Preparation method of KRAS G12D intermediate

Abstract

The invention relates to a preparation method of a KRAS G12D intermediate. Specifically, the method for preparing the compound as shown in the formula (V-1) is simple in preparation process route, and the cost can be remarkably reduced.

Description

Preparation method of KRAS G12D intermediate Technical Field

[0001] The present disclosure relates to methods for preparing KRAS G12D intermediates. Background Art

[0002] RAS is one of the most frequently mutated oncogenes in tumors, with approximately 30% of human malignancies linked to RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for approximately 85%. KRAS mutations are common in solid tumors and are highly prevalent in the three most lethal human cancers: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Of the KRAS gene mutations, 97% involve mutations at amino acid residues 12 or 13, with G12D being a key mutation. Analysis of data from European and American populations shows that G12D mutations occur in 36%, 12%, and 4% of patients with pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] Once activated, KRAS regulates multiple aspects of cell proliferation, survival, migration, and metabolism through numerous downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. KRAS mutations cause the protein to remain in an activated state, leading to persistent activation of downstream signaling pathways and promoting tumorigenesis.

[0004] Because the KRAS protein lacks traditional small molecule binding sites on its surface and has an extremely high affinity for guanylate, making it extremely difficult to inhibit, it has long been considered an undruggable drug target. However, given the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has been and remains a target of great interest in drug development. Currently, with the exception of KRAS G12C inhibitors, there is still a lack of KRAS inhibitors that are effective against other mutations, leaving most patients with KRAS mutations without treatment. G12D, as a mutant that is widely and highly expressed in various tumors, has important clinical significance for the development of inhibitors against it.

[0005] The related patent applications that have been published so far include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2021000885A1 and WO2022268051A1.

[0006] The compound represented by Formula V-1 is an important intermediate for the synthesis of KRAS G12D molecules. WO2021041671A discloses a synthesis method for similar intermediates, which uses heavy metal catalysts in multiple steps and is relatively costly.

[0007] In view of the consideration of reducing costs, the present disclosure provides a new method for preparing KRAS G12D intermediates.

[0008] Summary of the Invention

[0009] The present disclosure provides a method for preparing a compound of formula II, comprising the steps of preparing a compound of formula II from a compound of formula I:

[0010] in,

[0011] X is a halogen;

[0012] R 1 is hydrogen, alkyl optionally substituted by one or more substituents Q;

[0013] R 2 are the same or different and are each independently selected from alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR i R j , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents Q;

[0014] R 3 are the same or different and are each independently selected from alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR i R j , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents Q;

[0015] The substituent groups Q are each independently selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -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, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring aryl, and 5- to 12-membered fused heteroaryl;

[0016] R i 、R j Each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group; R k independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, -NR i R j wherein the alkyl and alkoxy groups are optionally selected from C1 to C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thioxo, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl. ;

[0017] n is 0, 1, 2, 3 or 4;

[0018] m is 0, 1, 2, or 3.

[0019] In some embodiments, R 1 It is hydrogen, or a C1-C6 alkyl group which is optionally substituted by one or more substituents Q.

[0020] In some embodiments, R 2 and R 3 Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, mercapto, oxo, -NR i R j , 3 to 10 membered cycloalkyl and 3 to 10 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents Q.

[0021] In some embodiments, R 2 and R 3 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, oxo, amino, 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl and heterocyclic group are optionally substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, carboxyl, nitro and cyano.

[0022] In some embodiments, R 2 and R 3Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo, hydroxyl and amino, wherein the alkyl and alkoxy are optionally substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, amino, carboxyl, nitro and cyano.

[0023] In some embodiments, R 2 and R 3 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen and hydroxy.

[0024] In some embodiments, R 2 Each is independently selected from halogen and C1-C6 alkoxy, and n is 2.

[0025] In some embodiments, the substituent groups Q are each independently selected from C1-C6 alkyl, halogen, hydroxyl, thiol, -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, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl or C2-C6 alkynyl.

