Preparation method for KRAS G12D intermediate

Abstract

This is a method for preparing the KRAS G12D intermediate. Specifically, it is a method for preparing the compound represented by formula (V-1), and the preparation process route is simple and significantly reduces costs. JPEG2026523268000051.jpg43170

Description

[Technical Field]

[0001] This disclosure relates to a method for preparing a KRAS G12D intermediate. [Background technology]

[0002] The RAS family is one of the most frequently mutational oncogenic genes in tumors, with approximately 30% of human malignancies being associated with RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, of which KRAS mutations are the most common, accounting for approximately 85%. KRAS mutations are frequently found in solid tumors, and are present at high frequencies in all three of the most deadly cancers in humans: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Of the KRAS gene mutations, 97% involve mutations in the 12th or 13th amino acid residue, with G12D being a significant mutation. Data analysis of Caucasian populations has shown that G12D mutations account for 36%, 12%, and 4% of patients with pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] After activation, KRAS regulates various functions such as cell proliferation, survival, migration, and metabolism through numerous downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. Following a mutation in the KRAS gene, the protein remains persistently activated, leading to continued activation of downstream signaling pathways and promoting tumor development.

[0004] The KRAS protein lacks a traditional small molecule binding site on its surface and exhibits extremely high affinity for guanylate, making it very difficult to inhibit. For a long time, it has been considered an undetectable drug target. However, due to the importance and universality of KRAS abnormal activation in cancer progression, KRAS has been, and continues to be, a highly regarded target in drug development. Currently, there is a lack of KRAS inhibitors effective against other mutations besides KRAS G12C inhibitors, meaning that most patients with KRAS mutations remain without treatment. Since G12D is a variant widely expressed in various tumors, the development of inhibitors targeting it is of clinical importance.

[0005] Related patent applications that have already been disclosed include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2021000885A1, and WO2022268051A1.

[0006] The compound represented by formula V-1 is an important intermediate for synthesizing the KRAS G12D molecule. WO2021041671A discloses a method for synthesizing a similar intermediate, which involves the use of heavy metal catalysts in multiple steps and is relatively expensive.

[0007] [ka] From the perspective of cost reduction, this disclosure provides a novel method for preparing the KRAS G12D intermediate. [Overview of the project]

[0008] This disclosure provides a method for preparing a compound represented by formula II, which includes the step of preparing a compound represented by formula II from a compound represented by formula I. [ka] Eventually, X is a halogen, R1 is an alkyl group which is hydrogen or optionally substituted with one or more substituents Q, R 2 are the same or different and each independently selected from an alkyl group, an alkoxy group, a halogen, a hydroxy group, a mercapto group, oxo, -NR i R j , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group are optionally substituted with one or more substituents Q, R 3 are the same or different and each independently selected from an alkyl group, an alkoxy group, a halogen, a hydroxy group, a mercapto group, oxo, -NR i R j , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group are optionally substituted with one or more substituents Q, Substituents Q are each independently a C1-C6 alkyl group, a halogen, a hydroxy group, a mercapto group, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered fused-ring aryl group and a 5- to 12-membered fused heteroaryl group, R i 、R j are each independently selected from a hydrogen atom, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, Rk These are independently hydrogen atoms, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, hydroxyl groups, and -NR groups. i R j Selected from among, of which the alkyl and alkoxy groups are optionally C1-C6 alkyl groups, halogens, hydroxyl groups, mercapto groups, and -NR groups. i R j , substituted with one or more substituents selected from oxo, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl groups, n is 0, 1, 2, 3, or 4. m is 0, 1, 2, or 3.

[0009] In some embodiments, R 1 is a hydrogen atom, and a C1-C6 alkyl group optionally substituted with one or more substituents Q.

[0010] In some embodiments, R 2 and R 3 These are, independently, C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, mercapto groups, oxo, and -NR groups. i R j The alkyl group is selected from a 3-10 member cycloalkyl group and a 3-10 member heterocyclyl group, and of these, the alkyl group, alkoxy group, cycloalkyl group and heterocyclyl group are optionally substituted with one or more substituents Q.

[0011] In some embodiments, R 2 and R 3Each of these groups is independently selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, oxo groups, amino groups, 3-10 membered cycloalkyl groups, and 3-10 membered heterocyclyl groups, of which the alkyl groups, alkoxy groups, cycloalkyl groups, and heterocyclyl groups are optionally substituted with one or more substituents selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, and cyano groups.

[0012] In some embodiments, R 2 and R 3 Each of these groups is independently selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, oxo groups, hydroxyl groups, and amino groups, and of these, the alkyl groups and alkoxy groups are optionally substituted with one or more substituents selected from C1-C6 alkyl groups, C1-C6 alkoxy groups, halogens, hydroxyl groups, amino groups, carboxyl groups, nitro groups, and cyano groups.

[0013] In some embodiments, R 2 and R 3 Each of these is independently selected from a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen, and a hydroxyl group.

[0014] In some embodiments, R 2 Each of these is independently selected from a halogen and a C1-C6 alkoxy group, and n is 2.

[0015] In some embodiments, substituent Q is independently a C1-C6 alkyl group, a halogen, a hydroxyl group, a mercapto group, or -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k ,-S(O)R k , -S(O)OR k ,-S(O)(O)R k , -S(O)(O)OR k ,-C(S)R kSelected from a nitro group, a cyano group, a C1-C6 alkoxy group, a C1-C6 alkylthioether group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.

