Preparation method of KRAS G12D intermediate

Abstract

The invention provides a preparation method of a KRAS G12D intermediate. Specifically, the invention provides a method for preparing a compound as shown in a formula III. The preparation process is simple in route and high in overall yield, and the cost can be remarkably reduced. # imgabs0 #

Description

Technical Field

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

[0002] RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignant tumors 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 major fatal human cancers: lung cancer (17%), colorectal cancer (33%) and pancreatic cancer (61%). Among the KRAS gene mutations, 97% are mutations in the 12th or 13th amino acid residues, among which G12D is an important mutation. Data analysis of European and American populations shows that in pancreatic cancer, colorectal cancer and non-small cell lung cancer, G12D mutations account for 36%, 12% and 4% of patients, respectively.

[0003] After KRAS is activated, it regulates cell proliferation, survival, migration, metabolism and other functions through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After the KRAS gene mutates, the protein remains in an activated state, resulting in continuous activation of downstream signaling pathways and promoting tumorigenesis.

[0004] Since the KRAS protein lacks small molecule binding sites in the traditional sense on its surface and has an extremely high affinity with guanosine, it is extremely difficult to inhibit. It has long been considered an undruggable drug target. However, due to the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has always been and remains a target of great interest in drug development. At present, in addition to KRAS G12C inhibitors, there is still a lack of KRAS inhibitors that are effective for other mutations, leaving most patients with KRAS mutations untreatable. G12D, as a mutant that is widely and highly expressed in a variety of tumors, has important clinical significance for the development of inhibitors against it.

[0005] The compound represented by formula III is an important intermediate for synthesizing KRAS G12D molecules. Patent applications WO2023274324A, CN 115557974A, WO2022268051A and WO2022188729A disclose methods for synthesizing the compound represented by formula III. The reaction route is relatively complicated, and the overall yield is low and the cost is also high.

[0006]

[0007] In view of simplifying the route, improving the yield and reducing the cost, the present disclosure provides a new method for preparing KRASG12D intermediate. Summary of the invention

[0008] The present disclosure provides a method for preparing a compound of formula III, comprising: 1) the step of subjecting the compound of formula I to an amination reaction to form a compound of formula II, and 2) the step of subjecting the compound of formula II to a ring-closing reaction to form a compound of formula III.

[0009]

[0010] in,

[0011] W1, W2, W3 and W4 are each independently selected from C or N;

[0012] R 1 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;

[0013] 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;

[0014] 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 jwherein 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. ;

[0015] n is 0, 1, 2, 3 or 4.

[0016] In some embodiments, R 1 Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, 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 by one or more substituents Q.

[0017] In some embodiments, R 1 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 heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are optionally substituted by one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, carboxyl, nitro and cyano.

[0018] In some embodiments, R 1 Each 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.

[0019] In some embodiments, R 1 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen and hydroxy.

[0020] In some embodiments, R 1 are each independently selected from halogen, and n is 3.

[0021] 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.

[0022] 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.

[0023] In some embodiments, W1, W3 and W4 are C and W2 is N.

[0024] In some embodiments, in the aforementioned method for preparing the compound of formula III, the amination reaction comprises the steps of: reacting the compound of formula I with an aminating agent under alkaline conditions to form a compound of formula II,

[0025]

[0026] Among them, R 1 , W1, W2, W3, W4 and n are as defined in Formula I.

[0027] In some embodiments, in the aforementioned method for preparing the compound represented by formula III, the amination reagent includes but is not limited to In some embodiments, in the aforementioned method for preparing the compound represented by formula III, the amination reagent is

[0028] In some embodiments, in the aforementioned method for preparing the compound shown in formula III, the reagent providing alkaline conditions includes but is not limited to sodium hydride, lithium diisopropylamide (LDA), lithium tetramethylpiperidinium (LiTMP), lithium bistrimethylsilylamide (LiHMDS), n-butyl lithium, isopropyl magnesium chloride (i-PrMgCl), isopropyl magnesium chloride lithium chloride (iPrMgCl-LiCl), cyclohexyl magnesium chloride, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl. In some embodiments, the reagent providing alkaline conditions is selected from LDA, LiTMP, i-PrMgCl, iPrMgCl-LiCl, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl. In some embodiments, the reagent providing alkaline conditions is selected from LDA, i-PrMgCl or TMPZnCl-LiCl.