[0026] In some embodiments, the substituent groups Q are each independently selected from C1-C6 alkyl, halogen, hydroxyl, NR i R j , oxo, -C(O)R k 、-C(O)OR k , cyano, C1-C6 alkoxy, C2-C6 alkenyl or C2-C6 alkynyl.

[0027] In some embodiments, the aforementioned method for preparing the compound of formula II comprises the step of preparing the compound of formula II-1 from the compound of formula I-1:

[0028] in,

[0029] X 1 is a halogen;

[0030] R 4 is a C1-C6 alkyl group optionally substituted by one or more substituents Q;

[0031] R 1 、R3 , X, Q and m are as defined in Formula I.

[0032] The present disclosure also provides a method for preparing a compound of formula III-1, comprising the aforementioned step of preparing a compound of formula II-1 from a compound of formula I-1, and further comprising the step of hydroxylating the compound of formula II-1 to obtain a compound of formula III-1:

[0033] Among them, R 1 、R 3 、R 4 、X 1 and m are as defined in Formula I-1.

[0034] The present disclosure also provides a method for preparing a compound of formula IV-1, comprising the aforementioned step of hydroxylating the compound of formula II-1 to obtain the compound of formula III-1, and further comprising the step of preparing the compound of formula IV-1 from the compound of formula III-1:

[0035] Among them, R 1 、R 3 、X 1 and m are as defined in formula I-1;

[0036] R 5 is a hydroxyl protecting group selected from benzyl, benzoyl, tert-butyryl, trimethylsilyl, tert-butyldiphenylsilyl, and methoxymethyl.

[0037] The present disclosure also provides a method for preparing a compound of formula V-1, comprising the aforementioned step of preparing a compound of formula IV-1 from a compound of formula III-1, and further comprising the step of preparing a compound of formula V-1 from the compound of formula IV-1:

[0038] Among them, R 1 、R 3 、R 5 、X 1 and m are as defined in Formula IV-1.

[0039] The present disclosure also provides a compound represented by formula f:

[0040] The present disclosure also provides a compound represented by formula I-2:

[0041] The present disclosure also provides a compound represented by formula II-2:

[0042] The present disclosure also provides a compound represented by formula III-2:

[0043] The present disclosure also provides a compound represented by formula IV-2:

[0044] The present disclosure also provides a method for preparing the compound of formula V-2, comprising the steps of:

[0045] In some embodiments, the method for preparing the compound represented by formula V-2 comprises the following specific steps:

[0046] The present disclosure also provides a method for preparing the compound represented by formula V-3, comprising the steps of:

[0047] The present disclosure also provides a method for preparing a KRAS G12D compound, comprising the aforementioned step of preparing a compound of formula II from a compound of formula I.

[0048] The compound of Formula II in the present disclosure is used to prepare a KRAS G12D compound. In some embodiments, the compound of Formula II is prepared according to the method provided in the present disclosure.

[0049] The present disclosure also provides a method for preparing a compound represented by formula A, comprising the aforementioned steps of preparing a compound represented by formula V-2, and further comprising the following steps:

[0050] WO2022268051A discloses a method for preparing the compound represented by formula A, which is incorporated herein in its entirety.

[0051] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) prepared according to the aforementioned method, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0052] The "amino protecting group" described in the present disclosure is a group known in the art that can be appropriately used for amino protection, as described in the literature ("Protective Groups in Organic Synthesis", 5Th. Ed. TW Greene & P. ​​GMW Wuts). As an example, the amino protecting group is selected from tert-butyloxycarbonyl, acetyl, benzyl, allyl or p-methoxybenzyl, or the amino protecting group, together with the nitrogen atom to which it is bound, forms a lactam, such as phthaloyl. The method for removing the protecting group can also refer to the method for removing the amino protecting group in the literature ("Protective Groups in Organic Synthesis", 5Th. Ed. TW Greene & P. ​​GMW Wuts), and the relevant content is introduced into this specification. As an example, the benzyl group is removed by hydrogen / metal catalyst, wherein the metal catalyst is selected from but not limited to at least one of palladium carbon, palladium hydroxide, platinum oxide, palladium, palladium on alumina, platinum on activated carbon and Raney nickel, preferably palladium carbon and palladium hydroxide; the tert-butyloxycarbonyl (Boc) group is removed under acidic conditions, and the reagent providing the acidic conditions is preferably selected from methanesulfonic acid, hydrochloric acid and trifluoroacetic acid.

