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CN112996784B - Indole derivatives and their use in medicine - Google Patents

Indole derivatives and their use in medicine Download PDF

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CN112996784B
CN112996784B CN201980060963.1A CN201980060963A CN112996784B CN 112996784 B CN112996784 B CN 112996784B CN 201980060963 A CN201980060963 A CN 201980060963A CN 112996784 B CN112996784 B CN 112996784B
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段茂圣
田世鸿
刘佳乐
熊艳林
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Beijing Yuezhikangtai Biomedicines Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

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Abstract

Disclosed are compounds of formula (I), methods of preparation, and pharmaceutical compositions containing the compounds, and their use as inhibitors of vascular endothelial growth factor receptor kinase, particularly for the treatment of diseases associated with vascular endothelial growth factor receptor kinase dysfunction, such as cancer. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Indole derivatives and their use in medicine
Technical Field
The invention relates to an indole derivative, a preparation method thereof, a pharmaceutical composition containing the indole derivative and application of the indole derivative serving as a Vascular Endothelial Growth Factor Receptor (VEGFR) kinase inhibitor, in particular to application of the indole derivative in preparation of a medicament for treating diseases related to vascular endothelial growth factor receptor kinase dysfunction such as cancers.
Background
Angiogenesis is a tightly regulated multi-step process involving the interaction of a variety of growth factors (including VEGFs, bFGF and PDGFs) with their receptors.
Vascular endothelial growth factor (vascular endothelial growth factor, VEGF) is a vascular endothelial cell-specific heparin-binding growth factor, and VEGF induces the formation of new blood vessels in vivo by binding to Vascular Endothelial Growth Factor Receptor (VEGFR). This process stimulates physiological or pathological angiogenesis while also regulating vascular permeability. Thus, expression of VEGFR and its activity are closely related to the density of tissue microvessels and the number of new blood vessels. The VEGFR family includes VEGFR-1, VEGFR-2 and VEGFR-3.
Neovascularization plays a very important role in the growth, development and metastasis of tumors. The new blood vessel of the tumor provides oxygen and nutrients for the solid malignant tumor, promotes the further growth of the tumor, and provides a propagation path for the metastasis and diffusion of the tumor. Thus, inhibiting tumor neovascularization is an effective method of treating a variety of cancers.
Although several small molecule VEGFR kinase inhibitors are used clinically, either multi-target drugs (e.g., sorafenib, regorafenib) or side effects are significant and patient compliance is affected. Therefore, the development of novel VEGFR kinase inhibitors with high activity and high selectivity still has wide requirements and prospects in clinical application.
Disclosure of Invention
Through intensive research, the inventor designs and synthesizes a series of indole derivatives which show the inhibition activity of VEGFR kinase and can be developed into medicines for treating diseases related to the VEGFR kinase activity.
Accordingly, it is an object of the present invention to provide a compound represented by the general formula (I),
Figure GPA0000302101330000021
or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
Wherein:
x is CH or N;
R 1 selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 2 selected from nitrogen-containing heterocyclyl, optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 3 selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 4 selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 5 Selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
R 6 selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more groups selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.
In a preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are, in particular,
R 1 selected from alkyl groups, preferably C 1 -C 6 Alkyl further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.
In another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are, in which,
R 2 selected from 4 to 10 membered nitrogen-containing heterocyclyl, preferably 4 to 10 membered monocyclic nitrogen-containing heterocyclyl, nitrogen-containing spiro heterocyclyl, nitrogen-containing fused heterocyclyl or nitrogen-bridged heterocyclyl;
the nitrogen-containing heterocyclyl is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl.
In another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are, in which,
R 2 selected from the group consisting of:
Figure GPA0000302101330000041
optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
wherein:
y is selected from CH 2 NH, O, or S, S (O) y ；
R a Selected from the group consisting of amino, hydroxyl, ester, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
i is 0, 1 or 2;
j is 0, 1 or 2;
m is 0, 1 or 2;
y is 1 or 2;
ring A is C 3 -C 6 Saturated or unsaturated rings.
In another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are, in which,
R 2 selected from the group consisting of:
Figure GPA0000302101330000042
in another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are those in which R 3 Selected from hydrogen or halogen.
In another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are those in which R 4 Selected from hydrogen or halogen.
In another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are those in which R 5 Selected from hydrogen or halogen.
In another preferred embodiment of the present invention, the compounds of the formula (I) according to the invention are those in which R 6 Selected from alkyl groups, preferably C 1 -C 6 An alkyl group.
Typical compounds of the invention include, but are not limited to, the following:
Figure GPA0000302101330000051
Figure GPA0000302101330000061
Figure GPA0000302101330000071
Figure GPA0000302101330000081
Figure GPA0000302101330000091
Figure GPA0000302101330000101
Figure GPA0000302101330000111
Figure GPA0000302101330000121
or a meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
The present invention further provides a process for preparing a compound of formula (I) according to the present invention, comprising the steps of:
Figure GPA0000302101330000122
the compound Ij and acyl chloride compound are subjected to condensation reaction in alkaline medium to obtain a compound (I) of a general formula;
Wherein the base is preferably K 2 CO 3 The solvent is preferably DMF;
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 x is as defined in claim 1.
The invention further provides a pharmaceutical composition comprising a compound of formula (I) according to the invention, and a pharmaceutically acceptable carrier or excipient.
The invention further provides application of the compound shown in the general formula (I) or the pharmaceutical composition containing the compound in preparation of vascular endothelial growth factor receptor kinase inhibitors.
The invention further provides the use of a compound of formula (I) or a pharmaceutical composition comprising the same according to the invention for the manufacture of a medicament for the treatment of a disease associated with dysfunction of vascular endothelial growth factor receptor kinase, preferably bladder cancer, breast cancer, cervical cancer, colorectal cancer, intestinal cancer, gastric cancer, head and neck cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, brain cancer, bone cancer, soft tissue cancer, leukemia and lymphoma, more preferably brain cancer, thyroid cancer, liver cancer, lung cancer, kidney cancer, breast cancer, gastric cancer and colorectal cancer.
The compounds of formula (I) of the present invention may form pharmaceutically acceptable acid addition salts with acids according to methods conventional in the art to which the present invention pertains. The acid includes inorganic acids and organic acids, and hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like are particularly preferable.
The compounds of formula (I) of the present invention may form pharmaceutically acceptable base addition salts with bases according to methods conventional in the art to which the present invention pertains. The base includes inorganic bases and organic bases, acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like, and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecaethyleneoxycetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
It is well known to those skilled in the art that the amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The invention can contain the compound shown in the general formula (I) and pharmaceutically acceptable salt, hydrate or solvate thereof as active ingredients, and is mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and a clinically acceptable dosage form. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not exert other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or in combination with other agents for the treatment of diseases associated with VEGF activity. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably the substituent is one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or formate.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure GPA0000302101330000161
the term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
Figure GPA0000302101330000171
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure GPA0000302101330000172
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or formate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably from 4 to 10 ring atoms, of which 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably 1, 2, 5-oxadiazolyl, pyranyl, or morpholinyl. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring of 5 to 20 members sharing one atom (referred to as the spiro atom) between them, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:
Figure GPA0000302101330000181
The term "fused heterocyclyl" refers to 5 to 20 membered rings in the system each sharing an adjacent ring with other rings in the systemA polycyclic heterocyclic group of a pair of atoms, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi-electron system, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
Figure GPA0000302101330000182
the term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
Figure GPA0000302101330000183
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
Figure GPA0000302101330000184
etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or formate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure GPA0000302101330000191
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or formate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure GPA0000302101330000192
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or formate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or formate groups.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2 。
The term "oxo" refers to = O.
The term "carboxy" refers to-C (O) OH.
The term "mercapto" refers to-SH.
The term "ester group" refers to a-C (O) O (alkyl) or-C (O) O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
The term "acyl" refers to compounds containing a-C (O) R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Synthesis method of compound of the invention
To accomplish the objects of the present invention, the present invention employs the following synthetic schemes for preparing the compounds of the general formula (I) of the present invention.
Figure GPA0000302101330000211
Scheme 1
Step 1: the beta-acyl ethyl acetate (Ib) and o-nitrofluorobenzene (Ia) undergo substitution reaction under the action of alkali to form a substituted nitrobenzene intermediate (Ic); the base is preferably potassium tert-butoxide, and the solvent is preferably THF;
step 2: hydrolysis of the substituted nitrobenzene intermediate (Ic) under acidic conditions with concomitant decarboxylation to form the asymmetric ketone intermediate (Id); the acid is preferably acetic acid and concentrated sulfuric acid;
step 3: the fluoro substituent on the phenyl group of the asymmetric ketone intermediate (Id) is hydrolyzed in an alkaline medium to form a p-nitrophenol intermediate (Ie); the base is preferably NaOAc;
Step 4: reducing nitro group into amino group by the p-nitrophenol intermediate (Ie) under the action of a reducing agent, and simultaneously carrying out intramolecular cyclization reaction in an acid medium to form indole intermediate (If); the reducing agent is preferably iron powder, and the acid is preferably acetic acid;
step 5: introduction of R at the 3-position of indole by electrophilic substitution 4 Forming a substituted indole intermediate (Ig); for example when R 4 When the compound is chlorine, introducing the chlorine to a 3-position through electrophilic substitution reaction between an indole intermediate (If) and NCS;
step 6: the indole intermediate (Ig) and chloroquinazoline (Ih) or chloroquinoline (Ih') undergo substitution reaction under alkaline conditions to form an intermediate (Ii), wherein the base is preferably 2, 6-lutidine, and the catalyst is preferably DMAP;
step 7: catalytic hydrogenation of intermediate (Ii) to remove benzyl protecting groups to form 7-hydroxyquinoline or quinazoline intermediate (Ij), the catalyst preferably being palladium on carbon;
step 8: condensing 7-hydroxyquinoline or quinazoline intermediate (Ij) with carbamoyl chloride in alkaline medium to obtain a general formula compound (I); the base is preferably K 2 CO 3 The solvent is preferably DMF.
Chloroquinazoline (Ih) or chloroquinoline (Ih') is prepared synthetically by schemes 2 and 3, respectively:
Figure GPA0000302101330000221
scheme 2
Step 1: chlorination reaction is carried out between thionyl chloride and 4-hydroxy-7-alkoxy quinazoline-6-yl acetate (Ih 1) to form 4-chloro-7-alkoxy quinazoline-6-yl acetate intermediate (Ih 2);
Step 2: the 4-chloro-7-alkoxyquinazolin-6-yl acetate intermediate (Ih 2) is firstly deacetylated under the action of a base, and the free 4-chloro-6-hydroxy-7-alkoxyquinazolin is then reacted with benzyl bromide to form the 4-chloro-6-benzyloxy-7-alkoxyquinazolin intermediate (Ih), wherein the base is preferably K 2 CO 3 The solvent is preferably acetone.
Figure GPA0000302101330000222
Scheme 3
Step 1: acetylation of phenolic hydroxyl groups of p-nitrophenol intermediate (Ih '1) with acetyl chloride in alkaline medium to form 1-acetoxy-2-alkoxy-4-nitrophenol intermediate (Ih' 2), said base preferably being pyridine;
step 2: catalytic hydrogenation of 1-acetyl-2-alkoxy-4-nitrobenzene intermediate (Ih '2) to form 1-acetoxy-2-alkoxy-4-aminobenzene intermediate (Ih' 3), the catalyst preferably being Pd/C and the solvent preferably being ethanol;
step 3: performing an addition-condensation reaction on the 1-acetoxy-2-alkoxy-4-aminobenzene intermediate (Ih '3) and 5- (ethoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione through a Michael addition reaction mode to form a 4- (((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-methylene) amino) -2-alkoxyphenylacetate intermediate (Ih' 4);
step 4: decarboxylation and intramolecular cyclization of the 4- (((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-methylene) amino) -2-alkoxyphenylacetate intermediate (Ih '4) at elevated temperature to form the 6-acetoxy-7-alkoxy-4-oxo-1, 4-dihydroquinoline intermediate (Ih' 5), the high temperature reaction solvent preferably being diphenyl ether and biphenyl;
Step 5: 6-acetoxy-7-alkoxy-4-oxo-1, 4-dihydroquinoline intermediate (Ih' 5) with POCl 3 Forming a 4-chloro-6-acetoxy-7-alkoxyquinoline intermediate (Ih' 6);
step 6: alkaline hydrolysis of the 4-chloro-6-acetoxy-7-alkoxyquinoline intermediate (Ih '6) to form 4-chloro-6-hydroxy-7-alkoxyquinoline intermediate (Ih' 7), the base preferably being NaOH;
step 7: the 4-chloro-6-hydroxy-7-alkoxyquinoline intermediate (Ih '7) is reacted with benzyl bromide under the action of a base, preferably K, to form the 4-chloro-6-benzyloxy-7-alkoxyquinoline intermediate (Ih') 2 CO 3 The solvent is preferably DMF.
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 X is defined as formula (I).
Drawings
FIG. 1 is a graph showing the growth of tumors in the MDA-MB-231 model of human xenograft breast cancer after initiation of treatment in test example 2.
FIG. 2 is a graph showing the body weight change of the experimental animals after the initiation of the treatment in test example 2.
Detailed Description
The compounds of the present invention and their preparation are further understood by the examples which illustrate some methods of making or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.
The compounds of the present invention are prepared using convenient starting materials and general preparation procedures. Typical or preferential reaction conditions are given in the present invention, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But other reaction conditions can be adopted unless specifically stated. The optimization conditions may vary with the particular reactants or solvents used, but in general, both the reaction optimization steps and conditions can be determined.