[0029] In some embodiments, in the aforementioned method for preparing the compound shown in formula III, the amination reaction is carried out under the catalysis of a transition metal catalyst, and the transition metal catalyst includes but is not limited to nickel, copper, zinc, zirconium, ruthenium, rhodium, palladium, silver, iridium, and platinum catalysts. In some embodiments, the transition metal catalyst is a copper catalyst. In some embodiments, the copper catalyst includes but is not limited to CuI, CuCl, CuBr, CuCN, CuSCN, CuCl2, CuBr2, and Cu(SCN)2. In some embodiments, the copper catalyst is CuCl.

[0030] In some embodiments, in the aforementioned method for preparing the compound of formula III, the ring-closing reaction comprises the steps of: reacting the compound of formula II with chlorosulfonyl isocyanate to form the compound of formula III,

[0031]

[0032] Among them, R 1 , W1, W2, W3, W4 and n are as defined in Formula I.

[0033] In some embodiments, in the aforementioned method for preparing the compound represented by formula III, the ring-closing reaction is carried out under acidic conditions.

[0034] The present disclosure also provides a method for preparing a compound of formula III-1, comprising: 1) the compound of formula I-1 is subjected to an amination reaction to form a compound of formula II-1, and 2) the compound of formula II-1 is subjected to a ring-closing reaction to form a compound of formula III-1.

[0035]

[0036] In some embodiments, in the aforementioned method for preparing the compound of formula III-1, the amination reaction comprises the steps of: reacting the compound of formula I-1 with an aminating agent under alkaline conditions to form the compound of formula II-1,

[0037]

[0038] In some embodiments, in the aforementioned method for preparing the compound of formula III-1, the amination reagent includes but is not limited to In some embodiments, in the aforementioned method for preparing the compound represented by formula III-1, the amination reagent is

[0039] In some embodiments, in the aforementioned method for preparing the compound shown in formula III-1, the reagent providing alkaline conditions includes but is not limited to sodium hydride, lithium diisopropylamide (LDA), lithium tetramethylpiperidinium (LiTMP), lithium bistrimethylsilylamide (LiHMDS), n-butyl lithium, isopropyl magnesium chloride (i-PrMgCl), isopropyl magnesium chloride lithium chloride (iPrMgCl-LiCl), cyclohexyl magnesium chloride, TMPMgCl, TMPMg-LiCl or TMPZnCl-LiCl. In some embodiments, the reagent providing alkaline conditions is selected from LDA, LiTMP, i-PrMgCl, iPrMgCl-LiCl, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl. In some embodiments, the reagent providing alkaline conditions is selected from LDA, i-PrMgCl or TMPZnCl-LiCl.

[0040] In some embodiments, in the aforementioned method for preparing the compound shown in formula III-1, the amination reaction is carried out under the catalysis of a transition metal catalyst, and the transition metal catalyst includes but is not limited to nickel, copper, zinc, zirconium, ruthenium, rhodium, palladium, silver, iridium, and platinum catalysts. In some embodiments, the transition metal catalyst is a copper catalyst. In some embodiments, the copper catalyst includes but is not limited to CuI, CuCl, CuBr, CuCN, CuSCN, CuCl2, CuBr2, and Cu(SCN)2. In some embodiments, the copper catalyst is CuCl.

