TW202408520A - KRAS G12D inhibitor and application thereof in medicine - Google Patents

Abstract

Provided are a compound of formula (I), and a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and an application thereof as a medicament for the treatment and/or prevention of diseases mediated by KRAS.

Description

KRAS G12D inhibitors and their medical applications

The present invention relates to the field of medical technology, and in particular to a compound of formula (I), its stereoisomers, tautomers, deuterated compounds or pharmaceutical salts, a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a drug for treating cancer.

Clinical data show that RAS is the gene with the highest mutation rate in human tumors. About 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, and 43% of multiple myeloma. And 32% of lung adenocarcinomas have RAS gene mutations. The most common mutation mode of RAS is point mutation, which often occurs in codons 12, 13, and 61. Among them, mutations in codon 12 are the most common, such as G12C, G12D or G12V.

Currently, drug development targeting KRAS mutations is one of the current hot spots in new drug research. KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered late clinical stages; while MIRATI is leading the way in the development of G12D inhibitors (WO2021041671A1).

KRAS has been a target of interest for drug developers due to the importance of abnormal KRAS activation in cancer progression and the prevalence of KRAS gene mutations in human cancers. Despite progress in this area, there is still a need for improved inhibitors of KRAS G12D mutant proteins in this area to meet more clinical needs.

The technical problem to be solved by the present invention is to overcome the problem of lack of KRAS G12D mutant protein inhibitors in the prior art, and to provide a compound represented by general formula (I) and its application. The compound represented by general formula (I) provided by the present invention has a good inhibitory effect on KRAS G12D mutant protein.

The present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt: (I) Wherein, X is selected from bond, NH, O or S; Selected from single bond or double bond; L is selected from bond, -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclyl- C _0-3 alkylene-, the -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14-membered heterocyclyl-C _{0 -3} alkylene-optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl; the ring A Selected from C _5-14 cycloalkyl, 5-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, said C _5-14 cycloalkyl or 5-14 membered heterocyclyl Selected from a single ring, a condensed ring, a spiro ring or a bridged ring, the C _5-14 cycloalkyl, 5-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl; Selected from or ,in, is a double bond, Selected from Z configuration or E configuration; R ₂ is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, the C _{3- 14} -cycloalkyl, 3-14-membered heterocyclyl, C _6-18- membered aryl or 5-18-membered heteroaryl is optionally further substituted by one or more R _a ; R _{a is} independently selected from H, hydroxyl, Cyano, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -C _0-3 alkylene -OR _b , -OC(=O)C _1-6 alkyl group, -C _0-3 alkylene -SR _b , -C _0-3 alkylene -N(R _b ) ₂ , -C _0-3 alkylene -S(=O)R _b , -C _{0 -3} alkylene-S(=O) ₂ R _b , -C _0-3 alkylene -SR _b , -C _0-3 alkylene -S(R _b ) ₅ , -C _0-3 alkylene Base -C(=O)R _b , -C _0-3 alkylene -C(=O)OR _b , -C _0-3 alkylene -C(=O)N(R _b ) ₂ , C _{2 -6} alkenyl, C _2-6 alkynyl, -C _0-3 alkylene -C _3-14 cycloalkyl, -C _0-3 alkylene -(3-14 membered heterocyclyl), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl), the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene -C _3-14 cycloalkyl, -C _0-3 alkylene -(3- 14-membered heterocyclyl), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl) optionally further substituted by one or more R _b substituted, each R _b is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl; R ₃ or R ₄ are independently Selected from H, halogen, cyano, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 haloalkyl, C _{1- 6} haloalkoxy, hydroxyl or hydroxyalkyl, the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl is optionally further replaced by a Or substituted by multiple halogens, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl; R ₅ is selected from H, halogen, -C _0-3 alkylene Cyano group, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 haloalkyl; R ₆ is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 Haloalkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, the C _1-6 alkyl, C _1-6 haloalkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, Substituted with C _1-6 alkyl or C _1-6 alkoxy; m is selected from 0, 1, 2, 3 or 4.

In some embodiments, X in formula (I) is O.

In some embodiments, L in formula (I) is selected from -C _1-3 alkylene- or -C _3-14 cycloalkyl-C _0-3 alkylene-.

In some embodiments, Ring A in formula (I) is selected from C _5-14 cycloalkyl or 5-14 membered heterocyclyl.

In some embodiments, the 5-14 membered heterocyclic group in formula (I) is a fused ring.

In some embodiments, the fused ring in formula (I) is selected from , , , , , , , , , , , , , or .

In some embodiments, in formula (I) Selected from or .

In some embodiments, R ₆ in formula (I) is independently selected from H, halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C _1-6 alkyl substituted.

In some embodiments, in formula (I) Selected from or .

In some embodiments, in formula (I) Selected from , , , , , , , , or .

In some embodiments, R ₂ in formula (I) is selected from C _6-18 aryl or 5-18 membered heteroaryl, and the C _6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R _a , R _a independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 Alkynyl or -C _0-3 alkylene -C _3-14 cycloalkyl.

In some embodiments, _R in formula (I) is selected from , , , , , , , , or , described , , , , , , , , ,or Optionally further substituted by one or more _Ra independently selected from H, hydroxyl, cyano, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _2-6 alkene base, C _2-6 alkynyl or -C _0-3 alkylene -C _3-14 cycloalkyl.

In some embodiments, _R2 in formula (I) is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ₃ in formula (I) is selected from H, hydroxyl, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy or C _3-14 cycloalkyl-O-.

In some embodiments, _R3 in formula (I) is selected from H, hydroxyl, methyl, , or .

In some embodiments, R ₄ in formula (I) is selected from H, halogen, C _1-6 alkoxy or C _1-6 haloalkoxy, preferably F.

In some embodiments, _R5 in formula (I) is H.

In some embodiments, formula (I) is selected from (IA) or (IB): (IA) (IB) Wherein, the definitions of X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in formula (I).

In some embodiments, formula (I) is selected from (IA-1) and (IB-1): (IA-1) (IB-1) Wherein, the definitions of X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in formula (I).

In some embodiments, the compound of formula (I) is selected from (IA-1) and (IB-1), wherein: R ₂ is selected from C _6-18 aryl or 5-18 membered heteroaryl, said C _6- The _18- aryl or 5-18-membered heteroaryl is optionally further substituted by one or more R _a ; the R _a is independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene -C _3-14 cycloalkyl, -C _0-3 Alkyl-(3-14 membered heterocyclyl), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl); R ₃ Or R ₄ is independently selected from H, halogen, cyano, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 Haloalkyl, C _1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl The radical is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl; X is selected from bond, NH, O or S; L is selected from bond or -C _1-3 alkylene-; R ₆ is independently selected from H, halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl optionally further Substituted by one or more halogen, hydroxyl, cyano, amino, nitro or C _1-6 alkyl.

The present invention provides a compound represented by the general formula (I), its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts: (I) wherein X is selected from a bond, NH, O or S; is selected from a single bond or a double bond; L is selected from a bond, -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene-, wherein the -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene- is optionally further substituted with one or more halogens, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; the ring A is selected from C _5-14 cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl, wherein the C _{The C5-14} cycloalkyl or 5-14 membered heterocyclic group is selected from a monocyclic ring, a fused ring, a spirocyclic ring or a bridged ring, and the _C5-14 cycloalkyl, 5-14 membered heterocyclic group, _C6-18 aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more halogens, _C1-6 alkyl, _C1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl groups; Selected from or ,in, For double keys, R ₂ is selected from C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl, and the C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more _Ra ; Ra _is independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, -C _0-3 alkylene-OR _b , -OC(═O)C _1-6 alkyl, -C _0-3 alkylene-SR _b , -C _0-3 alkylene-N(R _b ) ₂ , -C _0-3 alkylene-S(═O)R _b , -C -C _0-3 alkylene-S(═O) ₂ R _b , -C _0-3 alkylene-SR _b , -C _0-3 alkylene-S(R _b ) ₅ , -C _0-3 alkylene-C(═O)R _b , -C _0-3 alkylene-C(═O)OR _b , -C _0-3 alkylene-C(═O)N(R _b ) ₂ , C _2-6 alkenyl, C 2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclic group), -C _0-3 alkylene _- C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl), the C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C 2-6 the alkylene-C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclo), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl) is optionally further substituted by one or more R _b , each R _b is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 halogenated alkyl; R ₃ or R ₄ is independently selected from H, halogen, cyano, amino, -NHR _a , -N(R _a ) ₂ , nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O—, C _1-6 halogenated alkyl, C 1-6 R5 is selected from H, halogen, _-C0-3 alkylene cyano, _C1-6 alkyl, _C1-6 alkoxy or C1-6 halogenated alkyl; R6 is selected from H, halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 halogenated alkyl, C3-14 cycloalkyl, _3-14 membered heterocyclic group, C6-18 aryl or 5-18 membered heteroaryl, the _C1-6 alkyl, _C1-6 alkoxy, C3-14 cycloalkyl-O-, halogenated alkyl or hydroxyl alkyl is optionally further substituted by one or more halogen, _C1-6 alkyl, C1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; _R5 is selected from H, halogen, _-C0-3 alkylene cyano, _C1-6 alkyl, C1-6 alkoxy or _C1-6 halogenated alkyl; _R6 is selected from H, halogen, hydroxyl, cyano, _C1-6 alkyl, _C1-6 halogenated alkyl, _C3-14 cycloalkyl, 3-14 membered heterocyclic group, _C6-18 aryl or 5-18 membered heteroaryl, the C C _1-6 alkyl, C _1-6 halogenated alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclo, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, hydroxyl, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy groups; m is selected from 0, 1, 2, 3 or 4.

In some embodiments, X in formula (I) is O.

In some embodiments, L in formula (I) is selected from -C _1-3 alkylene- or -C _3-14 cycloalkyl-C _0-3 alkylene-.

In some embodiments, Ring A in formula (I) is selected from C _5-14 cycloalkyl or 5-14 membered heterocyclyl.

In some embodiments, the 5-14 membered heterocyclic group in formula (I) is a fused ring.

In some embodiments, the fused ring in formula (I) is selected from , , , , , , , , , , , , , or .

In some embodiments, in formula (I) Selected from or .

In some embodiments, R ₆ in formula (I) is independently selected from H, halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, the C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C _1-6 alkyl substituted.

In some embodiments, in formula (I) Selected from or .

In some embodiments, in formula (I) Selected from , , , , , , , , , or .

In some embodiments, R ₂ in formula (I) is selected from C _6-18 aryl or 5-18 membered heteroaryl, and the C _6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R _a , R _a independently selected from H, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl or -C _0-3 alkylene -C _3-14 cycloalkyl.

In some embodiments, _R in formula (I) is selected from , , , , , , , , , or , described , , , , , , , , , ,or Optionally further substituted by one or more _Ra independently selected from H, hydroxy, cyano, amino, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl or -C _0-3 alkylene -C _3-14 cycloalkyl.

In some embodiments, _R2 in formula (I) is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ₃ in formula (I) is selected from H, hydroxyl, halogen, cyano, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy or C _3-14 cycloalkyl-O-.

In some embodiments, _R3 in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy, , , , or .

In some embodiments, R ₄ in formula (I) is selected from H, halogen, C _1-6 alkoxy or C _1-6 haloalkoxy, preferably F.

In some embodiments, R ₅ in formula (I) is H.

In some embodiments, formula (I) is selected from (IA) or (IB): (IA) (IB) Wherein, the definitions of X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in formula (I).

In some embodiments, formula (I) is selected from (IA-1) or (IB-1): (IA-1) (IB-1) Wherein, the definitions of X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in formula (I).

In some embodiments, the compound of formula (I) is selected from (IA-1) and (IB-1), wherein: R ₂ is selected from C _6-18 aryl or 5-18 membered heteroaryl, wherein the C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more _Ra ; wherein Ra _is independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclo), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl); R ₃ or R ₄ are independently selected from H, halogen, cyano, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, hydroxyl or hydroxyalkyl, wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, halogenated alkyl or hydroxyalkyl is optionally further substituted with one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; X is selected from a bond, NH, O or S; L is selected from a bond or -C _1-3 alkylene-; R ₆ is independently selected from H, halogen, C 1-6 alkyl, C _1-6 alkoxy, C 3-14 cycloalkyl-O-, halogenated alkyl or hydroxyalkyl; The C _3-14 cycloalkyl, 3-14 _membered heterocyclic group _, C _6-18 aryl or 5-18 membered heteroaryl group is optionally further substituted by one or more halogens, hydroxyls, cyanos, aminos, nitros or C _1-6 alkyls.

In some embodiments, formula (I) is selected from (IA-1-1) or (IB-1-1): or The R ₂ is selected from , described Optionally further substituted by one or more _Ra independently selected from H, hydroxy, cyano, amino, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl or -C _0-3 alkylene-C _3-14 cycloalkyl; the R ₄ is selected from hydrogen or halogen; the R ₆ is selected from hydrogen or halogen; the R ₇ is selected from alkyl, haloalkyl or cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.

The present invention provides a compound represented by the general formula (I), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof: (I) wherein X is selected from a bond, NR _a , O or S; is selected from a single bond or a double bond; L is selected from a bond, -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene-; the -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene- is optionally further substituted with one or more halogens, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; the ring A is selected from C _5-14 cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl; the C _5-14 membered cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro, hydroxyl, replaced by; Selected from or ;in, or wherein two R ₆ in the above-mentioned group may form, together with the atoms to which they are attached, a C _3-8 cycloalkyl group or a 3-8 membered heterocyclic group, wherein the C _3-8 cycloalkyl group or the 3-8 membered heterocyclic group may be further substituted by one or more _Ra ; R ₂ is selected from a C _3-14 cycloalkyl group, a 3-14 membered heterocyclic group, a C _6-18 aryl group or a 5-18 membered heteroaryl group; wherein the C _3-14 cycloalkyl group, the 3-14 membered heterocyclic group, the C _6-18 aryl group or the 5-18 membered heteroaryl group may be further substituted by one or more _Ra ; R ₃ or R ₄ is independently selected from H, halogen, cyano, amino, -NHR _a , -N(R _a ) ₂ , nitro, C _1-6 alkyl group, C _1-6 alkoxy group, C wherein the C _1-6 alkyl, C _1-6 alkoxy, C 3-14 cycloalkyl-O-, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy or hydroxyl group; wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C 1-6 halogenated alkyl or C _1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, cyano, amino, nitro or hydroxyl groups; R ₅ is selected from H, halogen, -C _0-3 alkylene cyano, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 halogenated alkyl; R ₆ is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 halogenated alkyl, C wherein _{the C 1-6 alkyl} , C _1-6 halogenated alkyl, C _3-14 cycloalkyl, C _6-18 aryl or _5-18 heteroaryl is optionally further substituted with one or more halogen, hydroxyl, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy groups; each R _a is independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C 1-6 halogenated alkyl, C _1-6 alkoxy, -C _0-3 alkylene-OR _b , -OC(═O)C _1-6 alkyl, -C _0-3 alkylene-SR _b , _{-C 0-3 alkylene} -N(R _b ) ₂ , -C _0-3 alkylene-S(═O)R _b , -C _0-3 alkylene-S(═O) ₂ R _b , -C _0-3 alkylene-SR _b , -C _0-3 alkylene-S(R _b ) ₅ , -C _0-3 alkylene-C(═O)R _b , -C 0-3 alkylene-C(═O)OR _b , -C _0-3 alkylene-C(═O)N(R _b ) ₂ , C 2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C 0-3 alkylene-(3-14 membered heterocyclo), -C 0-3 alkylene-C 6-18 aryl, or -C _0-3 alkylene-(5-18 membered heteroaryl); the C _1-6 alkyl, C _2-6 alkynyl, -C _0-3 alkylene-C 3-14 cycloalkyl, -C 0-3 alkylene-(3-14 membered heterocyclo), -C _0-3 alkylene-C _6-18 aryl, or -C _0-3 alkylene-(5-18 membered heteroaryl) C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclo), -C _0-3 alkylene-C _6-18 aryl or -C 0-3 alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R _b ; each R _b is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 halogenated alkyl; m is selected from 0 _{, 1,} 2, 3 or 4.

In some embodiments, X in formula (I) is O.

In some embodiments, L in formula (I) is selected from -C _1-3 alkylene- or -C _3-14 cycloalkyl-C _0-3 alkylene-.

In some embodiments, Ring A in Formula (I) is selected from C _5-14 cycloalkyl or 5-14 membered heterocyclic group.

In some embodiments, the 5-14 membered heterocyclic group in formula (I) is a fused ring.

In some embodiments, the fused ring in formula (I) is selected from , , , , , , , , , , , , , or .

In some embodiments, in formula (I) Selected from or .

In some embodiments, R ₆ in formula (I) is independently selected from H, halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl; the C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogens , hydroxyl, cyano, amino, nitro or C _1-6 alkyl substituted.

In some embodiments, in formula (I) Selected from or ; or Optionally, it may be further substituted with one or more halogens, C _1-6 alkyls or replaced.

In some embodiments, in formula (I) Selected from or ; or Optionally further one or more replaced.

In some embodiments, in formula (I) Selected from , , , , , , , , , or ;in, Indicates Z configuration or E configuration.

In some embodiments, in formula (I) Selected from , , , or .

In some embodiments, R ₂ in formula (I) is selected from C _6-18 aryl or 5-18 membered heteroaryl; the C _6-18 aryl or 5-18 membered heteroaryl is optionally further Substituted by one or more R _a , R _a independently selected from H, hydroxyl, cyano, amino, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _{2 -6} alkynyl or -C _0-3 alkylene -C _3-14 cycloalkyl.

In some embodiments, _R2 in formula (I) is selected from , , , , , , , , , or ; wherein said , , , , , , , , , ,or Optionally further substituted with one or more _Ra independently selected _from H, hydroxyl, cyano, amino, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl or _-C0-3 alkylene- _C3-14 cycloalkyl.

In some embodiments, _R2 in formula (I) is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, R ₃ in formula (I) is selected from H, hydroxyl, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _3-14 Cycloalkyl-O-.

In some embodiments, _R3 in formula (I) is selected from H, halogen, hydroxyl, methyl, methoxy, , , , or .

In some embodiments, R ₄ in formula (I) is selected from H, halogen, C _1-6 alkoxy or C _1-6 halogenated alkoxy; preferably F.

In some embodiments, _R5 in formula (I) is H.

In some embodiments, formula (I) is selected from (IA) or (IB): (IA) (IB) Wherein, the definitions of the ring A, X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in formula (I).

In some embodiments, formula (I) is selected from (IA-1) or (IB-1): (IA-1) (IB-1) wherein X, L, R ₂ , R ₃ , R ₄ and R ₆ are as defined in formula (I).

In some embodiments, formula (I) is selected from (IA-1') or (IB-1'): (IA-1') (IB-1') Wherein, the definitions of X, L, R ₂ , R ₃ , R ₄ , R ₆ and R _a are as described in formula (I).

In some embodiments, the compound of formula (I) is selected from (IA-1), (IB-1), (IA-1') or (IB-1'), wherein: the R ₂ is selected from C _6-18 aryl or 5-18 membered heteroaryl; wherein the C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more _Ra , wherein Ra _is independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclo), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl); The _R3 or _R4 is independently selected from H, halogen, cyano, amino, nitro, _C1-6 alkyl, C1-6 alkoxy, _C3-14 cycloalkyl-O-, _C1-6 halogenated alkyl, C1-6 halogenated alkoxy or hydroxyl; wherein the _C1-6 alkyl, _C1-6 alkoxy, _C3-14 cycloalkyl-O-, _C1-6 halogenated alkyl or _C1-6 halogenated alkoxy is optionally further substituted by one or more halogen, _C1-6 alkyl, _C1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; the X is selected from a bond, NH, O or S; the L is selected from a bond or _-C1-3 alkylene-; the _R6 is independently _selected from H, halogen, _C1-6 alkyl, C1-6 alkoxy, C3-14 cycloalkyl-O-, _C1-6 halogenated alkyl or C1-6 halogenated alkoxy _The C _3-14 cycloalkyl, 3-14 membered heterocyclic group _, C _6-18 aryl or 5-18 membered heteroaryl group is optionally further substituted by one or more halogens, hydroxyls, cyanos, aminos, nitros or C _1-6 alkyls.

In some embodiments, formula (I) is selected from (IA-1-1) or (IB-1-1): or The _R2 is selected from , Optionally further substituted by one or more _Ra , said _Ra independently selected from H, hydroxyl, cyano, amino, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl or _-C0-3 alkylene- _C3-14 cycloalkyl; said _R4 selected from hydrogen or halogen; said _R6 selected from hydrogen or halogen; said _R7 selected from _C1-6 alkyl, _C1-6 halogenated alkyl or _C3-14 cycloalkyl; preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.