In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protecting or deprotecting conditions are well known to those skilled in the art. For example, T.W.Greene and G.M.Wuts in organic preparation of protecting groups (3 rd edition, wiley, new York,1999 and literature citations) describe in detail the protection or deprotection of a large number of protecting groups.
The separation and purification of the compounds and intermediates may be carried out by any suitable method or procedure depending on the particular needs, such as filtration, extraction, distillation, crystallization, column chromatography, thin layer chromatography, high performance liquid chromatography or a combination thereof. The specific methods of use thereof may be found in the examples described herein. Of course, other similar isolation and purification means may be employed. It can be characterized using conventional methods, including physical constants and spectral data.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift at 10 -6 Units of (ppm) are given. NMR was performed using Bruker dps 400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
MS was determined using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: waters).
The liquid phase was prepared using a Waters 2545 high performance liquid chromatograph (Waters 2489/UV/visual detector, 2767 sample MGR, single C18,5 μm 20mmx250 mm) (manufacturer: waters).
The microwave reaction used was an initiator+EU type microwave reactor (manufacturer: biotage).
The thin layer chromatography silica gel plate uses Qingdao ocean chemical GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses Qingdao ocean silica gel of 100-200 meshes and 200-300 meshes as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art or may be purchased from commercial establishments, beijing couplings, sigma, carbofuran, yi Shiming, shanghai Shuya, shanghai Enoki, an Naiji chemistry, shanghai Pico, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The reaction solvent, the organic solvent or the inert solvent are each expressed as a solvent which does not participate in the reaction under the reaction conditions described, and include, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride, diethyl ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. The examples are not specifically described, and the solution refers to an aqueous solution.
The chemical reactions described in the present invention are generally carried out at atmospheric pressure. The reaction temperature is between-78 ℃ and 200 ℃. The reaction time and conditions are, for example, between-78 ℃ and 200 ℃ at one atmosphere, completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is typically 16 hours. The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using the following system of developing agents: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: the volume ratio of acetone and solvent is adjusted according to the polarity of the compound.
The eluent system for column chromatography and the developing agent system for thin layer chromatography used for purifying the compound include: a: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, the volume ratio of the solvent is regulated according to the polarity of the compound, and small amount of alkaline or acidic reagent such as triethylamine and acetic acid can be added for regulation.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention.
Preparation example 1: preparation of 4-fluoro-2-methyl-1H-indol-5-ol (a)
Figure GPA0000302101330000251
Step 1: preparation of 3- (2, 3-difluoro-6-nitrophenyl) -1-ethoxypentane-2, 4-dione (a 1)
Potassium tert-butoxide (39.6 g,353 mmol) was added to a round bottom flask containing 150mL of anhydrous tetrahydrofuran at 0deg.C, and ethyl 3-oxobutyrate (41 g,318 mmol) was slowly added dropwise. The reaction mixture was stirred at 0deg.C for 0.5 hours, and 1,2, 3-trifluoro-4-nitrobenzene (25 g,141 mmol) was added. After the addition, the reaction was allowed to warm to room temperature and stirred overnight. After completion of the reaction, filtration, concentration of the filtrate under reduced pressure, dilution with ethyl acetate (100 mL) and washing of the organic phase with 1N hydrochloric acid solution to pH < 5, further washing with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration of the filtrate under reduced pressure gave crude 3- (2, 3-difluoro-6-nitrophenyl) -1-ethoxypentane-2, 4-dione (a 1) (40 g).
LC-MS(ESI)：m/z 301.1[M+H + ]。
Step 2: preparation of 1- (2, 3-difluoro-6-nitrophenyl) propan-2-one (a 2)
3- (2, 3-difluoro-6-nitrophenyl) -1-ethoxypentane-2, 4-dione (a 1) (40 g,132.78 mmol) was added to a reaction flask containing acetic acid (400 mL) and sulfuric acid (50 mL) at room temperature, and the reaction mixture was heated to reflux overnight. After the completion of the reaction, the reaction mixture was cooled to room temperature, concentrated, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (100 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=5:1) to give 1- (2, 3-difluoro-6-nitrophenyl) propan-2-one (a 2) (23 g, yellow oil, 71% yield).
LC-MS(ESI)：m/z 216.0[M+H + ]。
Step 3: preparation of 1- (2-fluoro-3-hydroxy-6-nitrophenyl) propan-2-one (a 3)
1- (2, 3-difluoro-6-nitrophenyl) propan-2-one (a 2) (23 g,107 mmol) and sodium acetate (9.6 g,118 mmol) were added to a reaction flask containing DMF (200 mL) at room temperature, and the reaction was heated to 100deg.C and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=2:1) to give 1- (2-fluoro-3-hydroxy-6-nitrophenyl) propan-2-one (a 3) (13 g, yellow solid, yield 57%).
LC-MS(ESI)：m/z 214.0[M+H + ]。
Step 4: preparation of 4-fluoro-2-methyl-1H-indol-5-ol (a)
1- (2-fluoro-3-hydroxy-6-nitrophenyl) propan-2-one (1.0 g,4.67 mmol) and iron powder (15.7 g,28 mmol) were added to a reaction flask containing acetic acid (10 mL) at room temperature, the reaction mixture was heated to 70℃and stirred for 6 hours, after completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=2:1) to give 4-fluoro-2-methyl-1H-indol-5-ol (a) (700 mg, grey solid, yield 90%).
LC-MS(ESI)：m/z 166.0[M+H + ]。
Preparation example 2: preparation of 3-chloro-4-fluoro-2-methyl-1H-indol-5-ol (b)
Figure GPA0000302101330000261
To a reaction flask containing dichloromethane (2 mL) was added 4-fluoro-2-methyl-1H-indol-5-ol (a) (100 mg,0.60 mmol) and N-chlorosuccinimide (80 mg,0.60 mmol) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=2:1) to give 3-chloro-4-fluoro-2-methyl-1H-indol-5-ol (b) (40 mg, grey solid, 33% yield).
LC-MS(ESI)：m/z 200.0/202.0[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.23(s，1H)，9.02(s，1H)，6.91(d，J＝8.7Hz，1H)，6.72(t，J＝8.4Hz，1H)，2.29(s，3H)。
Preparation example 3: preparation of 7-fluoro-2-methyl-1H-indol-5-ol (c)
Figure GPA0000302101330000262
In analogy to the procedure for the preparation of intermediate (a) except for the replacement of 1,2, 3-trifluoro-4-nitrobenzene with 1,3, 5-trifluoro-2-nitrobenzene, 7-fluoro-2-methyl-1H-indol-5-ol (c) was prepared (50 mg, grey solid, 20% yield in four steps).
LC-MS(ESI)：m/z 166.08[M+H + ]。
Preparation example 4: preparation of 4, 7-difluoro-2-methyl-1H-indol-5-ol (d)
Figure GPA0000302101330000271
In analogy to the procedure for the preparation of intermediate a, except for the replacement of 1,2, 3-trifluoro-4-nitrobenzene with 1,2,3, 5-tetrafluoro-4-nitrobenzene, 4, 7-difluoro-2-methyl-1H-indol-5-ol (d) was prepared (270 mg, grey solid, four-step yield 10%).
LC-MS(ESI)：m/z 184.1[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.28(s，1H)，6.50(dd，J＝11.6，6.4Hz，1H)，6.12(s，1H)，2.34(s，3H)。
Preparation example 5: preparation of 7-chloro-2-methyl-1H-indol-5-ol (e)
Figure GPA0000302101330000272
Step 1: preparation of 3, 5-difluoro-4-nitrophenol (e 1)
3, 5-difluorophenol (13 g,99.9 mmol) was dissolved in a reaction flask containing DCM (250 mL). After the reaction mixture was cooled to 0 ℃, nitric acid (7 ml, 70%) was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes, quenched with ice water (500 mL), allowed to stand for separation, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=5:1) to give 3, 5-difluoro-4-nitrophenol (e 1) (6.5 g, white solid, yield: 37.3%).
LC-MS(ESI)：m/z 174.16[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ6.76(d，J＝1.8Hz，1H)，6.72(d，J＝1.7Hz，1H)，5.76(s，1H)。
Step 2: preparation of 1, 3-difluoro-5-methoxy-2-nitrobenzene (e 2)
In a reaction flask containing DMF (42 mL) was added 3, 5-difluoro-4-nitrophenol (e 1) (6.5 g,37.1 mmol), methyl iodide (7.9 g,55.6 mmol) and potassium carbonate (10.23 g,74.2 mmol), respectively. After stirring the reaction mixture at room temperature overnight, it was diluted with ethyl acetate, and the organic phase was washed successively with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=5:2) to give 1, 3-difluoro-5-methoxy-2-nitrobenzene (e 2) (4.0 g, yellow oil, yield: 56.9%).
Step 3: preparation of 3-fluoro-5-methoxy-2-nitroaniline (e 3)
1, 3-difluoro-5-methoxy-2-nitrobenzene (4.0 g,2115 mmol) was added to a reaction flask previously charged with ammonia in methanol (60 mL, 7.0M). After stirring the reaction mixture at room temperature under sealed condition overnight, the mixture was concentrated under reduced pressure to give a crude 3-fluoro-5-methoxy-2-nitroaniline (e 3) which was used directly in the next reaction.
LC-MS(ESI)：m/z 187.02[M+H + ]。
Step 4: preparation of 1-chloro-3-fluoro-5-methoxy-2-nitrobenzene (e 4)
To a reaction flask containing acetonitrile (5 mL) was added tert-butyl nitrite (575 mg,5.6 mmol) and copper chloride (750 mg,5.6 mmol). After cooling the reaction solution to 0deg.C, a solution of 3-fluoro-5-methoxy-2-nitroaniline (e 3) (520 mg,2.8 mmol) in acetonitrile (10 mL) was added dropwise. After addition, the mixture was warmed to room temperature and stirred for 2 hours, quenched with water. The reaction mixture was extracted with ethyl acetate (3×50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=10:1) to give 1-chloro-3-fluoro-5-methoxy-2-nitrobenzene (e 4) (400 mg, yellow solid, yield: 69.7%).
Step 5: preparation of ethyl 2- (3-chloro-5-methoxy-2-nitrophenyl) -3-oxobutyrate (e 5)
In a reaction flask containing anhydrous tetrahydrofuran (8 mL) were charged potassium tert-butoxide (326 mg,2.91 mmol), ethyl acetoacetate (378 mg,1.5 mmol), and 1-chloro-3-fluoro-5-methoxy-2-nitrobenzene (e 4) (400 mg,1.95 mmol). The reaction mixture was heated to reflux for 24 hours. After the completion of the reaction, the mixture was diluted with ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=5:2) to give ethyl 2- (3-chloro-5-methoxy-2-nitrophenyl) -3-oxobutanoate (e 5) (410 mg, yellow oil, yield: 66.7%).
LC-MS(ESI)：m/z 316.00[M+H + ]。
Step 6: preparation of 1- (3-chloro-5-methoxy-2-nitrophenyl) propan-2-one (e 6)
To a reaction flask containing acetic acid (40 mL) and sulfuric acid (24 mL) was added ethyl 2- (3-chloro-5-methoxy-2-nitrophenyl) -3-oxobutanoate (e 5) (4.0 g,12.7 mmol) at room temperature. The reaction was heated to reflux overnight. After the reaction was completed, cooled to room temperature, the reaction solution was concentrated, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (2×100 ml), and the combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=5:2) to give 1- (3-chloro-5-methoxy-2-nitrophenyl) propan-2-one (e 6) (1.5 g, yellow oil, yield 48.7%).
Step 7: preparation of 7-chloro-5-methoxy-2-methyl-1H-indole (e 7)
1- (3-chloro-5-methoxy-2-nitrophenyl) propan-2-one (e 6) (1.5 g,6.16 mmol) and iron powder (2.06 g,36.9 mmol) were added to a reaction flask containing acetic acid (20 mL) at room temperature. The reaction mixture was heated to 100℃and stirred for 1 hour, after the completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), and the organic phase was washed successively with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=10:3) to give 7-chloro-5-methoxy-2-methyl-1H-indole (e 7) (1.0 g, yellow oil, yield 83.3%).
LC-MS(ESI)：m/z 196.06，198，01[M+H + ]。
Step 8: preparation of 7-chloro-2-methyl-1H-indol-5-ol (e)
In a reaction flask containing DCM (30 mL) was added 7-chloro-5-methoxy-2-methyl-1H-indole (e 7) (1.0 g,5.11 mmol). The mixture was cooled to-78℃and boron tribromide (12.8 mL,25.6mmol,2M in tetrahydrofuran) was added dropwise. After the completion of the dropwise addition, the reaction solution was slowly warmed to-10℃and stirred for 4 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane (80 mL), and the organic phase was washed with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=10:3) to give 7-chloro-2-methyl-1H-indol-5-ol (e) (800 mg, yellow solid, yield 82.1%).
LC-MS(ESI)：m/z 182.03，184.14[M+H + ]。
Preparation example 6: preparation of 6- (benzyloxy) -4-chloro-7-methoxyquinazoline (f)
Figure GPA0000302101330000291
Step 1: preparation of 4-chloro-6-acetyl-7-methoxyquinazolin-6-yl acetate (f 1)
4-hydroxy-7-methoxyquinazolin-6-yl acetate (An Naiji chemical) (10 g,4.26 mmol) and DMF (0.25 mL) were added to a reaction flask containing thionyl chloride (100 mL) at room temperature, and the reaction was heated to reflux for 2 hours. After cooling to room temperature, 20mL of diethyl ether was added and filtered to give the crude 4-chloro-7-methoxyquinazolin-6-yl acetate (f 1) (10 g, grey solid).
