Method for preparing KRAS g12d intermediate

Abstract

The present disclosure provides a method for preparing a KRAS G12D intermediate. Specifically, the present disclosure provides a method for preparing a compound represented by formula IV-1. The preparation process has a simple route, the overall yield is high, and the cost can be significantly reduced.

Description

Process for preparing KRAS G12D intermediate TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and particularly relates to a method for preparing KRAS G12D intermediate. BACKGROUND

[0002] RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are related to mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, among which KRAS mutations are the most common, accounting for about 85%. KRAS mutations are common in solid tumors, and high-frequency mutations exist in the three most deadly cancers in humans: lung cancer (17%), colorectal cancer (33%) and pancreatic cancer (61%). Among the genetic mutations of KRAS, 97% are mutations in the 12th or 13th amino acid residues, and G12D is an important mutation. Data analysis of European and American populations shows 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 KRAS is activated, it regulates cell proliferation, survival, migration and metabolism and other functions through a large number of downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After KRAS gene mutation, the protein is continuously in an activated state, leading to continuous activation of downstream signaling pathways and promoting tumor occurrence.

[0004] Due to the lack of traditional small molecule binding sites on the surface of KRAS protein and the extremely high affinity with guanylate, it is extremely difficult to be inhibited, and it has been considered as an undruggable drug target for a long time. However, due to the importance and universality of KRAS abnormal activation in cancer progression, KRAS has always been and still is a target of great concern for drug development. At present, in addition to KRAS G12C inhibitors, there are still no effective KRAS inhibitors for other mutations, so that most patients with KRAS mutations still have no drugs to treat. G12D, as a widely expressed mutant in various tumors, has important clinical significance for developing inhibitors against it.

[0005] The compound shown in formula IV-1 is an important intermediate for synthesizing KRAS G12D molecules. Patent applications WO2023274324A, CN 115557974A, WO2022268051A and WO2022188729A disclose synthesis methods of the compound shown in formula IV-1, the reaction route is relatively complex, the overall yield is relatively low, and the cost is also relatively high.

[0006] In view of the considerations of simplifying the route, improving the yield, and reducing the cost, the present disclosure provides a new method for preparing a KRAS G12D intermediate. SUMMARY

[0007] A method for preparing a compound of Formula II, comprising the step of reacting a compound of Formula I with an aminating agent under the condition of a basic reagent to prepare a compound of Formula II:

[0008] wherein,

[0009] W1, W2, W3, W4, and W5 are each independently selected from C or N;

[0010] R 1 are the same or different, and each is independently selected from alkyl, alkoxy, cyano, halogen, hydroxyl, thiol, 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;

[0011] Each substituent group Q is independently selected from C1-C6 alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thioxo, -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 alkylthio, 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;

[0012] R i , R j are each independently selected from a hydrogen atom, a hydroxyl group, a C1-C6 alkyl group, and a C1-C6 alkoxy group; R k is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a hydroxyl group, -NR i R j , wherein the alkyl group, the alkoxy group are optionally substituted with one or more substituents selected from a C1-C6 alkyl group, a halogen, a hydroxyl group, a thiol group, -NR i R jone or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halogen, hydroxy, oxo, amino, carboxy, nitro, cyano, C1-C6alkylthio, C2-C6alkenyl, C2-C6alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0013] n is 0, 1, 2, 3, or 4.

[0014] In some embodiments, R 1 each is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, hydroxy, oxo, -NR i R j , 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclyl, wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents Q.

[0015] In some embodiments, R 1 each is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, hydroxy, oxo, amino, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclyl, wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halogen, hydroxy, amino, carboxy, nitro, cyano.

[0016] In some embodiments, R 1 each is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, oxo, hydroxy, and amino, wherein said alkyl, alkoxy are optionally substituted with one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halogen, hydroxy, amino, carboxy, nitro, cyano.

[0017] In some embodiments, R 1 each is independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, and hydroxy.

[0018] In some embodiments, R 1 each is independently selected from the group consisting of halogen, and n is 3.