In some embodiments, formula (I) is selected from (IA-1'-1) or (IB-1'-1): (IA-1'-1) or (IB-1'-1) wherein _R2 is selected from , Optionally further substituted by one or more _Ra , wherein _{Ra is} independently selected from H, hydroxyl, cyano, amino, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl or _-C0-3 alkylene- _C3-14 cycloalkyl; wherein _R4 is selected from hydrogen or halogen; wherein _R6 is selected from hydrogen or halogen; wherein _R7 is selected from _C1-6 alkyl, _C1-6 halogenated alkyl or _C3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.

The present invention provides a compound represented by the general formula (I), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof: (I) wherein X is selected from a bond, NR _a , O or S; is selected from a single bond or a double bond; L is selected from a bond, -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene-; the -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene- is optionally further substituted with one or more halogens, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; the ring A is selected from C _5-14 cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl; the C _5-14 membered cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro, hydroxyl, replaced by; Selected from or ;in, or The two _R6 in the above-mentioned group may form a _C3-8 cycloalkyl group or a 3-8 membered heterocyclic group together with the atoms to which they are connected, and the _C3-8 cycloalkyl group or the 3-8 membered heterocyclic group may be further substituted by one or more _Ra ; _R2 is selected from _C3-14 cycloalkyl group, a 3-14 membered heterocyclic group, a _C6-18 aryl group or a 5-18 membered heteroaryl group; the _C3-14 cycloalkyl group, the 3-14 membered heterocyclic group, the _C6-18 aryl group or the 5-18 membered heteroaryl group may be further substituted by one or more _Ra ; _R3 is independently selected from _C1-6 alkoxy, _C3-14 cycloalkyl-O- or _C1-6 halogenated alkoxy; the _C1-6 alkoxy, C wherein the C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl, C 1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, cyano, amino, nitro or hydroxyl groups; R ₄ is independently selected from H, halogen, cyano, amino, -NHR _a , -N(R _a ) ₂ , nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy group or hydroxyl group; the C _1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C _1-6 halogenated alkyl or C 1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl or C _1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C _R5 is selected from H, halogen, _{-C0-3 alkylene cyano, C1-6 alkyl} , _C1-6 alkoxy or _C1-6 halogenated alkyl; _R6 is selected from H, halogen, hydroxyl, cyano, _C1-6 alkyl, _C1-6 halogenated alkyl, _C3-14 cycloalkyl, _3-14 membered heterocyclic group, C6-18 aryl or 5-18 membered heteroaryl; the C1-6 alkyl, _C1-6 halogenated alkyl, _C3-14 cycloalkyl, 3-14 membered heterocyclic group, _C6-18 aryl or 5-18 membered heteroaryl group is selected from H, halogen, _-C0-3 alkylene cyano, _C1-6 alkyl, _C1-6 alkoxy or C1-6 halogenated alkyl; The _6-18 membered aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy groups; R _{a is} each independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, -C _0-3 alkylene-OR _b , -OC(═O)C _1-6 alkyl, -C _0-3 alkylene-SR _b , -C _0-3 alkylene-N(R _b ) ₂ , -C _0-3 alkylene-S(═O)R _b , -C _0-3 alkylene-S(═O) ₂ R _b , -C _0-3 alkylene-SR _b , -C _0-3 alkylene-S(R _b ) ₅ , -C -C _0-3 alkylene-C (= O) R _b , -C _0-3 alkylene-C (= O) OR _b , -C _0-3 alkylene-C (= O) N (R _b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclic group), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl); the C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclic group), -C -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl) is optionally further substituted by one or more R _b ; each R _b is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 halogenated alkyl, -C (= O) C _1-6 alkyl or -C (= O) O C _1-6 alkyl; m is selected from 0, 1, 2, 3 or 4.

In some embodiments, each R _b in formula (I) is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 halogenated alkyl.

In some embodiments _{, the} Or 5-18 membered heteroaryl, the C _5-14 cycloalkyl or 5-14 membered heterocyclyl is selected from a single ring, a condensed ring, a spiro ring or a bridged ring, the C _5-14 cycloalkyl, The 5-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, Substituted by cyano, amino, nitro or hydroxyl; Selected from or ,in, is a double bond, Selected from Z configuration or E configuration; R ₃ is independently selected from C _1-6 alkoxy, C _3-14 cycloalkyl-O- or C _1-6 haloalkoxy, the C _1-6 alkoxy base or C _3-14 cycloalkyl-O- is further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxyl; R ₄ is selected from H, halogen, cyano, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 haloalkyl, C _1-6 haloalkoxy, hydroxyl or hydroxyalkyl, the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, haloalkyl or hydroxyalkyl optionally further Substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, haloalkyl, cyano, amino, nitro or hydroxy; each R _b is independently H, halogen, hydroxy, Cyano, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl.

In some embodiments, X in formula (I) is O.

In some embodiments, L in formula (I) is selected from -C _1-3 alkylene- or -C _3-14 cycloalkyl-C _0-3 alkylene-.

In some embodiments, the ring A in formula (I) is selected from C _5-14 cycloalkyl or 5-14 membered heterocyclic group.

In some embodiments, the 5-14 membered heterocyclic group in formula (I) is a fused ring.

In some embodiments, the fused ring described in formula (I) is selected from , , , , , , , , , , , , , or .

In some embodiments, the formula (I) Selected from or .

In some embodiments, R ₆ in formula (I) is independently selected from H, halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl Or 5-18 membered heteroaryl; the C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more Substituted by halogen, hydroxyl, cyano, amino, nitro or C _1-6 alkyl.

In some embodiments, as described in Formula (I) Selected from or ; said or may optionally be further substituted by one or more halogens, C _1-6 alkyl or replaced.

In some embodiments, the formula (I) Selected from or ; or Optionally further one or more replaced.

In some embodiments, as described in Formula (I) Selected from , , , , , , , , , or ;in, Indicates Z configuration or E configuration.

In some embodiments, as described in Formula (I) Selected from , , , or .

In some embodiments, _R2 in formula (I) is selected from _C6-18 aryl or 5-18 membered heteroaryl; the _C6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more _Ra , and _{Ra is} independently selected from H, hydroxyl, cyano, amino, halogen, _C1-6 alkyl, _C1-6 alkoxy, _{C2-6 alkenyl, C2-6 alkynyl} or _-C0-3 alkylene- _C3-14 cycloalkyl.

In some embodiments, _R2 in formula (I) is selected from , , , , , , , , , or ; wherein said , , , , , , , , , ,or Optionally further substituted with one or more _Ra independently selected _from H, hydroxyl, cyano, amino, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl or _-C0-3 alkylene- _C3-14 cycloalkyl.

In some embodiments, _R2 in formula (I) is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, _R3 in formula (I) is selected from _C1-6 alkoxy or _C3-14 cycloalkyl-O-.

In some embodiments, R ₃ in formula (I) is selected from methoxy, , , or .

In some embodiments, _R4 in formula (I) is selected from H, halogen, _C1-6 alkoxy or _C1-6 halogenated alkoxy; preferably F.

In some embodiments, R ₅ in Formula (I) is H.

In some embodiments, the compound of formula (I) described in formula (I) is selected from formula (IA) or (IB): (IA) (IB) Wherein, the definitions of the ring A, X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in the above general formula (I).

In some embodiments, the compound of formula (I) is selected from formula (IA-1) or (IB-1): (IA-1) (IB-1) wherein X, L, R ₂ , R ₃ , R ₄ and R ₆ are as defined in the above general formula (I).

In some embodiments, the compound of formula (I) is selected from formula (IA-1') or (IB-1'): (IA-1') (IB-1') wherein X, L, R ₂ , R ₃ , R ₄ , R ₆ and _Ra are as defined in the above general formula (I).

In some embodiments, in formula (IA-1), (IB-1), (IA-1') or (IB-1'), R ₂ is selected from C _6-18 aryl or 5-18 membered heteroaryl; wherein the C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more _Ra , wherein _{Ra is} independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclo), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl); R ₃ is selected from C wherein the C _1-6 alkoxy, C _3-14 cycloalkyl-O- or C _1-6 halogenated alkoxy is optionally further substituted _by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, cyano, amino, nitro or hydroxyl; R ₄ is selected from H, halogen, cyano, amino, nitro, C _{1-6 alkyl, C 1-6 alkoxy} , _{C 3-14} cycloalkyl-O-, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy or hydroxyl; wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl or C _1-6 The C _1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, cyano, amino, nitro or hydroxyl groups; the X is selected from a bond, NH, O or S; the L is selected from a bond or -C _1-3 alkylene-; the R ₆ is independently selected from H, halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl, the C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl group is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or C _1-6 alkyl substituted.

In some embodiments, formula (I) is selected from formula (IA-1-1) or (IB-1-1): or The R ₂ is selected from , described Optionally further substituted by one or more _Ra independently selected from H, hydroxy, cyano, amino, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl or -C _0-3 alkylene-C _3-14 cycloalkyl; the R ₄ is selected from hydrogen or halogen; the R ₆ is selected from hydrogen or halogen; the R ₇ is selected from C _1-6 alkyl, C _1-6 haloalkyl or C _3-14 cycloalkyl; preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.

In some embodiments, formula (I) is selected from (IA-1'-1) or (IB-1'-1): (IA-1'-1) or (IB-1'-1) The R ₂ is selected from , described Optionally further substituted by one or more _Ra independently selected from H, hydroxy, cyano, amino, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl or -C _0-3 alkylene-C _3-14 cycloalkyl; the R ₄ is selected from hydrogen or halogen; the R ₆ is selected from hydrogen or halogen; the R ₇ is selected from C _1-6 alkyl, C _1-6 haloalkyl or C _3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl.

In some embodiments, the compound in formula (I) is selected from: .

In some embodiments, the intermediate compound involved in the compound of formula (I) is selected from: , , , , , , , , or .

The present invention also provides a method for preparing the intermediate compound M13, which comprises the following steps: reacting the racemate M9 with a chiral acid to generate a corresponding salt, and ionizing it under alkaline conditions to obtain an S-configuration free base M13.

In some embodiments of the present invention, the chiral acid is selected from L-(-)-di-p-methylbenzoyltartaric acid, L-(-)-dibenzoyltartaric acid or L-(-)-di-p-methoxybenzoyltartaric acid.

In some embodiments of the present invention, the preparation method of the intermediate compound M13 comprises the following steps: 1) reacting the racemate M9 with the chiral acid L-(-)-di-p-methylbenzoyltartaric acid (DPLT) to generate the corresponding compound M13-1, 2) ionizing under alkaline conditions to obtain the S-configuration free base M13.

In some embodiments of the present invention, the preparation method of intermediate M13 further comprises the following steps: 1) Preparation of M13-1: M9 is dissolved in organic solvent 1, heated and stirred to dissolve, to obtain a solution of M9; L-(-)-di-p-methylbenzoyltartaric acid is dissolved in organic solvent 2 to form an acid solution; the acid solution is slowly added dropwise to the solution of M9, and after the acid solution is added dropwise and dissolved, organic solvent 3 is added dropwise to the reaction solution, and after the addition is completed, the temperature is slowly lowered, crystallization is carried out, the sample is filtered, and the filter cake is vacuum dried to obtain a crude product of ( S )-DPLT salt, and the crude product of ( S )-DPLT salt is recrystallized in organic solvent 4 to obtain ( S )-DPLT salt M13-1; 2) Preparation of M13 Weigh M13-1 into a reactor, add organic solvent 5, stir to dissolve; add purified water and alkali to the reaction solution, adjust the pH of the aqueous phase to 11-12, and stir; stir the aqueous phase with organic solvent 6 and then separate and extract; wash the organic phase, dry it, filter the dried organic phase, and concentrate the filtrate to obtain M13.

Preferably, the organic solvent 1 in step 1) is selected from 2-methyltetrahydrofuran, ethanol, acetonitrile, ethyl ketone, ethyl ketone/H ₂ O (19/1, volume ratio), acetonitrile/water (30/1 , volume ratio) or mixtures thereof.

Preferably, the organic solvent 2 in step 1) is selected from ethyl acetate, ethanol, isopropyl alcohol, ethyl ketone, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof.

Preferably, the organic solvent 3 in step 1) is selected from ethyl acetate, isopropyl alcohol, isopropyl acetate, methyl tert-butyl ether, n-heptane or a mixture thereof.

Preferably, the organic solvent 4 in step 1) is selected from isopropyl alcohol/acetonitrile ethanol/acetonitrile/ethyl acetate, methanol/acetonitrile/ethyl acetate, ethanol/ethyl ketone/ethyl acetate, ethanol/methyl Tert-butyl ether, isopropyl alcohol/2-methyltetrahydrofuran F, methanol/2-methyltetrahydrofuran or ethanol/acetonitrile/ethyl acetate. Preferably, the organic solvent 5 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran F, ethyl acetate or a mixture thereof.

Preferably, the organic solvent 6 in step 2) is selected from dichloromethane/methanol, 2-methyltetrahydrofuran or ethyl acetate.

The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt .

The present invention provides the use of the compound represented by structural formula (I) or its pharmaceutical composition in the preparation of medicines.

The present invention further provides a better technical solution for the application.

Preferably, the application is application in the preparation of a drug for treating and/or preventing cancer.

Preferably, the application is for the preparation of a medicament for treating a disease mediated by KRAS G12D. Preferably, the disease is cancer.

Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, hepatocholangiocarcinoma, myeloproliferative syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann's cell carcinoma, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

The present invention also provides a method for treating and/or preventing a disease, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I), its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts thereof or a pharmaceutical composition containing the same.

The present invention also provides a method for treating and/or preventing a disease mediated by KRAS G12D, comprising administering to a subject a therapeutically effective amount of at least any one compound represented by structural formula (I), its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the same.

The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I), its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts thereof or a pharmaceutical composition containing the same.

Preferably, in the above method, the KRAS G12D-mediated disease is cancer.

Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocellular carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, Squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

For example, unless otherwise specified, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.

In the present invention, unless otherwise stated, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, " _1-6 " in "C _1-6 alkyl" refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.

"Alkoxy" refers to the oxygen ether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.

The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the alkylene's point of attachment to the rest of the compound. Similarly, "C _1-3 " in C _1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

The term "haloalkyl" refers to the aforementioned alkyl group in which one or more H has been replaced by a halogen atom, such as C _1-6 haloalkyl.

The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to a C, and forms a sulfenyl or sulfonyl group or an N-oxide group when attached to a heteroatom.

In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocyclic ring" refers to a polyunsaturated carbon ring or heterocyclic ring having aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

The term "aryl", as used herein, unless otherwise stated, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group including atoms of a carbocyclic ring. Preferably, it is a C _6-18 aryl group, and more preferably, the aryl group is a C _6-10 monocyclic or bicyclic aromatic ring group. Preferred are phenyl and naphthyl; the most preferred is naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.

The term "heterocyclic group" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic group, wherein the heteroatom is selected from N, O and/or S. The heterocyclic group may include a monocyclic or polycyclic group (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclic group may be connected to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, the heterocyclic group has 3 to 14 members, and the "3 to 14 members" in the heterocyclic group has 3 to 14 members, and the heterocyclic group has 3 to 14 members, wherein the "3 to 14 members" in the heterocyclic group has 3 to 14 members, and the heterocyclic group has 3 to 14 members, wherein the "3 to 14 members" in the heterocyclic group has 3 to 14 members, wherein the heterocyclic group has 5 to 14 members, and the heterocyclic group has 3 to 8 members, and the heterocyclic group has 3 to 6 members. wherein the nitrogen or sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized. Examples of these heterocyclic groups include but are not limited to , cyclobutane, pyrrolidinyl, piperidinyl, piperazinyl, oxo-piperazinyl, oxo-piperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfonyl, thiomorpholinylsulfonyl and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

The term "heteroaryl", in the present invention, unless otherwise specified, refers to a monocyclic or polycyclic (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Preferred is a 5-18 membered heteroaryl group, wherein the "5-18 members" in the 5-18 membered heteroaryl group refers to a heteroaryl group consisting of 5-18 ring atoms of C, N, O or S, and more preferred is a 5-10 membered heteroaryl group. Examples of heteroaryl groups include but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, oxazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolyl or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclo or cycloalkyl ring, wherein the ring that is attached to the parent structure is the heteroaryl ring.

The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Preferred C _3-14 cycloalkyl, where "C _3-14 " means that the cycloalkyl can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 rings atom. Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is connected to the parent structure The rings joined together are cycloalkyl.

The term "substituted" means that one or more hydrogen atoms in the group are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), C _1-8 alkyl, C _3-12 cycloalkyl, -OR ¹ , -SR ¹ , =O, =S, -C(O)R ₁ , -C(S)R ¹ , =NR ¹ , -C(O)OR ¹ , -C(S)OR ¹ , -NR ¹ R ² , -C(O)NR ¹ R ² , cyano, nitro, -S(O) ₂ R ¹ , -OS(O ₂ )OR ¹ , -OS(O) ₂ R ¹ , -OP(O)(OR ¹ )(OR ² ); wherein R ¹ and R ² are independently selected from -H, C _1-6 alkyl, C _1-6 haloalkyl or C _3-6 cycloalkyl. In some embodiments, substituents are independently selected from a group comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert- _butoxy , _-SCH3 , _-SC2H5 , formaldehyde, -C( _OCH3 ), cyano, nitro, _-CF3 , _-OCF3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a bond.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.

When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low price), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low price), potassium, sodium, and zinc. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Nontoxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2- Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiridine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine , Methylglucosamine, morpholine, guazine, guadine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. .

When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, parapexic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydriodic acid, perchloric acid, cyclohexane sulfonic acid, salicylic acid, 2-naphthalene sulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

The drug precursors of the compounds of the present invention are included in the protection scope of the present invention. Generally, the drug precursors refer to functional derivatives that are easily converted into the desired compounds in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of the compounds of the present invention, which can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues after being administered to a recipient.

The compounds described in the present invention may contain one or more asymmetric centers, and diastereoisomers and optical isomers may arise therefrom. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.

When the compound represented by formula (I) exists as tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

Substitution of compounds of formula (I) with heavier isotopes (e.g., deuterium) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention to an organism.

In the present invention, "a", "an", "the", "at least one" and "one or more" can be used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, Powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

The term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of a disease and/or side effects resulting from a disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of a disease, i.e., preventing its development; or (b) relieving the symptoms of a disease, i.e., causing regression of the disease or symptoms.

The term "effective amount" means (i) treating or preventing a specified disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying the symptoms described herein. An amount of a compound of the invention that is sufficient to induce the onset of one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.

Excellent effects of the present invention: The compounds of the present invention have excellent activities in terms of enzymatic activity, cell activity, PK, bioavailability, etc., and can be used to treat and/or prevent diseases mediated by KRAS G12D. In particular, compared with MART1133 (comparison compound D1), the compound of the present invention has higher whole blood exposure and lower clearance rate in intravenous administration; it has better PO exposure in oral administration. AUC) and oral bioavailability (F%), the oral absorption of the compound of the present invention is significantly better than that of MART1133.

In order to make the above content clearer and specific, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.

Unless otherwise stated, all temperatures herein refer to degrees Celsius. Room temperature refers to 18-25℃.

The following abbreviations are used in the examples: DMF: N , N -dimethylformamide; NIS: N -iodosuccinimide; THF: tetrahydrofuran; EA: ethyl acetate; PE: petroleum ether; DCM : Dichloromethane; MeOH: methanol; mCPBA: m-chloroperoxybenzoic acid; CsF: cesium fluoride; TBDPSCl: tert-butyldiphenylsilyl chloride; DPPA: diphenylphosphate azide; CDI: N,N'-Carbonyldiimidazole; DIEA: N,N-diisopropylethylamine; CataCXium A Pd G3: methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'- Biphenyl-2-yl)palladium(II); SphosPdG2: Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl)palladium(II); DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; PyBOP: 1H-benzotriazole-1 -Tripyrrolidinyl hexafluorophosphate; mCPBA: m-chloroperbenzoic acid; LAH: lithium aluminum tetrahydride; TFA: trifluoroacetic acid; t -BuOK: potassium tert-butoxide; t -BuOH: tert-butanol ; Tol: toluene; DMAP: 4-dimethylaminopyridine; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; ( S )-DPLT: ( S )-di-p-methylbenzyl Tartaric acid.

Synthesis of intermediate M1 :

Step 1: Synthesis of Compound M1-1

Dissolve compound M1-0 (208 g) in anhydrous MeOH (2 L) at room temperature, add trisene chloride (286 mL) dropwise at 0°C, control the temperature at 5°C and react for 1 hour. After the reaction is completed, Concentrate the reaction solution, add anhydrous DCM (1 L) to dilute, add the diluted liquid dropwise to saturated sodium bicarbonate solution at 0°C, separate the layers, wash the organic layer with saturated brine (500 mL), and dry over anhydrous sodium sulfate. Concentrate. The concentrate was purified by column chromatography (EA:DCM=0-50%) to obtain product M1-1 (240 g, 95% yield). ESI-MS m/z = 258.1[M+H] ⁺ .