[0041] In some embodiments, in the aforementioned method for preparing the compound of formula III-1, the ring-closing reaction comprises the steps of: reacting the compound of formula II-1 with chlorosulfonyl isocyanate to form the compound of formula III-1,

[0042]

[0043] In some embodiments, in the aforementioned method for preparing the compound represented by formula III-1, the ring-closing reaction is carried out under acidic conditions.

[0044] The present disclosure also provides a method for preparing a KRAS G12D compound, comprising the aforementioned step of preparing a compound of formula III from a compound of formula I.

[0045] In some embodiments, the KRAS G12D compound is a compound represented by Formula X,

[0046]

[0047] in,

[0048] Q is N or CR 2a ;

[0049] Ring A is an aryl group or a fused heteroaryl group;

[0050] Ring B is selected from heterocyclyl, aryl and heteroaryl;

[0051] R 2a and R 4a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl and cycloalkyl;

[0052] Each R 1 and R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0053] R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or

[0054] R 5a , R 5b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

[0055] r is 0, 1, 2, or 3;

[0056] p is 0, 1, 2, 3, 4 or 5; and

[0057] q is 0, 1, 2, 3, 4 or 5.

[0058] In some embodiments, Ring A is a naphthyl ring or a benzoheterocyclic ring.

[0059] In some embodiments, Ring B is a 3- to 8-membered heterocyclyl.

[0060] In some embodiments, R 2a and R 4a Each is independently selected from a hydrogen atom or a halogen.

[0061] In some embodiments, each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, amino, cyano and C 1-6 Hydroxyalkyl.

[0062] In some embodiments, R 5a and R 5b is a hydrogen atom; or R 5a , R 5b Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group.

[0063] In some embodiments, each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Hydroxyalkyl.

[0064] The compounds represented by formula X in the present disclosure include but are not limited to:

[0065]

[0066]

[0067] The compound of formula III in the present disclosure is used to prepare KRAS G12D compound. In some embodiments, the compound of formula III is prepared according to the method provided in the present disclosure.

[0068] The present disclosure also specifically provides a method for preparing a compound of formula X-1, comprising the aforementioned steps of preparing a compound of formula III-1, and further comprising the following steps:

[0069]

[0070] The reagents for 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.

[0071] 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.

[0072] Detailed description of the invention

[0073] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0074] 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 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.

[0075] 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 alkyl.

[0076] The term "alkynyl" refers to an unsaturated aliphatic straight or branched hydrocarbon group and contains one or more carbon-carbon triple bonds. Exemplary alkynyls include C2-C8, C2-C7, C2-C6, C2-C4, C3-C12 and C3-C6 alkynyls. Including but not limited to ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl and pent-1,4-diynyl. The alkynyl used in any context herein is optionally substituted in the same manner as an alkyl.

[0077] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 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, etc.; 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, hydroxyl, 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.

[0078] 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, but excluding the ring portion of -OO-, -OS- or -SS-, 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:

[0079]

[0080] etc.

[0081] 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:

[0082] wait.

[0083] The heterocycloalkyl group 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.

[0084] The term "cycloalkenyl" refers to an unsaturated monocyclic or polycyclic hydrocarbon substituent containing one or more carbon-carbon double bonds. The cycloalkenyl group contains 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, 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:

[0085]

[0086] 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 Alkoxy.

[0087] The term "cycloalkynyl" refers to an unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing one or more carbon-carbon triple bonds. The cycloalkynyl group contains 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, 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:

[0088]

[0089] 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.

[0090] 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, but does not include -OO-, -OS- or -SS- ring parts, 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. In addition, the heterocycloalkenyl group can be fused to an aryl or heteroaryl group. Exemplary heterocyclic groups include, but are not limited to:

[0091] Where R a , R b are independently selected from hydrogen, C 1-6 Alkyl or aryl, R c Selected from hydrogen or C 1-6In 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.

[0092] 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,

[0093] 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. The heterocycloalkynyl group contains 3 to 20 carbon atoms, including C2-C8, C4-C6, C8-C12, C14-C18, 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:

[0094]

[0095] 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.