[0019] In some embodiments, each substituent group Q is independently selected from the group consisting of C1-C6alkyl, halogen, hydroxy, thiol, -NR i R j , oxo, thioxo, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)ORk , -C(S)R k , nitro, cyano, C1-C6alkoxy, C1-C6alkylsulfidyl, C2-C6alkenyl or C2-C6alkynyl.

[0020] In some embodiments, each substituent group Q is independently selected from C1-C6alkyl, halogen, hydroxyl, NR i R j , oxo, -C(O)R k , -C(O)OR k , cyano, C1-C6alkoxy, C2-C6alkenyl or C2-C6alkynyl.

[0021] In some embodiments, W1, W3, W4and W5are C, and W2is N.

[0022] In some embodiments, the aminating reagent includes, but is not limited to

[0023] In some embodiments, the aminating reagent is

[0024] In some embodiments, the basic reagent is an organometallic reagent.

[0025] In some embodiments, the organometallic reagent includes, but is not limited to, Grignard reagents, organolithium reagents, organozinc reagents.

[0026] In some embodiments, the organometallic reagent includes, but is not limited to, lithium diisopropylamide, lithium tetramethylpiperidide, lithium bis(trimethylsilyl)amide, n-butyllithium, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride, cyclohexylmagnesium chloride, TMPMgCl, TMPMgCl-LiCl, or TMPZnCl-LiCl.

[0027] In some embodiments, the organometallic reagent is selected from lithium diisopropylamide, lithium tetramethylpiperidide, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride, TMPMgCl, TMPMgCl-LiCl, or TMPZnCl-LiCl.

[0028] In some embodiments, the metal reagent is selected from TMPZnCl-LiCl.

[0029] In some embodiments, the method is performed under catalysis of a transition metal catalyst.

[0030] In some embodiments, the transition metal catalyst includes, but is not limited to, nickel, copper, zinc, zirconium, ruthenium, rhodium, palladium, silver, iridium, platinum catalyst.

[0031] In some embodiments, the transition metal catalyst is a copper catalyst.

[0032] In some embodiments, the copper catalyst includes, but is not limited to, Cul, CuCl, CuBr, CuCN, CuSCN, CuCl2, CuBr2, and Cu(SCN)2.

[0033] In some embodiments, the copper catalyst is Cul.

[0034] In some embodiments, the method includes a step of preparing a compound of Formula II-1 from a compound of Formula I-1:

[0035] wherein W1, W2, W3, W4, R 1 and n are as defined in general Formula I.

[0036] The present disclosure also provides a method of preparing a compound of Formula III-1, comprising a step of:

[0037] The present disclosure also provides a method of preparing a compound of Formula IV-1, comprising a step of:

[0038] In some embodiments, the compound of Formula I-1 is reacted with an aminating agent in the presence of a base to prepare the compound of Formula II-1.

[0039] In some embodiments, the base is selected from the group consisting of lithium diisopropyl amide, lithium tetramethylpiperidide, isopropyl magnesium chloride, isopropyl magnesium chloride lithium chloride, TMPMgCl, TMPMgCl-LiCl, or TMPZnCl-LiCl, preferably TMPZnCl-LiCl.

[0040] In some embodiments, the aminating agent is selected from the group consisting of preferably

[0041] In some embodiments, the compound of Formula I-1 is reacted with an aminating agent in the presence of a base to prepare the compound of Formula II-1, the base is TMPZnCl-LiCl, and the aminating agent is

[0042] The present disclosure also provides a method of preparing a compound of Formula IV-2, comprising a step of:

[0043] The present disclosure also provides a method of preparing a KRAS G12D compound, comprising the aforementioned method of preparing a compound of Formula II, a compound of Formula IV-1, or a compound of Formula IV-2.

[0044] In some embodiments, the KRAS G12D compound is a compound of Formula X,

[0045] wherein,

[0046] Q is N or CR 2a ;

[0047] Ring A is aryl or fused heteroaryl;

[0048] Ring B is selected from the group consisting of heterocyclyl, aryl, and heteroaryl;

[0049] R 2a and R 4a are the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl, and cycloalkyl;

[0050] each R 2 and R 3 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0051] R 5a and R 5b are the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, cyano, hydroxyl, and hydroxyalkyl; or

[0052] R 5a , R 5b together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more same or different substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl, and hydroxyalkyl;

[0053] r is 0, 1, 2, or 3;

[0054] p is 0, 1, 2, 3, 4, or 5; and

[0055] q is 0, 1, 2, 3, 4, or 5.