Step 2: Synthesis of Compound M1-2

At room temperature, compound M1-1 (235 g) was dissolved in anhydrous THF (2.4 L), and lithium aluminum tetrahydride (69.4 g) was added in batches at 0°C. After the addition, the mixture was stirred at 60°C for 30 min. After the reaction was completed, the reaction solution was cooled, and water (69.4 mL) was added dropwise under an ice bath, followed by a 15% aqueous sodium hydroxide solution (69.4 mL), and finally water (208.2 mL). Anhydrous sodium sulfate was added for drying, and the filtrate was filtered and concentrated to obtain product M1-2 (165 g, 90% yield), which was directly used in the next step. ESI-MS m/z = 202.1[M+H] ⁺ .

Step 3: Synthesis of compound M1-3

At room temperature, compound M1-2 (160 g) was dissolved in trifluoroacetic acid (500 mL), water (67 mL) was added, and the mixture was reacted at 60°C overnight. The reaction liquid was concentrated to obtain crude product M1-3 (320 g, 259%), which was directly used in the next step. ESI-MS m/z = 156.1[M+H] ⁺ .

Step 4: Synthesis of Compound M1-4

At room temperature, compound M1-3 (308 g) was dissolved in DMF (350 mL), imidazole (540 g) was added at 0°C, and TBDPSCl (170 mL) was added dropwise. After the addition, the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water and EA were added to dilute the mixture, and the aqueous phase was extracted with EA for 3 times. The organic phases were combined, washed with saturated brine 3 times, dried with anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:PE=0-15%) to obtain product M1-4 (192 g, 25% yield). ESI-MS m/z = 394.1[M+H] ⁺ .

Step 5: Synthesis of Compound M1

Dissolve compound M1-4 (187 g) and difluoromethyl (2-pyridyl) terine (184 g) in anhydrous DMF (1.4 L) at room temperature, and add potassium tert-butoxide (potassium tert-butoxide) dropwise at -50°C. 107 g) of DMF (460 mL) solution. After the dropwise addition, control the temperature to react at -40°C for 2 hours. After the reaction is completed, add saturated ammonium chloride solution dropwise at -50°C until the solution becomes weakly acidic, and naturally warm to React at room temperature for 18 hours, filter to obtain the filtrate, add EA (1.4 L) to dilute, filter again to obtain the filtrate, and concentrate. The concentrate was purified by column chromatography (MeOH:DCM=0-10%) to obtain product M1 (60 g, 67% yield). ¹ H NMR (500 MHz, DMSO-d6) δ 3.95-3.92 (m, 1H), 3.70-3.67 (m, 1H), 3.32-3.27 (m, 2H), 2.94-2.89 (m, 1H), 2.69- 2.66(m, 1H), 2.50-3.45(m, 1H), 1.99-1.92(m, 2H), 1.88-1.75(m, 2H). ESI-MS m/z = 190.1[M+H] ⁺ .

Synthesis of intermediate M2 :

Step 1: Synthesis of Compound M2-1

At room temperature, add 2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butyl alcohol (390.00 mL), triethylamine (128.27 mL), powdered 4Å molecular sieve (90.00 mL) (pre-activated) in sequence, and reflux for half an hour (internal temperature 87°C) under nitrogen protection. Then cool naturally to room temperature, then add DPPA (99.44 mL), raise the temperature to reflux, and keep the temperature for 5 hours. The reaction mixture was cooled to below 40°C, and then EA 500 mL was added for dilution; the mixture was further cooled to room temperature, and the molecular sieve added was removed by filtration with diatomaceous earth as the filter aid; the filter residue was rinsed with EA 1500 mL for multiple times and then dried; the filtrate was collected, and washed and separated with 700 mL of water and 700 mL of saturated salt water in turn; the organic phase was dried with anhydrous sodium sulfate; the mixture was filtered, the desiccant was removed, and the concentrate was purified by column chromatography (PE/EA=30:1~20:1), and the eluent was concentrated to finally obtain the product M2-1 (68.2 g, yield 89.88%). ESI-MS m/z: 247.1 [M+H] ⁺ .

Step 2: Synthesis of Compound M2-2

Dissolve compound M2-1 (65.00 g) in CH ₃ CN (82.00 mL) at room temperature, cool in a water bath, slowly add hydrochloric acid (4M/dioxane) (38.43 g), and stir the reaction at room temperature for about After 16 hours, a white solid precipitated and was in a suspended state. The reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, drained, and the filtrate was discarded. Collect the filter cake, add it to a mixture of 700 mL saturated sodium bicarbonate aqueous solution and 700 mL ethyl acetate, alkalize, extract and separate the liquids; extract the aqueous phase with 350 mL of ethyl acetate and separate the liquids; combine the ethyl acetate phases , add 300 mL of saturated sodium chloride aqueous solution for washing and separation; dry the organic phase with anhydrous sodium sulfate, filter, remove the desiccant, and concentrate to obtain product M2-2 (36.3 g, yield 94.0%). ESI-MS m/z: 147.1 [M+H] ⁺ .

Step 3: Synthesis of compound M2-3

At room temperature, compound M2-2 (36.00 g) was dissolved in acetonitrile (180.00 mL), NIS (66.32 g) and p-toluenesulfonic acid (2.12 g) were added, and the mixture was heated to 70°C under nitrogen protection. The reaction solution was cooled to 50°C, 900 mL of water was added, and a white solid powder was precipitated. The mixture was slurried for half an hour; filtered, and the filter cake was rinsed with water and dried. The filter cake was collected, 1200 mL of ethyl acetate was added to dissolve completely, and then washed twice with 350 mL of saturated sodium sulfite aqueous solution, and then washed and separated with 350 mL of saturated salt water. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain product M2-3 (63.2 g, yield 94.43%). ESI-MS m/z: 272.9 [M+H] ⁺ .

Step 4: Synthesis of Compound M2-4

At room temperature, compound M2-3 (57.50 g) was dissolved in DMF (22.00 mL), zinc cyanide (32.22 g), tetrakistriphenylphosphine palladium (12.19 g) and powdered 4Å molecular sieve (20.00 mL) were added, and heated to 100°C in a nitrogen atmosphere for about 7 hours. The oil bath was removed, and the mixture was naturally cooled to room temperature and waited for post-treatment. The reaction mixture was filtered with diatomaceous earth and dried; the filtrate was collected and concentrated at 60-70°C to obtain a pale yellow solid crude product. The residue was rinsed with 500 mL of ethyl acetate and dried; the rinse liquid was collected, combined with the crude product, and concentrated again until no liquid was distilled out; 700 mL of ethyl acetate was added to dissolve the concentrated solid crude product, and then washed 3 times with 250 mL of saturated sodium chloride each time, and separated. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a light yellow solid, and 160 mL of PE/EA=3/1 mixture was added, slurried for half an hour, filtered, and dried. The filter cake was collected, concentrated in a 45°C water bath, and then pumped to constant weight with a high vacuum oil pump; the product M2-4 (36.1 g, yield 99.7%) was finally obtained. ESI-MS m/z: 172.0 [M+H] ⁺ .

Step 5: Synthesis of Compound M2-5

At room temperature, add concentrated sulfuric acid (61.37 mL) to a 500 mL single-necked flask, cool to below 10°C in an ice-water bath, add compound M2-4 (39.30 g) in batches, stir for 10 minutes after addition, keep warm at 60°C in an oil bath in a nitrogen atmosphere, and react for about 1 hour. Cool the reaction solution to room temperature, then carefully add it to 1100 mL of ice-water mixture, dilute and quench, and a small amount of yellow solid precipitates. After stirring for 10 minutes, filter; collect the filter cake, use 50 mL of saturated sodium bicarbonate aqueous solution, slurry for 20 minutes, filter again, collect the two filtrates, and combine; then slowly add sodium carbonate solid, adjust the pH to about 7, and a white solid powder precipitates. Stir for half an hour, filter, and dry; rinse the filter cake with 100 mL of water each time, and dry it, for a total of 2 rinses. Collect the filter cake, put it in a vacuum oven, and dry it at 55°C to constant weight to obtain the product M2-5 (33.6 g, yield 77.37%). ESI-MS m/z: 190.0 [M+H] ⁺ .

Step 6: Synthesis of Compound M2-6

At room temperature, add tetrahydrofuran (470.00 mL). After nitrogen replacement, add sodium hydride (10.00 g) under the protection of slight nitrogen flow, heat in an oil bath, keep at 40~45°C, and stir for 15 minutes; then add the compound in batches After the addition of M2-5 (18.95 g) is completed, the mixture is kept warm and mechanically stirred for 20 minutes. Then CDI (24.31 g) is carefully added in batches. After the addition is completed, the mixture is stirred for 15 minutes. The oil bath is heated to raise the temperature, and the mixture is kept warm and refluxed for reaction. Use an ice water bath to cool the reaction solution to below 10°C, then add 500 mL of saturated ammonium chloride aqueous solution. If a light yellow solid precipitates, add 1000 mL of water; then transfer to a 5 L beaker, add 3000 mL of water; stir for 1 hour. Filter and drain; collect the filter cake, place it in a vacuum oven, and dry it at 50~55°C to constant weight to obtain product M2-6 (18.3 g, yield 84.93%). ESI-MS m/z: 216.0 [M+H] ⁺ .

Step 7: Synthesis of Compound M2-7

Compound M2-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl ₃ (180.00 mL) at room temperature. Under a nitrogen atmosphere, the reaction was heated and kept at 100°C for about 2.5 hours. Concentrate under reduced pressure to remove phosphorus oxychloride, and add 100 mL of DCM twice; dissolve the concentrated residue in 400 mL of methylene chloride, then add dropwise to 500 mL of saturated aqueous sodium bicarbonate solution, cool with ice water; stir for 15 minutes Then, separate the liquids; for the aqueous phase, extract and separate the liquids with 300 mL of methylene chloride; combine the methylene chloride phases, wash with 300 mL of saturated sodium chloride aqueous solution, and separate the liquids; dry over anhydrous sodium sulfate, filter, concentrate, and concentrate. The product M2-7 (10.95 g, yield 51.94%) was obtained through silica gel column purification (PE/EA=90/10~75/25). ESI-MS m/z: 251.9 [M+H] ⁺ .

Step 8: Synthesis of Compound M2

Compound M2-7 (10.50 g) and DIEA (17.18 mL) were dissolved in DCM (120.00 mL) at room temperature, cooled in a water bath, and tert-butyl 3,8-diazabicyclo [3.2. 1] Octane-8-carboxylate (9.27 g), and then stirred at room temperature for about 10 minutes. Add 120 mL of methylene chloride, wash and separate with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and pass the concentrate through a silica gel column (PE/EA=90/10 ~75/25) and beating purification (40 mL EA+160 mL PE) to obtain compound M2 (15.9 g, yield 89.26%).

Synthesis of intermediate M3 :

Step 1: Synthesis of Compound M3-1

Compound M3-0 (500 mg), styrene (373 mg) and Grubbs 2nd generation catalyst (405.72 mg) were dissolved in anhydrous DCM (20 mL) at room temperature and reacted at 50°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography to obtain the target compound M3-1 (400 mg).

Step 2: Synthesis of Compound M3

Compound M3-1 (400 mg) was dissolved in anhydrous THF (10 mL) at room temperature, LAH (160 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction is completed, lower to 0°C, first slowly add 170 uL water, then add 170 uL 15% sodium hydroxide aqueous solution, and finally add 510 uL water, react at room temperature for 15 minutes, add anhydrous sodium sulfate to dry, and then dry with diatomaceous earth. Filter and concentrate the filtrate to obtain the target compound M3 (277 mg).

Synthesis of intermediate M4 :

Step 1: Synthesis of Compound M4-1

Compound M3-0 (800 mg), p-chlorostyrene (795 mg) and Grubbs 2nd generation catalyst (325 mg) were dissolved in anhydrous DCM (20 mL) at room temperature, and the reaction was carried out at 50°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography to obtain the target compound M4-1 (729 mg). ESI-MS m/z = 320.1[M+H] ⁺ .

Step 2: Synthesis of Compound M4

Compound M4-1 (729 mg) was dissolved in anhydrous THF (10 mL) at room temperature, LAH (260 mg) was added at 0°C, and the temperature was raised to 70°C for 30 min. After the reaction is completed, lower to 0°C, first slowly add 280 uL water, then add 280 uL 15% sodium hydroxide aqueous solution, and finally add 840 uL water, react at room temperature for 15 minutes, add anhydrous sodium sulfate to dry, and filter with diatomaceous earth , the filtrate was concentrated to obtain the target compound M4 (563 mg). ESI-MS m/z = 264.1[M+H] ⁺ .

Synthesis of intermediate M5 :

Step 1: Synthesis of Compound M5-1

At room temperature, compound M3-0 (400 mg), methylene cyclopentane (236 mg) and Grubbs 2nd generation catalyst (325 mg) were dissolved in anhydrous DCM (20 mL) and reacted at 50°C overnight. After the reaction was completed, the reaction solution was reduced in pressure and concentrated to a small amount, and directly wet loaded for column chromatography purification to obtain the target compound M5-1 (410 mg).

Step 2: Synthesis of Compound M5

Compound M5-1 (410 mg) was dissolved in anhydrous THF (10 mL), LAH (204 mg) was added at 0°C, and the temperature was raised to 70°C for reaction for 30 min. After the reaction was completed, the temperature was lowered to 0°C, 210 uL of water was slowly added, and then 210 uL of 15% sodium hydroxide aqueous solution was added, and then 630 uL of water was added, and the reaction was carried out at room temperature for 15 min, anhydrous sodium sulfate was added for drying, diatomaceous earth was filtered, and the filtrate was concentrated to obtain the target compound M5 (370 mg).

Synthesis of intermediate M6 :

Step 1: Synthesis of compound M6-1

At room temperature, M3-0 (1.00 g), 2,3-dimethyl-2-ene (2.01 g) were added to DCM (20.00 mL), and then Grubbs 2nd generation catalyst (0.41 g) was added. _N2 was replaced three times. Under _N2 protection, the reaction was raised to 50°C and stirred for 20 hours. The reaction was cooled and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the target compound M6-1 (0.2 g, yield 9.04%).

Step 2: Synthesis of Compound M6

At room temperature, add M6-1 (0.20 g) to THF (4.00 mL), and add LAH (0.10 g) in batches under ice bath. Heat the reaction to 70°C and stir for 1 hour. Cool the reaction, add H ₂ O (100 uL) dropwise under ice bath, then add 15% NaOH (100 uL) solution dropwise, and finally add H ₂ O (300 uL) dropwise, stir at room temperature for 10 minutes, then add anhydrous sodium sulfate to dry and stir for 5 minutes. Filter, rinse the filter cake with EA, and reduce the pressure and concentrate the filtrate to obtain the target compound M6 (0.18 g).

Synthesis of intermediate M7 :

Step 1: Synthesis of Compound M7-1

Dissolve compound M3-0 (0.5 g), Togni's reagent II (1.51 g) and tetrabutylammonium iodide (0.44 g) in 1,4-dioxane (10 mL) at room temperature. Nitrogen, react at 80°C for 10 hours, concentrate the reaction solution directly, and separate and purify the concentrate through a chromatography column (DCM/EA = 2/1) to obtain the product M7-1 (0.45 g, 68% yield).

Step 2: Synthesis of Compound M7

Dissolve compound M7-1 (0.3 g) in tetrahydrofuran at room temperature, add lithium aluminum tetrahydrofuran (123 mg) in an ice bath, then add borane in tetrahydrofuran (3.2 mL), react immediately after 1 minute Quench the reaction with water until bubbles no longer appear, add 15% sodium hydroxide (0.3 mL), and then add water (0.9 mL). After stirring and quenching is complete, add sodium sulfate to dry, filter the filtrate, and concentrate to obtain product M7 ( 80 mg, 33% yield).

Synthesis of intermediate M8 :

The compound ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalene-1-yl)ethynyl)triisopropylsilane (10 g) was added to a 100 mL single-necked bottle, and 30 mL of hydrochloric acid (4 M/Dioxane) was added. After reacting at room temperature for half an hour, a saturated sodium bicarbonate solution was added to neutralize the reaction solution under ice bath, filtered, and the filter cake was washed twice with water. After dissolving with EA, it was dried with anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (PE: EA = 82: 18) to obtain the target intermediate M8 (9.1 g).

Synthesis of intermediate M9 :

At room temperature, dissolve 2-methylene-5-oxo-1,3,6,7-tetrahydropyrrolizine-8-carboxylic acid ethyl ester (10.00 g) in THF (150.00 mL) in a reaction flask, slowly add LAH (3.63 g), control the temperature below 60°C, and stir for 0.2 h after addition. Cool to 0°C, add 3.6 ml of water to quench the reaction, then add 3.6 ml of 15% sodium hydroxide aqueous solution, and finally add 10.8 ml of water, stir for 10 min, add anhydrous magnesium sulfate to dry, stir for 10 min, filter, wash the filter cake with EA three times, and concentrate the mother liquor to obtain the target intermediate M9 (6.5 g, 89.34% yield).

Synthesis of intermediate M10 :

Step 1: Synthesis of compound M10-1

4-Amino-2,6-dichloropyridine (63 g) was added to a 1 L three-necked flask, and 440 mL ACN and 180 mL water were added. Selectfluor (164 g) was added at 45 °C, and the reaction was exothermic, and it was allowed to cool naturally in the air. After reacting for 10 min, a saturated sodium sulfite solution was added under an ice bath to quench the reaction, and EA was extracted 3 times. The organic phase was collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE: EA = 10: 1) to obtain the target compound M10-1 (42.6 g). ESI-MS m/z: 163.9 [M+H] ⁺ .

Step 2: Synthesis of Compound M10-2

M10-1 (54 g) was added to a 1 L three-necked flask, and 500 mL of ACN, NIS (80 g) and TsOH (5.1 g) were added. After heating to 70°C for 1 h, 2.5 L of water was added dropwise, filtered, and the filter cake was dissolved with EA. After separation, the organic phase was concentrated to obtain the target compound M10-2 (94 g). ESI-MS m/z: 307.2 [M+H] ⁺ .

Step 3: Synthesis of Compound M10-3

M10-2 (88 g) was added to a 1 L three-necked flask, and 500 mL of DMF and CuCN (31 g) were added. After heating to 125 °C and reacting for 16 h, 2 L of water was added dropwise, and then added to 2 L of water, filtered, the filter cake was washed with water, and dissolved in EA. The aqueous phase was extracted with EA twice, and the organic phase was collected and combined, and concentrated to obtain the target product M10-3 (55.4 g). ESI-MS m/z: 207.0 [M] ^- .

Step 4: Synthesis of Compound M10-4

M10-3 (88 g) was added to a 250 mL three-necked flask, and 83 mL of concentrated sulfuric acid and 9 mL of water were added. After reacting at 60°C for 16 h, 70 mL of concentrated sulfuric acid and 5 mL of water were added, and the reaction was continued for 24 h. The reaction solution was cooled to 0°C, and slowly poured into 2 L of ice water, filtered, and the filter cake was washed with water and dissolved in EA. The filtrate was extracted twice with EA, and the organic phase was collected and combined, concentrated, and slurried with PE:EA=1:1. Filter to obtain the target product M10-4 (59 g). ESI-MS m/z: 224.1 [M+H] ⁺ .

Step 5: Synthesis of Compound M10-5

M10-4 (58 g) was added to a 1 L three-necked flask, and 650 mL THF was added. After the temperature was raised to 40°C, NaH (16 g) was slowly added in batches. After stirring for 10 minutes, the temperature was raised to 60°C, and N,N'-thiocarbonyldiimidazole (69 g) was slowly added. After reacting for 1 hour, add saturated ammonium chloride solution to quench the reaction, add dilute hydrochloric acid dropwise to adjust the pH to 4-5, and spin off THF. Filter, wash the filter cake with water, dissolve the methanol, and concentrate the organic phase to obtain crude product M10-5 (85 g). ESI-MS m/z: 267.0 [M+H] ⁺ .

Step 6: Synthesis of Compound M10

Add M10-5 (74 g) to a 1 L three-necked flask, add 750 mL ACN, add methyl iodide (22 mL), and add an aqueous solution (100 mL) of sodium methoxide (23 g). After reacting at room temperature for 15 minutes, add the reaction solution to 3.5L of water, add dilute hydrochloric acid to adjust the pH to 4-5, filter, and beat the filter cake with a mixed solvent of PE:EA=2:1. Filter, and the filter cake is the target product M10 (42.2 g). ESI-MS m/z: 281.2 [M+H] ⁺ .