LC-MS(ESI)：m/z 253.0/255.2[M+H + ]。
Step 2: preparation of 6- (benzyloxy) -4-chloro-7-methoxyquinazoline (f)
To a reaction flask containing acetone (15 mL) was added 4-chloro-7-methoxyquinazolin-6-yl acetate (f 1) (1.0 g,4.75 mmol), bromobenzyl (975 mg,5.70 mmol) and potassium carbonate (1.3 g,9.5 mmol) at room temperature. The reaction was stirred at room temperature overnight. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the mixture, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=2:1) to give 6- (benzyloxy) -4-chloro-7-methoxyquinazoline (f) (600 mg, white solid, yield 42%).
LC-MS(ESI)：m/z 301.1/303.1[M+H + ]。
Preparation example 7: preparation of 2, 4-dimethylpiperazine-1-carbonyl chloride (g)
Figure GPA0000302101330000301
Step 1: preparation of tert-butyl 2, 4-dimethylpiperazine-1-carboxylate (g 1)
To a reaction flask containing dichloromethane 100 (mL) was added tert-butyl 2-methylpiperazine-1-carboxylate (5.0 g,24.97 mmol), aqueous formaldehyde (2.6 mL,37.45 mmol) and sodium triacetoxyborohydride (8.0 g,37.45 mmol) at room temperature. The reaction was stirred at room temperature overnight. After the reaction was completed, it was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (3×50 mL), the combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent PE: ea=2:1) to give tert-butyl 2, 4-dimethylpiperazine-1-carboxylate (g 1) (5.0 g, colorless liquid, yield 94%).
LC-MS(ESI)：m/z 215.2[M+H + ]。
Step 2: preparation of 1, 3-dimethylpiperazine hydrochloride (g 2)
In a reaction flask containing dichloromethane (50 mL) was added tert-butyl 2, 4-dimethylpiperazine-1-carboxylate (g 1) (5.0 g,23.23 mmol) and dioxane hydrochloride solution (10 mL,4M dioxane solution) at room temperature. The reaction solution was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 1, 3-dimethylpiperazine hydrochloride (g 2) (5.0 g, white solid) as a crude product.
LC-MS(ESI)：m/z 115.1[M+H + ]。
Step 3: preparation of 2, 4-dimethylpiperazine-1-carbonyl chloride (g)
1, 3-dimethylpiperazine hydrochloride (720 mg,4.38 mmol) and sodium bicarbonate (1.5 g,17.52 mmol) were added to a reaction flask containing anhydrous dichloromethane (20 mL) at room temperature. The reaction was cooled to 0deg.C, triphosgene (650 mg,2.19 mmol) was added in portions, and the mixture was stirred at room temperature for 6 hours after the addition. After completion of the reaction, the mixture was concentrated under reduced pressure to give 2, 4-dimethylpiperazine-1-carbonyl chloride (g) (1.5 g, white solid).
LC-MS(ESI)：m/z 177.1/179.2[M+H + ]。
Preparation example 8: preparation of 3, 4-dimethylpiperazine-1-carbonyl chloride (h)
Figure GPA0000302101330000311
1, 2-dimethylpiperazine (500 mg,4.38 mmol) and sodium bicarbonate (1.5 g,17.52 mmol) were added to a reaction flask containing anhydrous dichloromethane (20 mL) at room temperature. The reaction was cooled to 0deg.C, triphosgene (650 mg,2.19 mmol) was added in portions, and the mixture was stirred at room temperature for 6 hours after the addition. After completion of the reaction, 3, 4-dimethylpiperazine-1-carbonyl chloride (h) (1.5 g, white solid) was obtained by concentration under reduced pressure.
LC-MS(ESI)：m/z 177.1/179.2[M+H + ]。
Preparation example 9: preparation of (1R, 4R) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl chloride (i)
Figure GPA0000302101330000312
The same procedure as for the preparation of intermediate g was followed except for replacing tert-butyl 2-methylpiperazine-1-carboxylate with tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate to give (1R, 4R) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl chloride (i) (1.5 g, white solid).
LC-MS(ESI)：m/z 175.1/177.1[M+H + ]。
Preparation example 10: preparation of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j)
Figure GPA0000302101330000313
The same procedure as in the preparation of intermediate g was followed except that (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester was used instead of 2-methylpiperazine-1-carboxylic acid tert-butyl ester to obtain (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) (1.5 g, white solid).
LC-MS(ESI)：m/z 177.1/179.1[M+H + ]。
Preparation example 11: preparation of (S) -2, 4-dimethylpiperazine-1-carbonyl chloride (k)
Figure GPA0000302101330000321
The same procedure as for the preparation of intermediate g was followed except that (S) -2-methylpiperazine-1-carboxylic acid tert-butyl ester was used instead of 2-methylpiperazine-1-carboxylic acid tert-butyl ester to obtain (S) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (k) (1.5 g, white solid).
LC-MS(ESI)：m/z 177.1/179.1[M+H + ]。
Preparation example 12: preparation of (R) -3-methylmorpholine-4-carboxylic acid chloride (l)
Figure GPA0000302101330000322
In the same manner as in the preparation of intermediate h, except that (R) -3-methylmorpholine was used instead of 1, 2-dimethylpiperazine, (R) -3-methylmorpholine-4-carboxylic acid chloride (l) (1.5 g, white solid) was prepared.
LC-MS(ESI)：m/z 164.0/162.0[M+H + ]。
Preparation example 13: preparation of 5- (ethoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (m)
Figure GPA0000302101330000323
Into a 250mL reaction flask were charged isopropyl malonate (25 g,0.17 mmol) and triethyl orthoformate (77 g,0.51 mmol) at room temperature. The reaction mixture was stirred at 80℃for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure to give 5- (ethoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (m) (34 g, red oil).
Preparation example 14: preparation of 6- (benzyloxy) -4-chloro-7-methoxyquinoline (n)
Figure GPA0000302101330000324
Figure GPA0000302101330000331
Step 1: preparation of 2-methoxy-4-nitrophenylacetate (n 1)
2-methoxy-4-nitrophenol (45 g,0.27 mol) and pyridine (25.3 g,0.32 mol) were added to a reaction flask containing anhydrous DCM (450 mL) at room temperature. The reaction mixture was cooled to 0deg.C, acetyl chloride (25.1 g,0.32 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 minutes after completion of the dropwise addition. After the completion of the reaction, the reaction solution was washed with water, the aqueous phase was extracted 3 times with methylene chloride, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-methoxy-4-nitrophenylacetate (n 1) (50.7 g, yellow solid, yield: 90.2%).
Step 2: preparation of 4-amino-2-methoxyphenylacetic acid ester (n 2)
2-methoxy-4-nitrophenylacetate (n 1) (50.7 g,0.24 mol) and 10% palladium on carbon (55% water) (2.5 g) were added to a reaction flask containing ethanol (500 mL) at room temperature. The reaction solution was replaced with hydrogen three times and stirred overnight under a hydrogen atmosphere. After the reaction was completed, filtration was performed, and the filtrate was concentrated under reduced pressure to give 4-amino-2-methoxyphenylacetate (n 2) (44.4 g, black oil).
LC-MS(ESI)：m/z 182.1[M+H + ]。
Step 3: preparation of 4- (((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-methylene) amino) -2-methoxyphenylacetic acid ester (n 3)
4-amino-2-methoxyphenylacetate (n 2) (44.4 g,0.25 mol) and 5- (ethoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (m) (66 g,0.33 mol) were placed in a reaction vessel containing ethanol (800 mL) at room temperature. The reaction was heated to reflux and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to 0 ℃, a solid was precipitated, filtered, and the precipitate was washed with ethanol (100 ml x 3) and dried to give 4- (((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-methylene) amino) -2-methoxyphenylacetic acid ester (n 3) (54.7 g, yellow solid, yield: 66.6%).
LC-MS(ESI)：m/z 336.2[M+H + ]。
1 H NMR(400MHz，Chloroform-d)δ11.26(d，J＝14.3Hz，1H)，8.59(d，J＝14.3Hz，1H)，7.09(d，J＝8.4Hz，1H)，6.85-6.79(m，2H)，3.88(s，3H)，2.32(s，3H)，1.76(s，6H)。
Step 4: preparation of 7-methoxy-4-oxo-1, 4-dihydro-quinolin-6-yl acetate (n 4)
4- (((2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-methylene) amino) -2-methoxyphenylacetate (n 3) (21.9 g,65.3 mmol) was added to a reaction flask containing diphenyl ether (219 g) and biphenyl (96 g) at room temperature, the reaction mixture was stirred at 190℃for 1.5 hours, after completion of the reaction, cooled to 60℃and poured into petroleum ether (1.2L), a solid was precipitated, and the precipitate was filtered, washed with petroleum ether (200 mL) and dried to give 7-methoxy-4-oxo-1, 4-dihydroquinolin-6-yl acetate (n 4) (13 g, yellow solid, yield: 85.4%).
LC-MS(ESI)：m/z 234.1[M+H + ]。
Step 5: preparation of 4-chloro-7-methoxyquinolin-6-yl acetate (n 5)
To a reaction flask containing chloroform (60 mL) was added 7-methoxy-4-oxo-1, 4-dihydroquinolin-6-ylacetate (n 4) (5.5 g,23.6 mmol) and phosphorus oxychloride (11.8 mL,118 mmol) at room temperature. The reaction was heated to reflux and stirred for 6 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the organic phase was washed with water, saturated sodium bicarbonate solution and saturated brine in this order. Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=2:1) to give 4-chloro-7-methoxyquinolin-6-yl acetate (n 5) (4.3 g, yellow solid, yield: 72.4%).
LC-MS(ESI)：m/z 252.13[M+H + ]。
Step 6: preparation of 4-chloro-7-methoxy-6-hydroxyquinoline (n 6)
To a reaction flask containing ethanol (30 mL) and water (5 mL) was added 4-chloro-7-methoxyquinolin-6-yl acetate (n 5) (3.5 g,13.9 mmol) and sodium hydroxide (612 mg,15.3 mmol) at 0deg.C. The reaction mixture was stirred for 1 hour. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain crude 4-chloro-7-methoxy-6-hydroxyquinoline (n 6). Directly used in the next reaction.
LC-MS(ESI)：m/z 210.1[M+H + ]。
Step 7: preparation of 6- (benzyloxy) -4-chloro-7-methoxyquinoline (n)
In a reaction flask containing DMF (30 mL) was charged 4-chloro-7-methoxy-6-hydroxyquinoline (n 6) (2.8 g,13.4 mmol), potassium carbonate (3.7 g,26.8 mmol) and benzyl bromide (3.4 g,20.1 mmol). The reaction solution was stirred at room temperature for 6 hours. After completion of the reaction, water (100 mL) was added to dilute and extracted with ethyl acetate (30 ml×3), and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: EA/2:1) to give 6- (benzyloxy) -4-chloro-7-methoxyquinoline (n) (3.3 g, yellow solid, yield: 82.5%).
LC-MS(ESI)：m/z 300.1[M+H + ]。
Preparation example 15: preparation of 2-ethoxy-4-nitrophenol (o)
Figure GPA0000302101330000341
Step 1: preparation of 1, 2-diethoxy-4-nitrobenzene (o 1)
1, 2-Diethoxybenzene (100 g,0.27 mol) was added to a reaction flask containing acetic acid (500 mL) at room temperature. After dissolution, the mixture was cooled to 0℃with an ice-water bath, and 65% concentrated nitric acid (58 g) was slowly added dropwise. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour, at which time a large amount of solids were precipitated. The reaction mixture was poured into cold water (1500 mL), filtered, and the precipitate was washed with water (500 mL. Times.3) and dried to give 1, 2-diethoxy-4-nitrobenzene (o 1) (123.7 g, yellow solid, yield: 97.4%).
1 H NMR(400MHz，Chloroform-d)δ7.88(dd，J＝8.9，2.7Hz，1H)，7.74(d，J＝2.6Hz，1H)，6.89(d，J＝8.9Hz，1H)，4.18(dq，J＝9.8，7.0Hz，4H)，1.55-1.48(m，6H)。
Step 2: preparation of 2-ethoxy-4-nitrophenol (o)
1, 2-diethoxy-4-nitrobenzene (107 g,0.5 mol) and potassium hydroxide (112 g,2 mol) were added to a reaction flask containing ethylene glycol monoethyl ether (500 mL) and water (1L) at room temperature. After the addition, the reaction mixture was heated to reflux and stirred for 72 hours, after the reaction was completed, cooled to room temperature, the reaction solution was poured into cold water, the pH was adjusted to be acidic with concentrated hydrochloric acid, a large amount of precipitate was precipitated, filtered, and the precipitate was washed with water (500 ml x 3) and dried to give 2-ethoxy-4-nitrophenol (o) (85 g, yellow solid, yield: 87.6%).
1 H NMR(400MHz，Chloroform-d)δ7.87(dd，J＝8.8，2.5Hz，1H)，7.74(d，J＝2.5Hz，1H)，6.98(d，J＝8.8Hz，1H)，6.25(s，1H)，4.26-4.20(m，2H)，1.51(t，J＝7.0Hz，3H)。
Preparation example 16: preparation of 6- (benzyloxy) -4-chloro-7-ethoxyquinoline (p)
Figure GPA0000302101330000351
The same procedures used in preparation example 14 were repeated except for using 2-ethoxy-4-nitrophenol (o) in place of 2-methoxy-4-nitrophenol to give 6- (benzyloxy) -4-chloro-7-ethoxyquinoline (p) (yellow solid, yield: 8%).