[0056] In some embodiments, Ring A is a naphthalene ring or a benzo-heterocycle.

[0057] In some embodiments, Ring B is a 3- to 8-membered heterocyclyl.

[0058] In some embodiments, R 2a and R 4a are each independently selected from a hydrogen atom or a halogen.

[0059] In some embodiments, each R 2 are the same or different, and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a haloalkyl group, a hydroxyl group, an amino group, a cyano group, and a C 1-6 hydroxyalkyl group.

[0060] In some embodiments, R 5a and R 5b are a hydrogen atom; or R 5a , R 5b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group.

[0061] In some embodiments, each R 3 are the same or different, and each is independently selected from a hydrogen atom, a halogen, and a C 1-6 hydroxyalkyl group.

[0062] The compounds of Formula X in the present disclosure include, but are not limited to:

[0063] The present disclosure also specifically provides a method for preparing a compound of Formula X-1, comprising the steps of preparing a compound of Formula IV-2 as described above, and further comprising the following steps:

[0064] The reagents for acidic conditions provided by the present disclosure 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, TMSOTf.

[0065] 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.

[0066] Detailed description of the invention

[0067] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0068] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups, of from 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers of the latter group, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituent groups can be substituted at any available attachment point, preferably one or more groups, independently selected from halo, hydroxyl, oxo, cyano, amino, C 1- 6alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl being optionally substituted with halo, hydroxyl, nitro, cyano, or amino.

[0069] The term "alkenyl" refers to unsaturated aliphatic straight-chain or branched hydrocarbon groups, and 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, ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like. Alkenyl groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0070] The term "alkynyl" refers to unsaturated aliphatic straight-chain or branched hydrocarbon groups, and 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. 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.

[0071] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably containing from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. Cycloalkyl groups can be substituted or unsubstituted, and when substituted, the substituent groups can be substituted at any available attachment point, preferably one or more groups, independently selected from halo, hydroxyl, oxo, cyano, amino, C 1-6 alkyl, C 1-6alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with halogen, hydroxy, nitro, cyano or amino.

[0072] The term "heterocycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic ringed hydrocarbon substituents containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) m (m is an integer from 0 to 2) ring members, but excluding -O-O-, -O-S- or -S-S- ring members, the remaining ring members being carbon. Preferably, the heterocycloalkyl group contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, the heterocycloalkyl group contains 3 to 7 ring atoms. Non-limiting examples of "heterocycloalkyl" groups include:

[0073] and the like.

[0074] The heterocycloalkyl ring can be fused to an aryl or heteroaryl ring, wherein the ring that is attached to the parent structure is the heterocycloalkyl group. Non-limiting examples of this include:

[0075] and the like.

[0076] The heterocycloalkyl group can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted with halogen, hydroxy, nitro, cyano or amino.

[0077] The term "cycloalkenyl" refers to unsaturated monocyclic or polycyclic ringed hydrocarbon substituents, and contains one or more carbon-carbon double bonds. Cycloalkenyl groups contain 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, C16-C20 cycloalkenyl groups. Additionally, the cycloalkenyl group can be fused to an aryl or heteroaryl group. Exemplary cycloalkenyl groups include, but are not limited to:

[0078] Additionally, the cycloalkenyl group can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, C 1-3 alkyl or C 1-3 alkoxy.

[0079] The term "cycloalkynyl" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent and contains one or more carbon-carbon triple bonds. Cycloalkynyl groups contain 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, C16-C20 cycloalkynyl groups. Additionally, the cycloalkynyl group can be fused to an aryl or heteroaryl group. Exemplary cycloalkynyl groups include, but are not limited to:

[0080] Additionally, the cycloalkynyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halo, C 1-3 alkyl or C 1-3 alkoxy.