Synthesis of intermediate M11 :

Step 1: Synthesis of Compound M11-1

Dissolve potassium tert-butoxide (5.2 g) and methyltriphenylphosphonium bromide (14.1 g) in diethyl ether (100 mL), under nitrogen protection, cool to below 0°C, stir for 30 min, and slowly add compound 1-(tert-butoxide) Butyl) 2-methyl-4-oxopyrrolidine-1,2-dicarboxylate (8.0 g) was added to the diethyl ether solution, and the reaction was carried out at 35°C for 3 hours. Quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was separated and purified by column chromatography (PE:EA 0%-15%) to obtain compound M11-1 ( 3.8 g).

Step 2: Synthesis of Compound M11-2

Dissolve compound M11-1 (3.8 g) in tetrahydrofuran (40 mL), cool to -78°C, slowly add bistrimethylsilylamine (35 mL), stir at -78°C for 1 h, and slowly add 3-chloro -2-Chloromethylpropene, move to room temperature and react for 16 hours. The reaction solution was added to water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (PE:EA 0%-20%) to obtain compound M11-2 (3.3 g).

Step 3: Synthesis of Compound M11-3

Compound M11-2 (3.3 g) was dissolved in dichloromethane (35 mL), trifluoroacetic acid (12 mL) was added, and the reaction was carried out at room temperature for 16 h. The reaction solution was concentrated, adjusted to pH=8 with ammonia methanol, and the liquid was concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH 0%-10%) to obtain compound M11-3 (2.0 g).

Step 4: Synthesis of compound M11

Compound M11-3 (2.0 g) was dissolved in tetrahydrofuran (20 mL), and aluminum lithium hydroxide (0.4 g) was added in batches. The reaction mixture was reacted at room temperature for 1 h. The reaction solution was quenched, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH 0%-10%) to obtain intermediate M11 (1.6 g). ESI-MS m/z: 166 [M+H] ⁺ .

Synthesis of intermediate M12 :

At room temperature, compound M7-1 (0.3 g) was dissolved in tetrahydrofuran, and lithium aluminum tetrahydrogen (123 mg) was added under an ice bath, and then a tetrahydrofuran solution of borane (3.2 mL) was added. The ice bath was removed and the reaction was allowed to react for 5 minutes. The reaction was complete as monitored by LC-MS, and the reaction was quenched with water until no more bubbles were generated. 15% sodium hydroxide (0.3 mL) was added, and then water (0.9 mL) was added. After stirring and quenching, sodium sulfate was added to dry, and the filtrate was filtered and dried to obtain product M12 (164 mg, 73% yield).

Preparation of intermediate M13 :

1) Preparation of L-(-)-di-p-methylbenzoyl tartaric acid salt of M13 compound

Weigh 11 g of M9 into the reaction kettle, add 330 ml of acetonitrile/water (30/1, volume ratio) mixed solvent, stir and dissolve at 50°C to obtain an M9 solution; weigh 26.5 gL-(-)-di Add 330 ml of ethyl acetate solvent to a round-bottomed flask to prepare an acid solution. At the system temperature of 50°C, slowly drop the acid solution into the M9 solution. After the dropwise addition of the acid solution is completed, add 330 ml of ethyl acetate dropwise to the reaction solution. After the dropwise addition is completed, slowly cool down to 10°C, and Aging at 10°C for half an hour. The sample was filtered, and the filter cake was vacuum dried at 40°C overnight to obtain 13.9 g ( S )-DPLT salt crude product (solid isomer ratio: 9.2%:90.8%). The crude ( S )-DPLT salt was recrystallized in ethanol/acetonitrile (1/1, volume ratio 1:1) to obtain 11.6 g ( S )-DPLT salt M13-1 (isomer ratio 0.8%:99.2%) .

Single crystal cultivation and identification: Compound M13-1 was weighed and dissolved in 1 ml of a mixed solvent of butanone/water (19/1, v/v). The clarified sample was transferred to a butanone atmosphere for gas-liquid diffusion overnight to obtain a single crystal sample. The bulk polarizing microscope image of the single crystal sample is shown in Figure 1, and the single crystal structure analysis is shown in Figure 2. The single crystal structure information is shown below. Sample PF5000420-A1 temperature 296 K Light source wavelength 1.54 Å CuK _α radiation Chemometric C ₂₀ H ₁₈ O ₈ •C ₉ H ₁₅ NO Calculate molecular weight 539.56 Crystal system Orthorhombic system Space Group P2 ₁ 2 ₁ 2 ₁ Unit cell parameters a=7.4994(1), b=8.9892(1), c=41.6541(12)Å, α=β=γ=90° Asymmetric units Z=4 Unit cell volume 2808.05(6)Å ³ Calculate crystal density 1.276g/cm ³ Flack parameters 0.1(2) R ₁ parameter 0.0445 wR ₂ parameters 0.1323 GOOF=S parameter 1.033

2) Preparation of M13

Weigh 20.0 g M13-1 (R/S isomer ratio is 0.8%:99.2%) into the reaction kettle, add 200 ml methylene chloride/methanol (10/1, volume ratio), stir to dissolve; add to the reaction kettle Add 160 ml of purified water to the reaction solution, add 1M sodium hydroxide to the reaction solution under stirring, adjust the pH of the water phase to 11~12, stir for half an hour and separate the liquids; use dichloromethane/methanol (10/1) for the water phase. , volume ratio) solvent 200ml, stir for 20 minutes and then separate and extract, repeat twice; combine the organic phases, wash the organic phase with 200ml of pure water, and then wash with 200ml of saturated brine, and finally dry the organic phase with anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated. After concentration, it was evaporated twice with an ACN jacket to obtain 5.17g ( S )-(2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol M13, R/ The S isomer ratio is 0.8%:99.2%.

Example 1 : Compound 4- ( 4- ( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octane -3- yl) -2- ( 2- (difluoromethylene) Tetrahydro -1H- pyrroline -7a ( 5H ) -yl )methoxy) -8 -fluoropyridin [4,3-d] pyrimidin -7 -yl) -5 -ethynyl-6- fluoronaphthalene - 2- Synthesis of alcohol

Step 1: Synthesis of compound 1-1

Dissolve compound M2 (0.6 g) and sodium hydride (0.11 g) in anhydrous THF (2 mL) at room temperature. Add the THF solution of compound M1 (0.53 g) dropwise at room temperature, and react at room temperature for 0.5 hours. . After the reaction, the liquid was added dropwise to the saturated ammonium chloride solution at 0°C, EA was added to separate the layers to obtain an organic layer, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:DCM=0-40%) to obtain product 1-1 (0.54 g, 66% yield). ESI-MS m/z = 581.1[M+H] ⁺ .

Step 2: Synthesis of compound 1-2

At room temperature, under nitrogen protection, compound 1-1 (0.3 g), cataCXium A Pd G3 (40 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (0.53 g) and potassium phosphate (0.33 g) were dissolved in THF (6 mL) and water (1 mL), and the temperature was raised to 70°C for 3 hours. After the reaction was completed, EA was added to separate the liquid to obtain an organic layer, which was washed once with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (EA:DCM=0-30%) to obtain product 1-2 (0.31 g, 63% yield). ESI-MS m/z = 931.1[M+H] ⁺ .

Step 3: Synthesis of Compound 1-3

Dissolve compound 1-2 (0.31 g) in DMF (3 mL), add cesium fluoride (0.5 g) in batches at room temperature, after the reaction is completed, drop 15 mL of water into the reaction liquid, and a large amount of solid will precipitate , filtered to obtain the solid and dried to obtain product 1-3 (0.31 g, 76% yield). ESI-MS m/z = 775.1[M+H] ⁺ .

Step 4: Synthesis of Compound 1

Compound 1-3 (0.31 g) was dissolved in DCM (3 mL) at room temperature, and trifluoroacetic acid (1 mL) was added thereto. After the reaction was completed, the reaction solution was added dropwise to protected hydrogen carbonate at 0°C. To the sodium solution, DCM was added to separate the layers to obtain an organic layer, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was preparatively purified by Pre-HPLC to obtain product 1 (31 mg, 13% yield). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.15 (s, 1H), 9.04 (s, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.17 (t, J = 2.3 Hz, 1H), 4.47 (d, J = 12.4 Hz, 1H), 4.30 (d, J = 12.2 Hz, 1H) , 4.14 (dd, J = 10.6, 4.2 Hz, 1H), 4.08 (dd, J = 10.6, 2.3 Hz, 1H), 3.93 (dd, J = 4.0, 1.0 Hz, 1H), 3.68 – 3.60 (m, 2H ), 3.55 (s, 3H), 3.30 (s, 1H), 3.00 (dq, J = 10.0, 4.7, 4.1 Hz, 1H), 2.63 (d, J = 14.7 Hz, 1H), 2.56 (q, J = 8.2 Hz, 1H), 2.41 (d, J = 15.8 Hz, 1H), 1.97 (td, J = 10.9, 10.1, 6.9 Hz, 1H), 1.91 – 1.82 (m, 1H), 1.78 (q, J = 7.5 Hz, 2H), 1.65 (s, 4H). ¹⁹ F NMR (471 MHz, DMSO- d ₆ ) δ -90.97 (dd, J = 64.9, 20.6 Hz, 1F), -91.46 (dd, J = 64.9, 38.2 Hz, 1F), -110.76 (d, J = 3.8 Hz, 1F), -140.20 (d, J = 3.1 Hz, 1F).

Example 2 : Compound 4- ( 4- ( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octane -3- yl) -2- ( 2- (difluoromethylene) Tetrahydro -1H- pyrroline -7a ( 5H ) -yl )methoxy) -8- fluoro -5- isopropoxypyridin [4,3-d] pyrimidin -7 -yl) -5 - ethynyl- Synthesis of 6- fluoronaphthalene -2- ol

Step 1: Synthesis of compound 2-1

Dissolve isopropanol (1.23 ml) in tetrahydrofuran (30 ml), add NaH (0.64 g), react at room temperature for 10 minutes, lower the temperature to 0°C, add 5,7-dichloro-8-fluoro-2-(methylthio)pyridin[4,3-d]pyrimidin-4-ol, and move to room temperature for 1 hour. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract twice with EA, wash once with saturated salt water, dry with anhydrous sodium sulfate, and concentrate in vacuo to obtain 2-1 (2.06 g). ESI-MS m/z: 304.26 [M+H] ⁺ .

Step 2: Synthesis of compound 2-2

2-1 (2.06 g) and tert-butyl (1R, 5S)-3,8-diazocyclo[3.2.1]octane-8-carboxylate (1.73 g) were dissolved in DMF (20 ml), and DBU (4.13 g) was added thereto, and finally PyBOP (5.29 g) was added, and the mixture was reacted at room temperature for 10 minutes. After the reaction was complete, water (100 ml) was slowly added dropwise to the reaction solution, and a large amount of solid precipitated. The solid was filtered, dissolved with EA, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain 2-2 (1.35 g, yield 40.0%). ESI-MS m/z: 498.11 [M+H] ⁺ .

Step 3: Synthesis of Compound 2-3

2-2 (500 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxobenzene) Formaldehyde-2-yl) naphth-1-yl) ethynyl) triisopropylsilane (705.54 mg), potassium carbonate (416.29 mg), [1,1'-bis(diphenylphosphine)ferrocene]di Palladium chloride dichloromethane complex (81.99 mg) was dissolved in 1,4-dioxane (8.00 ml) and water (2.00 ml), and the reaction was carried out in a sealed jar at 130°C for 1 h in a nitrogen-protected atmosphere. When the reaction is complete, dilute the reaction solution with EA and water, extract it once with EA, wash it once with saturated brine, dry it over anhydrous sodium sulfate, and concentrate it. The concentrate is purified by column chromatography to obtain 2-3 (713 mg, yield 88.32 %). ESI-MS m/z:805.49 [M+H] ⁺ .

Step 4: Synthesis of Compound 2-4

Dissolve 2-3 (713 mg) in dichloromethane (10.00 ml) and add tert-butyldimethylsilyl chloride (668.22 mg) and imidazole (422.57 mg) to react at room temperature for 0.5 h. After the reaction is complete, dilute the reaction solution with DCM and water, extract it with DCM again, wash it with saturated salt water, dry it with anhydrous sodium sulfate, concentrate it, and purify the concentrate by column chromatography to obtain 2-4 (770 mg, yield 94.56%).

Step 5: Synthesis of Compound 2-5

Dissolve 2-4 (770 mg) in DCM (10.00 mL), add mCPBA (578.80 mg), and react at room temperature for 0.5 h. Dilute the reaction solution with DCM, add saturated sodium bicarbonate to quench the reaction, extract with DCM again, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify the concentrate by column chromatography to obtain 2-5 (290 mg).

Step 6: Synthesis of Compound 2-6

M1 was dissolved in THF (3.00 mL), NaH (17.17 mg) was added, and 2-5 (170.00 mg) was added thereto, and the mixture was reacted at room temperature for 0.5 h. The reaction was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC to obtain 2-6 (163 mg). ESI-MS m/z: 530.53 [M/2+H] ⁺ .

Step 7: Synthesis of Compounds 2-7

Dissolve 2-6 (163.00 mg) in DMF (3.00mL), add CsF (701.32 mg), and react at room temperature for 6 h. The reaction solution was diluted with EA and water, extracted once with EA, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain 2-7 (73 mg). ESI-MS m/z: 789.11 [M+H] ⁺ .

Step 8: Synthesis of Compound 2

Dissolve 2-7 (73.00 mg) in DCM (2.00 mL), add boron trifluoride etherate (0.23 mL), and react at room temperature for 0.5 h. Add the reaction solution into a cold saturated sodium carbonate solution, extract twice with DCM: MeOH = 10:1, wash once with saturated salt water, dry over anhydrous sodium sulfate, concentrate, and separate and purify the concentrate by Pre-TLC to obtain compound 2 (37.9 mg). ESI-MS m/z: 689.25 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 10.14 (s, 1H), 10.14 (s, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.20 (s, 1H), 7.20 (s, 1H), 5.37-5.21 (m, 1H), 4.16-4.02 (m, 3H), 3.87 (d, J = 3.64 (d, J = 14.4 Hz, 1H), 3.45 (dd, J = 45.7, 19.5 Hz, 4H), 3.05-2.91 (m, 1H), 2.67-2.53 (m, 2H), 2.40 (d, J = 15.9 Hz, 2H), 2.04-1.72 (m, 4H), 1.45-1.65 (m,3H), 1.30 (dd, J = 6.2, 2.0 Hz, 4H).

Example 3 : Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl) -8 - fluoro -5- isopropoxy -2- (( 2 -methyltetrahydro -1H- pyrrolizin -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2- ol

Step 1: Synthesis of compound 3-1

M9 (13.0 mg), after adding 1 mL of THF, add NaH (6.7 mg). After stirring at room temperature for 5 min, add 2-5 (40.0 mg). After reacting at room temperature for 30 minutes, the reaction solution was added to saturated ammonium chloride solution to quench the reaction. EA extracted twice, collected and combined the organic phases, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC to obtain the target product 3-1 (44.0 mg). ESI-MS m/z: 512.1 [M+H] ⁺ /2.

Step 2: Synthesis of compound 3-2

Add 3-1 (44.0 mg) to a 10 mL single-necked bottle, add 1 mL DMF, add CsF (129.7 mg), and react at room temperature for 4 h. Dilute the reaction solution with EA and water, extract twice with EA, collect and combine the organic phase, dry with anhydrous sodium sulfate, concentrate, and separate and purify the concentrate by Pre-TLC to obtain the target product 3-2 (16.6 mg). ESI-MS m/z: 759.8 [M+H] ⁺ .

Step 3: Synthesis of Compound 3

Dissolve 3-2 (100 mg) in DCM (2.00 mL), add boron trifluoride ether (0.4 mL), and react at room temperature for 0.5h. The reaction solution was added to cold saturated sodium carbonate solution and extracted twice with DCM. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain compound 3 (19.8 mg). ESI-MS m/z: 653.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 7.97 (dd, J = 9.1, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.37 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 5.31 (dd, J = 11.9, 6.0 Hz, 1H), 4.90 (s, 2H), 4.05 – 3.88 (m, 4H), 3.55 (d , J = 13.9 Hz, 2H), 3.20 (d, J = 14.5 Hz, 2H), 3.00 (s, 1H), 2.67 – 2.54 (m, 2H), 2.36 (d, J = 15.1 Hz, 2H), 2.00 – 1.61 (m, 9H), 1.31 (d, J = 6.0 Hz, 6H), 1.23 (s, 1H), 1.16 (t, J = 7.2 Hz, 1H).

Example 5 : Synthesis of 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -5- ethoxy -8- fluoro -2- (( 2 -methyltetrahydro -1H- pyrrolizine -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2- ol

Step 1: Synthesis of compound 5-1

NaH (357 mg, 60% purity) was added in batches to anhydrous THF (10 mL) solution of EtOH (0.31 mL). After stirring for 5 min, the reaction system was cooled to 0°C, and then powdered solid M10 (500 mg) was added in batches. The temperature was naturally raised to 22°C and stirred for 30 minutes. The reaction system was cooled to 0°C again, and saturated ammonium chloride solution (20 mL) was added dropwise to quench the reaction. 20 mL of ethyl acetate was added for extraction and separation. The aqueous phase was washed twice with ethyl acetate, and the organic phases were combined and dried with anhydrous sodium sulfate. After the organic phase was concentrated, the target compound 5-1 (600 mg) was directly used in the next reaction. ESI-MS m/z: 290.1 [M+H] ⁺ .

Step 2: Synthesis of compound 5-2

At room temperature, DBU (1.24 mL) and PyBOP (1.6 g) were added to a DMF (6 mL) solution of 5-1 (600 mg) and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (528 mg) in turn. The mixture was stirred at room temperature for 30 minutes and LCMS showed that the reaction was complete. 30 mL of saturated saline and 30 mL of EA were added to the reaction mixture for extraction. The organic phase was washed with saturated saline three times and dried over anhydrous sodium sulfate. The organic phase was further concentrated and purified by column chromatography (EA/PE = 0%-15%) to obtain the target compound 5-2 (420 mg). ESI-MS m/z: 484.3 [M+H] ⁺ .

Step 3: Synthesis of compound 5-3

After adding 5-2 (420 mg), M8 (569 mg), K ₂ CO ₃ (360 mg), Pd (dppf) Cl ₂ (106 mg) and 6 mL Dioxane/1.5 mL H ₂ O respectively into the microwave tube, After _N2 replacement for 10 minutes, microwave reaction at 130°C for 70 minutes. Add 20 mL each of EA and H ₂ O to the reaction solution, extract and separate the liquids. The aqueous phase is extracted twice with EA. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by column chromatography (EA/PE = 0%-30%) to obtain target compound 5-3 (400 mg). ESI-MS m/z: 790.2 [M+H] ⁺ .

Step 4: Synthesis of compound 5-4

Imidazole (241 mg) and TBSCl (382 mg) were added to a DCM (15 mL) solution of 5-3 (400 mg), and the reaction system was stirred at room temperature for 20 min. 15 mL of water was added to the reaction, and the liquid was extracted and separated. The aqueous phase was washed twice with 10 mL of DCM, and the organic phases were combined and washed once with 20 mL of saturated brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography (EA/PE = 0%-10%) to obtain the target compound 5-4 (270 mg).

Step 5: Synthesis of compound 5-5

Add m CPBA (198 mg) to a DCM (5 mL) solution of 5-4 (260 mg) and stir at room temperature for 30 minutes. Add 20 mL DCM and 20 mL saturated NaHCO ₃ solution to the reaction mixture, extract and separate the liquids, extract the aqueous phase twice with 10 mL DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the concentrate by column chromatography (EA/PE = 0%-30%) to obtain the target compound 5-5 (148 mg). ESI-MS m/z: 936.5. [M+H] ⁺ .

Step 6: Synthesis of Compound 5-6

To a solution of M9 (48 mg) in anhydrous THF (3 mL) was added NaH (25 mg), stirred for 10 minutes, and then 5-5 (148 mg) was added, and the system was stirred at room temperature for 15 min. After the reaction was completed, the system was cooled to 0°C, and a saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction. Ethyl acetate (20 mL) was added, and the liquid was extracted and separated. The aqueous phase was washed twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC (DCM/NH ₃ : MeOH (7 M) = 100:6) to obtain the target compound 5-6 (96 mg). ESI-MS m/z: 895.6 [M+H] ⁺ .

Step 7: Synthesis of Compounds 5-7

CsF (255 mg, 20.0 eq.) was added to a DMF (1 mL) solution of 5-6 (75 mg, 1.0 eq.), and the reaction system was stirred at 35°C for 2 hours. After the reaction was completed, 20 mL of saturated saline and 20 mL of EA were added to the reaction mixture, and the liquid was extracted. The organic phase was washed twice with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC (DCM/NH ₃ in MeOH (7 M) = 100:7) to obtain the target compound 5-7 (42 mg). ESI-MS m/z: 739.5 [M+H] ⁺ .