[0016] In some embodiments, substituent Q is independently a C1-C6 alkyl group, a halogen, a hydroxyl group, or NR i R j , oxo, -C(O)R k , -C(O)OR k It is selected from a cyano group, a C1-C6 alkoxy group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.

[0017] In some embodiments, a method for preparing the compound represented by formula II includes the step of preparing the compound represented by formula II-1 from the compound represented by formula I-1, [ka] Eventually, X 1 It is a halogen, R 4 is a C1-C6 alkyl group optionally substituted with one or more substituents Q, R 1 , R 3 X, Q, and m are as defined in general formula I.

[0018] This disclosure further provides a method for preparing a compound represented by formula III-1, comprising the steps of preparing a compound represented by formula II-1 from a compound represented by formula I-1, and further hydroxylating the compound represented by formula II-1 to obtain a compound represented by formula III-1. [ka] Eventually, R 1 , R 3 , R 4 , X 1 And m are as defined in general formula I-1.

[0019] This disclosure further provides a method for preparing a compound represented by formula IV-1, comprising the step of hydroxylating the compound represented by formula II-1 to obtain a compound represented by formula III-1, and further the step of preparing a compound represented by formula IV-1 from the compound represented by formula III-1. [ka] Eventually, R 1 , R 3 , X 1 And m are as defined in general formula I-1, R 5 This is a hydroxy protecting group, selected from benzyl group, benzoyl group, tert-butyroyl group, trimethylsilyl group, tert-butyldiphenylsilyl group, and methoxymethyl group.

[0020] This disclosure further provides a method for preparing a compound represented by formula V-1, comprising the step of preparing a compound represented by formula IV-1 from a compound represented by formula III-1, and further comprising the step of preparing a compound represented by formula V-1 from a compound represented by formula IV-1. [ka] Eventually, R 1 , R 3 , R 5 , X 1 And m are as defined in general formula IV-1.

[0021] This disclosure further provides a compound represented by formula f. [ka]

[0022] This disclosure further provides compounds represented by formula I-2. [ka] .

[0023] This disclosure further provides compounds represented by formula II-2. [ka] .

[0024] This disclosure further provides compounds represented by formula III-2. [ka] .

[0025] This disclosure further provides compounds represented by formula IV-2. [ka] .

[0026] This disclosure further provides a method for preparing the compound represented by formula V-2, which includes the following steps: [ka] .

[0027] In some embodiments, a method for preparing the compound represented by formula V-2 includes the following specific steps. [ka]

[0028] This disclosure further provides a method for preparing the compound represented by formula V-3, comprising the following steps: [ka] This disclosure further provides a method for preparing KRAS G12D compounds, which includes the above step of preparing a compound represented by formula II from a compound represented by formula I.

[0029] The compound represented by Formula II in this disclosure is used to prepare the KRAS G12D compound. In some embodiments, the compound represented by Formula II is prepared according to the method provided in this disclosure.

[0030] This disclosure further provides a method for preparing a compound represented by formula A, which includes the above step of preparing a compound represented by formula V-2, and further includes the following steps. [ka] .

[0031] WO2022268051A discloses a method for preparing the compound represented by formula A, which is incorporated herein by reference.

[0032] Another aspect of the present disclosure relates to a pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, meso compounds, racemic compounds, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, prepared by the above method, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0033] The “amino protecting groups” described herein are groups that can be appropriately used for amino group protection known in the art, and refer to the amino protecting groups in the literature ("Protective Groups in Organic Synthesis", 5th Ed. T.W. Greene & PGMWuts). For example, such amino protecting groups may be selected from tert-butoxycarbonyl, acetyl, benzyl, allyl, or p-methoxybenzyl groups, or the amino protecting group may form a lactam, such as a phthaloyl group, together with the nitrogen atom bonded to it. Methods for removing the protecting group may refer to the methods for removing amino protecting groups in the literature ("Protective Groups in Organic Synthesis", 5th Ed. T.W. Greene & PGMWuts), and relevant content is incorporated herein. As an example, the benzyl group is removed using a hydrogen / metal catalyst, and the metal catalyst is at least one selected from palladium carbon, palladium hydroxide, platinum oxide, palladium, alumina-coated palladium, platinum in activated carbon, and Raney nickel, but is not limited to these, and is preferably palladium carbon or palladium hydroxide, and the tert-butoxycarbonyl group (Boc) is removed under acidic conditions, and the reagent that provides the acidic conditions is preferably methanesulfonic acid, hydrochloric acid, or trifluoroacetic acid.

[0034] The hydride sources described in this disclosure are well known or can be determined by those skilled in the art and are at least one selected from lithium aluminum tetrahydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium borohydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and hydrogen / metal catalysts, but are not limited thereto. Furthermore, the metal catalyst is at least one selected from palladium carbon, palladium hydroxide, platinum oxide, palladium, alumina-coated palladium, platinum in activated carbon, and Raney nickel, but is not limited thereto, and is preferably palladium carbon or palladium hydroxide.

[0035] A salt of the compound represented by formula (IB) described herein is a substance that forms a salt by reacting the compound of formula (IB) with an acid, the acid used may be hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, etc., and hydrochloric acid is preferred.

[0036] The reagents for basic conditions provided in this disclosure include organic bases and inorganic bases, the organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and sodium n-butoxide, and the inorganic bases include, but are not limited to, sodium, potassium, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0037] The acidic reagents provided in this disclosure include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf.