[0096] 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.

[0097] Similarly, "cycloalkoxy" and "heterocycloalkoxy" are the same as defined above for "alkoxy".

[0098] 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, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from C 1-6alkoxy, 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 by halogen, hydroxy, cyano or amino.

[0099] Similarly, "cycloalkylthio" and "heterocycloalkylthio" are the same as defined above for "alkylthio".

[0100] A "monovalent group" refers to a compound that "formally" eliminates a monovalent atom or group. A "subunit" refers to a compound that "formally" eliminates two monovalent or one divalent atoms or groups.

[0101] 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. Alkylene containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available connection point, preferably one or more of the following groups, independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0102] Similarly, the definitions of "alkyleneoxy", "alkenylene", "alkenyleneoxy", "cycloalkylene" and "heterocycloalkylene" are the same as "alkylene".

[0103] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share 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 connected to the parent structure is an aryl ring, non-limiting examples of which include:

[0104]

[0105] 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 C1-6 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 with one or more selected from halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution.

[0106] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is 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, thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.

[0107] 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:

[0108]

[0109] The heteroaryl group 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.

[0110] The term "spirocyclic" refers to a compound in which two rings share one atom. Non-limiting examples of spirocycloalkyls include:

[0111]

[0112] 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:

[0113]

[0114] The term "bridged ring" refers to a structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. According to the number of constituent rings, bridged cycloalkyl groups can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0115]

[0116] The term "heterocycle" refers to a ring having atoms other than carbon atoms, and includes heterocycloalkyl and heteroaryl rings.

[0117] The term "hydroxy" refers to an -OH group.

[0118] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0119] The term "cyano" refers to -CN.

[0120] The term "amino" refers to -NH2.

[0121] The term "nitro" refers to -NO2.

[0122] The term "oxo" refers to a =0 substituent.

[0123] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. When the substituent is keto or oxo (i.e., =O), two (2) hydrogen atoms on the atom are replaced.

[0124] 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

[0125] The present disclosure will be explained in more detail below in conjunction with 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.

[0126] The preparation method of the compound represented by formula X-1 in the present application has been recorded in the patent document with application number WO2022268051A, and all the contents of the aforementioned application document are incorporated into the present disclosure.

[0127] Example 1: Preparation of the compound represented by formula IV

[0128]

[0129] Add 65g of hydroxylamine hydrochloride and 730g of acetone to a 2L single-mouth bottle, cool to 0°C; add 158g of sodium bicarbonate, heat to 25°C and stir for 1h; add 120g of TsCl to the system and continue stirring at 25°C for 12h. Pour the system into 1.2L of purified water, stir for 1h, filter, and the filter cake is the crude product; slurry the crude product with 1L of 60% acetone aqueous solution; filter, and dry the filter cake overnight to obtain the compound shown in formula IV (yield 123g, yield 85%).

[0130] 1 HNMR(400MHz, CDCl3):7.87(m,2H),7.35(m,2H),2.46(m,3H),1.97(m,6H)

[0131] Example 2: Preparation of the compound represented by formula II-1

[0132]

[0133] Under nitrogen protection, 2.1 g of the compound shown in formula I-1 (manufacturer: Anaiji Chemical, batch number ZODHRRNM) and 10 mL of THF were added to a 250 mL three-necked flask, and the temperature was reduced to -78 ° C. 15 mL of LDA (2.0 M in Hep / THF) was added while maintaining low temperature, and the reaction was stirred for 30 min; 1.3 g of ZnCl2 was added, and the temperature was slowly raised to 0 ° C; 0.3 g of CuCl and 1.5 mL of DMPU were added to the system, and the compound shown in formula IV was added in batches under an ice bath. After the addition, the temperature was raised to 25 ° C and the reaction was carried out for 2 h; 5 mL of concentrated hydrochloric acid was added to the system to quench the reaction, and MTBE / water was added to separate the two; the organic phase was alkalized with 2 M NaOH, the organic phase was discarded, the aqueous phase was acidified with 2 M HCl, extracted with MTBE, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the compound shown in formula II-1 (yield 2.0 g, yield 89%).