[0081] The term "heterocycloalkenyl" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, of which one or more ring atoms are a heteroatom selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2), but excluding a ring moiety of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon, and containing one or more carbon-carbon double bonds. Heterocycloalkenyl groups contain 3 to 20 carbon atoms, preferably C2-C8, C4-C6, C8-C12, C14-C18, C16-C20 heterocycloalkenyl groups. Additionally, the heterocycloalkenyl group can be fused to an aryl or heteroaryl group. Exemplary heterocycloalkyl groups include, but are not limited to:

[0082] wherein R a , R b are each independently selected from hydrogen, C 1-6 alkyl or aryl, R c is selected from hydrogen or C 1-6 alkyl. Additionally, the heterocycloalkenyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halo, C 1-3 alkyl or C 1-3 alkoxy.

[0083] The term "heterocycloalkenyl" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, of which one or more ring atoms are a heteroatom selected from nitrogen, oxygen, or S(O) m (wherein m is an integer from 0 to 2), but excluding a ring moiety of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon, and containing one or more carbon-carbon double bonds. Heterocycloalkenyl groups contain 3 to 20 carbon atoms, preferably C2-C8, C4-C6, C8-C12, C14-C18, C16-C20 heterocycloalkenyl groups. Additionally, the heterocycloalkenyl group can be fused to an aryl or heteroaryl group. Exemplary heterocycloalkyl groups include, but are not limited to:

[0084] but does not include a cyclic moiety of -0-0-, -0-S-, or -S-S-, the remaining ring atoms being carbon, and containing one or more carbon-carbon triple bonds. Heterocycloalkynyl groups contain from 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, C16-C20 heterocycloalkynyl groups. Additionally, heterocycloalkynyl groups can be fused to aryl or heteroaryl groups. Exemplary heterocycloalkynyl groups include, but are not limited to:

[0085] Additionally, heterocycloalkynyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halo, C 1-3 alkyl, or C 1-3 alkoxy.

[0086] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, butyloxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from halo, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl, or heterocycloalkyl being optionally substituted with halo, hydroxy, nitro, cyano, or amino.

[0087] Similarly, "cycloalkoxy," "heterocycloalkoxy" are defined as above for "alkoxy."

[0088] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkylthio groups include methylthio, ethylthio, propylthio, butylthio. Alkylthio groups can be optionally substituted or unsubstituted, and 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, said alkoxy, cycloalkyl, heterocycloalkyl, cycloalkoxy, heterocycloalkoxy, alkylthio, cycloalkylthio, heterocycloalkylthio being optionally substituted with halo, hydroxy, cyano, or amino.

[0089] Similarly, "cycloalkylthio," "heterocycloalkylthio" are defined as above for "alkylthio."

[0090] A "monovalent radical" refers to the "formal" removal of a single valence atom or group from a compound. An "acyl" refers to the "formal" removal of a single valence atom or group from a compound.

[0091] The term "alkylene" denotes the moiety remaining after removal of two hydrogen atoms from an alkane molecule and includes straight chain and branched chain divalent groups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH2-), ethylene (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, the alkylene group can be substituted or unsubstituted, and when substituted, the substituents can be on any available attachment point, preferably one or more groups independently selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0092] Similarly, "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene", "heterocycloalkylene" are defined as "alkylene".

[0093] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a completely conjugated pi-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0094] The aryl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, C 3-8 cycloalkenyl, 5- to 6-membered aryl or heteroaryl, said C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 8-membered cycloalkenyl, 5- to 6-membered aryl or heteroaryl optionally substituted with one or more groups selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0095] The term "heteroaryl" refers to a heteroaromatic system comprising from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably from 6 to 12 members, more preferably 5 or 6 members. Non-limiting examples include: imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, and the like.

[0096] The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0097] The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl or C 1-6 alkoxy.