[0038] The above reaction is preferably carried out in a solvent, and the solvents used include, but are not limited to, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, or N,N-dimethylformamide.

[0039] Detailed description of the invention Unless otherwise specified, terms used in the specification and claims have the following meanings:

[0040] The term "alkyl group" refers to saturated aliphatic hydrocarbon groups containing 1 to 20 carbon atoms in a linear or branched chain. These are alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups may be substituted or unsubstituted, and if substituted, the substituents may be substituted at any available linkage point, preferably independently of halogens, hydroxyl groups, oxo, cyano, amino, and C 1-6 Alkyl alkyl group, C 1-6 The alkyl group is substituted with one or more groups selected from an alkoxy group, a 3- to 6-membered cycloalkyl group, or a 3- to 6-membered heterocycloalkyl group, and the alkyl group, alkoxy group, cycloalkyl group, or heterocycloalkyl group may be optionally substituted with a halogen, a hydroxyl group, a nitro group, a cyano group, or an amino group.

[0041] The term "alkenyl group" refers to an unsaturated aliphatic linear or branched hydrocarbon group containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkenyl groups. These include, but are not limited to, vinyl groups (i.e., vinyl), 1-propenyl groups, 2-propenyl groups (i.e., allyl groups), 2-methyl-1-propenyl groups, 1-butenyl groups, and 2-butenyl groups (i.e., clotyl groups). Alkenyl groups used in any context herein may be optionally substituted in a manner similar to alkyl groups.

[0042] The term "alkynyl group" refers to an unsaturated aliphatic linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds. Exemplary alkynyl groups include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12, and C3-C6 alkynyl groups. This includes, but is not limited to, ethynyl, propi-1-inyl, buty-1-inyl, pento-1-inyl, pento-4-inyl, and pento-1,4-diinyl groups. Alkynyl groups used in any context herein may be optionally substituted in a manner similar to alkyl groups.

[0043] The term "cycloalkyl group" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, where the cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl groups, while polycyclic cycloalkyl groups include cycloalkyl groups of spiro rings, fused rings, and crosslinked rings. Cycloalkyl groups may be substituted or unsubstituted, and if substituted, the substituents may be substituted at any available linkage point, preferably independently of halogens, hydroxyl groups, oxo, cyano, amino, and C 1-6 Alkyl alkyl group, C 1-6 The group is one or more groups selected from an alkoxy group, a 3-6 membered cycloalkyl group, or a 3-6 membered heterocycloalkyl group, and the alkyl group, alkoxy group, cycloalkyl group, or heterocycloalkyl group is optionally substituted with a halogen, hydroxyl group, nitro group, cyano group, or amino group.

[0044] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituents containing 3 to 20 ring atoms, of which one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatoms are selected from (where m is an integer from 0 to 2), but do not contain the -OO-, -OS-, or -SS- ring portions, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, and more preferably 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl groups" are: [ka] This includes, etc.

[0045] The above heterocycloalkyl ring may be condensed with an aryl group or a heteroaryl ring, and the ring linked to the parent structure is a heterocycloalkyl group, and non-limiting examples thereof are: [ka] This includes, among others.

[0046] The heterocycloalkyl group may be optionally substituted or left unsubstituted. If substituted, the substituents are preferably, independently, a halogen, a hydroxyl group, an oxo group, a cyano group, an amino group, and C. 1-6 Alkyl alkyl group, C 1-6 The group is one or more groups selected from an alkoxy group, a 3-6 membered cycloalkyl group, or a 3-6 membered heterocycloalkyl group, and the alkyl group, alkoxy group, cycloalkyl group, or heterocycloalkyl group is optionally substituted with a halogen, hydroxyl group, nitro group, cyano group, or amino group.

[0047] The term "cycloalkenyl group" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing one or more carbon-carbon double bonds. Cycloalkenyl groups contain 3 to 20 carbon atoms and include C2-C8, C4-C6, C8-C12, C14-C18, and C16-C20 cycloalkenyl groups. Cycloalkenyl groups may also be condensed with aryl or heteroaryl groups. Exemplary cycloalkenyl groups are: [ka] This includes, but is not limited to, the following:

[0048] Furthermore, the cycloalkenyl group may or may not be substituted, and if substituted, the substituent may be substituted at any available linking point, preferably independently of a halogen, C 1-3 Alkyl alkyl group or C 1-3 It is one or more groups selected from alkoxy groups. The term "cycloalkynyl group" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing one or more carbon-carbon triple bonds. Cycloalkynyl groups contain 3 to 20 carbon atoms and include C2-C8, C4-C6, C8-C12, C14-C18, and C16-C20 cycloalkynyl groups. Cycloalkynyl groups may also be condensed with aryl or heteroaryl groups. Exemplary cycloalkynyl groups are: [ka] This includes, but is not limited to, the following:

[0049] Furthermore, the cycloalkynyl group may or may not be substituted, and if substituted, the substituent may be substituted at any available linking point, preferably independently of a halogen, C 1-3 Alkyl alkyl group or C 1-3 It is one or more groups selected from alkoxy groups.

