WO2022198904A1 - 一种kras抑制剂关键中间体及其制备方法 - Google Patents

一种kras抑制剂关键中间体及其制备方法 Download PDF

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WO2022198904A1
WO2022198904A1 PCT/CN2021/113480 CN2021113480W WO2022198904A1 WO 2022198904 A1 WO2022198904 A1 WO 2022198904A1 CN 2021113480 W CN2021113480 W CN 2021113480W WO 2022198904 A1 WO2022198904 A1 WO 2022198904A1
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compound
formula
halogen
preparation
alkyl
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PCT/CN2021/113480
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French (fr)
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陈友喜
龚亮
向清
毛文涛
赵雯雯
赵伟峰
钱文建
陈磊
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202180093279.0A priority Critical patent/CN116848111A/zh
Publication of WO2022198904A1 publication Critical patent/WO2022198904A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/22—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 systems contains four or more hetero rings

Definitions

  • the invention relates to a key intermediate of a KRAS inhibitor and a preparation method thereof.
  • RAS represents a group of closely related monomeric globular proteins (21 kDa molecular weight) that have 189 amino acids and are associated with the plasma membrane and bind GDP or GTP. Under normal developmental or physiological conditions, RAS is activated upon receipt of growth factors and various other extracellular signals, and is responsible for regulating functions such as cell growth, survival, migration, and differentiation. RAS acts as a molecular switch, and the on/off state of RAS proteins is determined by nucleotide binding, with the active signaling conformation bound to GTP and the inactive conformation bound to GDP. When RAS contains bound GDP, it is in a dormant or quiescent or off state and is "inactive".
  • RAS When cells respond to exposure to certain growth-promoting stimuli, RAS is induced to convert bound GDP to GTP. With GTP bound, RAS is "on” and is able to interact with and activate other proteins (its “downstream targets”).
  • the RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP and thereby turn itself into the off state. Switching RAS off requires exogenous proteins called GTPases activating proteins (GAPs), which interact with RAS and greatly facilitate the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus an extended signal to the cell that tells it to continue growing and split. So these signals allow cells to grow and divide, and overactive RAS signaling may ultimately lead to cancer.
  • RAS proteins contain a G domain responsible for the enzymatic activity of RAS, guanine nucleotide binding and hydrolysis (GTPase reaction). It also includes a C-terminal extension called the CAAX box, which can be post-translationally modified and target the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate-binding loop (P-loop).
  • P-loop represents the pocket in the protein that binds nucleotides, and this is the rigid part of the domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, threo amino acid 26 and lysine 16).
  • the G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein as it switches between rest and load states capability is often denoted as a "spring loaded” mechanism.
  • the main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the ⁇ -phosphate of GTP, which allows switch I and switch II regions, respectively, to maintain their active conformations. After hydrolysis of GTP and release of phosphate, both relax to the inactive GDP conformation.
  • KRAS mutations are prevalent in the three most lethal cancer types in the United States: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%). KRAS mutations are also found in other cancer types including carcinoma, diffuse large B-cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell carcinoma, etc. Rarely found ( ⁇ 2%).
  • NSCLC non-small cell lung cancer
  • KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D.
  • KRAS mutations in lung cancer including G12C
  • KRAS mutations frequently co-occur with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutated RAS to transform cells into highly malignant and aggressive tumor cells.
  • KRAS inhibitors At present, there is fierce competition for clinical development of KRAS inhibitors at home and abroad.
  • the KRAS enzyme inhibitor AMG-510 developed by Amgen Inc has entered the pre-registration stage for the prevention and treatment of advanced solid tumors, metastatic colorectal cancer and metastatic Diseases such as non-small cell lung cancer.
  • MRTX-849 developed by Mirati Therapeutics Inc which has entered clinical phase III.
  • KRAS inhibitors significantly control and alleviate disease progression in patients with non-small cell lung cancer and significantly reduce tumor size in patients with advanced lung and colorectal cancer.
  • 4f is an important intermediate in the preparation of Example 4, and its method has problems such as long reaction steps, small batch size, and low yield. Among them, the yields of compounds 4d and 4f are both low, which is not conducive to industrial production. It is necessary to further Improve the preparation method of 4f.
  • the object of the present invention is to provide a new synthesis method to prepare the compound shown in formula (I), by changing the starting materials, optimizing the reaction conditions, changing the ways such as post-processing methods to improve the product
  • the method is simple and easy to control, the starting materials are simple and easy to purchase, the reaction conditions are simple and controllable, the post-reaction treatment method is simple, and the reaction yield is significantly improved, which is beneficial to industrial scale-up production.
  • the present invention provides a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • X 1 is selected from halogen, preferably bromine or chlorine;
  • R 1 is selected from hydrogen atom, halogen, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further selected by one or more groups selected from halogen, hydroxyl, cyano, alkyl or alkoxy Substituents are substituted; R 1 is preferably a hydrogen atom;
  • R 3 is selected from aryl or heteroaryl; wherein said aryl or heteroaryl is optionally further substituted by one or more alkyl groups or halogens; R 3 is preferably heteroaryl, more preferably pyridyl;
  • R 4 is selected from hydrogen atom, bromine, chlorine, alkyl or alkoxy; wherein said alkyl or alkoxy is optionally further selected from one or more halogens, hydroxyl, cyano, alkyl or alkoxy substituted by the substituent of the group; R 4 is preferably bromine or chlorine.
  • Compounds of formula (I) include, but are not limited to:
  • the present invention provides a preparation method of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, the method comprising:
  • the compound of formula (ID) is dissolved in an organic solvent, and under the action of an alkaline reagent, the temperature is raised to 80-100° C. for ring-closing reaction to obtain the compound of formula (I);
  • X 1 is selected from halogen, preferably bromine or chlorine;
  • X 2 is selected from halogen, preferably bromine or chlorine;
  • R 1 and R 3 to R 4 are as described in formula (I).
  • a preferred version of the present invention is a preparation method of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, wherein the organic solvent is selected from tetrahydrofuran, toluene, methyl tert-butyl ether, 1,4-dioxane or acetonitrile, preferably tetrahydrofuran.
  • a preferred embodiment of the present invention is a method for preparing a compound of formula (I) or a stereoisomer, tautomer or salt thereof, wherein the temperature for increasing the temperature is 90°C.
  • a preferred version of the present invention is a preparation method of a compound of formula (I) or a stereoisomer, tautomer or salt thereof, wherein the basic reagent is selected from cesium carbonate, potassium carbonate, sodium carbonate, Potassium acetate or lithium carbonate, preferably cesium carbonate.