[0098] The term "spirocyclic" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyl groups include:

[0099] The term "fused ring" refers to a compound in which two or more rings are joined by sharing two adjacent atoms. Non-limiting examples of fused cycloalkyl groups include:

[0100] The term "bridged ring" refers to a structure in which two or more cyclic structures share two non-adjacent ring atoms with each other. Depending on the number of rings that make up the structure, the bridged cycloalkyl group can be a bicyclic, tricyclic, tetracyclic or polycyclic ring, preferably a bicyclic, tricyclic or tetracyclic ring, more preferably a bicyclic or tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

[0101] The term "heterocycle" refers to a ring structure in which the atoms that make up the ring include atoms other than carbon, including heterocycloalkyl and heteroaromatic rings.

[0102] The term "hydroxy" refers to an -OH group.

[0103] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0104] The term "cyano" refers to -CN.

[0105] The term "amino" refers to -NH2.

[0106] The term "nitro" refers to -NO2.

[0107] The term "oxo" refers to a =O substituent.

[0108] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms, of a group are independently of each other replaced with the corresponding number of substituents. When the substituent is a ketone or oxo (i.e., =O), then two (2) hydrogens on the atom are replaced.

[0109] The purity or content of the compounds 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

[0110] The present disclosure will be explained in more detail below in conjunction with the examples, which 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.

[0111] The preparation method of the compound represented by formula X-1 in the present application has been described in the patent document with application number WO2022268051A, and the entire content of the aforementioned application document is incorporated into the present disclosure.

[0112] Example 1: Preparation of an aminating agent

[0113] Into a 2L single-mouth flask, 65g of hydroxylamine hydrochloride, 730g of acetone, and 158g of sodium bicarbonate were added, and the temperature was lowered to 0°C; the temperature was raised to room temperature, and the reaction was stirred for 1h; 120g of TsCl was added to the system, and the stirring was continued for 12h. The system was poured into 1.2L of purified water, stirred for 1h, filtered, and then the crude product was obtained; the crude product was slurried with 1L of 60% acetone aqueous solution; filtered and dried overnight to obtain the aminating agent represented by formula a (123g, yield 85%).

[0114] 1 HNMR (400MHz, CDCl3): 7.87 (m, 2H), 7.35 (m, 2H), 2.46 (m, 3H), 1.97 (m, 6H)

[0115] Example 2: Preparation of the compound represented by formula II-2

[0116] A solution of 96.1 g of 2,2,6,6-tetramethylpiperidine in 500 mL of THF was cooled to -20 °C, 250 mL of butyl lithium solution was added, and stirring was performed for 20-30 min. 85.6 g of ZnCl2 was added to the system, and after the addition was completed, the system was allowed to warm to room temperature and stirring was continued for 20 min. After the system was cooled to 5-10 °C, 100 g of the compound of formula I-2 (purchased from Adamas) was added, and after the addition was completed, the system was allowed to warm to room temperature and stirring was continued for 1-2 h. 2.1 g of CuCl, 120 g of DMPU were added to the system, and after stirring was completed, the system was cooled to -10 °C. 142.8 g of amino reagent dissolved in 500 mL of THF was added dropwise, and after the addition was completed, the system was allowed to warm to room temperature and the reaction was allowed to proceed overnight. After the reaction was confirmed to be complete by TLC detection, 500 mL of 6M aqueous HCl was added dropwise at 0 °C, 500 mL of water was added, and the mixture was filtered through celite. Most of the THF was removed by distillation, and the filtrate was filtered. The filter cake was dispersed in 1 L of 60-65 wt% aqueous ethanol, and the mixture was warmed to 80-85 °C and stirred for 2 h. The mixture was filtered hot, 1 L of water was added to the filtrate, and the mixture was stirred to crystallize for 1 h. The mixture was filtered and dried to obtain 76.5 g of the compound of formula II-2 (yield 71%).