[0050] The term "heterocycloalkenyl group" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more ring atoms are nitrogen, oxygen, or S(O). mThe heteroatom is selected from (where m is an integer from 0 to 2), but does not contain the -OO-, -OS-, or -SS- ring portion, the remaining ring atoms are carbon, and it contains one or more carbon-carbon double bonds. The heterocycloalkenyl group contains 3 to 20 carbon atoms, preferably C2-C8, C4-C6, C8-C12, C14-C18, or C16-C20 heterocycloalkenyl groups. The heterocycloalkenyl group may also be condensed with an aryl group or a heteroaryl group. An example of a heterocyclyl group is: [ka] This includes, but is not limited to, R a , R b These are hydrogen and C, respectively, independently. 1-6 Selected from alkyl groups or aryl groups, R c is hydrogen or C 1-6 Selected from alkyl groups. The heterocycloalkenyl group may be substituted or unsubstituted, and if substituted, the substituent may be substituted at any available linking point, preferably independently of a halogen, C 1-3 Alkyl alkyl group or C 1-3 It is one or more groups selected from alkoxy groups.

[0051] The term "heterocycloalkynyl group" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, of which one or more ring atoms are nitrogen, oxygen, or S(O). m (Among these, m is an integer from 0 to 2) is a heteroatom selected from, However, it does not contain the -OO-, -OS-, or -SS- ring portion, and the remaining ring atoms are carbon and contain one or more carbon-carbon triple bonds. Heterocycloalkynyl groups contain 3 to 20 carbon atoms and include C2-C8, C4-C6, C8-C12, C14-C18, and C16-C20 heterocycloalkynyl groups. Also, heterocycloalkynyl groups may be condensed with an aryl group or a heteroaryl group. An example of a heterocycloalkynyl group is, [ka] This includes, but is not limited to, the following:

[0052] Furthermore, the heterocycloalkynyl group may or may not be substituted, and if substituted, the substituent may be substituted at any available linkage point, preferably independently of a halogen and C. 1-3 Alkyl alkyl group or C 1-3 It is one or more groups selected from alkoxy groups.

[0053] The term "alkoxy group" refers to an -O-(alkyl group), and the definition of an alkyl group is as described above. Non-exclusive examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be optionally substituted or left unsubstituted. If substituted, the substituents are preferably, independently, halogen, hydroxyl, oxo, cyano, amino, and C. 1-6 Alkyl alkyl group, C 1-6 The group is one or more groups selected from an alkoxy group, a 3- to 7-membered cycloalkyl group, or a 3- to 7-membered heterocycloalkyl group, and the alkyl group, alkoxy group, cycloalkyl group, or heterocycloalkyl group may be optionally substituted with a halogen, hydroxyl group, nitro group, cyano group, or amino group.

[0054] Similarly, "cycloalkoxy groups" and "heterocycloalkoxy groups" are defined in the same way as "alkoxy groups" described above.

[0055] The term "alkylthio group" refers to -S-(alkyl group), and the definition of an alkyl group is as described above. Non-limiting examples of alkoxy groups include methylthio group, ethylthio group, propylthio group, and butylthio group. Alkylthio groups may be optionally substituted or left unsubstituted, and if substituted, the substituents are preferably independently C 1-6 Alkoxy group, 3-6 membered cycloalkyl group, 3-6 membered heterocycloalkyl group, 3-6 membered cycloalkoxy group, 3-6 membered heterocycloalkoxy group, C1-6 One or more groups selected from an alkylthio group, a 3- to 6-membered cycloalkylthio group, and a 3- to 6-membered heterocycloalkylthio group, and the above alkoxy group, cycloalkyl group, heterocycloalkyl group, cycloalkoxy group, heteroepoxy group, alkylthio group, cycloalkylthio group, and heterocycloalkylthio group are optionally substituted with a halogen, a hydroxy group, a cyano group, or an amino group.

[0056] <00OO408>Similarly, the "cycloalkylthio group" and "heterocycloalkylthio group" are defined in the same manner as the above "alkylthio group".

[0057] The "monovalent group" refers to an atom or group obtained by removing one monovalent from a compound "formally". The "subunit" refers to an atom or atomic group obtained by removing two monovalents or one divalent from a compound "formally".

[0058] The term "alkylene group" represents the portion remaining after removing two hydrogen atoms from an alkane molecule and includes linear and branched subunits of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include a methylene group (-CH2-), an ethylidene group (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, the alkylene group may or may not be substituted, and when substituted, the substituent may be substituted at any available linkage point, preferably independently a halogen, a hydroxy group, a cyano group, an amino group, C 1-6 alkyl group or C 1-6 one or more groups selected from an alkoxy group. Similarly, the definitions of "alkyleneoxy group", "alkenylene group", "alkenyleneoxy group", "cycloalkylene group", and "heterocycloalkylene group" are the same as those of the "alkylene group".

[0059] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π electron system, preferably 6- to 12-membered, and examples thereof include a phenyl group and a naphthyl group. The above aryl ring may be fused to a heteroaryl group, a heterocycloalkyl group or a cycloalkyl ring, and among them, the ring linked to the parent structure is an aryl ring, and non-limiting examples thereof are [Chemical Formula] including.

[0060] The aryl group may or may not be substituted, and when substituted, the substituents are preferably independently halogen, hydroxy group, oxo, nitro group, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C 3-8 cycloalkenyloxy group, 5- to 6-membered aryl group or heteroaryl group, and the above C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyloxy group, C 2-6 alkynyloxy group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, 3- to 8-membered cycloalkenyloxy group, 5- to 6-membered aryl group or heteroaryl group are optionally substituted with one or more substituents selected from halogen, hydroxy group, cyano group, amino group, C 1-6 alkyl group or C 1-6 alkoxy group.