  • the present invention provides a preparation method of a compound of formula (ID) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof,
  • the method includes:
  • the first step the compound of formula (IA) is dissolved in an organic solvent, cooled to -5 ⁇ 5°C, adding an alkaline reagent and triphosgene, and reacting at -5 ⁇ 5°C for 5 minutes to 3 hours, preferably 30 minutes, The reaction solution is filtered, and the filtrate is for subsequent use;
  • the second step dissolve the alkaline reagent in the organic solvent, cool down to -5 ⁇ 5°C, add nitromethane, stir and react at -5 ⁇ 5°C for 5 minutes to 3 hours, preferably 30 minutes, add the above-mentioned standby
  • the filtrate is reacted at room temperature to obtain the compound of formula (IB);
  • X 1 is halogen, preferably bromine or chlorine
  • X 2 is halogen, preferably bromine or chlorine.
  • R 1 , R 3 to R 4 are as described in formula (I).
  • a preferred embodiment of the present invention is a preparation method of a compound of formula (ID) or its stereoisomer, tautomer or its salt, wherein:
  • the organic solvent of the reaction is selected from methylene chloride, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1, One or more of 4-dioxane, acetonitrile, N,N-dimethylformyl or N,N-dimethylacetamide, preferably tetrahydrofuran;
  • the organic solvent of the reaction is selected from methylene chloride, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1, One or more of 4-dioxane, acetonitrile, N,N-dimethylformyl or N,N-dimethylacetamide, preferably tetrahydrofuran;
  • step (i) first step, the temperature of described cooling is selected from 0 °C;
  • step (i) second step the temperature of described cooling is selected from 0 °C;
  • the basic reagent described in the first step is selected from triethylamine, pyridine, 1,8-diazabicycloundec-7-ene, 4-dimethylaminopyridine, tetramethyl Ethylenediamine or N,N-diisopropylethylamine, preferably triethylamine.
  • the alkaline reagent described in the second step is selected from potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate, preferably potassium tert-butoxide.
  • a preferred version of the present invention a preparation method of a compound of formula (ID) or its stereoisomer, tautomer or its salt, is characterized in that:
  • the solvent of the reaction is selected from methylene chloride, methanol, ethanol, isopropanol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane
  • methylene chloride methanol, ethanol, isopropanol, n-butanol, ethyl acetate, toluene, tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane
  • hexacyclic ring acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide, preferably acetonitrile;
  • step (ii) the temperature of the reaction is selected from 15 to 30°C, preferably 25°C;
  • the basic reagent is selected from triethylamine, pyridine, 1,8-diazabicycloundec-7-ene, 4-dimethylaminopyridine, tetramethylethylenediamine or N,N-diisopropylethylamine, preferably N,N-diisopropylethylamine.
  • the coupling reagent is selected from bis(tetramethylene) fluoroformamide and/or tetramethylfluorourea hexafluorophosphate, preferably tetramethylfluorourea hexafluorophosphate .
  • the present invention provides a method for preparing a compound of formula (I) or a stereoisomer, tautomer or salt thereof of the compound of formula (II), the method comprising:
  • the compound of formula (I) and the compound of formula (IE) are dissolved in a solvent, and under the action of a palladium catalyst and a basic reagent, under the protection of argon, the temperature is raised to 90-120° C. to carry out Suzuki coupling reaction to obtain the compound of formula (II);
  • Ring A is selected from aryl, heteroaryl or fused ring; Ring A is preferably aryl, more preferably phenyl;
  • M is selected from -B(OH) 2 , -BF 3 K or
  • X 1 is selected from halogen, preferably bromine or chlorine;
  • R 2 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a nitro group, a cyano group or an amino group; wherein said alkyl group or alkoxy group is optionally further modified by one or more substituted by a substituent selected from alkyl or halogen; R 2 is preferably halogen or alkoxy;
  • n is selected from 0, 1 or 2.
  • R 1 and R 3 to R 4 are as described in formula (I).
  • a preferred embodiment of the present invention is a method for preparing a compound of formula (I), a compound of formula (II) or a stereoisomer, tautomer or salt thereof, wherein the compound of formula (I) is The molar ratio of the compound of formula (IE), the palladium catalyst and the basic reagent is 1:(1.2-3):(0.01-0.1):(2-4), preferably 1:2:0.05:3.
  • a preferred embodiment of the present invention is a method for preparing a compound of formula (I) or a stereoisomer, tautomer or salt thereof from a compound of formula (II), wherein the palladium catalyst is tetrakis phenylphosphine) palladium.
  • a preferred embodiment of the present invention is a method for preparing a compound of formula (I), a compound of formula (II) or a stereoisomer, tautomer or salt thereof, wherein the basic reagent is selected from carbonic acid Cesium, potassium carbonate, sodium carbonate, potassium acetate or lithium carbonate, preferably sodium carbonate.
  • a preferred embodiment of the present invention is a method for preparing the compound of formula (I) or its stereoisomer, tautomer or salt thereof from a compound of formula (I), wherein the temperature for increasing the temperature is 100° C. .
  • a preferred embodiment of the present invention is a method for preparing the compound of formula (I) or its stereoisomer, tautomer or salt thereof from a compound of formula (I), wherein the solvent is selected from N,N - dimethyl methylamine, dimethyl sulfoxide, (1,4-dioxane/water) or (toluene/water), preferably a mixed solvent of 1,4-dioxane/water, wherein 1, The volume ratio of 4-dioxane and water is (3-10):1, preferably 5:1.
  • the present invention provides the use of a compound of formula (I) or formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof in the preparation of a KRAS inhibitor.
  • the present invention provides a compound of formula (I) or formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which can be used to prepare the compound
  • Alkyl when taken as a group or part of a group is meant to include C1 - C20 straight or branched chain saturated aliphatic hydrocarbon groups.
  • C 1 -C 20 means containing 1 to 20 carbon atoms, for example, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms , 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms , 17 carbon atoms, 18 carbon atoms, 19 carbon atoms or 20 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzom- Dioxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl,
  • Heteroaryl groups can be substituted or unsubstituted. Heteroaryl groups can contain 6 to 10 (eg, 6, 7, 8, 9, or 10) atoms.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2), and the remaining ring atoms are carbon .
  • the condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutically acceptable salts” refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use.
  • the temperature range of room temperature is 15-30 degreeC, Preferably it is 25 degreeC.
