2)中，所述氢化反应包括在Pd/C催化剂的催化下，用氢气对化合物C01进行氢化；其中，Pd/C催化剂为5wt％-10wt％Pd/C，且以化合物C01的质量计，5wt％-10wt％Pd/C的添加比例范围为5％～20％；Preferably, in step (2), the hydrogenation reaction includes hydrogenation of compound C01 with hydrogen under the catalysis of a Pd/C catalyst; wherein the Pd/C catalyst is 5wt%-10wt% Pd/C, and Based on the mass of compound C01, the addition ratio of 5wt%-10wt% Pd/C ranges from 5% to 20%;
    优选地，在步骤(3)中，所述溶剂3选自THF、DMF、DCM中的至少一种。Preferably, in step (3), the solvent 3 is selected from at least one of THF, DMF, and DCM.
  7. 一种药物组合物，其包含作为活性成分的权利要求1～5任一项所述的化合物或化合物的药学上可接受的盐或化合物的溶剂化物，以及药学上可接受的载体；优选地，所述药物组合物的制剂形式为口服制剂或注射剂。A pharmaceutical composition comprising as an active ingredient the compound or a pharmaceutically acceptable salt of the compound or a solvate of the compound according to any one of claims 1 to 5, and a pharmaceutically acceptable carrier; preferably, The preparation form of the pharmaceutical composition is oral preparation or injection.
  8. 权利要求1～5任一项所述的化合物或化合物的药学上可接受的盐或化合物的溶剂化物，或权利要求6或7所述的药物组合物在制备治疗因蛋白激酶VEGFR2、EGFR、FGFR、RET中的任一种的异常活性所引起的疾病的药物中的应用。The compound according to any one of claims 1 to 5 or the pharmaceutically acceptable salt of the compound or the solvate of the compound, or the pharmaceutical composition according to claim 6 or 7 is used in the preparation of therapeutic protein kinases VEGFR2, EGFR, FGFR , Application in medicine for diseases caused by any abnormal activity of RET.
  9. 根据权利要求8所述的应用，其中，所述疾病为癌症或肿瘤血管形成；The application according to claim 8, wherein the disease is cancer or tumor angiogenesis;
    可选地，所述疾病为卵巢癌、肾癌、甲状腺髓样癌、肝癌、胃癌、食管癌、肺癌、胆管癌、胆道癌、结直肠癌、乳腺癌、前列腺癌、胰腺癌、黑色素瘤中的至少一种。Optionally, the disease is ovarian cancer, kidney cancer, medullary thyroid cancer, liver cancer, gastric cancer, esophageal cancer, lung cancer, cholangiocarcinoma, biliary tract cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, melanoma At least one of.
  10. 一种治疗癌症或肿瘤血管形成的方法，其中，所述方法包括对需要治疗的患者给予有效剂量的权利要求7所述的药物组合物。A method for treating cancer or tumor angiogenesis, wherein the method comprises administering an effective dose of the pharmaceutical composition according to claim 7 to a patient in need of treatment.
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