Step 8: Synthesis of compound 5

BF ₃ .Et ₂ O (0.14 mL, 20.0 eq.) was added to a solution of 5-7 (40 mg, 1.0 eq.) in anhydrous DCM (1 mL), and the resulting system was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction system was cooled to 0°C, then quenched by adding saturated Na ₂ CO ₃ (10 mL), extracted by adding DCM/MeOH (10:1, 20 mL), and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC (DCM/NH ₃ :MeOH (7 M) = 9:1) to obtain the target compound 5 (29 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.68 (dd, J = 8.8, 5.9 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.17 (t, J = 8.8 Hz, 1H), 4.97 – 4.85 (m, 2H), 4.46 – 4.38 (m, 1H), 4.36 – 4.27 (m, 1H), 4.24 – 4.16 (m, 2H), 3.56 (d, J = 17.8 Hz, 3H), 3.44 (d, J = 12.5 Hz, 1H), 3.31 – 3.20 (m, 2H), 2.86 – 3H). 3.74 (m, 1H), 2.76 (m, 2H), 2.71 – 2.64 (m, 1H), 2.44 – 2.33 (m, 2H), 2.24 – 2.12 (m, 2H), 1.95 – 1.87 (m, 2H), 1.81 – 1.57 (m, 5H), 1.32 (t, J = 7.1 Hz, 2H), 1.29 – 1.23 (m, 3H). ESI-MS m/z: 639.5 [M+H] ⁺ .

Example 6 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -2- (( 2- (difluoromethylene) Tetrahydro -1H- pyrrozine -7a ( 5H ) -yl )methoxy) -5- ethoxy -8- fluoropyrido [4,3d] pyrimidin -7- yl) -5 -ethynyl- 6- Synthesis of fluoronaphthalene -2- ol

Step 1: Synthesis of compound 6-1

NaH (25 mg) was added to a solution of M1 (113 mg) in anhydrous THF (6 mL). After stirring for 10 min, 5-5 (148 mg) was added and the system was stirred at room temperature for 30 min. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction, ethyl acetate (20 mL) was added, the liquids were extracted and separated, the aqueous phase was washed twice with ethyl acetate, and the organic phase was The combined mixture was dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH ₃ :MeOH (7 M) = 100:5) to obtain target compound 6-1 (240 mg). ESI-MS m/z: 985.5 [M+H] ⁺ .

Step 2: Synthesis of compound 6-2

To a solution of 6-1 (240 mg) in DMF (2.0 mL) was added CsF (353 mg), and the reaction was allowed to stir at 35°C for 3 hours. After the reaction, 20 mL of saturated saline and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC ( DCM/NH ₃ : MeOH (7 M) = 100:6) to obtain the target compound 6-2 (144 mg). ESI-MS m/z: 775.4 [M+H] ⁺ .

Step 3: Synthesis of Compound 6

BF ₃ .Et ₂ O (0.46 mL) was added to a solution of 6-2 (140 mg) in anhydrous DCM (3 mL), and the resulting system was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction system was cooled to 0°C, then quenched by adding saturated Na ₂ CO ₃ (10 mL), extracted by adding DCM/MeOH (10:1, 20 mL), and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH ₃ :MeOH (7 M) = 7:1) to obtain the target compound 6 (90 mg). ¹ H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 7.97 (dd, J = 9.0, 6.0 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.20 (s, 1H), 4.42 – 4.27 (m, 2H), 4.10 (dd, J = 26.8, 10.6 Hz, 2H), 3.96 (s, 1H), 3.87 (s, 1H), 3.64 (d, J = 14.1 Hz, 1H), 3.51 (s, 2H), 3.47 – 3.34 (m, 3H), 3.02 – 2.95 (m, 1H), 97 – 1.84 (m, 1H), 1.73 – 1.76 (m, 2H), 1.66 – 1.51 (m, 5H), 1.40 (s, 1H), 1.32 (t, J = 7.0 Hz, 3H). ESI-MS m/z: 651.5 [M+H] ⁺ .

Example 7 : Compound 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octane -3- yl )-8- fluoro -5- methoxy -2- ((2 -methylenetetrahydro -1H- pyrrolidin -7a(5H)-yl ) methoxy ) pyridin [ 4,3-d] pyrimidin -7 -yl )-5- ethyne -6 - fluoronaphthalene- Synthesis of 2- alcohols

Step 1: Synthesis of compound 7-1

After adding MeOH (1.80 mL) and anhydrous THF respectively to the reaction flask, cool down in an ice water bath for 5 min, slowly add NaH (2.86 g) in batches, stir for 5 min, add powdered solid M10 (4.00 g) in batches, and naturally liter Stir the reaction to room temperature 22°C for 10 minutes; cool down the reaction in an ice-water bath for 5 minutes, add 100 mL of saturated NH ₄ Cl dropwise to quench, add 200 mL of ethyl acetate, extract, wash the aqueous phase twice with ethyl acetate, and combine the organic The phase was evaporated to dryness under reduced pressure to obtain target compound 7-1 (4.23 g). ESI-MS m/z: 276.0 [M+H] ⁺ .

Step 2: Synthesis of compound 7-2

At room temperature, 7-1 (4.23 g), (1R, 5S)-3,8-diazobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.91 g), DBU (11.47 mL) and anhydrous DMF (10.0 mL) were added to the reaction bottle in sequence, stirred at room temperature to dissolve, and finally PyBOP (12.00 g) was added and stirred at room temperature for 0.5 h. 200 mL of saturated NaCl tap water was added to the reaction, and 200 mL of EA was used to wash twice, extract and separate, the organic phase was evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE/EA = 3:1) to obtain the target compound 7-2 (2.57 g). ESI-MS m/z: 470.3 [M+H] ⁺ .

Step 3: Synthesis of compound 7-3

After adding 7-2 (0.70 g), M8 (1.40 g), K ₂ CO ₃ (0.63 g), Pd (dppf) Cl ₂ (0.20 g) and 7 mL Dioxane/ 1 mL H ₂ O into a microwave tube, N ₂ was replaced for 2 min and microwaved at 140°C for 0.5 h. DCM and H ₂ O (20 mL each) were added to the reaction solution for extraction. The aqueous phase was washed twice with DCM, the organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE/EA = 4:1) to obtain the target compound 7-3 (1.23 g). ESI-MS m/z: 776.4 [M+H] ⁺ .

Step 4: Synthesis of compound 7-4

After adding 7-3 (1.13 g), TBSCl (1.10 g), imidazole (0.69 g) and anhydrous DCM (15 mL) to the reaction bottle, stir and react at room temperature for 20 min. Add 15 mL of saturated NaCl tap water to the reaction, extract and separate, wash the aqueous phase with 10 mL DCM twice, evaporate the organic phase under reduced pressure, and purify the concentrate by column chromatography (PE/EA = 10:1) to obtain the target compound 7-4 (1.06 g). ESI-MS m/z: 890.3 [M+H] ⁺ .

Step 5: Synthesis of compound 7-5

After adding 7-4 (1.00 g), m CPBA (0.47 g) and anhydrous DCM (15 mL) to the reaction bottle, the reaction was stirred at room temperature for 15 min. 20 mL of saturated NaHCO ₃ was added to the reaction, the liquid was extracted, the aqueous phase was washed twice with 10 mL of DCM, the organic phase was evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE/EA = 3:1) to obtain the target compound 7-5 (0.40 g). ESI-MS m/z: 923.0 [M+H] ⁺ .

Step 6: Synthesis of Compound 7-6

Add M4 (0.11 g) and solvent anhydrous THF (1 mL) to the reaction flask respectively, slowly add NaH (0.25 g) in batches, stir for 10 min, then add 7-5 (0.33 g), and stir the reaction at room temperature. 15 minutes. The reaction solution was cooled down in an ice-water bath for 5 min, quenched by adding 20 mL of saturated NH ₄ Cl dropwise, and 20 mL of ethyl acetate was added for extraction. The aqueous phase was washed twice with ethyl acetate, the organic phases were combined, evaporated to dryness under reduced pressure, and the concentrate Purification by column chromatography (DCM/NH ₃ :MeOH = 20:1) gave the target compound 7-6 (0.32 g). ESI-MS m/z: 881.6 [M+H] ⁺ .

Step 7: Synthesis of Compound 7-7

After adding 7-6 (0.32 g), CsF (0.55 g) and anhydrous DMF (3 mL) to the reaction bottle, the reaction was stirred at room temperature for 5.0 h. 20 mL of saturated NaCl was added to the reaction, the liquid was extracted, the aqueous phase was washed twice with 20 mL of EA, the organic phase was evaporated under reduced pressure, and the concentrate was purified by column chromatography (DCM/NH ₃ in MeOH = 20:1) to obtain the target compound 7-7 (0.18 g). ESI-MS m/z: 725.5 [M+H] ⁺ .

Step 8: Synthesis of compound 7

After adding 7-7 (0.18 g) and anhydrous DCM (3 mL) to the reaction bottle, add BF ₃ .Et ₂ O (0.30 mL) and react at room temperature for 0.5 h. After the reaction, cool down in an ice-water bath for 5 min, add saturated Na ₂ CO ₃ (10 mL) dropwise to quench, add DCM/MeOH (10:1, 20 mL) for extraction, evaporate the organic phase to dryness under reduced pressure, and pass the concentrate through a column. Chromatography purification (DCM/NH ₃ in MeOH = 8:1) gave the target compound 7 (126.0 mg, 82.60% yield). ¹ H NMR (500 MHz, MeOD) δ 7.81 (dd, J = 9.1, 5.7 Hz, 1H), 7.31 – 7.22 (m, 3H), 5.48 (s, 1H), 4.96 (d, J = 1.5 Hz, 2H ), 4.22 (dt, J = 10.5, 6.8 Hz, 2H), 3.99 (s, 3H), 3.70 (d, J = 14.2 Hz, 1H), 3.55 (s, 3H), 3.45 (d, J = 13.0 Hz , 1H), 3.34 – 3.25 (m, 3H), 3.12 (dt, J = 10.6, 5.5 Hz, 1H), 2.79 – 2.64 (m, 2H), 2.44 (dd, J = 15.8, 1.8 Hz, 1H), 2.17 – 2.07 (m, 1H), 2.01 – 1.85 (m, 2H), 1.84 – 1.72 (m, 4H), 1.65 (s, 1H). ESI-MS m/z: 625.3 [M+H] ⁺ .

Example 8 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -2- (( 2- (difluoromethylene) Tetrahydro -1H- pyrrozine -7a ( 5H ) -yl )methoxy) -8- fluoro -5- methoxypyrido [4,3d] pyrimidin -7 -yl) -5 -ethynyl -6- Synthesis of fluoronaphthalene -2- ol

Step 1: Synthesis of compound 8-1

Compound M1 (274.91 mg), THF (4.00 mL), NaH (69.74 mg) were added to the reaction bottle, and then 7-5 (670.00 mg) was added, and the reaction was carried out at room temperature for 0.4 h. The reaction solution was cooled in an ice-water bath for 5 min, saturated NH ₄ Cl 20 mL was added dropwise for quenching, 20 mL of ethyl acetate was added, and the extraction was carried out. The aqueous phase was washed twice with ethyl acetate, and the organic phases were combined and evaporated to dryness under reduced pressure. The concentrate was purified by column chromatography (DCM/NH ₃ : MeOH = 20:1) to obtain the target compound 8-1 (470 mg, yield 70.45%). ESI-MS m/z: 917.44 [M+H] ⁺ .

Step 2: Synthesis of compound 8-2

Add compound 8-1 (300.00 mg), DMF (3.00 mL), and CsF (441.88 mg) to the reaction bottle, and react at room temperature for 3 h. Add 20 mL water and 20 mL EA to the reaction, extract and separate the liquids, wash the aqueous phase with 20 mL EA again, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by Pre-TLC (DCM: MeOH: ammonia water = 15:1 :0.15), and the target compound 8-2 (200.00mg, 90.37%) was obtained. ESI-MS m/z: 761.30 [M+H] ⁺ .

Step 3: Synthesis of compound 8

Add compound 8-2 (190.00 mg), DCM (3.00 mL), boron trifluoride ether (0.63 mL) into the reaction bottle, and react at room temperature for 2 h. After the reaction was completed, the temperature was cooled in an ice-water bath for 5 min, then the reaction solution was dropped into saturated Na ₂ CO ₃ (10 mL) to quench, DCM/MeOH (10:1, 20 mL) was added for extraction, and the organic phase was evaporated under reduced pressure. Dry, and the concentrate was purified by Pre-TLC (DCM: MeOH: ammonia = 8.5:1:0.15) to obtain target compound 8 (122.00 mg, 73.95%). ESI-MS m/z: 661.30 [M+H]+. ¹ H NMR (500 MHz, MeOD) δ 7.88 – 7.77 (m, 1H), 7.34 – 7.21 (m, 3H), 4.40 – 4.21 (m, 3H), 4.12 (s, 1H), 4.01 (s, 3H) , 3.80 (d, J = 14.3 Hz, 1H), 3.64 – 3.53 (m, 3H), 3.46 (dd, J = 31.7, 13.6 Hz, 2H), 3.33 (m, 1H), 3.14 (d, J = 5.3 Hz, 1H), 2.75 (dd, J = 52.0, 11.6 Hz, 2H), 2.50 (d, J = 15.7 Hz, 1H), 2.13 (s, 1H), 2.04 – 1.87 (m, 3H), 1.81 (m , 3H), 1.69 (s, 1H).

Example 9 : Synthesis of Compound 4- ( 4- ( 1R , 5S ) -3,8 - diazabicyclo [3.2.1] octan -3- yl) -5- cyclopropoxy -8- fluoro -2- ( 2 -methylenetetrahydro -1H- pyrrolidin - 7a ( 5H ) -yl )methoxy)pyrido [4,3 - d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2- ol

Step 1: Synthesis of compound 9-1

After adding cyclopropanol (0.41 g) and anhydrous THF respectively to the reaction bottle, NaH (0.29 g) was slowly added in batches at room temperature. After stirring for 5 min, powdered solid M10 (4.00 g) was added in batches and the reaction was stirred for 10 min; For the reaction, 100 mL of saturated NH ₄ Cl was added dropwise to quench, and 200 mL of ethyl acetate was added for extraction. The aqueous phase was washed twice with ethyl acetate, and the organic phases were combined and concentrated under reduced pressure to obtain the target compound 9-1 (0.82 g). ESI-MS m/z: 301.7 [M+H] ⁺ .

Step 2: Synthesis of compound 9-2

At room temperature, 9-1 (0.86 g), (1R, 5S)-3,8-diazobicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.21 g), DIPEA (0.99 mL) and anhydrous DMF (5.0 mL) were added to the reaction bottle in sequence, stirred at room temperature to dissolve, and finally PyBOP (2.97 g) was added, and stirred at room temperature for 0.5 h. 50 mL of tap water was added to the reaction, and 50 mL of EA was used to wash twice, and the extraction was separated. The organic phase was evaporated under reduced pressure, and the concentrate was purified by column chromatography (PE/EA = 3:1) to obtain the target compound 9-2 (0.97 g). ESI-MS m/z: 496.0 [M+H] ⁺ .

Step 3: Synthesis of compound 9-3

Compound 9-2 (377 mg), intermediate M8 (200 mg), potassium phosphate (172 mg), cataCXium A Pd G3 (29.30 mg) were dissolved in 1,4-dioxane (5.00 ml) and water (2.00 ml), and reacted overnight at 70°C in a sealed tube under a nitrogen atmosphere. After the reaction was complete, the reaction solution was diluted with EA and water, extracted once with EA, washed once with saturated salt water, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by column chromatography to obtain 9-3 (300 mg). ESI-MS m/z: 802.1 [M+H] ⁺ .

Step 4: Synthesis of compound 9-4

Dissolve 9-3 (300 mg) in dichloromethane (5.00 ml), add tert-butyldimethylsilyl chloride (281.85 mg) and imidazole (127.31 mg), and react at room temperature for 0.5 h. When the reaction is complete, dilute the reaction solution with DCM and water, extract once with DCM, wash once with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The concentrate is purified by column chromatography to obtain 9-4 (1.0 g). ESI-MS m/z:916.3[M+H] ⁺ .

Step 5: Synthesis of compound 9-5

Dissolve 9-4 (1.0 g) in DCM (5.00 mL), add mCPBA (376.70 mg), and react at room temperature for 0.5 h. Dilute the reaction solution with DCM, add saturated sodium bicarbonate to quench the reaction, extract once with DCM, wash once with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate, and purify the concentrate by column chromatography to obtain 9-5 (200 mg). ESI-MS m/z: 948.3 [M + H] ⁺ .

Step 6: Synthesis of compound 9-6

M9 was dissolved in THF (3.00 mL), NaH (15.17 mg) was added, and 9-5 (200.00 mg) was added thereto, and the mixture was reacted at room temperature for 0.5 h. The reaction was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC to obtain 9-6 (200 mg). ESI-MS m/z: 907.5 [M+H] ⁺ .

Step 7: Synthesis of compound 9-7

Dissolve 9-6 (200.00 mg) in DMF (3.00mL), add CsF (3000 mg), and react at room temperature for 1 h. The reaction solution was diluted with EA and water, extracted once with EA, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by Pre-TLC to obtain 9-7 (70 mg). ESI-MS m/z: 751.1 [M+H] ⁺ .

Step 8: Synthesis of compound 9

Dissolve 9-7 (70.00 mg) in DCM (2.00 mL), add boron trifluoride ether (27 mg), and react at room temperature for 0.5 h. The reaction solution was added to cold saturated sodium bicarbonate solution, extracted twice with DCM:MeOH=10:1, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was further purified through the preparative liquid phase to obtain target compound 9 (7.9 mg). ESI-MS m/z: 651.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 7.45 (dd, J = 9.1, 5.7 Hz, 1H), 7.38-7.36 (m, 1H), 7.23-7.22 (m, 1H), 4.90 (s, 5H), 4.27-4.24 (m, 1H), 4.04-4.90 (m, 5H), 3.70 (d, J = 14.2 Hz, 1H), 3.55 (s, 3H), 3.45 (d, J = 13.0 Hz, 1H), 3.12 (dt, J = 10.6, 5.5 Hz, 1H), 2.79 – 2.64 (m, 2H), 2.44 (dd, J = 15.8, 1.8 Hz, 1H), 2.17 – 2.07 (m, 1H) , 2.01 – 1.85 (m, 2H), 1.84 – 1.72 (m, 4H), 1.65 (s, 1H). 0.73 – 0.68 (m, 4H).

Example 39 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8 - fluoro -5- methoxy -2- ( ( 2- methyltetrahydro -1H- pyrrolazine -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5- ethyl- 6 - fluoronaphthalene- Synthesis of 2- alcohols

Step 1: Synthesis of compound 39-1:

The intermediate M8 (500 mg) was dissolved in 3 mL of DMF, and then CsF (1.94 g) was added. The reaction was carried out at room temperature for 1.5 h. The reaction solution was extracted with EA and water. The organic phase was retained, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 39-1 (550 mg), which was directly used in the next reaction.

Step 2: Synthesis of compound 39-2:

The compound 39-1 (300 mg) from the previous step was dissolved in 5 mL of methanol, and then Pd/C (50 mg) was added. The atmosphere was replaced with hydrogen 5 times, and the reaction was carried out at room temperature for 20 min. The filtrate was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 39-2 (208 mg).

Step 3: Synthesis of compound 39-3:

Compound 39-2 (403 mg), intermediate 7-2 (300 mg), CataCXium A Pd G3 (93 mg) and K ₃ PO ₄ (300 mg) were dissolved in THF (4 mL) and H ₂ O (1 mL), reacted at 80 ^° C for 3 h under nitrogen protection, cooled to room temperature, extracted with EA and water, retained the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 39-3 (330 mg).

Step 4: Synthesis of compound 39-4:

Compound 39-3 (330 mg) was dissolved in DCM (5 mL), and then TBSCl (800 mg) and imidazole (550 mg) were added in sequence. The reaction was allowed to react at room temperature for 0.5 h. The reaction solution was extracted with DCM and water, and the organic phase was retained. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 39-4 (270 mg).

Step 5: Synthesis of compound 39-5:

Dissolve compound 39-4 (270 mg) in DCM (5 mL), then add m-CPBA (270 mg), react at room temperature for 0.5 h, add an appropriate amount of saturated sodium sulfite solution, stir for 20 min, quench with DCM and water The reaction solution was extracted, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain target compound 39-5 (150 mg).

Step 6: Synthesis of compound 39-6:

Dissolve intermediate M9 (90 mg) in anhydrous THF (2 mL), then add NaH (30 mg), react at room temperature for 20 min, then add compound 39-5 (150 mg), and react at room temperature for 30 min. . Add an appropriate amount of saturated ammonium chloride solution to quench, extract the reaction solution with EA and water, retain the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain target compound 39-6 (59 mg).