LC-MS(ESI)：m/z314.1，316.1[M+H + ]。
Preparation example 17: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q)
Figure GPA0000302101330000352
Step 1: preparation of 6- (benzyloxy) -4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinoline (q 1)
In a reaction flask containing 2, 6-lutidine (20 mL) was charged 6- (benzyloxy) -4-chloro-7-methoxyquinoline (n) (1.7 g,5.7 mmol), 4-fluoro-2-methyl-1H-indol-5-ol (a) (1.04 g,6.3 mmol) and 4-dimethylaminopyridine (696 mg,5.7 mmol) at room temperature. The reaction was heated to reflux and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent DCM: meoh=10; 1) to give 6- (benzyloxy) -4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinoline (q 1) (1.5 g, yellow solid, yield 62.5%).
LC-MS(ESI)：m/z 429.3[M+H + ]。
Step 2: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q)
To a reaction flask containing methanol (30 mL) was added 6- (benzyloxy) -4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinoline (q 1) (1.5 g,3.5 mmol) and 10% palladium on carbon (55% water) (300 mg) at room temperature. The reaction solution was replaced with hydrogen three times and stirred overnight under a hydrogen atmosphere. After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) (yellow solid).
LC-MS(ESI)：m/z 339.2[M+H + ]。
Preparation example 18: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r)
Figure GPA0000302101330000361
The same procedures used in preparation example 17 were repeated except for using 6- (benzyloxy) -4-chloro-7-ethoxyquinoline (p) instead of 6- (benzyloxy) -4-chloro-7-methoxyquinoline (n), to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r) (2.0 g, yellow solid, two-step yield: 57.7%).
LC-MS(ESI)：m/z 353.2[M+H + ]。
Preparation example 19: preparation of (S) -3-methylmorpholine-4-carboxylic acid chloride (S)
Figure GPA0000302101330000362
To a reaction flask containing anhydrous dichloromethane (20 mL) was added (S) -3-methylmorpholine (200 mg,1.97 mmol) and potassium carbonate (2.2 g,15.76 mmol) at room temperature. The reaction was cooled to 0deg.C and triphosgene (290.8 mg,0.98 mmol) was added in portions. After the addition, the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, filtration, washing with methylene chloride (20 mL) and concentration of the filtrate under reduced pressure gave the crude product (S) -3-methylmorpholine-4-carboxylic acid chloride (S) (white solid). Directly used in the next reaction.
LC-MS(ESI)：m/z 164.1/166.1[M+H + ]。
Preparation example 20: preparation of 2-methylmorpholine-4-carboxylic acid chloride (t)
Figure GPA0000302101330000371
The same procedures used in preparation example 19 were repeated except for using 2-methylmorpholine instead of 3- (S) -3-methylmorpholine to obtain 2-methylmorpholine-4-formyl chloride (t).
LC-MS(ESI)：m/z 164.1/166.1[M+H + ]。
Preparation example 21: preparation of (S) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl chloride (u)
Figure GPA0000302101330000372
The same procedures used in preparation example 19 were repeated except for using (S) -octahydropyrrolo [1,2-a ] pyrazine instead of 3- (S) -3-methylmorpholine to obtain (S) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl chloride (u).
LC-MS(ESI)：m/z 188.17/120.20[M+H + ]。
Preparation example 22: preparation of (R) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl chloride (v)
Figure GPA0000302101330000373
The same procedures used in preparation example 19 were repeated except for using (R) -octahydropyrrolo [1,2-a ] in place of 3- (S) -3-methylmorpholine to prepare (R) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl chloride (v).
LC-MS(ESI)：m/z 188.17/120.20[M+H + ]。
Preparation example 23: preparation of (2R, 6S) -2, 6-dimethylmorpholine-4-carbonyl chloride (w)
Figure GPA0000302101330000374
The same procedures used in preparation example 19 were repeated except for using (2R, 6S) -2, 6-dimethylmorpholine instead of 3- (S) -3-methylmorpholine to obtain (2R, 6S) -2, 6-dimethylmorpholine-4-carbonyl chloride (w).
LC-MS(ESI)：m/z 177.1/1179.1[M+H + ]。
Preparation example 24: preparation of (S) -3, 4-dimethylpiperazine-1-carbonyl chloride (x)
Figure GPA0000302101330000381
The same procedures used in preparation example 7 were repeated except for using (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of 2-methylpiperazine-1-carboxylic acid tert-butyl ester to obtain (S) -3, 4-dimethylpiperazine-1-carbonyl chloride (x).
LC-MS(ESI)：m/z 177.1/179.1[M+H + ]。
Preparation example 25: preparation of (R) -3, 4-dimethylpiperazine-1-carbonyl chloride (y)
Figure GPA0000302101330000382
The same procedures used in preparation example 7 were repeated except for using (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of 2-methylpiperazine-1-carboxylic acid tert-butyl ester to obtain (R) -3, 4-dimethylpiperazine-1-carbonyl chloride (y).
LC-MS(ESI)：m/z 177.1/179.1[M+H + ]。
Preparation example 26: preparation of (R) -4- (chloroformyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (z)
Figure GPA0000302101330000383
The same procedures used in preparation example 19 were repeated except for using (R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of 3- (S) -3-methylmorpholine to give (R) -4- (chloroformyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (z).
LC-MS(ESI)：m/z 262.1/264.1[M+H + ]。
Preparation example 27: preparation of (S) -4- (chloroformyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (aa)
Figure GPA0000302101330000384
The same procedures used in preparation example 19 were repeated except for using (S) -2-methylpiperazine-1-carboxylic acid tert-butyl ester instead of 3- (S) -3-methylmorpholine to give (S) -4- (chloroformyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (aa).
LC-MS(ESI)：m/z 262.1/264.1[M+H + ]。
Preparation example 28: preparation of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb)
Figure GPA0000302101330000391
The same procedures used in preparation example 19 were repeated except for using (R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of 3- (S) -3-methylmorpholine to give (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb).
LC-MS(ESI)：m/z 262.1/264.1[M+H + ]。
Preparation example 29: preparation of (S) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (cc)
Figure GPA0000302101330000392
The same procedures used in preparation example 19 were repeated except for using (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester instead of 3- (S) -3-methylmorpholine to obtain (S) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (cc).
LC-MS(ESI)：m/z 262.1/264.1[M+H + ]。
Preparation example 30: preparation of (1R, 4R) -5- (chloroformyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (dd)
Figure GPA0000302101330000393
The same procedures used in preparation example 19 were repeated except for using tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate instead of 3- (S) -3-methylmorpholine to give tert-butyl (1R, 4R) -5- (chloroformyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (dd).
LC-MS(ESI)：m/z 260.1/262.1[M+H + ]。
Preparation example 31: preparation of thiomorpholine-4-carboxylic acid chloride (ee)
Figure GPA0000302101330000394
By following a procedure analogous to preparation example 19 except substituting thiomorpholine for 3- (S) -3-methylmorpholine, thiomorpholine-4-carbonyl chloride (ee) was obtained.
LC-MS(ESI)：m/z 166.1/168.1[M+H + ]。
Preparation example 32: preparation of (2R, 6S) -4- (chloroformyl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (ff)
Figure GPA0000302101330000401
The same procedures used in preparation example 19 were repeated except for using (2R, 6S) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester instead of 3- (S) -3-methylmorpholine to give (2R, 6S) -4- (chloroformyl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (ff).
Preparation example 33: preparation of (S) -2-methylmorpholine-4-carbonyl chloride (gg)
Figure GPA0000302101330000402
The same procedures used in preparation example 19 were repeated except for using (S) -2-methylmorpholine instead of (S) -3-methylmorpholine to obtain (S) -2-methylmorpholine-4-formyl chloride (gg).
LC-MS(ESI)：m/z 164.0/166.0[M+H + ]。
Preparation example 34: preparation of (R) -2-methylmorpholine-4-carboxylic acid chloride (hh)
Figure GPA0000302101330000403
The same procedures used in preparation example 19 were repeated except for using (R) -2-methylmorpholine instead of (S) -3-methylmorpholine to give (R) -2-methylmorpholine-4-formyl chloride (hh).
LC-MS(ESI)：m/z 164.1/166.1[M+H + ]。
Preparation example 35: preparation of 4-benzyl-4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (ii)
Figure GPA0000302101330000404
Step 1: preparation of ethyl N-benzyl-N- (1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carbonyl) glycinate (ii 1)
In a reaction flask containing DCM (120 mL) was added ethyl N-benzylglycinate (8.1 g,42 mmol), 1- (benzyloxycarbonylamino) cyclopropanecarboxylic acid (9.9 g,42 mmol), EDCI (12 g,63 mmol) and HOBT (8.5 g,63 mmol) at 0deg.C. The reaction was stirred at room temperature for 12 hours. Then quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (120 ml x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent PE: ea=1:1) to give ethyl N-benzyl-N- (1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carbonyl) glycinate (ii 1) (10 g, yellow solid, yield: 58.2%).
LC-MS(ESI)：m/z 411.3[M+H + ]。
Step 2: preparation of 7-benzyl-4, 7-diazaspiro [2.5] octane-5, 8-dione (ii 2)
Ethyl N-benzyl-N- (1- (((benzyloxy) carbonyl) amino) cyclopropane-1-carbonyl) glycinate (9.5 g,23.1 mmol) and Pd/C (1 g, 10%) were added to a round-bottomed flask containing ethanol (100 mL). Sealing, replacing with hydrogen for three times, stirring the reaction solution at room temperature for 2 hours under the hydrogen atmosphere, and filtering. The filtrate was concentrated under reduced pressure to give 7-benzyl-4, 7-diazaspiro [2.5] octane-5, 8-dione (ii 2) (5 g, yellow solid, yield 94%).
LC-MS(ESI)：m/z 231.2[M+H + ]。
Step 3: preparation of 7-benzyl-4, 7-diazaspiro [2.5] octane (ii 3)
In a reaction flask containing THF (100 mL) was 7-benzyl-4, 7-diazaspiro [2.5] octane-5, 8-dione (3.6 g,15.6 mmol). The reaction mixture was cooled to 0deg.C and LiAlH4 (1.8 g,46.8 mmol) was added in portions and stirring was continued for 2 hours, after completion of the reaction, water (1.8 g) and 15% aqueous sodium hydroxide solution (1.8 g) were added in sequence to quench it, after stirring for 30 minutes, filtration was carried out, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent DCM: meOH=10:1) to give 7-benzyl-4, 7-diazaspiro [2.5] octane (ii 3) (2.5 g, yellow oil, yield: 79%).
LC-MS(ESI)：m/z 203.2[M+H + ]。
Step 4: preparation of 4-benzyl-4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (ii)
7-benzyl-4, 7-diazaspiro [2.5] octane (ii 3) (200 mg,0.98 mmol) and potassium carbonate (1 g,7.84 mmol) were added to a reaction flask containing anhydrous dichloromethane (20 mL) at room temperature. The reaction was cooled to 0deg.C and triphosgene (148 mg,0.5 mmol) was added in portions. After the addition, the reaction mixture was stirred at room temperature for 6 hours. After completion of the reaction, filtration, washing with methylene chloride (20 mL) and concentration of the filtrate under reduced pressure gave the crude product 4-benzyl-4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (ii) (white solid). Directly used in the next reaction.
Preparation example 36: preparation of 4- (2, 2-trifluoroacetyl) -4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (jj)
Figure GPA0000302101330000421
Step 1: preparation of 1- (7-benzyl-4, 7-diazaspiro [2.5] oct-4-yl) -2, 2-trifluoroethan-1-one (jj 1)
In a reaction flask containing DCM (10 mL) was added 7-benzyl-4, 7-diazaspiro [2.5] octane (ii 3) (390 mg,1.93 mmol), triethylamine (779 mg,7.72 mmol) and trifluoroacetic anhydride (319 mg,2.9 mmol) at 0deg.C. The reaction was stirred for 1 hour. Then quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (20 ml x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent PE: ea=1:1) to give 1- (7-benzyl-4, 7-diazaspiro [2.5] oct-4-yl) -2, 2-trifluoroethan-1-one (jj 1) (430 mg, yellow solid, yield: 75%).
LC-MS(ESI)：m/z 299.2[M+H + ]。
Step 2: preparation of 2, 2-trifluoro-1- (4, 7-diazaspiro [2.5] oct-4-ylethyl-1-one hydrochloride (jj 2)
1- (7-benzyl-4, 7-diazaspiro [2.5] oct-4-yl) -2, 2-trifluoroethan-1-one (jj 1) (430 mg,1.45 mmol), pd/C (100 mg, 10%) and concentrated hydrochloric acid (80 mg) were added to a round bottom flask containing ethanol (10 mL). Sealing, replacing with hydrogen for three times, stirring the reaction solution at room temperature for 2 hours under the hydrogen atmosphere, and filtering. The filtrate was concentrated under reduced pressure to give 2, 2-trifluoro-1- (4, 7-diazaspiro [2.5] oct-4-ylethyl-1-one hydrochloride (jj 2) (330 mg, yellow solid, yield 92%).
LC-MS(ESI)：m/z 209.1[M+H + ]。
Step 3: preparation of 4- (2, 2-trifluoroacetyl) -4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (jj)
2, 2-trifluoro-1- (4, 7-diazaspiro [2.5] oct-4-ylethyl-1-one hydrochloride (jj 2) (150 mg,0.62 mmol) and potassium carbonate (855 mg,6.2 mmol) were added to a reaction flask containing anhydrous dichloromethane (10 mL) at room temperature, the reaction mixture was cooled to 0 ℃, triphosgene (90 mg,0.3 mmol) was added in portions, the reaction mixture was stirred at room temperature for 6 hours, after completion of the reaction, filtration was performed, washing with dichloromethane (20 mL), and the filtrate was concentrated under reduced pressure to give the crude product 4- (2, 2-trifluoroacetyl) -4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (jj) (white solid).