[0117] 1 HNMR (400 MHz, DMSO-d6): 8.05 (s, 2H)

[0118] Example 3: Preparation of the compound of formula III-2

[0119] To a reaction kettle were added 81 g of the compound of formula II-2, 200 mL of NMP, and 200 mL of DMSO, and the mixture was stirred until the compound was dissolved. Then, 27 g of K2CO3 was added, and the mixture was stirred until the K2CO3 was dissolved. The mixture was cooled to -5 °C, and 58 g of 30 wt% H2O2 was added dropwise while controlling the internal temperature to be lower than 30 °C. The mixture was stirred overnight. After the reaction was confirmed to be complete by TLC detection, the temperature of the reaction system was lowered to about 5 °C. 250 mL of 10 wt% aqueous sodium bisulfite was added dropwise to the reaction system, and the mixture was stirred for 1-2 h. Then, 2 L of water and 2 L of ethyl acetate (EA) were added to the mixture, and the aqueous phase was extracted twice with 2 L of EA. The combined organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was distilled. Then, 250 mL of petroleum ether (PE) was added dropwise to the system, and the mixture was stirred at room temperature overnight. The mixture was filtered, and the filter cake was rinsed with PE / EA = 2:1. After drying, 79 g of the compound of formula III-2 was obtained (yield 89.7%).

[0120] 1 HNMR (400 MHz, DMSO-d6): 8.05 (s, 2H)

[0121] Example 4: Preparation of the compound of formula IV-2

[0122] Into a reaction bottle, 63.4 g of CDI, 730 ml of ACN, 73 g of the compound of formula III-2 were added, stirred uniformly, and then DIPEA was added; the reaction system was warmed to 45°C, and stirred for 3-4 h; TLC confirmed that the raw material was completely reacted; after being cooled to room temperature, it was stirred for 2 h, stirred in an ice bath for 0.5 h, filtered, and washed with dichloromethane; the obtained solid was added to 750 ml of 2M hydrochloric acid, heated and stirred for 2-3 h, cooled to room temperature, then 350 ml of water was added, stirred uniformly, filtered, and dried to obtain the compound of formula IV-2 (75.4 g, yield 92.5%).

[0123] 1 HNMR (400 MHz, DMSO-d6): 12.18 (s, 1H), 11.76 (s, 1H)

[0124] Example 5: Preparation of the compound of formula X-1

[0125] The method in WO2022268051A was used, and 2 g of the compound of formula IV-2 prepared in Example 4 was input, and finally 0.28 g of the compound of formula X-1 was obtained.

[0126] Example 6: Preparation of the compound of formula X-2

[0127] The method in WO2022199587A was used, and 1 g of the compound of formula IV-2 prepared in Example 4 was input, and finally 0.24 g of the compound of formula X-2 was obtained.

[0128] Example 7: Preparation of the compounds of formula X-3 and formula X-4

[0129] The method in WO2022188729A was used, and 1 g of the compound of formula IV-2 prepared in Example 4 was input, and finally 0.13 g of the compound of formula X-3 was obtained.

[0130] The method in WO2022188729A was used, and 1 g of the compound of formula IV-2 prepared in Example 4 was input, and finally 0.15 g of the compound of formula X-4 was obtained.

Claims

1. A process for preparing a compound of Formula II: ###00001### II or a salt thereof, comprising the step of reacting a compound of Formula I: ###00002### I with an aminating agent in the presence of a basic reagent to produce a compound of Formula II: ###00003### II. wherein W1, W2, W3, W4and W5are each independently selected from C or N; R 1 the same or different and each independently selected from the group consisting of alkyl, alkoxy, cyano, halogen, hydroxy, thiol, oxo, -NR i R j , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally substituted with one or more substituents Q; each substituent group Q is independently selected from the group consisting of C1-C6 alkyl, halogen, hydroxyl, thiol, -NR i R j , oxo, thioxo, -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 alkylsulfidyl, 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 independently is selected from the group consisting of a hydrogen atom, a hydroxyl group, a Ci-C6alkyl group, a Ci-C6alkoxy group; R k is independently selected from the group consisting of a hydrogen atom, a Ci-C6alkyl group, a Ci-C6haloalkyl group, a Ci-C6alkoxy group, a hydroxyl group, a -NR i R j , wherein said alkyl, alkoxy groups are optionally substituted with one or more substituents selected from the group consisting of a Ci-C6alkyl group, a halogen, a hydroxyl group, a thiol group, a -NR i R j , an oxo group, a thio group, a carboxyl group, a nitro group, a cyano group, a Ci-C6alkoxy group, a Ci-C6alkylsulfide group, a C2-C6alkenyl group, a C2-C6alkynyl group, a 3- to 10-membered cycloalkyl group, a 3- to 10-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; n is 0, 1, 2, 3 or 4.