[0053] The hydride source disclosed herein is well known or identifiable to those skilled in the art, and is selected from, but not limited to, at least one of lithium aluminum tetrahydride, lithium triethylborohydride, diisobutylaluminum hydride, sodium borohydride, sodium dihydrogen bis(2-methoxyethoxy)aluminate, and a hydrogen / metal catalyst. Furthermore, the metal catalyst is selected from, but not limited to, at least one of palladium on carbon, palladium hydroxide, platinum oxide, palladium, palladium on alumina, platinum on activated carbon, and Raney nickel, preferably palladium on carbon or palladium hydroxide.

[0054] The salt of the compound represented by formula (IB) described in the present disclosure is a substance formed by the reaction of the compound of formula (IB) with an acid. The acid used can be hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, etc., preferably hydrochloric acid.

[0055] The reagents for providing alkaline conditions in the present 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 bistrimethylsilylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, 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.

[0056] The reagents providing acidic conditions disclosed herein include, but are not limited to, hydrogen chloride, a 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.

[0057] The above reaction is preferably carried out in a solvent, and the solvent used includes but is 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.

[0058] Detailed Description of the Invention

[0059] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0060] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 20 carbon atoms. 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 various branched isomers thereof. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0061] The term "alkenyl" refers to an unsaturated aliphatic straight or branched hydrocarbon group and contains one or more carbon-carbon double bonds. Exemplary alkenyls include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12 and C3-C6 alkenyls. Including but not limited to, vinyl (i.e., vinyl (vinyl)), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl) etc. The alkenyl used in any context herein is optionally substituted in the same manner as an alkyl.

[0062] The term "alkynyl" refers to an unsaturated aliphatic straight 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. These include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and pent-1,4-diynyl. Alkynyl groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0063] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyls include spirocyclic, paracyclic, and bridged cycloalkyls. Cycloalkyls may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0064] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" include: ,etc.

[0065] The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0066] wait.

[0067] Heterocycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0068] The term "cycloalkenyl" refers to an unsaturated monocyclic or polycyclic hydrocarbon substituent containing one or more carbon-carbon double bonds. Cycloalkenyl groups contain from 3 to 20 carbon atoms and include C2-C8, C4-C6, C8-C12, C14-C18, and C16-C20 cycloalkenyl groups. In addition, the cycloalkenyl group can be fused to an aryl or heteroaryl group. Exemplary cycloalkenyl groups include, but are not limited to:

[0069] In addition, the cycloalkenyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, C 1-3 Alkyl or C 1-3 Alkyl group. (Adjust as needed!)

[0070] The term "cycloalkynyl" refers to an unsaturated monocyclic or polycyclic hydrocarbon substituent containing one or more carbon-carbon triple bonds. Cycloalkynyl groups contain 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, and C16-C20 cycloalkynyl groups. In addition, the cycloalkynyl group can be fused to an aryl or heteroaryl group. Exemplary cycloalkynyl groups include, but are not limited to:

[0071] In addition, the cycloalkynyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

[0072] The term "heterocycloalkenyl" refers to an unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon and contain 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, C16-C20 heterocycloalkenyl groups. In addition, the heterocycloalkenyl group can be fused to an aryl or heteroaryl group. Exemplary heterocyclic groups include, but are not limited to:

[0073] where R a 、R b are independently selected from hydrogen, C 1-6 Alkyl or aryl, R c Selected from hydrogen or C 1-6 In addition, the heterocycloalkenyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

[0074] The term "heterocycloalkynyl" refers to an unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) a heteroatom,

[0075] However, it does not include the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon and contain one or more carbon-carbon triple bonds. Heterocycloalkynyl groups contain 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, and C16-C20 heterocycloalkynyl groups. In addition, the heterocycloalkynyl group can be fused to an aryl or heteroaryl group. Exemplary heterocycloalkynyl groups include, but are not limited to:

[0076] In addition, the heterocycloalkynyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, C 1-3 Alkyl or C 1-3 Alkoxy.