[0061] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12 members, more preferably 5 or 6 members. For example, non-limiting examples include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, triazolyl, indazolyl, and benzimidazolyl groups. [ka] This includes, among others.

[0062] The above heteroaryl ring may be condensed with an aryl group, a heterocycloalkyl group, or a cycloalkyl ring, of which the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof are: [ka] Includes.

[0063] The heteroaryl group may be optionally substituted or left unsubstituted. If substituted, the substituents are preferably, independently, a halogen, a hydroxyl group, a cyano group, an amino group, and C. 1-6 Alkyl alkyl group or C 1-6 It is one or more groups selected from alkoxy groups.

[0064] The term "spiro ring" refers to a compound in which two rings share one atom. Non-exclusive examples of spirocycloalkyl groups include: [ka] Includes.

[0065] The term "condensed ring" refers to a compound formed by the condensation of two or more rings sharing two adjacent atoms. Non-exclusive examples of condensed cycloalkyl groups include: [ka] Includes.

[0066] The term "crosslinked ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Crosslinked cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic depending on the number of rings they comprise, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of crosslinked cycloalkyl groups include: [ka] Includes.

[0067] The term "heterocyclo" refers to a ring that contains not only carbon atoms but also other atoms, and includes heterocycloalkyl groups and heteroaromatic rings.

[0068] The term "hydroxyl group" refers to the -OH group.

[0069] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0070] The term "cyano group" refers to -CN.

[0071] The term "amino group" refers to -NH2.

[0072] The term "nitro group" refers to -NO2.

[0073] The term "oxo" refers to an =O substituent.

[0074] "Substitution" means that one or more hydrogen atoms in a group, preferably five or fewer, more preferably one to three hydrogen atoms, are substituted by a number of substituents that correspond to each other independently. If the substituent is a ketone or oxo (i.e., =O), two (two) hydrogen atoms on the atom are substituted.

[0075] The purity or content described herein is determined by HPLC detection, compound characterization data is obtained by nuclear magnetic resonance spectroscopy analysis, and the reagents used herein are commercially available. [Modes for carrying out the invention]

[0076] The present disclosure will be described in more detail below in combination with examples, but the examples of the present disclosure are merely for illustrating the technical concepts of the present disclosure, and the substance and scope of the present disclosure are not limited thereto.

[0077] Example 1: Preparation of 6-methoxy-3,4-dihydronaphthalene-1(2H)-one-methyloxime [ka] Compound a (100g, 1.0eq.) and ethanol (1000mL, 10V) were added to a 2L reaction flask and stirred at 15-25°C to dissolve. Methoxyamine hydrochloride (95g, 2.0eq.) and pyridine (108g, 2.4eq.) were added, and after addition was complete, the mixture was stirred at 15-25°C for 2-3 hours. The completion of the reaction was detected by HPLC, and the mixture was concentrated under reduced pressure to remove the ethanol. Ethyl acetate (500mL, 5V) was added and dissolved. The mixture was then washed once with 2M HCl (200mL, 2V), once with 5% sodium bicarbonate (200mL, 2V), once with saturated saline (200mL, 2V), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain 120g of crude product, with a yield of 104%.

[0078] 1H NMR(400MHz,CDCl3)δ7.91-7.94(d,1H),6.75-6.78(dd,2.7 Hz,1H),6.64-6.65(d,1H),3.96(s,3H),3.81(s,3H),2.70-2.74(t,4H),1.81-1.87(m,2H). LCMS(ESI): m / z 206[M+H]

[0079] Example 2: Preparation of 8-bromo-6-methoxy-3,4-dihydronaphthalene-1(2H)-one-methyloxime [ka] Compound b (96.7 g, 1.0 eq) and acetic acid (967 mL, 10V) were added to a reaction flask and stirred to dissolve. Under nitrogen gas protection, palladium acetate (3.17 g, 0.03 eq) and NBS (84.8 g, 1.0 eq) were added. The temperature was raised to 50-60°C and maintained for 1 hour. The end of the reaction was detected by HPLC, the temperature was lowered, and the mixture was concentrated under reduced pressure to remove the acetic acid. Ethyl acetate (967 mL, 10V) and H2O (483.5 mL, 5V) were added, and the layers were separated. The organic layers were successively washed once with 5% sodium bicarbonate (483.5 mL, 5V), then once with saturated sodium chloride (483.5 mL, 5V), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried to obtain 145 g of crude product, with a yield of 105%.

[0080] 1 H NMR(400MHz,CDCl3)δ7.07-7.08(d,1H),6.64-6.65(d,1H),4.01(s,3H),3.79(s,3H),2.72-2.75(t,2H),2.57-2.50(t,2H),1.79-1.67(m,2H) LCMS(ESI):m / z 284[M+H],286[M+3H]