Example 1: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl 2, 4-dimethylpiperazine-1-carboxylate (1)
Figure GPA0000302101330000431
Step 1: preparation of 6- (benzyloxy) -4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazoline (1 a)
To a reaction flask containing DMF (20 mL) was added 6- (benzyloxy) -4-chloro-7-methoxyquinazoline (f) (1.0 g,3.33 mmol), 4-fluoro-2-methyl-1H-indol-5-ol (a) (660 mg,3.99 mmol) and potassium carbonate (920 mg,6.66 mmol) at room temperature, and the reaction was heated to 90℃and stirred overnight. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the mixture, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent PE: ea=1:1) to give 6- (benzyloxy) -4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazoline (1.0 g, white solid, yield 59%).
LC-MS(ESI)：m/z 430.2[M+H + ]。
Step 2: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy 6-hydroxy-quinazoline (1 b)
To a reaction flask containing methanol (10 mL) was added 6- (benzyloxy) -4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazoline (1.0 g,2.32 mmol) and Pd/C (200 mg) at room temperature, and after the reaction solution was replaced three times with hydrogen, it was stirred under a hydrogen atmosphere for 1 hour. After completion of the reaction, filtration and concentration of the filtrate under reduced pressure gave the crude product 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy 6-hydroxy-quinazoline (1 b) (1.0 g, white solid).
LC-MS(ESI)：m/z 340.2[M+H + ]。
Step 3: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl 2, 4-dimethylpiperazine-1-carboxylate (1)
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-ol (50 mg,0.147 mmol), 2, 4-dimethylpiperazine-1-carbonyl chloride (g) (200 mg, crude) and potassium carbonate (41 mg, 0.254 mmol) were added to a reaction flask containing DMF (2 mL) at room temperature. The reaction was stirred at room temperature overnight. After completion of the reaction, ethyl acetate (5 mL) was added to dilute the mixture, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 30% -100%) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl 2, 4-dimethylpiperazine-1-carboxylate (15 mg, white solid, yield 21%).
LC-MS(ESI)：m/z 480.23[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.36(d，J＝2.4Hz，1H)，8.62(s，1H)，8.07(s，1H)，7.54(s，1H)，7.16(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.3Hz，1H)，6.25(dt，J＝2.1，1.0Hz，1H)，4.00(s，3H)，3.33(m，3H)，2.82-2.64(m，2H)，2.41(d，J＝0.9Hz，3H)，2.20(s，3H)，2.03(dd，J＝71.6，10.3Hz，2H)，1.34(s，3H)。
Example 2: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (1R, 4R) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (2)
Figure GPA0000302101330000441
The procedure was followed in the same manner as in example 1 except for using (1 r,4 r) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carbonyl chloride (i) in place of 2, 4-dimethylpiperazine-1-carbonyl chloride (g) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (1 r,4 r) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (2) (15 mg, white solid, three-step yield 11%).
LC-MS(ESI)：m/z 478.2[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.35(s，1H)，8.62(s，1H)，8.09(d，J＝5.2Hz，1H)，7.54(s，1H)，7.16(d，J＝8.6Hz，1H)，7.00(dd，J＝8.6，7.3Hz，1H)，6.32-6.18(m，1H)，4.01(s，3H)，3.47(s，2H)，2.90-2.76(m，2H)，2.54(s，2H)，2.47-2.19(m，6H)，1.91-1.75(m，2H)。
Example 3: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (3)
Figure GPA0000302101330000442
The same procedures used in example 1 were repeated except for using (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) instead of 2, 4-dimethylpiperazine-1-carbonyl chloride (g) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (2) (12 mg, white solid, three-step yield 9%).
LC-MS(ESI)：m/z 480.3[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ10.83(s，1H)，8.20(s，1H)，7.70(s，1H)，7.25(s，1H)，6.86(d，J＝8.5Hz，1H)，6.63(t，J＝8.4Hz，1H)，6.03(p，J＝1.0Hz，1H)，3.91(s，3H)，2.78(s，2H)，2.70-2.61(m，2H)，2.44-2.39(m，2H)，2.33(d，J＝0.9Hz，3H)，2.20(d，J＝3.9Hz，7H)。
Example 4: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (S) -2, 4-dimethylpiperazine-1-carboxylate (4)
Figure GPA0000302101330000451
The same procedures used in example 1 were repeated except for using (S) -2, 4-dimethylpiperazine-1-carbonyl chloride (k) instead of 2, 4-dimethylpiperazine-1-carbonyl chloride (g) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (S) -2, 4-dimethylpiperazine-1-carboxylate (3) (15 mg, white solid, three-step yield 12%).
LC-MS(ESI)：m/z 480.3[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ10.83(s，1H)，8.20(s，1H)，7.70(s，1H)，7.25(s，1H)，6.86(d，J＝8.5Hz，1H)，6.63(t，J＝8.4Hz，1H)，6.03(p，J＝1.0Hz，1H)，3.91(s，3H)，2.78(s，2H)，2.70-2.61(m，2H)，2.44-2.39(m，2H)，2.33(d，J＝0.9Hz，3H)，2.20(d，J＝3.9Hz，7H)。
Example 5: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -3-methylmorpholine-4-carboxylate (5)
Figure GPA0000302101330000452
The same procedures as in example 1 were repeated except for using (R) -3-methylmorpholine-4-carbonyl chloride (l) in place of 2, 4-dimethylpiperazine-1-carbonyl chloride (g). 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -3-methylmorpholine-4-carboxylate (5) was prepared (16 mg, white solid, three-step yield 12%).
LC-MS(ESI)：m/z 467.2[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.37(d，J＝2.4Hz，1H)，8.63(s，1H)，8.10(s，1H)，7.55(s，1H)，7.17(d，J＝8.6Hz，1H)，7.00(dd，J＝8.6，7.3Hz，1H)，6.27-6.22(m，1H)，4.01(s，3H)，3.93-3.83(m，2H)，3.71-3.57(m，3H)，3.47(dd，J＝12.9，9.9Hz，2H)，2.5(S，3H)，2.41(d，J＝1.0Hz，3H)。
Example 6: preparation of 4- ((3-chloro-4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (6)
Figure GPA0000302101330000461
In the same manner as in example 1, except that 3-chloro-4-fluoro-2-methyl-1H-indol-5-ol (b) was used instead of 4-fluoro-2-methyl-1H-indol-5-ol (a) and (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) was used instead of 2, 4-dimethylpiperazine-1-carbonyl chloride (g), 4- ((3-chloro-4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (6) was prepared (8 mg, white solid, three-step yield 10%).
LC-MS(ESI)：m/z 514.3/516.4[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.74(s，1H)，8.64(s，1H)，8.08(s，1H)，7.55(s，1H)，7.22(d，J＝8.7Hz，1H)，7.11(dd，J＝8.7，7.2Hz，1H)，4.01(s，3H)，3.32(m，2H)，2.81-2.64(m，2H)，2.5(s，3H)2.38(s，3H)，2.20(s，3H)，2.12(d，J＝10.9Hz，1H)，2.04-1.85(m，2H)。
Example 7: preparation of 4- ((7-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (7)
Figure GPA0000302101330000462
The same procedures used in example 1 were repeated except for using 7-fluoro-2-methyl-1H-indol-5-ol (c) in place of 4-fluoro-2-methyl-1H-indol-5-ol (a) and (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) in place of 2, 4-dimethylpiperazine-1-carbonyl chloride (g) to give 4- ((7-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (7) (18 mg, white solid, three-step yield 13%).
LC-MS(ESI)：m/z 480.2[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.51(d，J＝2.0Hz，1H)，8.62(s，1H)，8.02(s，1H)，7.51(s，1H)，7.17(d，J＝1.9Hz，1H)，6.90(dd，J＝11.5，2.0Hz，1H)，6.24(s，1H)，3.99(s，3H)，3.26(s，2H)，2.73(dd，J＝49.3，11.3Hz，3H)，2.5(s，3H)，2.41(s，3H)，2.20(s，3H)，2.12(d，J＝10.6Hz，2H)。
Example 8: preparation of 4- ((7-chloro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (8)
Figure GPA0000302101330000471
In the same manner as in example 1, except that 7-chloro-2-methyl-1H-indol-5-ol (e) was used instead of 4-fluoro-2-methyl-1H-indol-5-ol (a) and (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) was used instead of 2, 4-dimethylpiperazine-1-carbonyl chloride (g), 4- ((7-chloro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (8) (15 mg, white solid, three-step yield 15%) was prepared.
LC-MS(ESI)：m/z 496.2/498.2[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.36(t，j＝2.4Hz，1H)，8.62(s，1H)，8.02(s，1H)，7.51(s，1H)，7.31(d，J＝2.0Hz，1H)，7.10(d，J＝2.0Hz，1H)，6.26(dd，J＝2.1，1.1Hz，1H)，3.99(s，3H)，3.32(m，3H)，2.73(ddt，J＝50.3，11.2，1.9Hz，2H)，2.43(d，J＝0.9Hz，3H)，2.20(s，3H)，2.03(dd，J＝71.8，11.5Hz，2H)，1.33(s，3H)。
Example 9: preparation of 4- ((4, 7-difluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (9)
Figure GPA0000302101330000472
In the same manner as in example 1, except that 4, 7-difluoro-2-methyl-1H-indol-5-ol (d) was used in place of 4-fluoro-2-methyl-1H-indol-5-ol (a) and (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) was used in place of 2, 4-dimethylpiperazine-1-carbonyl chloride (g), 4- ((4, 7-difluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylic acid ester (9) (12 mg, white solid, three-step yield 8%) was prepared.
LC-MS(ESI)：m/z 498.3[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.84(t，J＝2.2Hz，1H)，8.65(s，1H)，8.06(s，1H)，7.54(s，1H)，7.06(dd，J＝10.6，5.5Hz，1H)，6.35(s，1H)，4.00(s，3H)，3.4(m，2H)，2.81-2.55(m，3H)，2.5(s，3H)，2.43(s，3H)，2.20(s，3H)，2.16-1.93(m，2H)。
Example 10: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (10)
Figure GPA0000302101330000481
Step 1: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-hydroxy-quinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (10 a)
4- ((4, 7-difluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (9) (50 mg,0.1 mmol) was added to a reaction flask containing anhydrous DCM (2 mL) at room temperature. The reaction mixture was cooled to-78℃and a solution of boron tribromide in tetrahydrofuran (0.25 mL, 2M) was added dropwise. After the addition, the reaction mixture was stirred for 1 hour at 0℃and after the completion of the reaction, quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent DCM: meoh=10:1) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-hydroxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (10 a) (22 mg, white solid, yield 41.2%).
LC-MS(ESI)：m/z 466.28[M+H + ]。
Step 2: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (10)
To a reaction flask containing acetone (2 mL) was added 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-hydroxyquinazolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (10 a) (20 mg,0.04 mmol), bromoethane (6.5 mg,0.06 mmol) and potassium carbonate (11 mg,0.08 mmol) at room temperature. The reaction mixture was heated to 60 ℃ and stirred for 2 hours. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 30% -100%) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinazolin-6-yl (R) -2,4 dimethylpiperazine-1-carboxylate (10) (8.8 mg, white solid, yield 41.5%).
LC-MS(ESI)：m/z 494.2[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.38(s，1H)，δ8.61(s，1H)，8.05(s，1H)，7.50(s，1H)，7.16(d，J＝8.6Hz，1H)，6.99(dd，J＝8.6，7.4Hz，1H)，6.25(s，1H)，4.27(dq，J＝6.2，3.6Hz，2H)，3.87(s，1H)，3.37(m，2H)，2.80(d，J＝11.3Hz，1H)，2.68(d，J＝11.1Hz，1H)，2.41(s，3H)，2.20(s，3H)，2.11(d，J＝10.9Hz，1H)，1.93(s，1H)，1.40(t，J＝6.9Hz，3H)，1.35(s，3H)。
Example 11: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (11)
Figure GPA0000302101330000491
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxy-quinoline (q) (100 mg,0.29 mmol), (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) (204 mg,1.16 mmol) and potassium carbonate (320 mg,2.32 mmol) were added to a reaction flask containing DMF (4 mL) at room temperature. The reaction solution was stirred at room temperature for 6 hours. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the mixture, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 30% -100%) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (11) (80 mg, white solid, yield 56.7%).
LC-MS(ESI)：m/z 479.25[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.3Hz，1H)，7.99(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.4，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.22(d，J＝70.6Hz，1H)，3.96(s，3H)，3.92(s，1H)，3.37(s，1H)，2.83-2.76(m，1H)，2.67(dt，J＝11.5，1.8Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.20(s，3H)，2.12(d，J＝10.0Hz，1H)，1.93(t，J＝11.7Hz，1H)，1.34(s，3H)。
Example 12: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -2-methylpiperazine-1-carboxylic acid ester (12)
Figure GPA0000302101330000492
Step 1: preparation of 4- (tert-butyl) -1- (4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (12 a)
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxy-quinoline (q) (200 mg,0.58 mmol), (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb) (310 mg,1.16 mmol) and potassium carbonate (640 mg,4.64 mmol) were added to a reaction flask containing DMF (6 mL) at room temperature. The reaction solution was stirred at room temperature for 6 hours. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the mixture, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH: dcm=1:20 as eluent) to give 4- (tert-butyl) -1- (4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (12 a) (240 mg, yellow solid, yield 72%).