[0077] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by halogen, hydroxy, nitro, cyano or amino.

[0078] Similarly, "cycloalkoxy" and "heterocycloalkoxy" are the same as the above-mentioned "alkoxy".

[0079] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methylthio, ethylthio, propylthio, butylthio. Alkylthio may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, independently selected from C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, C 1-6 Alkylthio, 3- to 6-membered cycloalkylthio, 3- to 6-membered heterocycloalkylthio, wherein the alkoxy, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocyclooxy, alkylthio, cycloalkylthio, heterocycloalkylthio are optionally substituted with halogen, hydroxy, cyano or amino.

[0080] Similarly, "cycloalkylthio" and "heterocycloalkylthio" are the same as defined above for "alkylthio".

[0081] A "monovalent group" is a compound formed by formally eliminating a monovalent atom or group. A "subunit" is a compound formed by formally eliminating two monovalent or one divalent atom or group.

[0082] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subgroups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point, preferably one or more of the following groups, independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkyl group. (Adjust as needed!)

[0083] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene" and "heterocycloalkylene" are the same as "alkylene".

[0084] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0085] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, 3- to 6-membered cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, 3 to 6 membered cycloalkoxy, 3 to 6 membered heterocycloalkoxy, 3 to 8 membered cycloalkenyloxy, 5 to 6 membered aryl or heteroaryl are optionally substituted by one or more selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0086] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0087] The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0088] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy (this needs to be adjusted according to the claims!).

[0089] The term "spirocyclic" refers to a compound in which two rings share one atom. Non-limiting examples of spiroalkyl groups include:

[0090] The term "cycloalkyl" refers to a compound in which two or more rings are joined by sharing two adjacent atoms. Non-limiting examples of cycloalkyl groups include:

[0091] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0092] The term "heterocycle" refers to a ring having atoms other than carbon atoms, and includes heterocycloalkyl and heteroaryl rings.

[0093] The term "hydroxy" refers to an -OH group.

[0094] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0095] The term "cyano" refers to -CN.

[0096] The term "amino" refers to -NH2.

[0097] The term "nitro" refers to -NO2.

[0098] The term "oxo" refers to a =0 substituent.

[0099] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), then two (2) hydrogen atoms on the atom are replaced.

[0100] The purity or content described in the present disclosure is determined by HPLC detection, and the compound characterization data is obtained by analyzing the nuclear magnetic resonance spectrum; the reagents used in the present disclosure can be purchased through commercial channels. DETAILED DESCRIPTION

[0101] The present disclosure will be explained in more detail below with reference to embodiments. The embodiments of the present disclosure are only used to illustrate the technical solutions of the present disclosure, and the essence and scope of the present disclosure are not limited thereto.

[0102] Example 1: Preparation of 6-methoxy-3,4-dihydronaphthalen-1(2H)-one-methyloxime

[0103] To a 2L reaction flask, compound a (100 g, 1.0 eq.) and ethanol (1000 mL, 10 V) were added, stirred and dissolved at 15-25 ° C, methoxyamine hydrochloride (95 g, 2.0 eq.) and pyridine (108 g, 2.4 eq.) were added, and stirred at 15-25 ° C for 2 to 3 h after the addition. The reaction was completed by HPLC detection, and the ethanol was removed by concentration under reduced pressure. Ethyl acetate (500 mL, 5 V) was added to dissolve, and the mixture was washed once with 2M HCl (200 mL, 2 V), once with 5% sodium bicarbonate (200 mL, 2 V), and once with saturated brine (200 mL, 2 V). It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 120 g of a crude product with a yield of 104%.

[0104] 1 H NMR(400MHz, CDCl3)δ7.91-7.94(d,1H),6.75-6.78(dd,2.7Hz,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).