Step 7: Synthesis of compound 39:

Compound 39-6 (59 mg) was dissolved in 2 mL of DCM, then TFA (1 mL) was added, and the reaction was carried out at room temperature for 20 min. Concentrate under reduced pressure, and the concentrate was purified by column chromatography to obtain target compound 39 (23 mg).

Example 55 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8 - fluoro -5- methoxy -2- ( ( 2- methyltetrahydro -1H- pyrrolazine -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5,6 -difluoronaphthalene -2- Synthesis of alcohol

Step 1: Synthesis of compound 55-1

Compound 7-2 (0.29 g), 5,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphthalene-2-ol (0.31 g), K ₂ CO ₃ (0.18 g), Pd (dppf) Cl ₂ (0.05 g) and 7 mL Dioxane/ 1 mL H ₂ O were added to the microwave tube, and then replaced with N ₂ for 2 min and microwaved at 140°C for 0.5 h. DCM and H ₂ O (20 mL each) were added to the reaction solution for extraction. The aqueous phase was washed twice with DCM, the organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE/EA = 4:1) to obtain the target compound 55-1 (0.31 g). ESI-MS m/z: 614.2 [M+H] ⁺ .

Step 2: Synthesis of Compound 55-2

After adding 55-1 (0.22 g), TBSCl (0.11 g), imidazole (0.05 g) and anhydrous DCM (5 mL) respectively to the reaction flask, the reaction was stirred at room temperature for 20 min. Add 15 mL saturated NaCl tap water to the reaction, extract and separate the liquids, wash the aqueous phase twice with 10 mL DCM, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA = 10:1) to obtain the target compound. 55-2 (0.21 g). ESI-MS m/z: 728.3 [M+H] ⁺ .

Step 3: Synthesis of compound 55-3

After adding 55-2 (0.2 g), m CPBA (0.17 g) and anhydrous DCM (5 mL) respectively to the reaction flask, the reaction was stirred at room temperature for 15 min. Add 10 mL saturated NaHCO ₃ to the reaction, extract and separate the liquids, wash the aqueous phase twice with 5 mL DCM, evaporate the organic phase to dryness under reduced pressure, and purify the concentrate by column chromatography (PE/EA = 3:1) to obtain the target compound. 55-3 (0.13 g). ESI-MS m/z: 760.1[M+H] ⁺ .

Step 4: Synthesis of compound 55-4

Add intermediate M9 (0.04 g) and anhydrous THF (1 mL) to the reaction flask, add NaH (0.02 g) slowly in batches, stir for 10 min, then add 55-3 (0.11 g), stir and react at room temperature for 15 min. Cool the reaction solution in an ice-water bath for 5 min, drop 2 mL of saturated NH ₄ Cl to quench, add 5 mL of ethyl acetate, extract, wash the aqueous phase with ethyl acetate twice, combine the organic phases, evaporate to dryness under reduced pressure, and purify the concentrate by column chromatography (DCM/NH ₃ :MeOH = 20:1) to obtain the target compound 55-4 (0.08 g). ESI-MS m/z: 719.3 [M+H] ⁺ .

Step 5: Synthesis of Compound 55

After adding 55-4 (0.08 g), trifluoroacetic acid (0.1 mL) and anhydrous DCM (2 mL) to the reaction bottle, the mixture was stirred at room temperature for 0.5 h. The reaction liquid was evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM/NH ₃ :MeOH = 8:1) to obtain the target compound 55 (20 mg, 41.0% yield). ¹ H NMR (500 MHz, DMSO) δ 10.25 (s, 1H), 7.75 – 7.72 (m, 1H), 7.60 – 7.54 (m, 1H), 7.38 – 7.29 (m, 2H), 4.89 (d, J = 1.5 Hz, 2H), 4.42 (s, 1H), 4.00 – 3.97 (m, 2H), 3.94 (s, 3H), 3.56 – 3.37 (m, 4H), 3.20 – 3.17 (m, 2H), 3.01 – 2.97 (m, 1H), 2.59 – 2.51 (m, 4H), 2.36 – 2.33 (m, 1H), 1.97 – 1.64 (m, 4H), 1.70 – 1.48 (m, 4H). ESI-MS m/z: 619.2 [M+H] ⁺ .

Example 109 : Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl) -2 -(( 2- (difluoromethylene)tetrahydro -1H- pyrrolidin -7a ( 5H ) -yl )methoxy) -8- fluoropyrido [4,3-d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2- amine

Step 1: Synthesis of Compound 109-1

The intermediate compound 1-1 (500 mg) and 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (882 mg) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL), potassium phosphate (548 mg) was added, and cataCXium A Pd G3 (63 mg) was added under nitrogen protection, and the temperature was raised to 70 ^o C for reaction for 3 hours. Stop heating, cool to room temperature, dilute with water (20 mL), extract twice with dichloromethane, 20 ml each time, combine the organic phases, wash the organic phases twice with water, dry over anhydrous sodium sulfate, mix the samples, and separate the products by column chromatography (DCM:MeOH = 20:1) to obtain 770 mg of the target compound 109-1.

Step 2: Synthesis of compound 109-2

Dissolve 109-1 (720 mg) in THF (20 mL), add triethylamine (0.34 mL) and DMAP (10 mg), cool to 0 ^o C under nitrogen protection, and add N-phenylbis(trifluoro Methanesulfonyl)imine (580 mg) was dissolved in THF (4 mL) and dropped into the above reaction solution. After the dripping was completed, the reaction was kept at room temperature for 10 min, then raised to room temperature and stirred for 2 h. After LCMS monitors the complete conversion of the raw materials, the reaction solution is quenched in saturated sodium bicarbonate solution (50 mL), extracted with DCM twice, 50 ml each time, combine the organic phases, wash twice with water, dry the organic phase over anhydrous sodium sulfate, and column layer The product was analyzed and separated (DCM:MeOH) = 25:1, and 686 mg of the target compound 109-2 was isolated.

Step 3: Synthesis of Compound 109-3

Compound 109-2 (200 mg), benzophenone imine (71 mg) and cesium carbonate (192 mg) were dissolved in 1,4-dioxane (3 mL), and BINAP (12 mg) was added under nitrogen protection. ) and palladium acetate (4.4 mg), raised to 100 ^o C and reacted for 2 h. After the reaction is completed, add water (10 mL) to dilute, extract with DCM twice, 15 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (DCM:MeOH) = 50:1 , 230 mg of target compound 109-3 was isolated.

Step 4: Synthesis of Compound 109-4

Dissolve 109-3 (200 mg) in a mixed solution of hydrochloric acid solution (5 ml, 2mol/L) and THF (10 mL), and stir at room temperature for 15 min. The reaction solution was quenched in saturated carbonic acid solution, extracted with DCM twice, 15 ml each time, the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product that was directly used in the next reaction without purification.

Step 5: Synthesis of Compound 109-5

Dissolve the above crude product in DMF (3 mL), add cesium fluoride (48 mg), and stir at room temperature for 15 min. Add water (10 mL), extract with DCM twice, 15 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, spin dry, and the crude product obtained is directly used in the next reaction without purification.

Step 6: Synthesis of Compound 109

Dissolve the above crude product in DCM (3 mL), under nitrogen protection, add boron trifluoride ether (0.12 ml) dropwise at room temperature, complete the addition, and stir at room temperature for 30 min. The reaction solution was quenched in saturated carbonic acid solution, extracted with DCM twice, 15 ml each time, the organic phases were combined, washed twice with water, the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by Pre-TLC (DCM:MeOH=100:12) to obtain compound 109 (22.3 mg, purity 99.09%). ESI-MS m/z: 630.5 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 9.06 (s, 1H), 7.77 (dd, J = 9.2, 5.9 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.07-7.01 (m, 2H ), 5.65 (s, 2H), 4.58 (d, J = 13.3 Hz, 1H), 4.40 (d, J = 12.9 Hz, 1H), 4.20-4.06 (m, 2H), 3.86-3.84 (m, 1H) , 3.82-3.62 (m, 3H), 3.04-2.96 (m, 1H), 2.70-2.54(m, 2H), 2.46-2.32 (m, 2H), 2.04-1.94 (m, 2H), 1.91-1.70 ( m, 4H), 1.49-1.18 (m, 4H).

Example 110 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8 - fluoro -2- (( 2- methyltetrakis) Synthesis of hydrogen -1H- pyrrolazine -7a ( 5H ) -yl )methoxy)pyrido [4,3d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2 -amine

Step 1: Synthesis of compound 110-1

Intermediate M9 (430 mg) was dissolved in anhydrous THF (20 mL), protected by nitrogen, sodium hydride (220 mg) was added, and then intermediate M2 (1g, 2.33mmol) was added, and stirred at room temperature for 4 hours. The reaction solution was quenched in anhydrous ammonium chloride (40 mL), extracted twice with ethyl acetate, 40 ml each time, and the organic phases were combined. The organic phases were washed twice with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH=40:1) to obtain 760 mg of compound 110-1.

Step 2: Synthesis of Compound 110-2

Dissolve 110-1 (760 mg) and intermediate M8 (980 mg) in a mixed solvent of 1,4-dioxane (15 mL) and water (3 mL), add potassium phosphate (888 mg), add cataCXium A Pd G3 (101 mg) under nitrogen protection, and heat to 100 ^° C for 3 hours. Stop heating, cool to room temperature, dilute with water (40 mL), extract twice with dichloromethane, 40 ml each time, combine the organic phases, wash the organic phases twice with water, dry over anhydrous sodium sulfate, and concentrate. The concentrate is purified by column chromatography (DCM:MeOH=20:1) to obtain 760 mg of compound 110-2.

Step 3: Synthesis of Compound 110-3

Compound 110-2 (760 mg) was dissolved in THF (20 mL), triethylamine (0.37 mL) and DMAP (11 mg) were added, and the temperature was lowered to 0 ^° C under nitrogen protection. N-phenylbis(trifluoromethanesulfonyl)imide (638 mg) was dissolved in THF (4 mL) and added dropwise to the above reaction solution. After the addition, the mixture was kept warm for 10 min, and then heated to room temperature and stirred for 1 h. The reaction solution was quenched in saturated sodium bicarbonate solution (50 mL), extracted twice with DCM, 50 ml each time, the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM: MeOH = 25:1) to obtain 635 mg of compound 110-3.

Step 4: Synthesis of compound 110-4

Dissolve 110-3 (635 mg), benzophenone imine (234 mg) and cesium carbonate (631 mg) in 1,4-dioxane (15 mL). Add BINAP (40 mg) and sodium acetate (15 mg) under nitrogen protection, and heat to 100 ^° C for 1 h. Dilute with water (40 mL), extract with DCM twice, 50 ml each time, combine the organic phases, wash with water twice, dry the organic phase with anhydrous sodium sulfate, and concentrate. The concentrate is purified by column chromatography (DCM: MeOH = 50:1) to obtain 560 mg of yellow oil 110-4.

Step 5: Synthesis of compound 110-5

Dissolve 110-4 (450 mg) in a mixed solution of hydrochloric acid solution (5 mL, 2 mol/L) and THF (10 mL), and stir at room temperature for 15 min. Quench the reaction solution in saturated sodium carbonate solution, extract with DCM twice, 30 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, concentrate to obtain crude product 110-5, and drop it directly without purification One step reaction.

Step 6: Synthesis of compound 110-6

Dissolve the above crude product in DMF (7 mL), add cesium fluoride (1.3 g), and stir at 35 ^° C for 30 min. Dilute with water (30 mL), extract with DCM twice, 3 ml each time, combine the organic phases, wash with water twice, dry the organic phase over anhydrous sodium sulfate, and concentrate. The crude product can be obtained by concentration, which can be directly put into the next reaction without purification.

Step 7: Synthesis of compound 110

Dissolve the above crude product in DCM (6 mL), under nitrogen protection, add boron trifluoride ether (0.34 mL) dropwise at room temperature, complete the addition, stir at room temperature for 10 min, quench the reaction solution in saturated carbonic acid solution, DCM Extract twice, 30 ml each time, combine the organic phases, wash twice with water, dry the organic phase over anhydrous sodium sulfate, and concentrate. The concentrate was separated and purified by Pre-TLC (DCM:MeOH=100:12) to obtain 110 (23.0 mg, purity 98.24%). [M+H] ⁺ =594.45. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 7.66 (dd, J = 9.1, 5.7 Hz, 1H), 7.20 (t, J = 8.9 Hz, 1H), 7.09 (dd, J = 15.6, 2.4 Hz, 2H), 4.93 (s, 2H), 4.72 – 4.60 (m, 1H), 4.55 – 4.43 (m, 1H), 4.24 – 4.12 (m, 2H), 3.92 (s, 2H), 3.76 – 3.64 (m, 4H), 3.58 (dd, J = 12.3, 4.8 Hz, 1H), 3.28 (d, J = 14.1 Hz, 1H), 3.22 – 3.15 (m, 1H), 2.86 – 2.75 (m, 2H ), 2.71 – 2.61 (m, 1H), 2.40 (d, J = 14.4 Hz, 1H), 2.19 (ddd, J = 17.4, 11.9, 7.2 Hz, 1H), 1.97 – 1.87 (m, 2H), 1.85- 1.75 (m, 2H), 1.72-1.54 (m, 4H).

Example 112 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8 - fluoro -2- (( 2- methyltetrakis) Synthesis of hydrogen -1H- pyrrolazine -7a ( 5H ) -yl )methoxy)pyrido [4,3d] pyrimidin -7- yl) -5- ethynyl- 1,6- difluoronaphthalen-2- amine

Step 1: Synthesis of Compound 112-1

Dissolve 110-5 (50 mg) in acetonitrile (2 mL), add fluorine reagent (8 mg), and stir at room temperature for 30 min. The reaction solution was quenched in saturated sodium sulfite solution (10 mL), extracted twice with DCM (10 mL), 10 ml each time, the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, and concentrated to obtain crude product 112-1 , directly vote for the next reaction.

Step 2: Synthesis of Compound 112-2

Dissolve the crude product 112-1 in the previous step in DMF (4 mL), add cesium fluoride (357 mg) and react at room temperature for 1 h. Dilute with water (20 mL), extract with DCM twice, 20 ml each time, wash twice with water and saturated brine, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain crude product 112-2, which is directly used in the next step of the reaction.

Step 3: Synthesis of Compound 112

The crude product of 112-2 from the previous step was dissolved in DCM (5 mL), and under nitrogen protection, boron trifluoride etherate (0.09 mL) was added dropwise at room temperature. After addition, the mixture was stirred at room temperature for 1 h. The reaction solution was quenched in saturated carbonic acid solution, extracted twice with DCM, 20 ml each time, and the organic phases were combined and washed twice with water. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated and purified by Pre-TLC (DCM:MeOH=100:12) to obtain the target compound 112 (9.2 mg, purity 98.29%). ESI-MS m/z: 612.5 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 10.86 (s, 1H), 9.63 (d, J = 8.8 Hz, 1H), 9.38 (s, 1H), 9.15 (s, 1H), 8.00 (dd, J = 9.0, 5.8 Hz, 1H), 7.51 (t, J = 9.1 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 5.22 (d, J = 11.9 Hz, 2H), 4.63 (ddd, J = 37.1, 25.8, 13.7 Hz, 1H), 4.30-4.10 (m, 4H), 4.03-3.70 (m, 4H), 3.70-3.55 (m, 1H), 3.25-3.10 (m, 1H), 2.99 – 2.87 (m, 1H), 2.77 (d, J = 15.9 Hz, 1H), 2.30-2.21(m, 1H), 2.19-2.11 (s, 1H), 2.09-1.87(m, 8H).

Example 120 : Compound 4-(4-((1R,5S)-3,8 -diazabicyclo [3.2.1] octan -3- yl )-5- chloro -2-((2-( di Fluoromethylene ) tetrahydro - 1H - pyrrolidin -7a( 5H )-yl ) methoxy ) -8- fluoropyridine [ 4,3- d ] pyrimidin -7 -yl )-5 - ethynyl6 -Synthesis of fluoronaphthalen -2- ol

Step 1: Synthesis of compound 120-1

At room temperature, compound M10 (0.7 g), DIEA (1.65 mL), POCl ₃ (0.7 mL) and anhydrous ACN (20 mL) were respectively weighed into the reaction bottle, and the reaction was carried out at 80°C for 0.5 hours. Samples were taken to monitor the completion of the reaction. The reaction solution was lowered to 0°C, and DIEA (1.24 mL) and (1R, 5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.59 g), raise to room temperature and react for 0.5 hours; when the reaction is completed, add saturated sodium chloride aqueous solution to the reaction solution, add EA to separate the layers to obtain the organic layer, dry over anhydrous sodium sulfate, and concentrate. The concentrate was purified by column chromatography (PE:EA = 0-25%) to give product 120-1 (0.73 g, 56% yield). ESI-MS m/z = 474.3 [M+H] ⁺ .

Step 2: Synthesis of Compound 120-2

At room temperature, under nitrogen protection, compound 120-1 (0.25 g), Pd(PPh ₃ ) ₄ (140 mg), M8 (0.49 g) and sodium carbonate (0.23 g) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and microwaved at 105°C for 2 hours. After the reaction was completed, EA was added to separate the organic layer, which was washed once with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA=0-20%) to obtain product 120-2 (0.22 g, 50% yield). ESI-MS m/z = 780.4 [M+H] ⁺ .

Step 3: Synthesis of Compound 120-3

At room temperature, compound 120-2 (0.22 g), TBSCl (65 mg), imidazole (58 mg) and DCM (5 mL) were weighed into the reaction bottle and reacted at room temperature for 0.5 h. After the reaction, saturated brine (15 mL) was added for washing, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (PE:EA=0-10%) to obtain product 120-3 (0.30 g). ESI-MS m/z = 894.5 [M+H] ⁺ .

Step 4: Synthesis of compound 120-4

At room temperature, compound 120-3 (0.30 g), m CPBA (70 mg) and DCM (10 mL) were weighed into the reaction bottle and reacted at room temperature for 1.0 h. After the reaction, saturated brine (15 mL) was added for washing, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (PE:EA=0-50%) to obtain product 120-4 (0.11 g). ESI-MS m/z = 910.7 [M+H] ⁺ .

Step 5: Synthesis of Compound 120-5

At room temperature, M1 (35 mg) and solvent anhydrous THF (0.5 mL) were weighed into the reaction bottle, and NaH (36 mg) was added. After reacting at room temperature for 10 min, 120-4 (83 mg) was added to the reaction and reacted at room temperature for 15 min; the reaction solution was cooled to 0°C, saturated NH ₄ Cl (20 mL) was added dropwise to quench, ethyl acetate (20 mL) was added, and extraction was performed. The aqueous phase was washed twice with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM/NH ₃ in MeOH = 15:1) to obtain the target compound 120-5 (74 mg). ESI-MS m/z: 921.6 [M+H] ⁺ .

Step 6: Synthesis of Compound 120-6

At room temperature, add 120-5 (74), CsF (129 mg) and anhydrous DMF (1 mL) to the reaction bottle, and react at room temperature for 2.0 h; add aq.NaCl aqueous solution (20 mL) and EA to the reaction. (20 mL), extract and separate the liquids, dry the organic phase over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure. The concentrate is purified by Pre-TLC (DCM/NH ₃ in MeOH = 12:1) to obtain the target compound 120-6 (49 mg). ESI-MS m/z: 765.4 [M+H] ⁺ .

Step 7: Synthesis of Compound 120

At room temperature, compound 120-6 (49 mg) was dissolved in DCM (1 mL), and boron trifluoride etherate (0.2 mL) was added. The reaction was allowed to react at room temperature for 10 min. After the reaction was completed, the reaction solution was added dropwise to a saturated sodium carbonate aqueous solution (10 mL) precooled to 0°C, and DCM was added to separate the organic layer, which was washed once with saturated salt water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by Pre-TLC (DCM/NH ₃ :MeOH = 8:1) to obtain the target compound 120 (10.7 mg, 25% yield). ¹ H NMR (500 MHz, MeOD) δ 7.88 (ddd, J = 16.4, 9.1, 5.7 Hz, 2H), 7.39 – 7.30 (m, 4H), 7.24 (d, J = 2.2 Hz, 1H), 7.08 (d, J = 10.3 Hz, 1H), 4.56 – 4.24 (m, 6H), 4.17 – 3.91 (m, 2H), 3.80 (dd, J = 29.2, 22.0 Hz, 7H), 3.50 – 3.40 (m, 3H), 3.35 (d, J = 8.2 Hz, 1H), 3.24 – 3.12 (m, 3H), 2.76 (ddd, J = 23.1, 3H), 1.77 – 1.63 (m, 3H). ESI-MS m/z: 541.5 [M+H] ⁺ .