  • the preparation method of the compound described in formula (I) or (II) of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition comprises the following steps:
  • X 1 is halogen, preferably bromine or chlorine
  • X 2 is halogen, preferably bromine or chlorine
  • M is selected from M is selected from -B(OH) 2 , -BF 3 K or
  • Ring A is selected from aryl, heteroaryl or fused ring; Ring A is preferably aryl, more preferably phenyl;
  • R 2 are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a nitro group, a cyano group or an amino group; wherein said alkyl group or alkoxy group is optionally further modified by one or more substituted by a substituent selected from alkyl or halogen; R 2 is preferably halogen or alkoxy;
  • n is selected from 0, 1 or 2;
  • R 1 and R 3 to R 4 are as described in the general formula (I).
  • Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
  • CD3OD Deuterated methanol.
  • Argon atmosphere means that the reaction flask is connected to an argon balloon with a volume of about 1 L.
  • the compound is purified by silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane Methyl chloride and ethyl acetate system; the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or basic reagents, such as acetic acid or triethylamine.
  • the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane Methyl chloride and ethyl acetate system; the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or basic reagents, such as
  • 2-Isopropyl-4-methylpyridin-3-amine 1a (20 g, 133.14 mmol) was dissolved in tetrahydrofuran (200 mL), cooled to 0°C, and triethylamine (35.03 g, 346.16 mmol, 48.25 mL) was added ;
  • Triphosgene 13.04g, 43.94mmol was dissolved in 50mL tetrahydrofuran, slowly added in above-mentioned reaction solution, continued reaction under ice bath for 30 minutes, filtered, and the filtrate obtained was for subsequent use;
  • Potassium tert-butoxide (17.93g, 159.76mmol ) was dissolved in tetrahydrofuran (12.89mL), cooled to 0°C, added nitromethane (8.13g, 133.13mmol, 7.13mL), continued to react at 0°C for 0.5 hours, added the above-mentioned standby filtr
  • 2,5,6-Trichloronicotinic acid 1c (10 g, 44.16 mmol), N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitroacetamide 1b (12.57 g, 52.99 mmol), N,N-diisopropylethylamine (11.41 g, 88.32 mmol) and tetramethylfluorourea hexafluorophosphate (17.50 g, 66.24 mmol) were dissolved in acetonitrile (100 mL) and reacted at room temperature 3 hours.
  • N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitro-3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanamide 1d (15.2 g, 34.10 mmol) was dissolved in tetrahydrofuran (120 mL), cesium carbonate (22.22 g, 68.21 mmol) was added, heated to 90° C., and reacted under reflux for 8 hours.
  • Extract with ethyl acetate 100 mL ⁇ 2), combine the organic phases, wash the organic phase with saturated brine (100 mL ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure.
  • the obtained residue was subjected to silica gel column chromatography Separation and purification (eluent: B system) to obtain 6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl )-3-nitro-1,8-naphthyridine-2,4(1H,3H)-dione 1 (10 g, 20.04 mmol) in 66.69% yield.
  • Example 4 Compared with the CN202011277650.2 document filed by the applicant on November 16, 2020, the preparation method of 4f is described in Example 4:
  • reaction starting material is changed, and the reaction step is shortened, and the production cost is reduced;
  • Example 2 of Example 1 of the present invention the post-reaction treatment is simple, and the product is not separated and purified by silica gel column chromatography, which greatly improves the yield and is beneficial to industrialized production.