[0105] LCMS (ESI): m / z 206 [M+H]

[0106] Example 2: Preparation of 8-bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one-methyloxime

[0107] Compound b (96.7 g, 1.0 eq) and acetic acid (967 mL, 10 V) were added to the reaction flask, stirred and dissolved, and palladium acetate (3.17 g, 0.03 eq) and NBS (84.8 g, 1.0 eq) were added under nitrogen. The temperature was raised to 50-60°C and maintained for 1 h. The reaction was completed by HPLC. The temperature was lowered and the acetic acid was removed by concentration under reduced pressure. Ethyl acetate (967 mL, 10 V) and H2O (483.5 mL, 5 V) were added. The layers were separated and the organic layer was washed once with 5% sodium bicarbonate (483.5 mL, 5 V) and once with saturated sodium chloride (483.5 mL, 5 V). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 145 g of crude product with a yield of 105%.

[0108] 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)

[0109] LCMS(ESI):m / z 284[M+H], 286[M+3H]

[0110] Example 3. Preparation of 8-bromo-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

[0111] Compound c (46 g, 1.0 eq) and 1,4-dioxane (184 mL, 4 V) were added to the reaction flask under nitrogen protection. 5 M sulfuric acid (552 mL, 12 V) was added and the temperature was raised to 40-50 ° C for 2-3 h. The reaction was completed by HPLC detection. The temperature was lowered and the internal temperature was controlled at 10-20 ° C. 12 M NaOH aqueous solution (220 g NaOH was configured into 460 mL solution) was added dropwise to adjust the pH value to 6-7. Ethyl acetate (460 mL, 10 V) was then added for extraction and separation. The organic layer was washed once with saturated sodium chloride (200 mL, 4.3 V), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 43 g of crude product. To the crude product was added ethyl acetate (46 mL, 1 V), the temperature was raised to reflux to dissolve, petroleum ether (300 mL, 6.5 V) was added, the temperature was kept at reflux for 30 min, and the mixture was filtered. The filtrate was heated to reflux, petroleum ether (130 mL, 2.8 V) was added thereto, the temperature was lowered to 0-5°C, the temperature was kept at reflux with stirring, and the filter cake was dried under vacuum to obtain 30 g of the title compound in a yield of 72%.

[0112] 1H 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).

[0113] LCMS(ESI):m / z 255[M+H], 257[M+3H]

[0114] Example 4. Preparation of 8-bromo-2-fluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

[0115] Compound d (30 g, 1.0 eq) and methanol (300 mL, 10 V) were added to the reaction flask and stirred to dissolve. Under nitrogen protection, selectfluor (48 g, 1.15 eq, manufacturer: Leyan, batch number: Lf0905165866) and concentrated sulfuric acid (0.6 mL, 0.02 V) were added, and the temperature was raised to 50-60°C and the reaction was maintained for 3 h. The reaction was completed by HPLC, and the temperature was lowered and concentrated under reduced pressure to remove methanol. Dichloromethane (450 mL, 15 V) and H2O (450 mL, 15 V) were then added for extraction and separation. The organic phase was washed once with 5% aqueous sodium bicarbonate solution (200 mL, 6.67 V) and once with saturated sodium chloride (200 mL, 6.67 V), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 31.4 g of crude product, with a yield of 97%.

[0116] 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)

[0117] LCMS(ESI):m / z 274[M+H], 276[M+3H]

[0118] Example 5. Preparation of 8-bromo-2,2-difluoro-6-methoxy-3,4-dihydronaphthalen-1(2H)-one

[0119] Compound e (30 g, 1.0 eq), DCM (300 mL, 10 V), and triethylamine (55.5 g, 5.0 eq) were added to the reaction flask and stirred to dissolve. Under nitrogen protection, the temperature was controlled at 15-25°C, and TBSOTf (58 g, 2.0 eq) was added dropwise. After the addition was complete, the mixture was stirred at 15-25°C for 1-2 h. The reaction was detected by HPLC and concentrated under reduced pressure to remove DCM. Under nitrogen protection, ACN (240 ml, 8 V) and selectfluor (42.8 g, 1.1 eq) were added and stirred at 15-25°C for 1-2 h. The reaction was detected by HPLC and the temperature was controlled at 15-25°C. Water (240 ml, 8 V) was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred at 15-25°C for 1 h. The mixture was filtered, and the filter cake was rinsed with a small amount of water and dried under vacuum to obtain 26 g of the title compound in an 81% yield.