[0081] Example 3: Preparation of 8-bromo-6-methoxy-3,4-dihydronaphthalene-1(2H)-one [ka] Compound c (46 g, 1.0 eq) and 1,4-dioxane (184 mL, 4V) were added to a reaction flask. Under nitrogen gas protection, 5M sulfuric acid (552 mL, 12V) was added, and the mixture was heated to 40-50°C and maintained at that temperature for 2-3 hours. The end of the reaction was detected by HPLC, the temperature was lowered, and the internal temperature was controlled to 10-20°C. A 12M aqueous NaOH solution (220 g of NaOH was prepared in 460 mL of solution) was added dropwise to adjust the pH to 6-7. Then ethyl acetate (460 mL, 10V) was added for extraction and separation of layers. The organic layer was washed once with saturated sodium chloride (200 mL, 4.3V), dried over anhydrous sodium sulfate, filtered, and concentrated until dry to obtain 43 g of crude product. Ethyl acetate (46 mL, 1 V) was added to the crude product, and the mixture was heated until refluxed and clarified. Petroleum ether (300 mL, 6.5 V) was added, the mixture was kept warm for 30 minutes, filtered, and the filtrate was heated until refluxed. Petroleum ether (130 mL, 2.8 V) was added to the filtrate, and the mixture was cooled to 0-5°C, kept warm, stirred, filtered, and the filtered cake was vacuum dried to obtain 30 g of the title compound, with a yield of 72%.

[0082] 1 H NMR (400MHz, CDCl3) δ7.10-7.11(d,1H),6.69-6.70(d,1H),3.84(s,3H),2.92-2.95(t,2H),2.63-2.67(t,2H),2.04-2.10(m,2H). LCMS(ESI):m / z 255[M+H],257[M+3H]

[0083] Example 4: Preparation of 8-bromo-2-fluoro-6-methoxy-3,4-dihydronaphthalene-1(2H)-one [ka] Compound d (30 g, 1.0 eq) and methanol (300 mL, 10V) were added to the reaction flask and stirred to dissolve. Under nitrogen gas protection, Select Fluor (48 g, 1.15 eq, manufacturer: Rakken, lot number: Lf0905165866) and concentrated sulfuric acid (0.6 mL, 0.02 V) were added, the temperature was raised to 50-60°C and maintained for 3 hours to allow the reaction to proceed. The end of the reaction was detected by HPLC, the temperature was lowered, and the mixture was concentrated under reduced pressure to remove methanol. Then, dichloromethane (450 mL, 15 V) and H2O (450 mL, 15 V) were added for extraction and phase separation. Each organic phase was washed once with 5% aqueous sodium bicarbonate solution (200 mL, 6.67 V), then once with saturated sodium chloride (200 mL, 6.67 V), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until dry to obtain 31.4 g of crude product, with a yield of 97%.

[0084] 1 H NMR(400MHz,CDCl3)δ7.12-7.13(d,1H),6.68-6.69(d,1H),4.96-5.13(m,1H),3.85(d,3H),3.11-3.17(m,2H),2.28-2.53(m,2H) LCMS(ESI):m / z 274[M+H],276[M+3H]

[0085] Example 5: Preparation of 8-bromo-2,2-difluoro-6-methoxy-3,4-dihydronaphthalene-1(2H)-one [ka] Compound e (30 g, 1.0 eq), DCM (300 mL, 10V), and triethylamine (55.5 g, 5.0 eq) were added to a reaction flask and stirred to dissolve. Under nitrogen gas protection, the temperature was controlled to 15-25°C, and TBSOTf (58 g, 2.0 eq) was added dropwise. After addition was complete, the mixture was kept warm at 15-25°C and stirred for 1-2 hours. The end of the reaction was detected by HPLC, and the mixture was concentrated under reduced pressure to remove DCM. Under nitrogen gas protection, ACN (240 mL, 8V) and Select Fluor (42.8 g, 1.1 eq) were added, and the mixture was stirred at 15-25°C for 1-2 hours. The completion of the reaction was detected by HPLC, the temperature was controlled to 15-25°C, and water (240 mL, 8V) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred at 15-25°C for 1 hour, filtered, the filter cake was rinsed with a small amount of water, and vacuum-dried to obtain 26 g of the title compound, with a yield of 81%.

[0086] 1 H NMR(400MHz,CDCl3)δ7.19-7.20(d,1H),6.71-6.72(d,1H),3.88(s,3H),3.14-3.17(m,2H),2.49-2.56(m,2H) LCMS(ESI):m / z 291[M+H],293[M+3H]

[0087] Example 6: Preparation of 8-bromo-1-ethylidene-2,2-difluoro-6-methoxy-1,2,3,4-tetrahydronaphthalene [ka] Ethyltriphenylphosphonium bromide (18.2 g, 1.5 eq) and tetrahydrofuran (76 mL, 8V) were added to the reaction flask, and the mixture was cooled in an ice bath under nitrogen gas protection. The temperature was controlled to 0-10°C, and NaHMDS (22.0 mL, 1.35 eq) was added dropwise. After the addition was complete, the mixture was reacted at 0-10°C for 15 minutes. The temperature was controlled to 0-10°C, and a solution of f (9.5 g, 1.0 eq) of tetrahydrofuran (47.5 mL, 5V) was added dropwise to the reaction flask. After the addition was complete, the temperature was raised to 60°C and the mixture was reacted for 2 hours. The end of the reaction was detected by HPLC, and the mixture was slowly cooled. The temperature was controlled to 0-10°C, saturated ammonium chloride (47.5 mL, 5V) and purified water (28.5 mL, 3V) were added dropwise to the reaction mixture, and the mixture was stirred to separate the layers. The aqueous phase was extracted once with ethyl acetate (47.5 mL, 5V), and the organic phases were combined. The mixture was washed once with saturated sodium chloride (28.5 mL, 3V), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until dry. Further, n-heptane (95 mL, 10V) was added and slurry was formed at room temperature (20-30°C) for 1 hour. The mixture was filtered and the filtrate was concentrated until dry to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 100 / 1) to obtain 8.78 g of the product, with a yield of 88.7% and a purity of 90.78%.