  • 6-Chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8- Naphthyridine-2,4(1H,3H)-dione 1 (800 mg, 1.60 mmol) was dissolved in phosphorus oxychloride (18 g, 117.39 mmol), heated to 100° C., and reacted for 3 hours. After the reaction, the reaction solution was poured into 100 mL of ice water, extracted with dichloromethane (100 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.

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Abstract

本发明涉及一种KRAS抑制剂关键中间体式(I)和式(II)及其制备方法。本发明通过改变起始原料，优化反应条件，更改后处理方法等途径，显著提高关键中间体的纯度和产率，降低成本，利于工业放大生产。

Description

一种KRAS抑制剂关键中间体及其制备方法 发明领域
本发明涉及一种KRAS抑制剂关键中间体及其制备方法。
背景技术
RAS代表一组紧密相关的单体球状蛋白质(21kDa分子量)，其具有189个氨基酸且与质膜相连并且结合GDP或GTP。在正常发育或生理条件下，RAS接收生长因子和各种其它细胞外信号而被激活，负责调节细胞生长、存活、迁移和分化等功能。RAS起分子开关作用，RAS蛋白的开/关状态通过核苷酸结合确定，活性信号传导构象结合GTP，非活性构象结合GDP。当RAS包含结合的GDP时，其处于休眠或静止或关闭状态，并且是“非活化的”。当细胞暴露于某些生长促进刺激物进行响应时，RAS被诱导将结合的GDP转换为GTP。随着GTP被结合，RAS是“开启的”，并且能够与其它蛋白相互作用且活化其它蛋白(其“下游靶标”)。RAS蛋白本身具有极低的将GTP水解回到GDP并由此将自身变为关闭状态的固有能力。将RAS转换为关闭需要称作GTP酶激活蛋白(GAPs)的外源性蛋白，其与RAS相互作用并且能大大促进GTP向GDP的转化。任何在RAS中的影响其与GAP相互作用或将GTP转化回到GDP的能力的突变，将会导致所述蛋白的延长的活化，并且因此产生到细胞的延长的信号，该信号告知其继续生长和分裂。因此这些信号会使得细胞生长和分裂，过度活化的RAS信号转导可能最终导致癌症。
在结构上，RAS蛋白包含负责RAS的酶促活性-----鸟嘌呤核苷酸结合和水解(GTP酶反应)的G结构域。其还包括含称为CAAX盒的C端延伸区，其可被转译后修饰并且使该蛋白靶向膜。G结构域在尺寸上大约为21-25kDa并含有磷酸结合环(P-环)。P-环表示蛋白中结合核苷酸的囊袋，并且这是具有保守氨基酸残基的结构域的刚性部分，所述保守氨基酸残基为核苷酸结合和水解所必需的(甘氨酸12、苏氨酸26和赖氨酸16)。G结构域还含有所谓的开关I区(残基30-40)和开关II区(残基60-76)，其均为蛋白的动态部分，由于该动态部分在静止和负载状态之间进行转换的能力而常常被表示为“弹簧加载”机制。主要相互作用为由苏氨酸-35和甘氨酸-60与GTP的γ-磷酸所形成的氢键，其使开关I区和开关II区分别维持它们的活性构象。在水解GTP和释放磷酸盐之后，此两者松弛成无活性的GDP构象。
在RAS家族成员中，致癌突变最常见于KRAS(85％)，而NRAS(12％)和HRAS(3％)则较为少见。KRAS突变在美国三大致命癌症类型中普遍存在：胰腺癌(95％)、结肠直肠癌(45％)和肺癌(25％)，在包括多发性骨髓瘤、子宫癌、胆管癌、胃癌、膀胱癌、弥漫性大B细胞淋巴瘤、横纹肌肉瘤、皮肤鳞状细胞癌、宫颈癌、睾丸生殖细胞癌等在内的其他癌症类型中也发现KRAS突变,而在乳腺癌、卵巢癌和脑癌中很少发现(<2％)。在非小细胞肺癌(NSCLC)中，KRAS G12C是最常见的突变，占所有KRAS突变的近一半，其次是 G12V和G12D。在非小细胞肺癌中，特定等位基因突变频率的增加多来自经典的由吸烟诱导的典型突变(G:C至T:A置换)，从而导致了KRAS G12C(GGT至TGT)和G12V(GGT至GTT)突变。
大型基因组学研究表明，肺癌KRAS突变，包括G12C，与NSCLC中其它已知的驱动致癌突变相互排斥，包括EGFR、ALK、ROS1、RET和BRAF，表明KRAS突变在肺癌中的独特性。而同时，KRAS突变经常与某些共突变同时发生，例如STK11、KEAP1和TP53，它们与突变的RAS合作将细胞转化为高度恶性和侵袭性的肿瘤细胞。
三种RAS癌基因构成了人类癌症中突变最频繁的基因家族。令人失望的是，尽管经过三十多年的研究努力，临床上仍然没有有效的抗RAS疗法，使用小分子靶向该基因是项挑战。因此，本领域迫切需要用于靶向RAS(例如，K-RAS，H-RAS和/或N-RAS)的小分子并且利用其治疗多种疾病，例如癌症。
目前，国内外对于KRAS抑制剂的临床开发竞争激烈，其中Amgen Inc公司研发的KRAS酶抑制剂AMG-510已经进入预注册阶段，用于预防和治疗晚期实体瘤、转移性结直肠癌和转移性非小细胞肺癌等疾病。同时还有其他在研的KRAS抑制剂，包括Mirati Therapeutics Inc公司研发的MRTX-849，已经进入临床三期。早期的临床研究表明，KRAS抑制剂显著控制和缓解非小细胞肺癌患者疾病进展，并且显著降低了晚期肺癌和大肠癌患者的肿瘤大小。
目前已经公开了一系列的KRAS抑制剂专利申请，其中包括WO2018217651、WO2020047192和WO2019099524等，但公开的一系列KRAS抑制剂的制备方法，产率较低，不利于工业放大生产，因此，仍有必要改进现有的制备方法。
申请人在2020年11月16日申请的CN202011277650.2文件中，实施例4中记载了4f的制备方法，具体反应如下：
Figure PCTCN2021113480-appb-000001
Figure PCTCN2021113480-appb-000002
其中，4f作为制备实施例4的重要中间体，其方法存在反应步骤长，批量小，产率低等问题，其中制备化合物4d和4f的产率均较低，不利于工业化生产，有必要进一步改进4f的制备方法。
发明内容
为了克服现有技术的不足之处，本发明的目的在于提供一种新的合成方法制备式(I)所示化合物，通过改变起始原料，优化反应条件，更改后处理方法等途径来提高产物的纯度和产率；该方法简单易控、起始原料简单易购买、反应条件简单可控、反应后处理方法简单，反应产率显著提高，利于工业放大生产。
本发明提供一种式(I)化合物或其立体异构体、互变异构体或其可药用的盐：
其中：
Figure PCTCN2021113480-appb-000003
其中：
X 1选自卤素，优选为溴或氯；
R 1选自氢原子、卤素、烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R 1优选为氢原子；
R 3选自芳基或杂芳基；其中所述的芳基或杂芳基任选进一步被一个或多个烷基或卤素所取代；R 3优选为杂芳基，更优选为吡啶基；
R 4选自氢原子、溴、氯、烷基或烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R 4优选为溴或氯。
式(I)化合物包括，但不限于：
Figure PCTCN2021113480-appb-000004
或其立体异构体、互变异构体或其可药用的盐。
本发明提供一种式(I)化合物或其立体异构体、互变异构体或其盐的制备方法，所述方法包括：
Figure PCTCN2021113480-appb-000005
将式(ID)化合物溶于有机溶剂中，在碱性试剂的作用下，升温至80～100℃进行关环反应，得到式(I)化合物；
其中：
X 1选自卤素，优选为溴或氯；
X 2选自卤素，优选为溴或氯；
R 1和R 3～R 4的定义如式(I)中所述。
本发明的优选方案，一种式(I)化合物或其立体异构体、互变异构体或其盐的制备方法，其中，所述的有机溶剂选自四氢呋喃、甲苯、甲基叔丁基醚、1,4-二氧六环或乙腈，优选为四氢呋喃。
本发明的优选方案，一种式(I)化合物或其立体异构体、互变异构体或其盐的制备方法，其中，所述升温的温度为90℃。
本发明的优选方案，一种式(I)化合物或其立体异构体、互变异构体或其盐的制备方法，其中，所述碱性试剂选自碳酸铯、碳酸钾、碳酸钠、乙酸钾或碳酸锂，优选为碳酸铯。
本发明提供一种式(ID)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，
Figure PCTCN2021113480-appb-000006
所述的方法包括：
步骤(i)：