[0120] 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)

[0121] LCMS(ESI):m / z 291[M+H], 293[M+3H]

[0122] Example 6. Preparation of 8-bromo-1-ethylidene-2,2-difluoro-6-methoxy-1,2,3,4-tetrahydronaphthalene

[0123] Add ethyltriphenylphosphonium bromide (18.2 g, 1.5 eq) and tetrahydrofuran (76 mL, 8 V) to a reaction flask under nitrogen atmosphere and cool in an ice-water bath. Add NaHMDS (22.0 mL, 1.35 eq) dropwise at 0-10°C. After addition, allow to react for 15 min at 0-10°C. Add a solution of f (9.5 g, 1.0 eq) in tetrahydrofuran (47.5 mL, 5 V) dropwise to the reaction flask at 0-10°C. After addition, raise the temperature to 60°C and react for 2 h. Monitor the reaction by HPLC and then slowly cool. The temperature was controlled at 0-10°C, and saturated ammonium chloride (47.5 mL, 5V) and purified water (28.5 mL, 3V) were added dropwise to the reaction solution. The layers were stirred and separated. The aqueous phase was extracted once with ethyl acetate (47.5 mL, 5V). The organic phases were combined, washed once with saturated sodium chloride (28.5 mL, 3V), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. Then, n-heptane (95 mL, 10V) was added and the mixture was slurried at room temperature (20-30°C) for 1 h. The mixture was filtered and the filtrate was concentrated to dryness to obtain a 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%.

[0124] 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)

[0125] Example 7, Preparation of 8-bromo-1-ethyl-2-fluoro-6-methoxynaphthalene

[0126] I-2 (10.3 g, 1.0 eq) and ethylene glycol dimethyl ether (103 mL, 10 V) were added to a reaction flask under nitrogen protection and temperature control at 0-20°C. Potassium tert-butoxide (5.72 g, 1.5 eq) was added. The temperature was raised to 80°C and the reaction was allowed to react for 2 h. The reaction was completed by HPLC, then cooled to room temperature, filtered through celite, and the filtrate was concentrated to dryness. The filtrate was dissolved in DCM (103 mL, 10 V) and washed with saturated ammonium chloride (51.5 mL, 5 V) once, purified water (51.5 mL, 5 V) once, and saturated sodium chloride (51.5 mL, 5 V) once. The product was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain 9.0 g of crude product with a yield of 93.5% and a purity of 79.8%. The crude product was used directly in the next step.

[0127] 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)

[0128] Example 8. Preparation of 4-bromo-5-ethyl-6-fluoronaphthalene-2-ol

[0129] To the reaction flask, add II-2 (8.9 g, 1.0 eq) and dichloromethane (89 mL, 10 V), place under nitrogen, and cool in an ice-water bath. Slowly add boron tribromide (10.2 g, 1.3 eq) dropwise at 0-10°C. Allow to warm to room temperature for 1 h. HPLC analysis confirms the reaction is complete. After quenching the reaction at 0-10°C, add purified water (44.5 mL, 5 V). Separate the layers and wash the organic phase once with saturated sodium bicarbonate (71.2 mL, 8 V), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 8.4 g of the product, with a yield of 99.3% and a purity of 83.1%. The crude product was used directly in the next step.

[0130] 1HNMR(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)

[0131] Example 9, Preparation of 8-bromo-1-ethyl-2-fluoro-6-methoxymethoxynaphthalene

[0132] To a reaction flask, III-2 (8.4 g, 1.0 eq), dichloromethane (84 mL, 10 V), and DIPEA (8.88 g, 2.2 eq) were added under nitrogen protection and cooled in an ice-water bath. Bromomethyl methyl ether (6.63 g, 1.7 eq) was added dropwise at 0-10°C. The reaction was allowed to react at room temperature (20-30°C) for 2 h. HPLC analysis confirmed the reaction was complete. Purified water (84 mL, 10 V) was added, stirred, and the layers separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The product was purified by column chromatography (PE / EA = 50 / 1) to obtain 7.05 g of the product with a yield of 72.1% and a purity of 91.02%.