Example 121 : Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl) -2 -(( 2- (difluoromethylene)tetrahydro -1H- pyrrolazin -7a ( 5H ) -yl )methoxy) -8- fluoropyridin [4,3d] pyrimidin -7- yl) -5- ethynyl -1,6- difluoronaphthalen -2- ol

Step 1: Synthesis of compound 121-1

The intermediate M8 (500.00 mg) was added to a 25 mL single-mouth bottle, acetonitrile (10.00 mL) was added, and then fluorine reagent (453.74 mg) was added, and the reaction was stirred at room temperature for 4 h. The reaction was completed by LCMS monitoring. EA and water were added to the reaction solution, extracted, and the organic phase was collected. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA, 15% EA) to obtain compound 121-1 (253.0 mg, yield 48.7%).

Step 2: Synthesis of compound 121-2

Add intermediate 1-1 (150.00 mg) into a 25 mL single-neck bottle, then add 121-1 (251.22mg), 1,4-dioxane (4.00 mL), water (0.80mL), PdCl ₂ ( dppf) (28.32 mg) and potassium carbonate (107.06 mg). Replace N2 three times, raise to 130°C and stir for 3 hours under _N2 protection. LCMS monitored reaction completion. Concentrate under reduced pressure and purify through column chromatography (DCM/MeOH, 5% MeOH) to obtain compound 121-2 (68.0 mg, yield 29.1%).

Step 3: Synthesis of compound 121-3

Compound 121-2 (58.00 mg) was added to a 25 mL single-neck bottle, N,N-dimethylformamide (1.50 mL) was added, and cesium fluoride (77.89 mg) was added. The reaction was stirred at room temperature for 2 hours. EA and water were added to the reaction solution, extracted, and the organic phase was collected. The organic phase was washed three times with saturated brine and dried over anhydrous sodium sulfate. Compound 121-3 was obtained through Pre-TLC separation and purification (DCM/MeOH=15/1) (28.0 mg, yield 58.3%).

Step 4: Synthesis of compound 121

Compound 121-3 (28.00 mg) was added to a 25 mL single-necked bottle, and DCM (1.50 mL) was added, followed by boron trifluoride etherate (0.30 mL). The reaction was stirred at room temperature for 5 minutes. The reaction solution was added to a saturated Na ₂ CO ₃ solution at 0°C. DCM/MeOH=5/1 and water were added, and the mixture was extracted 3 times. The organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was prepared by Pre-HPLC to obtain compound 121 (9.8 mg, yield 39.8%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 9.04 (s, 1H), 8.13 (dd, J = 9.3, 5.7 Hz, 1H), 7.60 (t, J = 9.0 Hz, 1H), 7.36 (dd, J = 8.6, 2.1 Hz, 1H), 4.46 (d, J = 12.5 Hz, 1H), 4.30 (d, J = 12.3 Hz, 1H), 4.17 – 4.02 (m, 3H), 3.64 (t, J = 11.9 Hz, 3H), 3.56 (d, J = 13.5 Hz, 4H), 3.03 – 2.95 (m, 2H), 2.61 (s, 2H), 2.56 3H]. D-terminal address: 3H. (d, J = 7.7 Hz, 1H), 2.41 (dt, J = 16.0, 3.9 Hz, 2H), 1.98 (ddt, J = 13.2, 9.7, 6.8 Hz, 3H), 1.86 (tt, J = 10.2, 5.2 Hz, 1H), 1.77 (ddd, J = 12.5, 8.8, 6.6 Hz, 2H). ESI-MS m/z: 694.41 [M+H] ⁺ .

Example 122 : Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -2 -(( 2- (difluoromethylene)tetrahydro -1H- pyrrolazin -7a ( 5H ) -yl )methoxy) -8- fluoro -5- ( 2,2,2 -trifluoroethoxy)pyrido [4,3d] pyrimidin -7- yl) -5- ethynyl - 6- fluoronaphthalen -2- ol

Step 1: Synthesis of compound 122-1

To a solution of EtOH (0.39 mL) in anhydrous THF (10 mL), NaH (357 mg, 60% purity) was added in batches. After stirring for 5 min, the reaction system was cooled to 0°C, and then powdered solid M10 (500 mg) was added in batches. , 1.0 eq.), naturally raised to room temperature 22°C and stirred for 30 minutes. Cool the reaction system to 0°C again, add saturated ammonium chloride solution (20 mL) dropwise to quench the reaction, add 20 mL of ethyl acetate for extraction and separation, wash the aqueous phase twice with ethyl acetate, combine the organic phases and wash with anhydrous After drying over sodium sulfate, the organic phase was concentrated to obtain the target compound crude product 122-1 (660 mg), which was directly used in the next reaction. ESI-MS m/z: 344.1 [M+H] ⁺ .

Step 2: Synthesis of compound 122-2

122-1 (660 mg) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (490 mg) in DMF (6 mL) solution, DBU (1.14 mL) and PyBOP (1.5 g) were added in sequence, and the reaction was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. Add 30 mL saturated brine and 30 mL EA to the reaction for extraction and separation. The organic phase was washed three times with saturated brine and dried over anhydrous sodium sulfate. The organic phase was further concentrated and purified by column chromatography (EA/PE = 0%). -15%) to obtain the target compound 122-2 (360 mg). ESI-MS m/z: 538.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 122-3

After adding 122-2 (360 mg), M8 (470 mg), K ₂ CO ₃ (277 mg), Pd (dppf) Cl ₂ (82 mg) and 6 mL Dioxane/1.5 mL H ₂ O respectively into the microwave tube, After N ₂ replacement for 10 minutes, microwave reaction at 135°C for 70 minutes. Add 20 mL each of EA and H ₂ O to the reaction solution, extract and separate the liquids. The aqueous phase is extracted twice with EA. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by column chromatography (EA/PE = 0%-30%) to obtain the target compound 122-3 (390 mg). ESI-MS m/z: 844.3 [M+H] ⁺ .

Step 4: Synthesis of Compound 122-4

To a solution of 122-3 (390 mg) in DCM (15 mL), imidazole (220 mg) and TBSCl (348 mg) were added, and the reaction system was allowed to stir at room temperature for 30 min. Add 15 mL of water to the reaction, extract and separate the liquids, wash the aqueous phase twice with 10 mL DCM, combine the organic phases and wash once with 20 mL saturated brine, then dry over anhydrous sodium sulfate and concentrate under reduced pressure, and the concentrate is passed through the column Chromatography purification (EA/PE = 0%-10%) gave the target compound 122-4 (320 mg).

Step 5: Synthesis of compound 122-5

To a solution of 122-4 (320 mg) in DCM (6 mL) was added m CPBA (230 mg) and stirred at room temperature for 70 minutes. Add 20 mL DCM and 20 mL saturated NaHCO ₃ solution to the reaction, extract and separate the liquids, and extract the aqueous phase twice with 10 mL DCM. The organic phases are combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate is purified by column chromatography ( EA/PE = 0%-20%) to obtain the target compound 122-5 (160 mg). ESI-MS m/z: 990.3. [M+H] ⁺ .

Step 6: Synthesis of compound 122-6

To the solution of M1 (54 mg) in anhydrous THF (3 mL), NaH (23 mg) was added, and after stirring for 10 min, 122-5 (140 mg) was added, and the system was stirred at room temperature for 15 min. After the reaction, the system was cooled to 0°C, saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction, ethyl acetate (20 mL) was added, extraction was carried out, and the water phase was washed twice with ethyl acetate, and the organic phase was The combined mixture was dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH ₃ :MeOH (7 M) = 100:5) to obtain target compound 122-6 (130 mg). ESI-MS m/z: 493.6 [M+2H] ⁺ /2.

Step 7: Synthesis of Compound 122-7

To a solution of 122-6 (130 mg) in DMF (1 mL) was added CsF (401 mg), and the reaction was allowed to stir at 35 °C for 1 h. After the reaction, 20 mL of saturated saline and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC ( DCM/NH ₃ : MeOH (7 M) = 100:7) to obtain the target compound 122-7 (94 mg). ESI-MS m/z: 829.5 [M+H] ⁺ .

Step 8: Synthesis of Compound 122

BF ₃ .Et ₂ O (0.27 mL) was added to a solution of 122-7 (90 mg) in anhydrous DCM (2 mL), and the resulting system was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction system was cooled to 0°C, then quenched by adding saturated Na ₂ CO ₃ (10 mL), extracted by adding DCM/MeOH (10:1, 20 mL), and the aqueous phase was extracted twice with the same mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH ₃ in MeOH (7 M) = 9:1) to obtain the target compound 122 (54 mg). ¹ H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 7.98 (dd, J = 9.1, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 7.24 (t, J = 2.2 Hz, 1H), 5.08 – 4.92 (m, 2H), 4.14 (dd, J = 10.6, 2.2 Hz, 1H), 4.09 (dd, J = 10.6, 3.0 Hz, 1H), 3.92 (d, J = 2.2 Hz, 1H), 3.64 (d, J = 14.0 Hz, 1H), 3.53 – 3.39 (m, 3H), 1.76 – 1.54 ( m, 4H), 3.53 – 3.73 (m, 2H), 1.29 – 1.63 (m, 5H), 1.30 (s, 2H). ESI-MS m/z: 737.4 [M+H] ⁺ .

Example 123 : Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl) -8- fluoro -2- (( 2- methyltetrahydro -1H- pyrrolizin -7a ( 5H ) -yl )methoxy) -5- ( 2,2,2 -trifluoroethoxy)pyridin [4,3d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2- ol

Step 1: Synthesis of compound 123-1

To a solution of M9 (62 mg) in anhydrous THF (3 mL) was added NaH (32 mg), stirred for 10 min, and then 122-5 (190 mg, 1.0 eq.) was added. The system was stirred at room temperature for 30 min. After the reaction was completed, the system was cooled to 0°C, and a saturated aqueous ammonium chloride solution (20 mL) was added dropwise to quench the reaction. Ethyl acetate (20 mL) was added, and the liquid was extracted. The aqueous phase was washed twice with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH ₃ : MeOH (7 M) = 100:7) to obtain the target compound 123-1 (84 mg). ESI-MS m/z: 949.5 [M+H] ⁺ .

Step 2: Synthesis of Compound 123-2

To a solution of 123-1 (84 mg) in DMF (1 mL) was added CsF (269 mg), and the reaction was allowed to stir at room temperature for 2 h. After the reaction, 20 mL of saturated saline and 20 mL of EA were added to the reaction, and the liquid was extracted and separated. The organic phase was washed twice with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC ( DCM/NH ₃ :MeOH (7 M) = 100:8) to obtain the target compound 123-2 (53 mg). ESI-MS m/z: 793.2 [M+H] ⁺ .

Step 3: Synthesis of compound 123

To a solution of 123-2 (53 mg) in anhydrous DCM (1 mL) was added BF ₃ .Et ₂ O (0.17 mL) and the resulting system was stirred at room temperature for 10 min. After the reaction is completed, cool the reaction system to 0°C, then add saturated Na ₂ CO ₃ (10 mL) to quench, add DCM/MeOH (10:1, 20 mL) for extraction, and continue to extract the aqueous phase twice with the same mixed solvent. . The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the concentrate was purified by Pre-TLC (DCM/NH ₃ in MeOH (7 M) = 8:1) to obtain target compound 123 (39 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.73 – 7.65 (m, 1H), 7.32 (d, J = 5.7 Hz, 1H), 7.28 – 7.26 (m, 1H), 7.21 – 7.14 (m, 1H), 4.98 – 4.92 (m, 4H), 4.26 (d, J = 10.3 Hz, 1H), 4.20 (d, J = 10.0 Hz, 1H), 3.93 – 3.79 (m, 1H), 3.63 – 3.38 (m, 5H) , 3.34 – 3.20 (m, 3H), 2.85 – 2.62 (m, 5H), 2.41 (d, J = 15.7 Hz, 1H), 2.33 (d, J = 15.5 Hz, 1H), 2.19 – 2.09 (m, 1H ), 1.98 – 1.86 (m, 2H), 1.83 – 1.71 (m, 2H), 1.65 – 1.46 (m, 2H). ESI-MS m/z: 693.5 [M+H] ⁺ .

Example 125 : Synthesis of Compound 3- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8 - fluoro -5- methoxy -2- (( 2 -methyltetrahydro -1H- pyrrolazin -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5- chloro -4- cyclopropylphenol

Step 1: Synthesis of Compound 125-1

Compound (3-bromo-5-chloro-4-cyclopropylphenoxy) (tert-butyl)dimethylsilane (2.00 g) was added to a 100 mL single-mouth bottle, and THF (30.00 mL) was added, _N2 protection Add n-BuLi (2.5M/n-hexane) (4.42 mL, 2.50mol/L) dropwise at -70°C. Stir at -70°C for 1 hour. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.73 mL) was added dropwise, and the mixture was raised to room temperature and stirred for 1 hour. The reaction solution was poured into saturated NH ₄ Cl solution, and extracted twice with EA. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA, 5% EA) to obtain compound 125- 1 (1.8 g yield 79.6%).

Step 2: Synthesis of compound 125-2

The intermediate 7-2 (400.00 mg) was added to a 25 mL single-mouth bottle, and 125-1 (695.93 mg), 1,4-dioxane (7.00 mL), water (1.00 mL), SphosPdG2 (61.24 mg) and potassium phosphate (541.98 mg) were added in sequence. _N2 was replaced three times, and the temperature was raised to 80°C and stirred for 2 hours under _N2 protection. The mixture was concentrated under reduced pressure and purified by column chromatography (PE/EA, 10-15% EA) to obtain compound 125-2 (528.0 mg, yield 86.6%).

Step 3: Synthesis of Compound 125-3

Compound 125-2 (434.00 mg) was added to a 25 mL single-neck bottle, dichloromethane (7.00 mL) was added, and mCPBA (418.17 mg) was added. The reaction was stirred at room temperature for 1 hour. Add saturated sodium sulfite solution to the reaction solution to quench, then add DCM and water, extract twice, collect the organic phase, wash the organic phase twice with saturated NaHCO ₃ solution, then wash with saturated brine, and dry over anhydrous sodium sulfate. Purification by column chromatography (PE/EA, 25% EA) gave compound 125-3 (284.0 mg, yield 51.5%).

Step 4: Synthesis of compound 125-4

Compound 125-3 (264.00 mg) was added to a 25 mL single-neck bottle, THF (4.00 mL) was added, and then intermediate M9 (108.11 mg) was added. Under ice bath, add sodium hydride (56.45 mg, 60%) in batches. The reaction was stirred at room temperature for 3.5 hours. Saturated NH ₄ Cl solution was added to the reaction solution to quench, and the mixture was concentrated under reduced pressure. Then add DCM and water, extract twice, collect the organic phase, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Purification by column chromatography (DCM/MeOH, 5-10% MeOH) gave compound 125-4 (119.0 mg, yield 41%).

Step 5: Synthesis of compound 125

Compound 125-4 (109.00 mg) was added to a 25 mL single-necked bottle, and DCM (3.00 mL) was added, followed by TFA (1.50 mL). The mixture was stirred at room temperature for 15 minutes. The mixture was concentrated under reduced pressure. The crude product was prepared by Pre-HPLC to obtain compound 125 (70.6 mg, yield 75.3%). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 10.78 (s, 1H), 10.17 (s, 1H), 9.37 (d, J = 95.1 Hz, 2H), 6.96 (d, J = 2.6 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 5.21 (dt, J = 13.4, 2.1 Hz, 2H), 4.65 – 4.54 (m, 2H), 4.32 – 4.09 (m, 6H), 3.98 (s, 5H), 3.65 (d, J = 14.3 Hz, 2H), 3.17 (dd, J = 12.5, 5.8 Hz, 1H), 2.93 (d, J = 3H), 1.75 (d, J = 16.1 Hz, 1H), 2.75 (d, J = 16.2 Hz, 1H), 2.25 (qd, J = 9.6, 5.3 Hz, 1H), 2.19 – 2.10 (m, 1H), 2.03 (dt, J = 9.2, 6.6 Hz, 2H), 1.95 – 1.89 (m, 2H), 1.84 (q, J = 5.9, 5.2 Hz, 2H), 0.63 (s, 2H) , 0.05 (s, 2H). ESI-MS m/z: 607.49 [M+H] ⁺ .

Example 141 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8- fluoro -5- methoxy -2- ( ( 2- methyltetrahydro -1H- pyrrolazine -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5- ethynyl- 6 - fluoronaphthalene- Synthesis of 2- amines

Step 1: Synthesis of compound 141-1

Compound 7-3 (1.43 g) was dissolved in dichloromethane (20 mL), m-chloroperoxybenzoic acid (1.59g) was added, and the reaction was carried out at room temperature for 1 h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate, extracted twice with DCM, and purified by column chromatography to obtain compound 141-1 (0.48 g, yield 32.24%). ESI-MS m/z: 808.51 [M+H]+.

Step 2: Synthesis of compound 141-2

Intermediate M9 (182.02 mg) was dissolved in tetrahydrofuran (5 mL), sodium hydride (118.8 mg) was added, and then compound 141-1 (480 mg) was added, and the mixture was reacted at room temperature for 10 minutes. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride, extracted twice with EA, and purified by column chromatography to obtain compound 141-2 (389 mg, yield 74.38%). ESI-MS m/z: 881.65 [M+H]+.

Step 3: Synthesis of Compound 141-3

Compound 141-2 (389 mg), DMAP (5.29 mg), and triethylamine (0.181 mL) were dissolved in tetrahydrofuran (5 mL), and finally 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (309.81 mg) was added and reacted at room temperature for 1 h. After the reaction was complete, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 141-3 (480 mg). ESI-MS m/z: 507.4 [M+H]+.

Step 4: Synthesis of Compound 141-4

Compound 141-3 (480 mg), benzophenone imine (171.70 mg), cesium carbonate (463.02 mg), Pd(OAc) ₂ (10.62 mg), BINAP (29.45 mg) were dissolved in 1,4-bis Oxygen hexacyclo (6 mL) was replaced with nitrogen and reacted at 100°C for 1 hour. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 141-4 (383 mg, yield 77.42%). ESI-MS m/z: 522.91 [M+H]+.

Step 5: Synthesis of Compound 141-5

Compound 141-4 (383 mg) was dissolved in tetrahydrofuran (8 mL), and 2N dilute hydrochloric acid (4 ml) was added to react at room temperature for 10 minutes. After the reaction was complete, the temperature was lowered to 0°C, and the compound was freed with saturated sodium carbonate, extracted twice with EA, washed once with saturated salt water, dried, filtered, and spun dry. The crude product was directly used in the next step to obtain compound 141-5 (380 mg). ESI-MS m/z: 880.67 [M+H] ⁺ .

Step 6: Synthesis of compound 141-6

Compound 141-5 (380 mg) was dissolved in N,N-dimethylformamide (5 mL), and cesium fluoride (1311.50 mg) was added and reacted at room temperature for 3 h. After the reaction was complete, the reaction solution was diluted with EA and water, extracted twice with EA, washed three times with saturated salt water, and purified by column chromatography to obtain compound 141-6 (215 mg, yield 68.81%). ESI-MS m/z: 724.53 [M+H]+.

Step 7: Synthesis of Compound 141

Compound 141-6 (215 mg) was dissolved in dichloromethane (5 mL), boron trifluoride ether (0.94 mL) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction was completed, the reaction solution was added to cold saturated sodium carbonate solution, extracted twice with DCM, dried, filtered and spin-dried, and purified by Pre-TLC to obtain compound 141 (120.70 mg, yield 65.06%). ESI-MS m/z: 624.48 [M+H]+. ¹ H NMR (500 MHz, DMSO) δ 7.77 (dd, J = 9.2, 5.9 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 7.04 ( d, J = 2.2 Hz, 1H), 5.63 (s, 2H), 4.90 (s, 2H), 4.11 – 3.92 (m, 3H), 3.88 (s, 4H), 3.81 (s, 1H), 3.55 (d , J = 14.0 Hz, 1H), 3.47 (s, 2H), 3.41 – 3.33 (m, 2H), 3.18 (d, J = 13.8 Hz, 1H), 3.03 – 2.94 (m, 1H), 2.62 – 2.53 ( m, 2H), 2.35 (d, J = 15.5 Hz, 1H), 2.05 – 1.64 (m, 4H), 1.63-1.52 (m, 4H), 1.23 (s, 1H).

Example 143 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -2 -(( 2- (difluoromethylene) Tetrahydro -1H- pyrrozine -7a ( 5H ) -yl )methoxy) -8- fluoro -5- methoxypyrido [4,3d] pyrimidin -7 -yl) -5 -ethynyl -6- Synthesis of fluoronaphthyl -2- amine

Step 1: Synthesis of compound 143-1

Compound 141-1 (88.96 mg) was dissolved in tetrahydrofuran (2 mL), sodium hydride (47.02 mg) was added, and then compound M1 (190 mg) was added, and the reaction was carried out at room temperature for 10 minutes. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride, extracted twice with EA, washed once with saturated brine, dried, filtered and concentrated. The crude product was directly used in the next step to obtain compound 143-1 (277 mg). ESI-MS m/z: 917.63 [M+H]+.