第一步：式(IA)化合物溶于有机溶剂中，降温至-5～5℃，加入碱性试剂和三光气，于-5～5℃反应5分钟～3小时后，优选为30分钟，将反应液过滤，滤液备用；
第二步：将碱性试剂溶于有机溶剂中，降温至-5～5℃，加入硝基甲烷，于-5～5℃搅拌反应5分钟～3小时后，优选为30分钟，加入上述备用滤液，于室温下反应，得到式(IB)化合物；
Figure PCTCN2021113480-appb-000007
步骤(ii)：在碱性试剂和偶联试剂的作用下，式(IB)化合物与式(IC)化合物反应得到式(ID)化合物；
Figure PCTCN2021113480-appb-000008
其中：
X 1为卤素，优选为溴或氯；
X 2为卤素，优选为溴或氯。
R 1、R 3～R 4的定义如式(I)中所述。
本发明的优选方案，一种式(ID)化合物或其立体异构体、互变异构体或其盐的制备方法，其中：
步骤(i)第一步中，所述反应的有机溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、甲苯、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙腈、N,N-二甲基甲酰或N,N-二甲基乙酰胺中的一种或多种，优选为四氢呋喃；
步骤(i)第二步中，所述反应的有机溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、甲苯、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙腈、N,N-二甲基甲酰或N,N-二甲基乙酰胺中的一种或多种，优选为四氢呋喃；
步骤(i)第一步中，所述降温的温度选自0℃；
步骤(i)第二步中，所述降温的温度选自0℃；
步骤(i)中，第一步中所述碱性试剂选自三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、四甲基乙二胺或N,N-二异丙基乙胺，优选为三乙胺。
步骤(i)中，第二步中所述碱性试剂选自叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化钾、碳酸钾或碳酸钠，优选为叔丁醇钾。
本发明的优选方案，一种式(ID)化合物或其立体异构体、互变异构体或其盐的制备方法，其特征在于：
步骤(ii)中，所述反应的溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、甲苯、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或多种，优选为乙腈；
步骤(ii)中，所述反应的温度选自15～30℃，优选为25℃；
步骤(ii)中，所述碱性试剂选自三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、四甲基乙二胺或N,N-二异丙基乙胺，优选为N,N-二异丙基乙胺。
步骤(ii)中，所述偶联试剂选自双(四亚甲基)氟代甲酰胺和/或四甲基氟代脲六氟磷酸酯，优选为四甲基氟代脲六氟磷酸酯。
本发明提供一种式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，所述方法包括：
Figure PCTCN2021113480-appb-000009
式(I)化合物和式(IE)化合物溶于溶剂中，在钯催化剂及碱性试剂的作用下，氩气保护，升温至90～120℃进行Suzuki偶联反应，得到式(II)化合物；
其中：
环A选自芳基、杂芳基或稠合环；环A优选为芳基，更优选为苯基；
M选自-B(OH) 2、-BF 3K或
Figure PCTCN2021113480-appb-000010
X 1选自卤素，优选为溴或氯；
R 2相同或不同，各自独立地选自氢原子、烷基、烷氧基、卤素、羟基、硝基、氰基或氨基；其中所述的烷基或烷氧基任选进一步被一个或多个选自烷基或卤素的取代基所取代；R 2优选为卤素或烷氧基；
n选自0、1或2。
R 1和R 3～R 4的定义如式(I)中所述。
本发明的优选方案，一种式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，其中，所述的式(I)化合物、式(IE)化合物、钯催化剂及碱性试剂的摩尔比为1:(1.2～3):(0.01～0.1)：(2～4)，优选为1:2:0.05:3。
本发明的优选方案，一种式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，其中，所述钯催化剂为四(三苯基膦)钯。
本发明的优选方案，一种式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，其中，所述碱性试剂选自碳酸铯、碳酸钾、碳酸钠、乙酸钾或碳酸锂，优选为碳酸钠。
本发明的优选方案，一种式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，其中，所述升温的温度为100℃。
本发明的优选方案，一种式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，其中，所述溶剂选自N,N-二甲基甲胺、二甲亚砜、(1,4-二氧六环/水)或(甲苯/水)，优选为1,4-二氧六环/水的混合溶剂，其中1,4-二氧六环和水的体积比为(3～10):1，优选为5:1。
本发明提供一种式(I)或式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐，在制备KRAS抑制剂中的用途。
本发明提供一种式(I)或式(II)所述的化合物或其立体异构体、互变异构体或其可药用的盐，其可用于制备化合物
Figure PCTCN2021113480-appb-000011
发明的详细说明
除非有相反陈述，否则本发明在说明书和权利要求书中所使用的部分术语定义如下：
“烷基”当作一基团或一基团的一部分时是指包括C 1-C 20直链或者带有支链的饱和脂肪烃基团。例如，C 1-C 20是指包含1至20个碳原子，例如，可包含1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子、6个碳原子、7个碳原子、8个碳原子、9个碳原子、10个碳原子、11个碳原子、12个碳原子、13个碳原子、14个碳原子、15个碳原子、16个碳原子、17个碳原子、18个碳原子、19个碳原子或20个碳原子。优选为C 1-C 10烷基，更优选为C 1-C 6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“芳基”是指含有一个或者两个环的碳环芳香系统，其中所述环可以以稠合的方式连接在一起。术语“芳基”包括单环或双环的芳基，比如苯基、萘基、四氢萘基的芳香基团。优选芳基为C 6-C 10芳基，更优选芳基为苯基和萘基，最优选为苯基。芳基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或9至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基，哒嗪基，嘧啶基，吡嗪基，噻吩基，异噁唑基，噁唑基，噁二唑基，咪唑基，吡咯基，吡唑基，三唑基，四氮唑基，噻唑基，异噻唑基，1，2，3-噻二唑基，苯并间二氧杂环戊烯基，苯并咪唑基，吲哚基，异吲哚基，1，3-二氧代-异吲哚基，喹啉基，吲唑基，苯并异噻唑基，苯并噁唑基和苯并异噁唑基。杂芳基可以是取代或未取代的。杂芳基可包含6至10个(例如6个、7个、8个、9个或10个)原子。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包括但不限于：
Figure PCTCN2021113480-appb-000012
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香系统，其中环原子选自0个、一个或多个选自氮、氧或S(O) r(其中r选自0、1或2)的杂原子，其余环原子为碳。稠合环优选包括双环或三环的稠合环，其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元，更优选为8至10元。“稠合环”的实施例包括但不限于：
Figure PCTCN2021113480-appb-000013
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C 1-C 6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“卤素”是指氟、氯、溴和碘。
“羟基”指-OH。
“氨基”指-NH 2。
“氰基”指-CN。