[0088] 1 HNMR (400MHz, CDCl3): δ7.04-7.05(d.,1H),6.64-6.67(m,2H),3.78(s,3H),2.67-2.71(m,2H),2.11-2.19(m,5H)

[0089] Example 7: Preparation of 8-bromo-1-ethyl-2-fluoro-6-methoxynaphthalene [ka]

[0090] I-2 (10.3 g, 1.0 eq) and ethylene glycol dimethyl ether (103 mL, 10V) were added to a reaction flask. Under nitrogen gas protection, the temperature was controlled to 0-20°C, and potassium tert-butoxide (5.72 g, 1.5 eq) was added. After addition was complete, the temperature was raised to 80°C and the reaction was allowed to proceed for 2 hours. The completion of the reaction was detected by HPLC, the temperature was lowered to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated until dry. It was dissolved in DCM (103 mL, 10V), then washed once with saturated ammonium chloride (51.5 mL, 5V), then once with purified water (51.5 mL, 5V), then once with saturated sodium chloride (51.5 mL, 5V), dried over anhydrous sodium sulfate, filtered, and concentrated until dry to obtain 9.0 g of crude product. The yield was 93.5% and the purity was 79.8%, and the crude product was used directly in the next reaction.

[0091] 1 HNMR (400MHz, CDCl3): δ7.58-7.59(d.,1H),7.54-7.56(m,1H),7.21-7.25( m,1H),7.09-7.10(d,1H),3.88(s,3H),3.49-3.55(m,2H),1.32-1.36(t,3H)

[0092] Example 8: Preparation of 4-bromo-5-ethyl-6-fluoronaphthalene-2-ol [ka] II-2 (8.9 g, 1.0 eq) and dichloromethane (89 mL, 10V) were added to a reaction flask, and the mixture was cooled in an ice bath under nitrogen gas protection. The temperature was controlled to 0-10°C, and boron tribromide (10.2 g, 1.3 eq) was slowly added dropwise. After the addition was complete, the temperature was allowed to rise naturally to room temperature and the reaction was allowed to proceed for 1 hour. The end of the reaction was detected by HPLC. The temperature was controlled to 0-10°C, and purified water (44.5 mL, 5V) was added dropwise to quench the reaction, and the mixture was separated into layers. The organic phase was washed once with saturated sodium bicarbonate (71.2 mL, 8V), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 8.4 g of product. The yield was 99.3% and the purity was 83.1%, and the crude product was used directly in the next reaction.

[0093] 1 HNMR(400MHz,CDCl3):δ7.54-7.55(d,1H),7.49-7.53(dd,1H),7.20-7.24( t,1H),7.12-7.13(d,1H),4.97(s,1H),3.48-3.55(m,2H),1.32-1.36(t,3H)

[0094] Example 9: Preparation of 8-bromo-1-ethyl-2-fluoro-6-methoxymethoxynaphthalene [ka] III-2 (8.4 g, 1.0 eq), dichloromethane (84 mL, 10V), and DIPEA (8.88 g, 2.2 eq) were added to a reaction flask, and the mixture was cooled in an ice bath under nitrogen gas protection. The temperature was controlled to 0-10°C, and bromomethyl methyl ether (6.63 g, 1.7 eq) was added dropwise. After the addition was complete, the mixture was reacted at room temperature (20-30°C) for 2 hours. Complete reaction was detected by HPLC, purified water (84 mL, 10V) was added, and the mixture was stirred to separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until dry. The filtrate was purified by column chromatography (PE / EA = 50 / 1) to obtain 7.05 g of product, with a yield of 72.1% and a purity of 91.02%.

[0095] 1 HNMR(400MHz,CDCl3):δ7.65-7.66(d,1H),7.55-7.59(dd,1H),7.35-7.36( d,1H),7.23-7.26(m,1H),5.25(s,2H),3.49-3.56(m,5H),1.32-1.36(t,3H)

[0096] Example 10: Preparation of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] IV-2 (5.0 g, 1.0 eq) and anhydrous tetrahydrofuran (50 mL, 10V) were added to the reaction flask, the mixture was purged with argon gas, and the reaction solution was cooled to -10°C under argon gas protection. The temperature was controlled to -10°C to -5°C, and isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution (15.96 mL, 1.3 eq) was added dropwise. After the addition was complete, the mixture was reacted at -10°C for 1 hour. The temperature was controlled to -10°C to -5°C, and isopropyl pinacolboronate (5.94 g, 2.0 eq) was added dropwise. After the addition was complete, the mixture was reacted at -10°C for 2 hours, and in-process control was performed by HPLC to confirm that the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution (25 mL, 5V) dropwise, and then purified water (50 mL, 10V) and ethyl acetate (25 mL, 5V) were added. The mixture was stirred to separate the layers, and the aqueous phase was extracted once more with ethyl acetate (15 mL, 3V). The organic phases were combined and washed once with saturated sodium chloride (25 mL, 5V). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until dry to obtain the crude product. Methanol (10 mL, 2V) was added to the crude product, the temperature was raised to 60°C and stirred to clarify, the temperature was slowly cooled and stirred to crystallize, filtered, and dried to obtain 4.78 g of the product. The yield was 83.1% and the purity was 98.68%.