LC-MS(ESI)：m/z 565.3[M+H + ]。
Step 2: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -2-methylpiperazine-1-carboxylic acid ester (12)
In a reaction flask containing DCM (4 mL) was added 4- (tert-butyl) -1- (4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl) (R) -2-methylpiperazine-1, 4-dicarboxylic acid ester (12 a) (100 mg,0.18 mmol) and a 1, 4-dioxane solution of hydrochloric acid (1 mL, 4M). After stirring the mixture at room temperature for 6 hours, it was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 10% -100%) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -2-methylpiperazine-1-carboxylic acid ester (12) (40 mg, white solid, 48.6%).
LC-MS(ESI)：m/z 465.35[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.45(d，J＝2.3Hz，1H)，8.56(d，J＝5.3Hz，1H)，7.99(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，3.96(s，3H)，3.80(d，J＝21.7Hz，2H)，3.19(s，1H)，2.98(d，J＝12.2Hz，1H)，2.90-2.83(m，2H)，2.69(d，J＝11.9Hz，1H)，2.42(d，J＝1.0Hz，3H)，1.33(s，3H)。
Example 13: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -2, 4-dimethylpiperazine-1-carboxylate (13)
Figure GPA0000302101330000501
The same procedures as in example 11 were repeated except that (S) -2, 4-dimethylpiperazine-1-carbonyl chloride (k) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j). 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -2, 4-dimethylpiperazine-1-carboxylate (13) (61 mg, white solid, yield 43.6%).
LC-MS(ESI)：m/z 479.25[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.3Hz，1H)，7.99(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.4，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.22(d，J＝70.6Hz，1H)，3.96(s，3H)，3.92(s，1H)，3.37(s，1H)，2.83-2.76(m，1H)，2.67(dt，J＝11.5，1.8Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.20(s，3H)，2.12(d，J＝10.0Hz，1H)，1.93(t，J＝11.7Hz，1H)，1.34(s，3H)。
Example 14: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -2-methylpiperazine-1-carboxylate (14)
Figure GPA0000302101330000511
The same procedures used in example 12 were repeated except for using (S) -tert-butyl 4- (chloroformyl) -2-methylpiperazine-1-carboxylate (cc) in place of tert-butyl (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylate (bb). 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -2-methylpiperazine-1-carboxylate (14) was prepared (35 mg, white solid, yield 53%).
LC-MS(ESI)：m/z 465.32[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.45(s，1H)，8.56(d，J＝5.3Hz，1H)，8.01(s，1H)，7.53(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(t，J＝8.1Hz，1H)，6.37(dd，J＝5.3，1.0Hz，1H)，6.28(s，1H)，4.08(s，1H)，3.96(s，3H)，3.87(s，1H)，3.09(s，1H)，2.96(d，J＝12.7Hz，1H)，2.77(d，J＝11.4Hz，3H)，2.42(s，3H)，1.04(d，J＝5.8Hz，3H)。
Example 15: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (15)
Figure GPA0000302101330000512
The procedure was followed, except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r) in place of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) in the same manner as in example 11. 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2, 4-dimethylpiperazine-1-carboxylate (15) was prepared (40 mg, white solid, yield 36%).
LC-MS(ESI)：m/z 493.32[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，δ8.55(d，J＝5.3Hz，1H)，7.98(s，1H)，7.50(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.4，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.33(s，1H)，4.21(qd，J＝7.0，2.8Hz，2H)，3.89(s，1H)，3.26(s，1H，2.80(d，J＝11.8Hz，1H)，2.71-2.64(m，1H)，2.42(d，J＝1.0Hz，3H)，2.20(s，3H)，2.11(d，J＝10.8Hz，1H)，1.92(s，1H)，1.40(t，J＝6.9Hz，3H)，1.34(s，3H)。
Example 16: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2-methylpiperazine-1-carboxylate (16)
Figure GPA0000302101330000521
The procedure was followed, except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (r)) in place of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), as in example 12. 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2-methylpiperazine-1-carboxylate (16) (35 mg, white solid, yield 53%).
LC-MS(ESI)：m/z 479.37[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(dd，J＝5.3，3.1Hz，1H)，7.98(s，1H)，7.51(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.2，1.1Hz，1H)，6.28(dt，J＝2.0，1.0Hz，1H)，4.22(dq，J＝7.0，3.9，3.3Hz，2H)，3.84(s，2H)，3.18(s，1H)，2.98(d，J＝11.9Hz，1H)，2.86(d，J＝8.3Hz，2H)，2.67(d，J＝10.2Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.18(d，J＝14.7Hz，1H)，1.43-1.38(m，3H)，1.34(s，3H)。
Example 17: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -2, 4-dimethylpiperazine-1-carboxylate (17)
Figure GPA0000302101330000522
In the same manner as in example 11, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -2, 4-dimethylpiperazine-1-carbonyl chloride (k) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j), 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -2, 4-dimethylpiperazine-1-carboxylate (17) (15 mg, white solid, yield 13.5%) was obtained.
LC-MS(ESI)：m/z 493.32[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，δ8.55(d，J＝5.2Hz，1H)，7.98(s，1H)，7.50(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(t，J＝8.1Hz，1H)，6.37(dd，J＝5.2，1.1Hz，1H)，6.31-6.25(m，1H)，4.33(s，1H)，4.22(qt，J＝7.1，3.3Hz，2H)，3.89(s，1H)，3.26(s，1H)，2.80(d，J＝11.3Hz，1H)，2.67(d，J＝11.4Hz，1H)，2.42(s，3H)，2.20(s，3H)，2.11(d，J＝10.9Hz，1H)，1.94(d，J＝13.6Hz，1H)，1.40(t，J＝6.9Hz，3H)，1.34(s，3H)。
Example 18: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -2-methylpiperazine-1-carboxylate (18)
Figure GPA0000302101330000531
In the same manner as in example 12, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (cc) was used instead of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb), 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -2-methylpiperazine-1-carboxylic acid ester (18) was prepared (10 mg, white solid, yield 49%).
LC-MS(ESI)：m/z 479.31[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.3Hz，1H)，7.97(s，1H)，7.50(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(t，J＝8.1Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dd，J＝2.2，1.2Hz，1H)，4.22(dq，J＝6.7，3.2Hz，2H)，3.83(s，2H)，3.15(s，1H)，2.95(s，1H)，2.83(d，J＝6.7Hz，2H)，2.64(s，1H)，2.44-2.36(m，3H)，2.18(d，J＝14.6Hz，1H)，1.40(t，J＝6.9Hz，3H)，1.33(s，3H)。
Example 19: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -3, 4-dimethylpiperazine-1-carboxylate (19)
Figure GPA0000302101330000532
The same procedures used in example 11 were repeated except for using (S) -3, 4-dimethylpiperazine-1-carbonyl chloride (x) instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -3, 4-dimethylpiperazine-1-carboxylate (19) (31.2 mg, white solid, yield 36.8%).
LC-MS(ESI)：m/z 479.35[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.2Hz，1H)，8.00(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.02(d，J＝19.9Hz，1H)，3.96(s，3H)，3.79(s，1H)，3.35(m，1H)，3.10(d，J＝12.8Hz，1H)，2.91(s，1H)，2.75(t，J＝14.3Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.23(s，3H)，2.15(s，1H)，1.03(s，3H)。
Example 20: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -3-methylpiperazine-1-carboxylic acid ester (20)
Figure GPA0000302101330000541
The same procedures used in example 12 were repeated except for using (S) -tert-butyl 4- (chloroformyl) -2-methylpiperazine-1-carboxylate (aa) in place of (R) -tert-butyl 4- (chloroformyl) -3-methylpiperazine-1-carboxylate (bb) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -3-methylpiperazine-1-carboxylate (20) (12 mg, white solid, yield 48%).
LC-MS(ESI)：m/z465.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.3Hz，1H)，8.02(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.2，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.08(d，J＝12.9Hz，1H)，3.96(s，3H)，3.87(d，J＝12.3Hz，1H)，3.12(s，1H)，3.00(d，J＝12.6Hz，1H)，2.81(s，2H)，2.59(d，J＝13.1Hz，1H)，2.42(d，J＝1.0Hz，3H)，1.05(s，3H)。
Example 21: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -3, 4-dimethylpiperazine-1-carboxylate (21)
Figure GPA0000302101330000542
In the same manner as in example 11, except that (R) -3, 4-dimethylpiperazine-1-carbonyl chloride (y) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j), 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -3, 4-dimethylpiperazine-1-carboxylate (21) (44 mg, white solid, yield 31.2%) was prepared.
LC-MS(ESI)：m/z 479.42[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.2Hz，1H)，8.00(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.02(d，J＝19.9Hz，1H)，3.96(s，3H)，3.79(s，1H)，3.35(m，1H)，3.10(d，J＝12.8Hz，1H)，2.91(s，1H)，2.75(t，J＝14.3Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.23(s，3H)，2.15(s，1H)，1.03(s，3H)。
Example 22: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (R) -3-methylpiperazine-1-carboxylic acid ester (22)
Figure GPA0000302101330000551
The same procedures used in example 12 were repeated except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) in place of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (R) -4- (chloroformyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (z) in place of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (R) -3-methylpiperazine-1-carboxylic acid ester (22) (22 mg, white solid, yield 64%).
LC-MS(ESI)：m/z 479.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.3Hz，1H)，7.99(s，1H)，7.50(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.30-6.27(m，1H)，4.23(t，J＝6.9Hz，2H)，4.09(s，1H)，3.88(s，2H)，3.12(s，1H)，3.01(d，J＝12.4Hz，2H)，2.80(s，2H)，2.42(d，J＝1.0Hz，3H)，1.41(d，J＝6.9Hz，3H)，1.06(d，J＝6.0Hz，3H)。
Example 23: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3, 4-dimethylpiperazine-1-carboxylate (23)
Figure GPA0000302101330000552
In analogy to the preparation of example 11, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (S) -3, 4-dimethylpiperazine-1-carbonyl chloride (x) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3, 4-dimethylpiperazine-1-carboxylate (23) (50 mg, white solid, yield 39.8%).
LC-MS(ESI)：m/z 493.42[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.45(s，1H)，8.55(d，J＝5.3Hz，1H)，7.98(s，1H)，7.50(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(t，J＝8.1Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.32-6.24(m，1H)，4.22(q，J＝6.9Hz，2H)，4.00(d，J＝17.8Hz，1H)，3.79(d，J＝17.4Hz，1H)，3.09(s，1H)，2.90(s，1H)，2.76(t，J＝16.9Hz，2H)，2.42(s，3H)，2.23(s，3H)，2.15(s，1H)，1.41(t，J＝6.9Hz，3H)，1.04(d，J＝6.1Hz，3H)。
Example 24: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3-methylpiperazine-1-carboxylate (24)
Figure GPA0000302101330000561
In the same manner as in example 12, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (S) -4- (chloroformyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (aa) was used instead of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3-methylpiperazine-1-carboxylic acid ester (24) (22 mg, white solid, yield 64%).
LC-MS(ESI)：m/z 479.35[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(t，J＝2.2Hz，1H)，8.55(d，J＝5.3Hz，1H)，7.99(s，1H)，7.50(s，1H)，7.22(dd，J＝8.5，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.0Hz，1H)，6.28(dt，J＝2.0，1.0Hz，1H)，4.21(t，J＝7.0Hz，2H)，4.08(s，1H)，3.89(s，1H)，3.10(s，1H)，2.99(d，J＝12.3Hz，1H)，2.78(s，2H)，2.58(m，1H)，2.42(d，J＝1.0Hz，3H)，1.40(t，J＝7.0Hz，3H)，1.05(d，J＝6.0Hz，3H)。
Example 25: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -3, 4-dimethylpiperazine-1-carboxylate (25)
Figure GPA0000302101330000562
In the same manner as in example 11, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (R) -3, 4-dimethylpiperazine-1-carbonyl chloride (y) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j), 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -3, 4-dimethylpiperazine-1-carboxylate (25) (31 mg, white solid, yield 27.5%).
LC-MS(ESI)：m/z 493.37[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.3Hz，1H)，7.98(s，1H)，7.50(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.2，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.22(q，J＝6.9Hz，2H)，4.02(s，1H)，3.79(d，J＝17.4Hz，1H)，3.27(s，1H)，3.09(s，1H)，2.95-2.74(m，2H)，2.42(d，J＝1.0Hz，3H)，2.23(s，3H)，2.15(s，1H)，1.41(t，J＝6.9Hz，3H)，1.04(d，J＝6.0Hz，3H)。
Example 26: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -3-methylmorpholine-4-carboxylic acid ester (26)
Figure GPA0000302101330000571
The same procedures used in example 11 were repeated except for using (R) -3-methylmorpholine-4-carbonyl chloride (l) instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -3-methylmorpholine-4-carboxylate (26) (50 mg, white solid, yield 36%).
LC-MS(ESI)：m/z 466.23[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.3Hz，1H)，8.02(s，1H)，7.54(s，1H)，7.22(dd，J＝8.5，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.38(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.15(s，1H)，3.97(s，3H)，3.88(dd，J＝11.2，3.4Hz，1H)，3.72-3.59(m，2H)，3.47(dd，J＝13.0，10.1Hz，3H)，2.42(d，J＝1.0Hz，3H)，1.33(s，3H)。
Example 27: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -3-methylmorpholine-4-carboxylic acid ester (27)
Figure GPA0000302101330000572
The same procedures used in example 11 were repeated except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (R) -3-methylmorpholine-4-carboxylic acid chloride (l) instead of (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -3-methylmorpholine-4-carboxylate (27) (40 mg, white solid, yield 36%).