2. The method of claim 1, wherein R 1 each independently is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, hydroxy, oxo, amino, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclyl, wherein said alkyl, alkoxy, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halogen, hydroxy, amino, carboxy, nitro, cyano; R is preferably selected from the group consisting of H, C1-C6alkyl, C1-C6alkoxy, halogen, oxo, hydroxy, and amino, wherein said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, hydroxy, amino, carboxy, nitro, cyano; 1 each independently is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halogen, oxo, hydroxy, and amino, wherein said alkyl, alkoxy is optionally substituted with one or more substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, hydroxy, amino, carboxy, nitro, cyano; More preferably, R 1 each independently is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, cyano, halogen, and hydroxy.

3. The method according to claim 1 or 2, said aminating agent being selected from preferably 4. The process according to any one of claims 1 to 3, wherein the basic reagent is an organometallic reagent.

5. The process according to claim 4, wherein the organometallic reagent is selected from the group consisting of Grignard reagents, organolithium reagents, organozinc reagents, preferably lithium diisopropylamide, lithium tetramethylpiperidide, lithium bis(trimethylsilyl)amide, n-butyllithium, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride, cyclohexylmagnesium chloride, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl, more preferably lithium diisopropylamide, lithium tetramethylpiperidide, isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl.

6. The process according to any one of claims 1 to 5, wherein the process is carried out under catalysis of a transition metal catalyst selected from the group consisting of nickel, copper, zinc, zirconium, ruthenium, rhodium, palladium, silver, iridium, platinum catalysts, preferably copper catalysts, more preferably Cul, CuCl, CuBr, CuCN, CuSCN, CuCl2, CuBr2and Cu(SCN)2, most preferably CuCl.

7. The method of any one of claims 1-6, comprising the step of preparing a compound of Formula II-1 from a compound of Formula I-1: wherein W1, W2, W3, W4, R 1 and n are as defined in claim 1.

8. A method of preparing a compound of Formula III-1 comprising the steps of: wherein W1, W2, W3, W4, R 1 and n are as defined in claim 1.

9. A method of preparing a compound of Formula IV-1 comprising the steps of: wherein W1, W2, W3, W4, R 1 and n are as defined in claim 1.

10. A process for the preparation of a KRAS G12D compound comprising a process according to any one of claims 1 to 9.

11. The method of claim 10, wherein the KRAS G12D compound is a compound of Formula X, wherein Q is N or CR 2a ; Ring A is aryl or fused heteroaryl; Ring B is selected from the group consisting of heterocyclyl, aryl and heteroaryl; R 2a and R 4a are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, and a cycloalkyl group; each R 2 and R 3 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 5a and R 5b are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group, and a hydroxyalkyl group; or R 5a , R 5b with the attached carbon atom form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more of the same or different substituents selected from the group consisting of halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, and hydroxyalkyl; r is 0, 1, 2 or 3; p is 0, 1, 2, 3, 4 or 5; and q is 0, 1, 2, 3, 4 or 5.

12. The process according to claim 11, wherein Ring A is a naphthalene ring or a benzo heterocycle.

13. The process according to claim 11 or 12, wherein Ring B is a 3- to 8-membered heterocyclyl.

14. The method according to any one of claims 11-13, wherein R 2a and R 4a are each independently selected from a hydrogen atom or a halogen.

15. The method according to any one of claims 11-14, wherein each R 2 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl, amino, cyano and C 1-6 Hydroxyalkyl.

16. The method of any one of claims 11-15, wherein R 5a and R 5b are hydrogen atoms; or R 5a , R 5b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group.

17. The method of any one of claims 11-16, wherein each R 3 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 hydroxyalkyl group.

18. The method according to any one of claims 11-17, which is a compound of formula:

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