“硝基”指-NO 2。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1-3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个取代基所取代。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。
室温的温度范围是15～30℃，优选为25℃。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案：
本发明式(I)或(II)所述的化合物或其可药用的盐或其药物组合物的制备方法，包括以下步骤：
Figure PCTCN2021113480-appb-000014
(i)式(IA)化合物溶于有机溶剂中，降温至-5～5℃，加入碱性试剂和三光气，于-5～5℃下反应5分钟～3小时，优选为30分钟后，将反应液过滤，滤液备用；将碱性试剂溶于有机溶剂中，降温至-5～5℃，加入硝基甲烷，于-5～5℃搅拌反应5分钟～3小时，优选为30分钟后，加入上述备用滤液，于室温下反应，得到式(IB)化合物；
(ii)在碱性试剂和偶联试剂的作用下，式(IB)化合物与式(IC)化合物反应得到式(ID)化合物；
(iii)将式(ID)化合物溶于有机溶剂中，在碱性试剂的作用下，升温至80～100℃ 进行关环反应，得到式(I)化合物；
(iv)式(I)化合物和式(IE)化合物溶于溶剂中，在钯催化剂及碱性试剂的作用下，氩气保护，升温至90～120℃进行Suzuki偶联反应，得到式(II)化合物；
其中：
X 1为卤素，优选为溴或氯；
X 2为卤素，优选为溴或氯；
M选自M选自-B(OH) 2、-BF 3K或
Figure PCTCN2021113480-appb-000015
环A选自芳基、杂芳基或稠合环；环A优选为芳基，更优选为苯基；
R 2相同或不同，各自独立地选自氢原子、烷基、烷氧基、卤素、羟基、硝基、氰基或氨基；其中所述的烷基或烷氧基任选进一步被一个或多个选自烷基或卤素的取代基所取代；R 2优选为卤素或烷氧基；
n选自0、1或2；
R 1和R 3～R 4的定义如通式(I)中所述。
具体实施方式
以下结合实施例用于进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
实施例给出了式(I)、式(II)和式(ID)表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本发明而不是对本发明的限制。 1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于上海皓鸿生物医药科技有限公司，上海韶 远试剂有限公司，上海毕得医药科技有限公司，萨恩化学技术(上海)有限公司和上海凌凯医药科技有限公司等。
CD 3OD：氘代甲醇。
CDCl 3：氘代氯仿。
DMSO-d 6：氘代二甲基亚砜。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用硅胶柱层析洗脱剂体系和薄层色谱法，其中洗脱剂体系选自：A：石油醚和乙酸乙酯体系；B：二氯甲烷和甲醇体系；C：二氯甲烷和乙酸乙酯体系；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如醋酸或三乙胺等。
实施例1
6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2,4(1H,3H)-dione
6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮
Figure PCTCN2021113480-appb-000016
第一步
N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitroacetamide
N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰胺
将2-异丙基-4-甲基吡啶-3-胺1a(20g,133.14mmol)溶于四氢呋喃(200mL)中，冷却至0℃，加入三乙胺(35.03g,346.16mmol,48.25mL)；将三光气(13.04g,43.94mmol)溶 于50mL四氢呋喃中，缓慢加入上述反应液中，冰浴下继续反应30分钟，过滤，得到的滤液备用；将叔丁醇钾(17.93g,159.76mmol)溶于四氢呋喃(12.89mL)中，冷却至0℃，加入硝基甲烷(8.13g,133.13mmol,7.13mL)，0℃继续反应0.5小时，加入上述备用滤液，转至室温反应过夜。减压浓缩，得到的残留物用硅胶柱层析法分离纯化(洗脱剂：A体系)，得到N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰胺1b(20g,84.30mmoll)，产率63.32％。
MS m/z(ESI)：238.1[M+1]
第二步
N-(2-isopropyl-4-methylpyridin-3-yl)-2-nitro-3-oxo-3-(2,5,6-trichloropyridin-3-yl)propanamide
N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基-3-氧代-3-(2,5,6-三氯吡啶-3-基)丙酰胺
将2,5,6-三氯烟酸1c(10g,44.16mmol)、N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基乙酰胺1b(12.57g,52.99mmol)、N,N-二异丙基乙胺(11.41g,88.32mmol)和四甲基氟代脲六氟磷酸酯(17.50g,66.24mmol)溶于乙腈(100mL)中，室温下反应3小时。析出淡黄色固体，过滤，干燥，得到N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基-3-氧代-3-(2,5,6-三氯吡啶-3-基)丙酰胺1d(15g,33.66mmol)，产率76.21％。
MS m/z(ESI)：444.8[M+1]
第三步
6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridine-2,4(1H,3H)-dione
6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮
将N-(2-异丙基-4-甲基吡啶-3-基)-2-硝基-3-氧代-3-(2,5,6-三氯吡啶-3-基)丙酰胺1d(15.2g,34.10mmol)溶于四氢呋喃(120mL)中，加入碳酸铯(22.22g,68.21mmol)，加热至90℃，回流反应8小时。反应结束后，过滤，将滤液减压浓缩，得到的残留物用硅胶柱层析法分离纯化(洗脱剂：B体系)，得到6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮1e(11.3g,27.61mmol)，产率80.97％。
MS m/z(ESI)：409.0[M+1]
第四步
6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮
将6,7-二氯-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮1e(12.3g,30.06mmol)和(2-氟-6-甲氧基苯基)硼酸1f(10.22g,60.11mmol)溶于1,4-二氧六环(50mL)和水(10mL)的混合溶剂中，加入四(三苯基膦)钯(1.74g,1.50mmol)和碳酸钠(9.56g,90.17mmol)，氩气保护下加热至100℃，反应过夜。乙酸乙酯萃取(100mL×2)，合并有机相，有机相用饱和食盐水洗涤(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得 到的残留物用硅胶柱层析法分离纯化(洗脱剂：B体系)，得到6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮1(10g,20.04mmol)，产率66.69％。
MS m/z(ESI)：498.9[M+1]
1H NMR(400MHz,DMSO-d 6)δ8.68(d,J＝5.9Hz,1H),8.47(s,1H),7.90(d,J＝5.8Hz,1H),7.41(q,J＝7.9Hz,1H),6.93(dd,J＝8.5,6.0Hz,1H),6.85(t,J＝8.7Hz,1H),3.66(d,J＝12.2Hz,3H),2.97-3.05(m,1H),2.18(d,J＝6.1Hz,3H),1.25(dd,J＝7.1,2.0Hz,3H),1.06(d,J＝7.0Hz,3H).