[0134] 1 HNMR(400MHz, CDCl3):6.43(s,2H),3.67(m,1H)

[0135] Example 3: Preparation of the compound represented by formula II-1

[0136] Under nitrogen protection, 4.2 g of tetramethylpiperidine and 10 mL of THF were added to a 250 mL three-necked flask, the temperature was lowered to -20 ° C, 18.7 mL of butyl lithium solution (1.6 M in heptane) was added dropwise, and the reaction was continued for 30 minutes after the addition was completed. 1.3 g of ZnCl2 was added, and the temperature was raised to 25 ° C and stirring was continued for 30 minutes; 2.1 g of the compound shown in formula I-1 (manufacturer: Anaiji Chemical, batch number ZODHRRNM) was added, and stirring was continued for 2 hours. 0.3 g of CuCl and 1.5 mL of DMPU were added to the system, and the compound shown in formula IV was added in batches under an ice bath. After the addition, the temperature was raised to 25 ° C and reacted for 2 hours; 5 mL of concentrated hydrochloric acid was added to the system to quench the reaction, and MTBE / water was added to separate; the organic phase was alkalized with 2 M NaOH, the organic phase was discarded, the aqueous phase was acidified with 2 M HCl, extracted with MTBE, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the compound shown in formula II-1 (yield 2.0 g, yield 89%).

[0137] 1HNMR(400MHz, CDCl3):6.43(s,2H),3.67(m,1H)

[0138] Example 4: Preparation of the compound represented by formula II-1

[0139] Under nitrogen protection, 2.1 g of the compound shown in formula I-1 (manufacturer: Anaiji Chemical, batch number ZODHRRNM) and 10 mL of THF were added to a 250 mL three-necked flask, and the temperature was lowered to 0°C. 30 mL of i-PrMgCl (1.0 M in Hep / THF) was added while maintaining low temperature, and the reaction was stirred for 30 min; 0.3 g of CuCl and 1.5 mL of DMPU were added to the system, and the amination reagent was added in batches under an ice bath. After the addition, the temperature was raised to 25°C and the reaction was continued for 2 h; 5 mL of concentrated hydrochloric acid was added to the system to quench the reaction, and MTBE / water was added to separate the two; the organic phase was alkalized with 2 M NaOH, the organic phase was discarded, the aqueous phase was acidified with 2 M HCl, extracted with MTBE, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the compound shown in formula II-1 (yield 2.1 g, yield 93%).

[0140] 1 HNMR(400MHz, CDCl3):6.43(s,2H),3.67(m,1H)

[0141] Example 5: Preparation of the compound represented by formula III-1

[0142]

[0143] In a 100mL single-mouth bottle, add 1.1g of the compound represented by formula II-1 and 10mL of DCM, cool to 0°C, add 1.1g of chlorosulfonic acid isocyanate dropwise, and after completion of the addition, heat to 25°C and react for 6h; the reaction solution is directly spin-dried, 5mL of concentrated hydrochloric acid is added, heated to reflux and react for 6h, and filtered after cooling to obtain the compound represented by formula III-1 (yield 1g, yield 80%).

[0144] 1 HNMR (400MHz, CD3OD): 12.18 (s, 1H), 11.76 (s, 1H).

[0145] Example 6: Preparation of the compound represented by formula X-1

[0146]

[0147] Using the method in WO2022268051A, 2 g of the compound represented by formula III-1 prepared in Example 5 was added to finally obtain 0.28 g of the compound represented by formula X-1.