LC-MS(ESI)：m/z480.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.3Hz，1H)，8.00(s，1H)，7.51(s，1H)，7.25-7.19(m，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.22(qt，J＝6.8，3.4Hz，3H)，3.95-3.73(m，2H)，3.72-3.61(m，2H)，3.60-3.39(m，2H)，2.42(d，J＝1.0Hz，3H)，1.45-1.28(m，6H)。
Example 28: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -3-methylmorpholine-4-carboxylic acid ester (28)
Figure GPA0000302101330000581
The same procedures used in example 11 were repeated except for using (S) -3-methylmorpholine-4-carboxylic acid chloride (S) instead of (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -3-methylmorpholine-4-carboxylic acid ester (28) (40 mg, white solid, yield 36%).
LC-MS(ESI)：m/z466.32[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.3Hz，1H)，8.02(s，1H)，7.54(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.38(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，0.9Hz，1H)，3.97(s，3H)，3.88(dd，J＝11.4，3.5Hz，1H)，3.70-3.61(m，2H)，3.47(t，J＝11.5Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.07(s，3H)，1.33(s，3H)。
Example 29: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3-methylmorpholine-4-carboxylic acid ester (29)
Figure GPA0000302101330000582
The same procedures used in example 11 were repeated except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (S) -3-methylmorpholine-4-carboxylic acid chloride (S) instead of (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (S) -3-methylmorpholine-4-carboxylate (29) (40 mg, white solid, yield 36%).
LC-MS(ESI)：m/z 480.32[M+H + ]。
1 H NMR(400MHz，DMSO-d6)δ11.45(s，1H)，8.55(d，J＝5.3Hz，1H)，8.00(s，1H)，7.51(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.0，1.0Hz，1H)，4.22(qt，J＝6.8，3.4Hz，3H)，3.89(dd，J＝11.4，3.5Hz，1H)，3.84-3.73(m，1H)，3.69(d，J＝11.5Hz，1H)，3.61(dd，J＝11.6，3.2Hz，1H)，3.46(t，J＝11.2Hz，2H)，2.42(d，J＝0.9Hz，3H)，1.40(t，J＝6.9Hz，3H)，1.34(s，3H)。
Example 30: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-ylsulforpholine-4-carboxylic acid ester (30)
Figure GPA0000302101330000591
The same procedures used in example 11 were repeated except for using thiomorpholine-4-carbonyl chloride (ee) instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-ylsulforpholine-4-carboxylate (30) (25 mg, white solid, yield 44%).
LC-MS(ESI)：m/z 482.29[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.43(s，1H)，8.55(d，J＝5.3Hz，1H)，8.02(s，1H)，7.52(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.1Hz，1H)，4.24(q，J＝6.9Hz，2H)，3.72(s，2H)，2.77(s，4H)，2.42(d，J＝1.0Hz，3H)，1.43(t，J＝6.9Hz，3H)。
Example 31: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (S) -2-methylmorpholine-4-carboxylic acid ester (31)
Figure GPA0000302101330000592
The same procedures used in example 11 were repeated except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (S) -2-methylmorpholine-4-carbonyl chloride (gg) instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (S) -2-methylmorpholine-4-carboxylate (31) (40 mg, white solid, yield 36%).
LC-MS(ESI)：m/z 480.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.3Hz，1H)，8.01(s，1H)，7.51(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.0，1.0Hz，1H)，4.23(q，J＝6.9Hz，2H)，4.09(s，1H)，3.94-3.80(m，2H)，3.56(s，2H)，3.02(s，1H)，2.71(d，J＝14.2Hz，1H)，2.42(d，J＝1.0Hz，3H)，1.41(t，J＝6.9Hz，3H)，1.14(d，J＝6.2Hz，3H)。
Example 32: preparation of 7-methoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl 2-methylmorpholine-4-carboxylate (32)
Figure GPA0000302101330000593
In the same manner as in example 11, except that (S) -2-methylmorpholine-4-carbonyl chloride (gg) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j), 7-methoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl 2-methylmorpholine-4-carboxylate (32) (15 mg, white solid, yield 36%) was prepared.
LC-MS(ESI)：m/z 465.25[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.56(d，J＝5.3Hz，1H)，8.03(s，1H)，7.54(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.38(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.05(dd，J＝23.0，13.2Hz，1H)，3.97(s，3H)，3.91-3.79(m，2H)，3.56(s，2H)，2.89(s，2H)，2.42(d，J＝0.9Hz，3H)，1.14(d，J＝6.2Hz，3H)。
Example 33: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2-methylmorpholine-4-carboxylic acid ester (33)
Figure GPA0000302101330000601
The same procedures used in example 11 were repeated except for using 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (hh) instead of (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (R) -2-methylmorpholine-4-carboxylate (33) (14 mg, white solid, yield 36%).
LC-MS(ESI)：m/z 480.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.2Hz，1H)，8.01(s，1H)，7.51(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.1Hz，1H)，4.23(q，J＝6.9Hz，2H)，4.06(s，1H)，3.89(dd，J＝11.3，3.5Hz，2H)，3.56(s，2H)，2.95(d，J＝54.8Hz，1H)，2.70(s，1H)，2.42(d，J＝1.0Hz，3H)，1.41(t，J＝6.9Hz，3H)，1.14(d，J＝6.2Hz，3H)。
Example 34: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (34)
Figure GPA0000302101330000602
In analogy to the preparation of example 11, except that (1R, 4R) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid chloride (i) was used instead of (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) was used to prepare 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (1 s,4 s) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (34) (13.3 mg, white solid, yield 59%).
LC-MS(ESI)：m/z 476.25[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.43(s，1H)，8.56(d，J＝5.2Hz，1H)，8.00(d，J＝3.6Hz，1H)，7.53(s，1H)，7.22(d，J＝8.6Hz，1H)，7.11-6.92(m，1H)，6.37(dd，J＝5.3，1.0Hz，1H)，6.32-6.24(m，1H)，3.96(s，3H)，3.23(dd，J＝10.2，2.1Hz，1H)，2.92-2.75(m，2H)，2.60(d，J＝9.7Hz，1H)，2.47-2.28(m，6H)，2.08-1.91(m，1H)，1.81(dd，J＝30.2，12.1Hz，2H)。
Example 35: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (35)
Figure GPA0000302101330000611
In analogy to the preparation of example 12, (1R, 4R) -5- (chloroformyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (dd) was used instead of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (1 s,4 s) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (35) (45 mg, white solid, yield 64%).
LC-MS(ESI)：m/z 463.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ1145(s，1H)，8.57(dd，J＝5.2，1.6Hz，1H)，8.02(d，J＝3.5Hz，1H)，7.54(d，J＝4.0Hz，1H)，7.22(d，J＝8.6Hz，1H)，7.00(t，J＝8.1Hz，1H)，6.38(d，J＝5.3Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，3.97(d，J＝3.9Hz，5H)，3.61(s，1H)，3.40-3.431(m，1H)，3.27(d，J＝10.2Hz，1H)，3.13-3.01(m，2H)，2.42(s，3H)，2.01-1.92(m，1H)，1.81-1.72(m，1H)。
Example 36: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (36)
Figure GPA0000302101330000612
In analogy to the preparation of example 12, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (1R, 4R) -5- (chloroformyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (dd) was used instead of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb) to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (1 s,4 s) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (36) (22 mg, white solid, yield 64%).
LC-MS(ESI)：m/z 477.31[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.45(d，J＝2.7Hz，1H)，8.55(dd，J＝5.3，1.8Hz，1H)，8.00(d，J＝2.3Hz，1H)，7.51(d，J＝4.3Hz，1H)，7.22(d，J＝8.6Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(d，J＝5.3Hz，1H)，6.28(q，J＝1.2Hz，1H)，4.21-4.24(m，2H)，3.95(d，J＝13.3Hz，1H)，3.59(s，1H)，3.39(d，J＝8.3Hz，2H)，3.25(s，1H)，3.07(dt，J＝15.3，7.8Hz，2H)，2.42(d，J＝1.0Hz，3H)，1.93(s，1H)，1.41(td，J＝7.0，3.7Hz，3H)。
Example 37: preparation of 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (37)
Figure GPA0000302101330000621
In analogy to the preparation of example 11, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q) and (1R, 4R) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid chloride (i) was used instead of (R) -2, 4-dimethylpiperazine-1-carboxylic acid chloride (j) was used to give 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) quinolin-6-yl (1 s,4 s) -5-methyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester (37) (40 mg, white solid, yield 35.9%).
LC-MS(ESI)：m/z 491.34[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(s，1H)，8.55(d，J＝5.3Hz，1H)，7.98(d，J＝3.6Hz，1H)，7.50(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(d，J＝5.2Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.27-4.19(m，2H)，3.77(m，1H)，3.54-3.47(m，2H)，3.22(dd，J＝10.2，2.1Hz，1H)，2.93-2.75(m，2H)，2.43-2.40(m，3H)，2.38(d，J＝7.3Hz，3H)，1.91-1.72(m，2H)，1.46-1.35(m，3H)。
Example 38: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (3 s,5 r) -3, 5-dimethylpiperazine-1-carboxylate (38)
Figure GPA0000302101330000622
In the same manner as in example 12, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (2R, 6 s) -4- (chloroformyl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (ff) was used instead of (R) -4- (chloroformyl) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (bb), 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (3 s, 5R) -3, 5-dimethylpiperazine-1-carboxylic acid ester (38) (29 mg, white solid, yield 64%).
LC-MS(ESI)：m/z493.36[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(t，J＝2.4Hz，1H)，8.55(d，J＝5.3Hz，1H)，8.17(s，1H)，7.99(s，1H)，7.50(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.22(q，J＝6.9Hz，2H)，4.14(d，J＝12.8Hz，1H)，3.92(d，J＝12.7Hz，1H)，2.89(d，J＝32.8Hz，2H)，2.74-2.62(m，2H)，2.42(d，J＝1.0Hz，3H)，1.40(t，J＝6.9Hz，3H)，1.06(d，J＝6.1Hz，6H)。
Example 39: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (2S, 6R) -2, 6-dimethylmorpholine-4-carboxylate (39)
Figure GPA0000302101330000631
In the same manner as in example 11, except that 7-ethoxy-4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -6-hydroxyquinoline (R) was used instead of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxyquinoline (q), and (2R, 6 s) -2, 6-dimethyl morpholine-4-carbonyl chloride (w) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j), 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-ethoxyquinolin-6-yl (2 s, 6R) -2, 6-dimethyl morpholine-4-carboxylate (39) (12 mg, white solid, yield 36%).
LC-MS(ESI)：m/z494.29[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ8.55(d，J＝5.3Hz，1H)，8.01(s，1H)，7.51(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.02-6.96(m，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.22(q，J＝6.9Hz，2H)，4.11(d，J＝13.2Hz，1H)，3.90(d，J＝13.1Hz，1H)，3.63(d，J＝18.7Hz，2H)，2.79(t，J＝12.0Hz，1H)，2.68-2.57(m，1H)，2.42(d，J＝1.0Hz，3H)，1.40(t，J＝6.9Hz，3H)，1.14(d，J＝6.1Hz，6H)。
Example 40: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -2-methylpiperazine-1-carboxylic acid ester (40)
Figure GPA0000302101330000632
The same procedures used in example 12 were repeated except for using (S) -tert-butyl 4- (chloroformyl) -3-methylpiperazine-1-carboxylate (cc) in place of (R) -tert-butyl 4- (chloroformyl) -3-methylpiperazine-1-carboxylate (bb) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -2-methylpiperazine-1-carboxylate (38) (38 mg, white solid, yield 64%).
LC-MS(ESI)：m/z 465.33[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.45(d，J＝2.3Hz，1H)，8.56(d，J＝5.3Hz，1H)，7.99(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，3.96(s，3H)，3.80(d，J＝21.7Hz，2H)，3.19(s，1H)，2.98(d，J＝12.2Hz，1H)，2.90-2.83(m，2H)，2.69(d，J＝11.9Hz，1H)，2.42(d，J＝1.0Hz，3H)，1.33(s，3H)。
Example 41: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carboxylic acid ester (41)
Figure GPA0000302101330000641
In analogy to the preparation of example 11, except that (R) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl chloride (v) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) was prepared 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (R) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl formate (41).
LC-MS(ESI)：m/z 491.36[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(d，J＝2.6Hz，1H)，8.56(d，J＝5.3Hz，1H)，8.00(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.2，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.31(d，J＝12.5Hz，1H)，4.15(dd，J＝31.3，12.7Hz，1H)，3.96(s，3H)，3.02(d，J＝9.4Hz，2H)，2.85(t，J＝11.8Hz，1H)，2.65(d，J＝13.6Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.10(q，J＝8.8Hz，2H)，1.83(s，1H)，1.71(q，J＝10.1，9.2Hz，2H)，1.39-1.26(m，2H)。
Example 42: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carboxylic acid ester (42)
Figure GPA0000302101330000642
In analogy to the preparation of example 11, except that (S) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl chloride (u) was used instead of (R) -2, 4-dimethylpiperazine-1-carbonyl chloride (j) was prepared 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl (S) -hexahydropyrrolo [1,2-a ] pyrazine-2 (1H) -carbonyl formate (42).