与申请人在2020年11月16日申请的CN202011277650.2文件中，实施例4中记载了4f的制备方法相比：
(1)反应起始原料改变，反应步骤缩短，降低了生产成本；
(2)本发明的实施例1的第二步中，反应后处理简单，产物不经过硅胶柱层析分离纯化，极大提高了产率，有利于工业化生产。
实施例2
(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
Figure PCTCN2021113480-appb-000017
Figure PCTCN2021113480-appb-000018
第一步
4,6-dichloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-1,8-naphthyridin-2(1H)-one
4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮
将6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2,4(1H,3H)-二酮1(800mg,1.60mmol)溶于三氯氧磷(18g,117.39mmol)中，加热至100℃，反应3小时。反应结束后，将反应液倒入100mL冰水中，以二氯甲烷(100mL×2)萃取，合并有机相，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到产物4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮2a(550mg,1.1mmol)，产率：68.75％。
MS m/z(ESI)：517.0[M+1] +
第二步
(3R,6R)-1-N-叔丁氧基羰基-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-3-甲酸甲酯
1-(tert-butyl)3-methyl(3R,6R)-4-(6-chloro-7-(2-fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-3-nitro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)-6-methylpiperazine-1,3-dicarboxylate
将4,6-二氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-1,8-萘啶-2(1H)-酮2a(550mg,1.1mmol)和(3R,6R)-1-N-叔丁氧基羰基-6-甲基哌嗪-3-甲酸甲酯2b(458.33mg,1.77mmol)溶于乙腈(10mL)中，氩气保护，90℃下反应16小时。反应结束后，加入100mL水，以乙酸乙酯萃取(100mL×2)，合并有机相，有机相用饱和食盐水洗涤(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法 (洗脱剂：B体系)纯化，得到产物(3R,6R)-1-N-叔丁氧基羰基-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-3-甲酸甲酯2c(400mg,541.13μmol)，产率：49.28％。
MS m/z(ESI)：739.1[M+1] +
第三步
tert-butyl (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2-methyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯
将(3R,6R)-1-N-叔丁氧基羰基-4-(6-氯-7-(2-氟-6-甲氧基苯基)-1-(2-异丙基-4-甲基吡啶-3-基)-3-硝基-2-氧代-1,2-二氢-1,8-萘啶-4-基)-6-甲基哌嗪-3-甲酸甲酯2c(40mg,54.11μmol)溶于甲醇(5mL)中，加入10％的钯碳(16.33mg,153.45μmol)，置换氢气3次后，氢气保护下室温反应2小时。反应结束后，将反应液过滤，将滤液减压浓缩，得到粗品产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯2d(36.5mg)。
MS m/z(ESI)：677.3[M+1] +
第四步
tert-butyl (2R,4aR)-11-chloro-10-(2-fluoro-6-methoxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-5,7-dioxo-1,2,4,4a,5,6,7,8-octahydro-3H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-3-carboxylate
(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯
将(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2-甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯2d (250mg,369.19μmol)和碳酸钾(100mg,723.56μmol)溶于丙酮(10mL)中，滴加碘甲烷(52.40mg,369.19μmol)，50℃下反应3小时。反应结束后，加入200mL水，以乙酸乙酯萃取(100mL×2)，合并有机相，有机相用饱和食盐水洗涤(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到的残留物用硅胶柱层析法(洗脱剂：B体系)纯化，得到产物(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯2e(160mg,231.48μmol)，产率：62.70％。
MS m/z(ESI)：691.3[M+1] +
第五步
(2R,4aR)-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione
(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-甲氧基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-5,7-二氧代-1,2,4,4a,5,6,7,8-八氢-3H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-3-羧酸叔丁酯2e(160mg,231.48μmol)溶于二氯甲烷(5mL)中，降温至0℃，滴加三溴化硼的二氯甲烷溶液(579.92mg,2.31mmol)，室温反应12小时。反应结束后，以二氯甲烷萃取(100mL×2)，合并有机相；水相用饱和碳酸钠溶液调至碱性，以乙酸乙酯萃取(100mL×2)，合并有机相。将萃取所得二氯甲烷溶液和乙酸乙酯溶液合并，用饱和食盐水洗涤(100mL×3)，以无水硫酸钠干燥，过滤，减压浓缩，得到粗品产物(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮2f(150mg,259.94μmol)。
MS m/z(ESI)：577.1[M+1] +
第六步
(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮
将(2R,4aR)-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮2f(150.00mg,259.94μmol)溶于二氯甲烷(20mL)中，降温至0℃，滴加三乙胺(78.91mg,779.83μmol)，缓慢滴加丙烯酰氯(70.58mg,779.83μmol)，25℃下继续反应2小时。反应结束后，加入20mL水，以二氯甲烷萃取(20mL×3)，合并有机相，以无水硫酸镁干燥，过滤，减压浓缩，得到的的残留物通过制备液相色谱仪分离纯化(分离柱：Boston Prime C18,150×30mm I.D.,5μm；流动相A：水(0.05％NH 3H 2O+10mM NH 4HCO 3)，流动相B：乙腈；流速：25mL/min)，得到(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮2(20mg)，产率：12.27％。
MS m/z(ESI)：631.2[M+1] +
实施例3和实施例4
(2R,4aR,8R)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-2,6-dimethyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione 3
(2R,4aR,8S)-3-acryloyl-11-chloro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropyl-4-methylpyridin-3-yl)-6-methyl-2,3,4,4a,6,8-hexahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c][1,8]naphthyridine-5,7-dione 4
(2R,4aR,8R)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮3
(2R,4aR,8S)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮4
Figure PCTCN2021113480-appb-000019
Figure PCTCN2021113480-appb-000020
将(2R,4aR)-3-丙烯酰基-11-氯-10-(2-氟-6-羟基苯基)-8-(2-异丙基-4-甲基吡啶-3-基)-2,6-二甲基-2,3,4,4a,6,8-六氢-1H-吡嗪并[1',2':4,5]吡嗪并[2,3-c][1,8]萘啶-5,7-二酮2(20mg)通过SFC手性拆分(柱型号：(s,s)WHELK-O1,250×30mm I.D.,5μm；流动相：A for CO 2and B for IPA(0.1％NH 3H 2O)；柱压：100bar；流速：70mL/min；检测波长：220nm；柱温：40℃)纯化后，得到化合物3和化合物4。
单一构型化合物3(较短保留时间)：
MS m/z(ESI)：631.1[M+1] +
8mg,13.41μmol；保留时间4.461分钟,手性纯度100％ee。
1H NMR(400MHz,DMSO-d 6)δ10.06(br s,1H),8.44(d,J＝4.9Hz,1H),8.31-8.16(m,1H),7.31-7.16(m,2H),7.11-6.82(m,1H),6.74-6.62(m,2H),6.23-6.10(m,1H),5.83-5.70(m,1H),5.12-4.31(m,3H),4.03-3.92(m,1H),3.81-3.73(m,1H),3.49-3.38(m,2H),3.27-3.15(m,1H),2.91-2.71(m,2H),1.81(br d,J＝9.0Hz,3H),1.61 1.50(m,3H),1.11(d,J＝6.6Hz,3H),0.96(br d,J＝6.6Hz,3H).
单一构型化合物4(较长保留时间)：
MS m/z(ESI)：631.1[M+1] +
6.25mg,10.62μmol；保留时间5.727分钟,手性纯度99.37％ee。
1H NMR(400MHz,DMSO-d 6)δ10.07(br s,1H),8.44(d,J＝4.8Hz,1H),8.29-8.19(m,1H),7.30-7.17(m,2H),7.08-6.82(m,1H),6.76-6.59(m,2H),6.24-6.11(m,1H),5.83-5.66(m,1H),5.12-4.28(m,3H),4.10-3.96(m,1H),3.75(m,1H),3.28-3.11(m,2H),2.97-2.77(m,1H),2.47-2.38(m,2H),1.99(br s,3H),1.62-1.49(m,3H),1.08-0.99(m,3H),0.86(br s,3H).