[0133] 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)

[0134] Example 10. Preparation of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0135] To the reaction flask, add IV-2 (5.0 g, 1.0 eq) and anhydrous tetrahydrofuran (50 mL, 10 V). Replace the atmosphere with argon and cool the reaction mixture to -10°C. Add a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (15.96 mL, 1.3 eq) dropwise at -10°C to -5°C. After completion, react at -10°C for 1 h. Add isopropyl pinacol borate (5.94 g, 2.0 eq) dropwise at -10°C to -5°C. After completion, react at -10°C for 2 h. The reaction was complete as determined by HPLC. Saturated ammonium chloride solution (25 mL, 5 V) was added dropwise to quench the reaction. Purified water (50 mL, 10 V) and ethyl acetate (25 mL, 5 V) were then added. The layers were separated by stirring. The aqueous phase was extracted once with ethyl acetate (15 mL, 3 V). The combined organic phases were washed once with saturated sodium chloride (25 mL, 5 V), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product. Methanol (10 mL, 2 V) was added to the crude product, the temperature was raised to 60°C, and the mixture was stirred to dissolve. The temperature was slowly lowered, and the mixture was stirred to separate crystals. The mixture was filtered and dried to obtain 4.78 g of the product, with a yield of 83.1% and a purity of 98.68%.

[0136] 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 of formula II, comprising the steps of preparing a compound of formula II from a compound of formula I: in, X is a halogen; R 1 is hydrogen, alkyl optionally substituted by one or more substituents Q; R 2 are the same or different and are each independently selected from alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR i R j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more substituents Q; R 3 are the same or different and are each independently selected from alkyl, alkoxy, halogen, hydroxy, mercapto, oxo, -NR i R j , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more substituents Q; The substituent groups Q are each independently selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -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, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 8- to 12-membered fused ring aryl, and 5- to 12-membered fused heteroaryl; R i , R j Each is independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group; R k independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, hydroxyl, -NR i R j wherein the alkyl and alkoxy groups are optionally selected from C1-C6 alkyl, halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, carboxyl, nitro, cyano, C1-C6 alkoxy, C1-C6 alkylthioether, C2-C6 alkenyl, C2-C6 alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl. ; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, or 3.

2. The method according to claim 1, characterized in that R 2 Each is independently selected from halogen and C1-C6 alkoxy, and n is 2.

3. The method according to claim 1 or 2, characterized in that: The method comprises the steps of preparing the compound represented by formula II-1 from the compound represented by formula I-1: in, X 1 is a halogen; R 4 is an alkyl group optionally substituted by one or more substituents Q; R 1 , R 3 , X, Q and m are as defined in claim 1.

4. A method for preparing a compound of formula III-1, comprising the method as claimed in claim 3, further comprising the step of hydroxylating the compound of formula II-1 to obtain the compound of formula III-1: in, R 1 , R 3 , R 4 , X 1 and m as defined in claim 3.

5. A method for preparing a compound of formula IV-1, comprising the method as claimed in claim 4, further comprising the step of preparing the compound of formula IV-1 from the compound of formula III-1: in, R 1 , R 3 , X 1 and m as defined in claim 1; R 5 is a hydroxyl protecting group, preferably selected from benzyl, benzoyl, tert-butyryl, trimethylsilyl, tert-butyldiphenylsilyl and methoxymethyl.

6. A method for preparing a compound of formula IV-1, comprising the method of claim 5, further comprising the step of preparing a compound of formula V-1 from the compound of formula IV-1: in, R 1 , R 3 , R 5 , X 1 and m as defined in claim 5.

7. Compound represented by formula f:

8. Compound represented by formula I-2:

9. Compound represented by formula II-2:

10. Compound represented by formula III-2:

11. The compound represented by formula IV-2 is:

12. A method for preparing a compound of formula V-2, comprising the steps of:

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

14. Use of the compound of formula II in the preparation of KRAS G12D compounds, wherein the compound of formula II is prepared according to the method of claim 1.

15. A method for preparing a compound of formula A, comprising the method according to any one of claims 1 to 12,

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