[0097] 1 HNMR (400MHz, CDCl3): δ7.55-7.58(m,1H),7.36-7.40(dd,2H),7.18-7.22(t,1H ),5.27(s,2H),3.50(s,3H),3.11-3.14(m,2H),1.44(s,12H),1.25-1.29(t,3H)

Claims

1. A method for preparing a compound represented by formula II, comprising the step of preparing a compound represented by formula II from a compound represented by formula I, 【Chemistry 1】 Eventually, X is a halogen, R １ is hydrogen, an alkyl group optionally substituted with one or more substituents Q, R ２ These are identical or different, and each is independently an alkyl group, alkoxy group, halogen, hydroxyl group, mercapto group, oxo, -NR ｉ R ｊ A cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group are selected, and of these, the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents Q. R ３ These are identical or different, and each is independently an alkyl group, alkoxy group, halogen, hydroxyl group, mercapto group, oxo, -NR ｉ R ｊ A cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group are selected, and of these, the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group are optionally substituted with one or more substituents Q. The substituent Q is each independently C １ -C ６ alkyl group, halogen, hydroxy group, mercapto group, -NR ｉ R ｊ , oxo, thio, -C(O)R ｋ , -C(O)OR ｋ , -S(O)R ｋ , -S(O)OR ｋ , -S(O)(O)R ｋ , -S(O)(O)OR ｋ , -C(S)R ｋ , nitro group, cyano group, C １ -C ６ alkoxy group, C １ -C ６ alkylthioether group, C ２ -C ６ alkenyl group, C ２ -C ６ alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, a 5- to 10-membered heteroaryl group, an 8- to 12-membered condensed-ring aryl group, and a 5- to 12-membered condensed heteroaryl group, and is selected from R ｉ , R ｊ These are, independently, a hydrogen atom, a hydroxyl group, and C. １ -C ６ Alkyl alkyl group, C １ -C ６ Selected from alkoxy groups, R ｋ These are, independently, hydrogen atoms and C １ -C ６ Alkyl alkyl group, C １ -C ６ Haloalkyl group, C １ -C ６ Alkoxy group, hydroxyl group, -NR ｉ R ｊ Selected from, of which the alkyl group and alkoxy group are optionally C １ -C ６ Alkyl group, halogen, hydroxyl group, mercapto group, -NR ｉ R ｊ , oxo, thio, carboxyl group, nitro group, cyano group, C １ -C ６ Alkoxy group, C １ -C ６ Alkylthioether group, C ２ -C ６ Alkenyl group, C ２ -C ６ Substituted with one or more substituents selected from an alkynyl group, a 3-10 membered cycloalkyl group, a 3-10 membered heterocyclyl group, a 6-10 membered aryl group, and a 5-10 membered heteroaryl group, n is 0, 1, 2, 3, or 4. m is 0, 1, 2, or 3. method.

2. R ２ These are halogen and C, respectively, independently. １ -C ６ A group selected from alkoxy groups, characterized in that n is 2. The method according to claim 1.

3. The method described above includes the step of preparing a compound represented by formula II-1 from a compound represented by formula I-1, 【Chemistry 2】 Eventually, X １ It is a halogen, R ４ is an alkyl group that is optionally substituted with one or more substituents Q, R １ , R ３ X, Q, and m are as defined in claim 1, The method according to claim 1 or 2.

4. A method for preparing a compound represented by formula III-1, comprising the method according to claim 3, further comprising the step of hydroxylating the compound represented by formula II-1 to obtain the compound represented by formula III-1, 【Transformation 3】 Eventually, R １ , R ３ , R ４ , X １ And m is as defined in claim 3, method.

5. A method for preparing a compound represented by formula IV-1, comprising the method according to claim 4, further comprising the step of preparing a compound represented by formula IV-1 from a compound represented by formula III-1, 【Chemistry 4】 Eventually, R １ , R ３ , X １ And m is as defined in claim 1, R ５ The protecting group is a hydroxyl group, preferably a benzyl group, a benzoyl group, a tert-butyroyl group, a trimethylsilyl group, a tert-butyldiphenylsilyl group, or a methoxymethyl group. method.

6. A method for preparing a compound represented by formula IV-1, comprising the method according to claim 5, further comprising the step of preparing a compound represented by formula V-1 from a compound represented by formula IV-1, 【Transformation 5】 Eventually, R １ , R ３ , R ５ , X １ And m is as defined in claim 5, method. 【Request Item 7】 【Transformation 6】 That is, The compound represented by formula f. 【Request Item 8】 【Chemistry 7】 That is, The compound represented by formula I-2. 【Request Item 9】 【Transformation 8】 That is, The compound represented by formula II-2. 【Request Item 10】 【Chemistry 9】 That is, The compound represented by formula III-2. 【Request Item 11】 【Chemistry 10】 That is, The compound represented by formula IV-2.

12. A method for preparing the compound represented by formula V-2, comprising the following steps: 【Chemistry 11】 , including, method.

13. A method for preparing a KRAS G12D compound, comprising the method according to claim 1, method.

14. The use of a compound represented by formula II in the preparation of a KRAS G12D compound, wherein the compound represented by formula II is prepared according to the method described in claim 1. use.

15. A method for preparing a compound represented by formula A, 【Chemistry 12】 , including the method according to any one of claims 1 to 12, method.

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