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引 用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (17)

  1. 一种式(I)所示的化合物或其立体异构体、互变异构体或其可药用的盐：
    Figure PCTCN2021113480-appb-100001
    其中：
    X 1选自卤素，优选为溴或氯；
    R 1选自氢原子、卤素、烷基或烷氧基，其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R 1优选为氢原子；
    R 3选自芳基或杂芳基；其中所述的芳基或杂芳基任选进一步被一个或多个烷基或卤素所取代；R 3优选为杂芳基，更优选为吡啶基；
    R 4选自氢原子、溴、氯、烷基或烷氧基；其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、烷基或烷氧基的取代基所取代；R 4优选为溴或氯。
  2. 根据权利要求1所述的式(I)化合物或其立体异构体、互变异构体或其可药用的盐，其中所述的化合物为：
    Figure PCTCN2021113480-appb-100002
  3. 一种根据权利要求1或2所述的式(I)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，所述方法包括：
    Figure PCTCN2021113480-appb-100003
    将式(ID)化合物溶于有机溶剂中，在碱性试剂的作用下，升温至80～100℃进行关环反应，得到式(I)化合物；
    其中：
    X 1选自卤素，优选为溴或氯；
    X 2选自卤素，优选为溴或氯；
    R 1和R 3～R 4的定义如权利要求1中所述。
  4. 根据权利要求3所述的制备方法，其特征在于，所述的有机溶剂选自四氢呋喃、甲苯、甲基叔丁基醚、1,4-二氧六环或乙腈，优选为四氢呋喃。
  5. 根据权利要求3所述的制备方法，其特征在于，所述升温的温度为90℃。
  6. 根据权利要求3所述的制备方法，其特征在于，所述碱性试剂选自碳酸铯、碳酸钾、碳酸钠、乙酸钾或碳酸锂，优选为碳酸铯。
  7. 一种根据权利要求3所述的式(ID)化合物或其立体异构体、互变异构体或其可药用的盐的制备方法，
    Figure PCTCN2021113480-appb-100004
    所述的方法包括：
    步骤(i)：
    第一步：式(IA)化合物溶于有机溶剂中，降温至-5～5℃，加入碱性试剂和三光气，于-5～5℃反应5分钟～3小时后，优选为30分钟，将反应液过滤，滤液备用；
    第二步：将碱性试剂溶于有机溶剂中，降温至-5～5℃，加入硝基甲烷，于-5～5℃搅拌反应5分钟～3小时后，优选为30分钟，加入上述备用滤液，于室温下反应，得到式(IB)化合物；
    Figure PCTCN2021113480-appb-100005
    步骤(ii)：在碱性试剂和偶联试剂的作用下，式(IB)化合物与式(IC)化合物反应得到式(ID)化合物；
    Figure PCTCN2021113480-appb-100006
    其中：
    X 1为卤素，优选为溴或氯；
    X 2为卤素，优选为溴或氯。
    R 1、R 3～R 4的定义如权利要求1中所述。
  8. 根据权利要求7所述的制备方法，其特征在于，
    步骤(i)第一步中，所述反应的有机溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、甲苯、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙腈、N,N-二甲基甲酰或N,N-二甲基乙酰胺中的一种或多种，优选为四氢呋喃；
    步骤(i)第二步中，所述反应的有机溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、甲苯、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙腈、N,N-二甲基甲酰或N,N-二甲基乙酰胺中的一种或多种，优选为四氢呋喃；
    步骤(i)第一步中，所述降温的温度选自0℃；
    步骤(i)第二步中，所述降温的温度选自0℃；
    步骤(i)中，第一步中所述碱性试剂选自三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、四甲基乙二胺或N,N-二异丙基乙胺，优选为三乙胺。
    步骤(i)中，第二步中所述碱性试剂选自叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化钾、碳酸钾或碳酸钠，优选为叔丁醇钾。
  9. 根据权利要求7所述的制备方法，其特征在于，
    步骤(ii)中，所述反应的溶剂选自二氯甲烷、甲醇、乙醇、异丙醇、正丁醇、乙酸乙酯、甲苯、四氢呋喃、甲基叔丁基醚、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种或多种，优选为乙腈；
    步骤(ii)中，所述反应的温度选自15～30℃，优选为25℃；
    步骤(ii)中，所述碱性试剂选自三乙胺、吡啶、1,8-二氮杂二环十一碳-7-烯、4-二甲氨基吡啶、四甲基乙二胺或N,N-二异丙基乙胺，优选为N,N-二异丙基乙胺。
    步骤(ii)中，所述偶联试剂选自双(四亚甲基)氟代甲酰胺和/或四甲基氟代脲六氟磷酸酯，优选为四甲基氟代脲六氟磷酸酯。
  10. 一种由权利要求1所述的式(I)化合物制备式(II)所述的化合物或其立体异构体、互变异构体或其盐的方法，所述方法包括：
    Figure PCTCN2021113480-appb-100007
    式(I)化合物和式(IE)化合物溶于溶剂中，在钯催化剂及碱性试剂的作用下，氩气保 护，升温至90～120℃进行Suzuki偶联反应，得到式(II)化合物；
    其中：
    环A选自芳基、杂芳基或稠合环；环A优选为芳基，更优选为苯基；
    M选自-B(OH) 2、-BF 3K或
    Figure PCTCN2021113480-appb-100008
    X 1选自卤素，优选为溴或氯；
    R 2相同或不同，各自独立地选自氢原子、烷基、烷氧基、卤素、羟基、硝基、氰基或氨基；其中所述的烷基或烷氧基任选进一步被一个或多个选自烷基或卤素的取代基所取代；R 2优选为卤素或烷氧基；
    n选自0、1或2。
    R 1和R 3～R 4的定义如权利要求1中所述。
  11. 根据权利要求10所述的方法，其特征在于，所述的式(I)化合物、式(IE)化合物、钯催化剂及碱性试剂的摩尔比为1:(1.2～3):(0.01～0.1)：(2～4)，优选为1:2:0.05:3。
  12. 根据权利要求10所述的方法，其特征在于，所述钯催化剂为四(三苯基膦)钯。
  13. 根据权利要求10所述的方法，其特征在于，所述碱性试剂选自碳酸铯、碳酸钾、碳酸钠、乙酸钾或碳酸锂，优选为碳酸钠。
  14. 根据权利要求10所述的方法，其特征在于，所述升温的温度为100℃。
  15. 根据权利要求10所述的方法，其特征在于，所述溶剂选自N,N-二甲基甲胺、二甲亚砜、(1,4-二氧六环/水)或(甲苯/水)，优选为1,4-二氧六环/水的混合溶剂，其中1,4-二氧六环和水的体积比为(3～10):1，优选为5:1。
  16. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐，在制备KRAS抑制剂中的用途。
  17. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体或其可药用的盐，其特征在于，可用于制备化合物
    Figure PCTCN2021113480-appb-100009
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