[0148] Example 7: Preparation of the compound represented by formula X-2

[0149]

[0150] Using the method in WO2022199587A, 1 g of the compound represented by formula III-1 prepared in Example 5 was added to finally obtain 0.24 g of the compound represented by formula X-2.

[0151] Example 8: Preparation of compounds represented by formula X-3 and formula X-4

[0152]

[0153] Using the method in WO2022188729A, 1 g of the compound represented by formula III-1 prepared in Example 5 was added to finally obtain 0.13 g of the compound represented by formula X-3.

[0154] Using the method in WO2022188729A, 1 g of the compound represented by formula III-1 prepared in Example 5 was added to finally obtain 0.15 g of the compound represented by formula X-4.

Claims

1. A method for preparing a compound of formula III, comprising: 1) the step of subjecting the compound represented by formula I to an amination reaction to form the compound represented by formula II, and 2) the step of forming a compound represented by formula III by a ring-closing reaction of the compound represented by formula II, in, W1, W2, W3 and W4 are each independently selected from C or N; R 1 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.

2. The method according to claim 1, wherein R 1 Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, 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; 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 or C2-C6 alkynyl.

3. The method according to claim 1 or 2, wherein R 1 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, oxo, amino, 3-10 membered cycloalkyl and 3-10 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, amino, carboxyl, nitro and cyano; Preferably, R 1 Each 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. More preferably, R 1 Each is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen and hydroxy.

4. The method according to any one of claims 1 to 3, wherein the amination reaction comprises: The step of reacting the compound represented by formula I with an aminating agent under alkaline conditions to form a compound represented by formula II, Among them, R 1 , W1, W2, W3, W4 and n are as defined in claim 1.

5. The method according to claim 4, wherein the amination agent is selected from Best 6. according to the method for claim 4 or 5, the alkaline agent is selected from sodium hydride, lithium diisopropylamide, lithium tetramethyl piperidine, bistrimethylsilyl lithium amide, n-butyl lithium, isopropyl magnesium chloride, isopropyl magnesium chloride lithium chloride, cyclohexyl magnesium chloride, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl, preferably lithium diisopropylamide, lithium tetramethyl piperidine, isopropyl magnesium chloride, isopropyl magnesium chloride lithium chloride, TMPMgCl, TMPMgCl-LiCl or TMPZnCl-LiCl.

7. The method according to any one of claims 1 to 6, wherein the ring-closing reaction comprises: The step of reacting the compound represented by formula II with chlorosulfonyl isocyanate to form the compound represented by formula III, Among them, R 1 , W1, W2, W3, W4 and n are as defined in claim 1.

8. A method for preparing a compound of formula III-1, comprising the steps of:

9. A method for preparing a KRAS G12D compound, comprising the method according to any one of claims 1 to 8.

10. The method according to claim 9, wherein the KRAS G12D compound is a compound represented by formula X, in, Q is N or CR 2a ; Ring A is an aryl group or a fused heteroaryl group; Ring B is selected from heterocyclyl, aryl and heteroaryl; R 2a and R 4a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxyl, hydroxyalkyl and cycloalkyl; Each R 1 and R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or R 5a , R 5b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl 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. The method according to claim 10 , wherein ring A is a naphthalene ring or a benzoheterocyclic ring.

12. The method according to claim 10 or 11, wherein ring B is a 3- to 8-membered heterocyclic group.

13. The method according to any one of claims 10 to 12, wherein R 2a and R 4a Each is independently selected from a hydrogen atom or a halogen.

14. The method according to any one of claims 10 to 13, wherein each R 1 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, amino, cyano and C 1-6 Hydroxyalkyl.

15. The method according to any one of claims 10 to 14, wherein R 5a and R 5b is a hydrogen atom; or R 5a , R 5b Together with the attached carbon atom, it forms a 3- to 6-membered cycloalkyl group.

16. The method according to any one of claims 10 to 15, wherein each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Hydroxyalkyl.

17. The method according to any one of claims 10 to 16, which is the following compound:

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

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