LC-MS(ESI)：m/z 491.36[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.44(d，J＝2.6Hz，1H)，8.56(d，J＝5.3Hz，1H)，8.00(s，1H)，7.53(s，1H)，7.22(dd，J＝8.6，0.8Hz，1H)，7.00(dd，J＝8.6，7.6Hz，1H)，6.37(dd，J＝5.2，1.1Hz，1H)，6.28(dt，J＝2.1，1.0Hz，1H)，4.31(d，J＝12.5Hz，1H)，4.15(dd，J＝31.3，12.7Hz，1H)，3.96(s，3H)，3.02(d，J＝9.4Hz，2H)，2.85(t，J＝11.8Hz，1H)，2.65(d，J＝13.6Hz，1H)，2.42(d，J＝1.0Hz，3H)，2.10(q，J＝8.8Hz，2H)，1.83(s，1H)，1.71(q，J＝10.1，9.2Hz，2H)，1.39-1.26(m，2H)。
Example 43: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4, 7-diazaspiro [2.5] octane-7-carboxylate (43)
Figure GPA0000302101330000651
Step 1: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4-benzyl-4, 7-diazaspiro [2.5] octane-7-carboxylate (43 a)
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxy-quinoline (q) (250 mg,0.74 mmol), 4-benzyl-4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (ii) (400 mg,1.5 mmol) and potassium carbonate (814 mg,5.9 mmol) were added to a reaction flask containing DMF (6 mL) at room temperature. The reaction solution was stirred at room temperature for 6 hours. After completion of the reaction, ethyl acetate (20 mL) was added to dilute the mixture, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (MeOH: dcm=1:20 as eluent) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4-benzyl-4, 7-diazaspiro [2.5] octane-7-carboxylate (43 a) (310 mg, yellow solid, yield 74%).
LC-MS(ESI)：m/z 567.3[M+H + ]。
Step 2: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4, 7-diazaspiro [2.5] octane-7-carboxylate (43)
To a round bottom flask containing ethanol (10 mL) was added 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinoline-6-4-benzyl-4, 7-diazaspiro [2.5] octane-7-carboxylate (43 a) (310 mg,0.55 mmol), pd/C (50 mg, 10%) and concentrated hydrochloric acid (50 mg). Sealing, replacing with hydrogen for three times, stirring the reaction solution at room temperature for 2 hours under the hydrogen atmosphere, and filtering. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 30% to 100%) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4, 7-diazaspiro [2.5] octane-7-carboxylate (43) (160 mg, yellow solid, yield 61%).
LC-MS(ESI)：m/z 477.24[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.45(t，J＝2.3Hz，1H)，8.56(d，J＝5.3Hz，1H)，8.27(s，1H)，8.04(s，1H)，7.54(s，1H)，7.23(d，J＝8.6Hz，1H)，7.01(dd，J＝8.6，7.6Hz，1H)，6.38(dd，J＝5.3，1.1Hz，1H)，6.29(dt，J＝2.2，1.1Hz，1H)，3.98(s，3H)，2.92(s，2H)，2.80(s，2H)，2.44-2.38(m，3H)，1.09(s，3H)，0.87(s，3H)。
Example 44: preparation of 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4, 7-diazaspiro [2.5] octane-4-carboxylate (44)
Figure GPA0000302101330000661
4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxy-6-hydroxy-quinoline (q) (150 mg,0.44 mmol), 4- (2, 2-trifluoroacetyl) -4, 7-diazaspiro [2.5] octane-7-carbonyl chloride (jj) (238 mg,0.88 mmol) and potassium carbonate (480 mg,3.52 mmol) were added to a reaction flask containing DMF (6 mL) at room temperature. After stirring the reaction solution at room temperature for 6 hours, heating to 50 ℃ and continuing stirring for 1 hour, after the reaction is completed, adding ethyl acetate (20 mL) for dilution, washing the organic phase with water and saline solution, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure. The residue was purified by preparative HPLC (C18, acetonitrile/water (0.1% formic acid): 30% -100%) to give 4- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -7-methoxyquinolin-6-yl 4, 7-diazaspiro [2.5] octane-4-carboxylate (44) (41 mg, white solid, 19% yield).
LC-MS(ESI)：m/z 477.3[M+H + ]。
1 H NMR(400MHz，DMSO-d 6 )δ11.43(s，1H)，8.56(d，J＝5.3Hz，1H)，7.97(d，J＝16.7Hz，1H)，7.53(s，1H)，7.22(d，J＝8.6Hz，1H)，7.00(t，J＝8.1Hz，1H)，6.37(dd，J＝5.3，1.1Hz，1H)，6.31-6.26(m，1H)，3.96(s，3H)，3.61(s，1H)，3.49(s，2H)，3.29(s，2H)，2.83(d，J＝20.6Hz，2H)，2.42(s，3H)，0.63(s，1H)，0.51(s，2H)。
Biological testing
Test example 1: enzyme Activity Inhibition (IC) of the Compounds of the invention on the kinases FLT1 (VEGFR 1), FLT4 (VEGFR 3) and KDR (VEGFR 2) 50 ) Evaluation experiment of (2)
The assay uses a mobility shift method (Mobility shift assay) to test compounds for their inhibitory activity at ATP concentrations of the corresponding kinase Km, respectively. The control is sporophore (staurosporine).
The concentration of test compound was 10-fold diluted starting at 10 μm. Test results (IC) 50 ) Is the average of two independent experiments.
Test materials:
kinase FLT1 (Invitrogen, cat.No.PR6731B, lot.No.33924Q), kinase FLT4 (Invitrogen, cat.No.PV4129, lot.No.38454G) and kinase KDR (Carna, cat. No.08-191, lot. No.07 CBS-0540), substrate peptide FAM-P22 (GL Biochem, cat.No112393, lot.No.P130408-ZB 112393), substrate peptide FAM-P30 (GLBiochem, cat.No.263631, lot.No.P141015-XF 263631), ATP (Sigma, cat. No. A7699-1G, CAS. No. 987-65-5), DMSO (Sigma, cat.No.D2650, lot.No.474382), EDTA (Sigma, cat.No.E5134, CAS. No. 60-00-4), HEPES (Sigma, cat. No. V900477-500G, CAS. No.7365-45-9, lot. No. WXBC 4716V), DTT (Sigma, cat. No. D0632-25g, CAS. No.3483-12-3, lot. No. SLBF 3964V), brij-35 (Sigma, cat. No. B4184, lot. No. 018K61251), 96-well plates (Corning, cat.No.3365, lot.No.22008026), 384-well plates (Corning, cat.No.3573, lot.No.12608008), sporon (MCE, cat. No. HY-15141, lot. No. 21226), control sorafenib (Dalian Mei Lun Biotechnology Co., cat# MB1666, lot #F1209A) and An Luoti Ni (synthesized according to patent US 20160326138).
The test steps are as follows:
1) Buffer solution preparation: 50mM HEPES,pH 7.5,0.00015%Brij-35.
2) Control sorafenib, an Luoti nib and test sample formulation: sorafenib, an Luoti and the compounds of the examples were formulated in 100% dmso at gradient concentrations and diluted to 10% dmso with the above buffers and added to 384 well plates. For example, the initial concentration of compound was 10uM, 500uM was prepared with 100% DMSO, 10 concentrations were diluted in a gradient, 10-fold diluted with buffer, 10% DMSO-containing compound dilutions were made, and 5ul to 384 well plates were transferred.
3) The kinases FLT1, FLT4 and KDR were diluted to optimal concentrations with the following buffers, respectively: 50mM HEPES,pH 7.5,0.00015%Brij-35,2mM DTT. Transfer 10ul to 384 well plates and incubate with compound for 10-15 min.
4) The substrates FAM-P22, FAM-P30 were diluted to optimal concentrations with the following buffers: 50mM HEPES,pH 7.5,0.00015%Brij-35, 10mM MgCl 2 ATP at Km. 10ul to 384 well plates were added to initiate the reaction and reacted at 28℃for 1 hour.
The reaction concentrations of the reagents in the test are shown in table 1 below.
TABLE 1
Figure GPA0000302101330000671
5) Conversion was read with a Caliper Reader (Perkin Elmer) and inhibition was calculated as the following equation, taking the average of two tests:
Inhibition (%) = (DMSO control-sample conversion/(DMSO control-background value) ×100%.
6) Fitting IC with XL-fit software 50 。
Enzyme Activity inhibition IC of the Compounds of the invention against kinases FLT1 (VEGFR 1), FLT4 (VEGFR 3) and KDR (VEGFR 2) 50 The values are shown in the table below.
TABLE 2 inhibition of VEGFR1, 2, 3 kinase by Compounds of the present invention IC 50 Value of
Figure GPA0000302101330000681
Figure GPA0000302101330000691
As shown in table 2 above, the compounds of the present invention exhibited higher inhibition of KDR (VEFGR 2) and FLT4 (VEGFR 3) kinase activities than the two positive control drugs.
Test example 2: in vivo pharmacodynamic evaluation of the inventive Compounds on the model of human xenograft breast cancer MDA-MB-231
Experimental materials:
MDA-MB-231 cells: purchased from ATCC under the number: HTB-26; BALB/c nude mice: purchased from si Bei Fu (beijing) biotechnology limited; sorafenib (Sorafenib): purchased from Shanghai macroleaf Biotech Co., ltd; cremophor: purchased from Beijing Solarbio Science & Technology co., ltd; solutol HS-15: purchased from beijing coupling technologies limited.
The experimental method comprises the following steps:
MDA-MB-231 cells were inoculated under the right anterior hypochondrium of female BALB/c nude mice, and the tumors were grown to an average volume of 150mm 3 (left and right)Group dosing was performed at time (day 10). 4 groups of 5 were divided into: vehicle control, low dose of example 11 compound (6 mg/kg), high dose of example 11 compound (25 mg/kg), sorafenib positive control (50 mg/kg). The solvent is 10% solutol HS-15 water solution, the compound of example 11 is dissolved in the solvent to prepare 0.6mg/ml solution, and then the solution is administrated by group by stomach infusion once a day for 21 days. Positive control Sorafenib dissolved in Cremophor/95% ethanol/H 2 O (12.5%/12.5%/75%) was prepared as a 5mg/ml solution and administered by gavage once a day for 21 days. Tumor volume and body weight were measured twice weekly and tumor-bearing mice body weight and tumor volume changes were recorded as a function of time of administration. After the experiment is finished, each group of mice is euthanized, tumor tissues are peeled off, and the mice are placed in order for photographing after weighing. The relative tumor volume increment rate (T/C%) and relative tumor growth inhibition rate (TGI%) were calculated for the treatment and control groups and the One-Way ANOVA test was used to conduct an inter-group statistical analysis of tumor volume, tumor weight and mouse weight (p < 0.05 considered significant differences) using IBM SPSS Statistics 22.0.0 statistical software.
Relative tumor inhibition rate TGI (%): TGI% = (1-T/C) ×100%. T/C% is the relative tumor proliferation rate, i.e., the percentage value of tumor volume relative to the treated and control groups at the end of the experiment. T and C are the Relative Tumor Volumes (RTV) at the end of the experiment for the treatment and control groups, respectively. The calculation formula is as follows: T/C% = TRTV/CRTV x 100% (TRTV: treatment group mean RTV; CRTV: vehicle control group mean RTV: RTV = Vt-V0, V0 is the tumor volume of the animal when grouped, vt is the tumor volume of the animal after treatment).
Experimental results:
at the end of the experiment, the tumor volumes of the low and high dose groups of the compound of example 11 and the Sorafenib positive drug control group are significantly reduced (p < 0.01) compared with the vehicle group, and the tumor inhibition rates of the treatment groups are 99.4%, 103.1% and 105.4%, respectively; the high and low dose groups of the compound of example 11 did not have significant differences in tumor volume (p > 0.05) from the Sorafenib positive drug control group (see figure 1).
The mice in each treatment group remained essentially stable in weight during the experiment, with a slight decrease in the high dose group of the compound of example 11 and the Sorafenib positive control group, but all mice generally performed well, with no withdrawal and no other abnormal manifestations. By the end of the experiment, the vehicle group mice had significantly higher body weight than each treatment group (p < 0.01) due to their large tumor-bearing capacity (see fig. 2).
Conclusion:
the compound has obvious anti-tumor effect on a human xenograft breast cancer MDA-MB-231 model, effectively inhibits tumor growth, and has a certain dose response relation trend; the tumor inhibiting effect of the high dose (25 mg/kg) and the low dose (6 mg/kg) is equivalent to that of the positive drug Sorafenib of 50 mg/kg; tumor-bearing mice exhibit good tolerability to the therapeutic amounts of the compound of example 11 in this experiment.

Claims (4)

1. A compound, as follows:
Figure FDA0004047108850000011
Figure FDA0004047108850000021
2. a pharmaceutical composition comprising a compound according to any one of claim 1, and a pharmaceutically acceptable carrier or excipient.
3. Use of a compound according to claim 1, or a pharmaceutical composition according to claim 2, in the preparation of a vascular endothelial growth factor receptor kinase inhibitor.
4. Use of a compound according to claim 1, or a pharmaceutical composition according to claim 2, in the manufacture of a medicament for the treatment of a disease associated with vascular endothelial growth factor receptor kinase dysfunction, said disease being bladder cancer, breast cancer, cervical cancer, intestinal cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, brain cancer, bone cancer, soft tissue cancer, leukemia and lymphoma.
CN201980060963.1A 2018-09-18 2019-09-11 Indole derivatives and their use in medicine Active CN112996784B (en)

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WO2003064413A1 (en) * 2002-02-01 2003-08-07 Astrazeneca Ab Quinazoline compounds
WO2005014582A1 (en) * 2003-08-06 2005-02-17 Astrazeneca Ab Quinazoline derivatives as angiogenesis inhibitors

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CA2900680C (en) * 2013-02-20 2021-08-10 Kala Pharmaceuticals, Inc. Quinoline and quinazoline compounds and uses thereof for treating and/or preventing diseases
MX362247B (en) * 2013-03-06 2019-01-09 Astrazeneca Ab Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor.

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WO2000047212A1 (en) * 1999-02-10 2000-08-17 Astrazeneca Ab Quinazoline derivatives as angiogenesis inhibitors
WO2003064413A1 (en) * 2002-02-01 2003-08-07 Astrazeneca Ab Quinazoline compounds
WO2005014582A1 (en) * 2003-08-06 2005-02-17 Astrazeneca Ab Quinazoline derivatives as angiogenesis inhibitors

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