Step 2: Synthesis of compound 143-2

Compound 143-1 (277 mg), DMAP (3.76 mg), triethylamine (0.129 mL) were dissolved in tetrahydrofuran (5 mL), and finally 1,1,1-trifluoro-N-phenyl-N-( Trifluoromethanesulfonamide (220.57 mg), react at room temperature for 1 hour. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 143-2 (168 mg). ESI-MS m/z: 525.39 [M+H]+.

Step 3: Synthesis of compound 143-3

Dissolve 143-2 (168 mg), benzophenone imine (57.16 mg), cesium carbonate (154.15 mg), Pd(OAc) ₂ (3.55 mg), BINAP (9.84 mg) in 1,4-dioxy Six rings (4 mL), replaced with nitrogen, reacted at 100°C for 1 hour. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, and purified by column chromatography to obtain compound 143-3 (161 mg, yield 93.12%). ESI-MS m/z: 540.96 [M+H]+.

Step 4: Synthesis of Compound 143-4

Compound 143-3 (161 mg) was dissolved in tetrahydrofuran (4 mL), 2N dilute hydrochloric acid (2 ml) was added, and the reaction was carried out at room temperature for 10 minutes. After the reaction is complete, lower the temperature to 0°C, use saturated sodium carbonate to free the compound, extract twice with EA, wash once with saturated brine, dry, filter and spin dry. The crude product is directly used in the next step to obtain compound 143-4 (160 mg). ESI-MS m/z: 916.65 [M+H]+.

Step 5: Synthesis of Compound 143-5

Compound 143-4 (160 mg) was dissolved in N,N-dimethylformamide (3 mL), and cesium fluoride (521.35 mg) was added and reacted at room temperature for 3 h. After the reaction was complete, the reaction solution was diluted with EA and water, extracted twice with EA, washed three times with saturated salt water, and purified by column chromatography to obtain compound 143-5 (102 mg, yield 76.62%). ESI-MS m/z: 760.52 [M+H]+.

Step 6: Synthesis of Compound 143

Compound 143-5 (102 mg) was dissolved in dichloromethane (2 mL), and boron trifluoride etherate (0.17 mL) was added to react at room temperature for 0.5 h. After the reaction was complete, the reaction solution was added to a cold saturated sodium carbonate solution, extracted twice with DCM, dried, filtered, and spun dry, and purified by Pre-TCL to obtain compound 143 (39.9 mg, yield 44.94%). ESI-MS m/z: 660.46 [M+H]+. ¹ H NMR (500 MHz, DMSO) δ 7.77 (dd, J = 9.2, 5.9 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.07 (s, 1H), 7.04 (d, J = 2.2 Hz, 1H), 5.63 (s, 2H), 4.15-4.02 (m, 3H), 3.88 (s, 4H), 3.80 (s, 1H), 3.64 (d, J = 14.1 Hz, 1H), 3.48 (s, 2H), 3.43 – 3.33 (m, 3H), 3.03 – 2.94 (m, 1H), 2.70 – 2.56 (m, 2H), 2.43 (d, J = 15.8 Hz, 1H), 2.09 – 1.72 (m, 4H), 1.67-1.49 (m, 4H), 1.24 (s, 1H).

Example 180 : Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl) -2 -(( 2,6 -dimethyltetrahydro -1H- pyrrolazin -7a ( 5H ) -yl )methoxy) -8- fluoro -5- methoxypyrido [4,3-d] pyrimidin -7- yl) -5- ethynyl- 6 -fluoronaphthalen -2- ol

Step 1: Synthesis of compound 180-1

Compound 7-3 (1.43 g) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (0.80 g) was added and reacted at room temperature for 1 h. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate, extracted twice with DCM, and the organic phases were combined and concentrated. The concentrate was purified by column chromatography to obtain compound 180-1 (0.48 g, yield 30.24%). ESI-MS m/z: 792 [M+H] ⁺ .

Step 2: Synthesis of compound 180-2

The intermediate M11 (87.1 mg) was dissolved in tetrahydrofuran (1 mL), sodium hydride (15.2 mg) was added, and then a solution of compound 180-1 (167 mg) in tetrahydrofuran (1 mL) was added, and the mixture was reacted at room temperature for 10 minutes. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride, extracted twice with EA, the organic phases were combined, concentrated, and the concentrate was separated and purified by column chromatography to obtain compound 180-2 (100 mg, yield 52.6%). ESI-MS m/z: 893 [M+H] ⁺ .

Step 2: Synthesis of Compound 180-3

Compound 180-2 (30 mg) was dissolved in N,N-dimethylformamide (2 mL), cesium fluoride (78 mg) was added, and the reaction was carried out at room temperature for 3 h. After the reaction was completed, the reaction solution was diluted with EA and water, extracted twice with EA, washed with saturated brine, the organic phases were combined, concentrated, and the concentrate was purified by column chromatography to obtain compound 180-3 (40 mg). ESI-MS m/z: 637 [M+H] ⁺ .

Step 3: Synthesis of Compound 180

Compound 180-3 (40 mg) was dissolved in dichloromethane (2 mL), boron trifluoride ether (0.03 mL) was added, and the reaction was carried out at room temperature for 0.5 h. After the reaction was complete, the reaction solution was added to cold saturated sodium carbonate solution, extracted twice with DCM, the organic phases were combined, concentrated, and the concentrate was separated and purified by Pre-TLC to obtain compound 180 (5.4 mg, yield 15.62%). ESI-MS m/z: 637.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO) δ 10.15 (s, 1H), 7.98 – 7.95 (m, 1H), 7.48 – 7.44 (m, 1H), 7.38 (s, 2H), 7.22 (s, 1H), 4.94 (d, J = 10.0 Hz, 5H), 4.05 (s, 2H), 3.89 (d, J = 5.0 Hz, 5H), 3.62 (d, J = 15.0 Hz, 2H), 3.47 (s, 2H), 3.2 (d, J = 15.0 Hz, 4H), 2.62 (d, J = 15.0 Hz, 3H), 2.02 – 1.99 (m, 1H), 1.61 (s, 4H).

Example 181 : Compound 4- ( 4- (( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] oct -3- yl) -8- fluoro -5- methoxy -2- ( ( 2- methyltetrahydro -1H- pyrrolazine -7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -6 - fluoro -5- vinylnaphthalene- Synthesis of 2- alcohols

Step 1: Synthesis of Compound 181-1

The compound 5-ethynyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)naphthalen-2-ol (200 mg) was dissolved in 3 mL of methanol, and then Pd/C (20 mg) was added. The hydrogen atmosphere was replaced 5 times, and the reaction was carried out at room temperature for 5 min. The filtrate was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 181-1 (120 mg).

Step 2: Synthesis of compound 181-2

Compounds 181-1 (120 mg), 7-2 (80 mg), CataCXium A Pd G3 (30 mg) and K ₃ PO ₄ (100 mg) were dissolved in THF (2 mL) and H ₂ O (0.5 mL) , react under nitrogen protection at 80 ^° C for 3 hours, cool to room temperature, extract the reaction solution with EA and water, retain the organic phase, dry it over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The concentrate is purified by column chromatography to obtain the target compound. 181-2 (95 mg).

Step 3: Synthesis of Compound 181-3

Compound 181-2 (95 mg) was dissolved in DCM (2 mL), and then TBSCl (220 mg) and imidazole (150 mg) were added in sequence. The reaction was allowed to react at room temperature for 0.5 h. The reaction solution was extracted with DCM and water, and the organic phase was retained. The phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 181-3 (90 mg).

Step 4: Synthesis of Compound 181-4

Compound 181-3 (90 mg) was dissolved in DCM (2 mL), and then m-CPBA (90 mg) was added. The reaction was allowed to react at room temperature for 0.5 h. An appropriate amount of saturated sodium sulfite solution was added and stirred for 20 min to quench. The reaction solution was extracted with DCM and water, and the organic phase was retained. It was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 181-4 (60 mg).

Step 5: Synthesis of Compound 181-5

Compound M9 (40 mg) was dissolved in anhydrous THF (1 mL), and then NaH (18 mg) was added and reacted at room temperature for 20 min. Compound 181-4 (60 mg) was then added and reacted at room temperature for 30 min. An appropriate amount of saturated ammonium chloride solution was added to quench the reaction solution, and the reaction solution was extracted with EA and water. The organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain the target compound 181-5 (35 mg).

Step 6: Synthesis of Compound 181

Compound 181-5 (35 mg) was dissolved in 1 mL of DCM, then TFA (0.5 mL) was added, and the reaction was carried out at room temperature for 20 min. Concentrate under reduced pressure, and the concentrate was purified by column chromatography to obtain target compound 181 (7.7 mg).

Example 214 Synthesis of Compound 4- ( 4 -(( 1R , 5S ) -3,8 -diazabicyclo [3.2.1] octan -3- yl) -8 - fluoro -5- methoxy -2- ((( S ) -2 -methyltetrahydro -1H- pyrrolizin - 7a ( 5H ) -yl )methoxy)pyrido [4,3-d] pyrimidin -7- yl) -5- ethynyl- 6- fluoronaphthalen -2- ol

Step 1: Synthesis of Compound 214-1

Dissolve M13 (4.84 g, 1.86 mmol) in anhydrous tetrahydrofuran (85 ml), add NaH (2.52 g, 3.71 mmol), lower the temperature to 5°C, dissolve compound 7-5 (17 g 1.24 mmol) in anhydrous tetrahydrofuran (170 ml), slowly add compound 7-5 dropwise to the reaction solution, control the temperature at 5-10°C, and continue to stir the reaction at 5-10°C until the raw material reacts completely. After the reaction is complete, saturated ammonium chloride is used to quench the reaction, EA (200 ml) and water (200 ml) are added to dilute the reaction solution, and the liquid is separated by stirring to obtain an organic phase, which is further extracted with EA (100 ml). The organic phases are combined and washed with saturated salt water (200 ml), dried over anhydrous sodium sulfate, filtered, spin-dried, and concentrated to obtain compound 214-1 (19.75 g).

ESI-MS m/z: 881.65 [M+H] ⁺ .

Step 2: Synthesis of Compound 214-2

Compound 214-1 (19.75 g 22.41 mmol) was dissolved in DMF, CsF (34.05 g 224.14 mmol) was added, and the mixture was reacted in an oil bath at 35°C for 4 h. After the reaction was complete, an ice bath was used to cool the temperature to 10°C, and water (800 ml) was slowly added dropwise to produce a large amount of solid, which was filtered to obtain a filter cake. It was dissolved in EA (200 ml), washed once with saturated saline (100 ml), and the organic phase was separated and purified by column chromatography (DCM: MeOH = 20: 1) to obtain compound 214-2 (14.82 g).

ESI-MS m/z: 725.51 [M+H] ⁺ .

Step 3: Synthesis of compound 214

Compound 214-2 (14.82 g 20.45 mmol) was dissolved in DCM (140 ml), and boron trifluoride ether (56 ml) was added. The mixture was reacted in an oil bath at 35°C for 0.5 h. After the reaction was complete, the filter cake was directly filtered. It was dissolved in a mixture of DCM: MeOH = 10:1, and the compound was freed with saturated sodium carbonate. The mixture was extracted three times with a mixture of DCM: MeOH = 10:1, washed once with saturated salt water, dried over anhydrous sodium sulfate, filtered, and spun dry. The crude product was dissolved in methanol, and the complex between the compound and boron trifluoride was decomposed at 50°C. After decomposition, the mixture was stirred with silica gel and purified by column chromatography (DCM: MeOH = 10:1) to obtain compound 214 (10.61 g).

ESI-MS m/z: 625.47 [M+H] ⁺

¹ H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.38 (d, J = 2.5 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 4.90 (s, 2H), 4.08 (s, 1H), 4.02 (dd, J = 10.4, 4.0 Hz, 1H), 3.98 – 3.93 (m , 1H), 3.90 (s, 1H), 3.88 (s, 3H), 3.54 (d, J = 14.1 Hz, 1H), 3.47 (s, 2H), 3.38 (d, J = 12.5 Hz, 1H), 3.32 (s, 1H), 3.18 (d, J = 13.9 Hz, 1H), 3.03 – 2.95 (m, 1H), 2.61 – 2.52 (m, 2H), 2.35 (d, J = 16.2 Hz, 1H), 2.03 – 1.73 (m, 4H), 1.71-1.64 (m, 1H), 1.63 – 1.44 (m, 4H), 1.23 (s, 1H).

The following examples were synthesized using the above method, or similar methods using corresponding intermediates. 4 [M+H] ⁺ :595.3 10 [M+H] ⁺ :687.3 11 [M+H] ⁺ :635.3 12 [M+H] ⁺ :671.3 13 [M+H] ⁺ :621.3 14 [M+H] ⁺ :657.3 15 [M+H] ⁺ :607.3 16 [M+H] ⁺ :643.3 17 [M+H] ⁺ :633.3 18 [M+H] ⁺ :669.3 19 [M+H] ⁺ :639.4 20 [M+H] ⁺ :675.3 21 [M+H] ⁺ :625.3 22 [M+H] ⁺ :661.3 23 [M+H] ⁺ :611.3 24 [M+H] ⁺ :647.3 25 [M+H] ⁺ :637.3 26 [M+H] ⁺ :673.3 27 [M+H] ⁺ :651.3 28 [M+H] ⁺ :687.3 29 [M+H] ⁺ :637.3 30 [M+H] ⁺ :673.3 31 [M+H] ⁺ :623.3 32 [M+H] ⁺ :658.3 33 [M+H] ⁺ :649.3 34 [M+H] ⁺ :685.3 35 [M+H] ⁺ :657.3 36 [M+H] ⁺ :693.3 37 [M+H] ⁺ :643.3 38 [M+H] ⁺ :679.3 40 [M+H] ⁺ :665.3 41 [M+H] ⁺ :655.3 42 [M+H] ⁺ :691.3 43 [M+H] ⁺ :669.3 44 [M+H] ⁺ :705.3 45 [M+H] ⁺ :655.3 46 [M+H] ⁺ :691.3 47 [M+H] ⁺ :641.3 48 [M+H] ⁺ :677.3 49 [M+H] ⁺ :667.3 50 [M+H] ⁺ :703.3 51 [M+H] ⁺ :647.3 52 [M+H] ⁺ :683.3 53 [M+H] ⁺ :633.3 54 [M+H] ⁺ :669.3 56 [M+H] ⁺ :655.2 57 [M+H] ⁺ :645.3 58 [M+H] ⁺ :681.2 59 [M+H] ⁺ :681.3 60 [M+H] ⁺ :707.3 61 [M+H] ⁺ :729.3 62 [M+H] ⁺ :763.3 63 [M+H] ⁺ :667.3 64 [M+H] ⁺ :693.3 65 [M+H] ⁺ :715.3 66 [M+H] ⁺ :749.3 67 [M+H] ⁺ :653.3 68 [M+H] ⁺ :679.3 69 [M+H] ⁺ :701.3 70 [M+H] ⁺ :735.3 71 [M+H] ⁺ :679.3 72 [M+H] ⁺ :705.3 73 [M+H] ⁺ :727.3 74 [M+H] ⁺ :761.3 75 [M+H] ⁺ :703.3 76 [M+H] ⁺ :689.3 77 [M+H] ⁺ :675.3 78 [M+H] ⁺ :701.3 79 [M+H] ⁺ :707.3 80 [M+H] ⁺ :689.3 81 [M+H] ⁺ :697.3 82 [M+H] ⁺ :685.3 83 [M+H] ⁺ :641.2 84 [M+H] ⁺ :607.2 85 [M+H] ⁺ :617.3 86 [M+H] ⁺ :613.2 87 [M+H] ⁺ :613.3 88 [M+H] ⁺ :625.2 89 [M+H] ⁺ :635.3 90 [M+H] ⁺ :645.3 91 [M+H] ⁺ :671.3 92 [M+H] ⁺ :705.5 93 [M+H] ⁺ :649.3 94 [M+H] ⁺ :615.2 95 [M+H] ⁺ :619.3 96 [M+H] ⁺ :579.3 97 [M+H] ⁺ :583.3 98 [M+H] ⁺ :646.3 99 [M+H] ⁺ :567.3 100 [M+H] ⁺ :623.3 101 [M+H] ⁺ :634.3 102 [M+H] ⁺ :623.2 103 [M+H] ⁺ :629.3 104 [M+H] ⁺ :647.2 105 [M+H] ⁺ :623.3 106 [M+H] ⁺ :645.3 107 [M+H] ⁺ :556.2 108 [M+H] ⁺ :613.2 111 [M+H] ⁺ :648.3 113 [M+H] ⁺ :588.3 114 [M+H] ⁺ :624.2 115 [M+H] ⁺ :606.3 116 [M+H] ⁺ :642.2 117 [M+H] ⁺ :612.3 118 [M+H] ⁺ :630.3 119 [M+H] ⁺ :599.3 124 [M+H] ⁺ :643.2 126 [M+H] ⁺ :651.3 127 [M+H] ⁺ :615.3 128 [M+H] ⁺ :649.3 129 [M+H] ⁺ :613.2 130 [M+H] ⁺ :609.3 131 [M+H] ⁺ :627.3 132 [M+H] ⁺ :681.2 133 [M+H] ⁺ :645.3 134 [M+H] ⁺ :681.3 135 [M+H] ⁺ :649.3 136 [M+H] ⁺ :672.3 137 [M+H] ⁺ :688.3 138 [M+H] ⁺ :642.3 139 [M+H] ⁺ :624.3 140 [M+H] ⁺ :606.3 142 [M+H] ⁺ :642.3 144 [M+H] ⁺ :638.3 145 [M+H] ⁺ :656.3 146 [M+H] ⁺ :674.3 147 [M+H] ⁺ :688.3 148 [M+H] ⁺ :670.3 149 [M+H] ⁺ :652.2 150 [M+H] ⁺ :650.3 151 [M+H] ⁺ :668.3 152 [M+H] ⁺ :686.3 153 [M+H] ⁺ :636.3 154 [M+H] ⁺ :618.3 155 [M+H] ⁺ :654.3 156 [M+H] ⁺ :710.2 157 [M+H] ⁺ :728.3 158 [M+H] ⁺ :664.3 159 [M+H] ⁺ :646.3 160 [M+H] ⁺ :628.3 161 [M+H] ⁺ :692.3 162 [M+H] ⁺ :686.3 163 [M+H] ⁺ :650.3 164 [M+H] ⁺ :632.3 165 [M+H] ⁺ :668.3 166 [M+H] ⁺ :704.3 167 [M+H] ⁺ :722.2 168 [M+H] ⁺ :678.3 169 [M+H] ⁺ :660.3 170 [M+H] ⁺ :642.3 171 [M+H] ⁺ :696.3 172 [M+H] ⁺ :714.3 173 [M+H] ⁺ :662.3 174 [M+H] ⁺ :644.3 175 [M+H] ⁺ :680.3 176 [M+H] ⁺ :732.3 177 [M+H] ⁺ :690.2 178 [M+H] ⁺ :672.2 179 [M+H] ⁺ :654.3 182 [M+H] ⁺ :618.3 183 [M+H] ⁺ :619.3 184 [M+H] ⁺ :625.3 185 [M+H] ⁺ :636.3 186 [M+H] ⁺ :650.3 187 [M+H] ⁺ :651.3 188 [M+H] ⁺ :632.3 189 [M+H] ⁺ :633.3 190 [M+H] ⁺ :664.3 191 [M+H] ⁺ :665.3 192 [M+H] ⁺ :646.3 193 [M+H] ⁺ :647.3 194 [M+H] ⁺ :662.3 195 [M+H] ⁺ :663.3 196 [M+H] ⁺ :644.3 197 [M+H] ⁺ :630.3 198 [M+H] ⁺ :631.3 199 [M+H] ⁺ :640.3 200 [M+H] ⁺ :641.3 201 [M+H] ⁺ :645.3 202 [M+H] ⁺ :644.3 203 [M+H] ⁺ :645.3 204 [M+H] ⁺ :654.3 205 [M+H] ⁺ :654.3 206 [M+H] ⁺ :656.3 207 [M+H] ⁺ :657.3 208 [M+H] ⁺ :666.3 209 [M+H] ⁺ :667.3 210 [M+H] ⁺ :698.3 211 [M+H] ⁺ :699.3 212 [M+H] ⁺ :708.3 213 [M+H] ⁺ :709.3

Comparative Example D1 : D1

For the preparation method of comparative compound MART1133 (D1), refer to Example 252 in WO2021041671A1.

biology test

Pharmacological experiments 1: Cell proliferation assay ( AGS ）

KRAS G12D mutant tumor cells AGS (ATCC® CRL-1739™) were plated at a cell density of 1×10 ³ /well in a low-adhesion 96-well plate and cultured in a cell culture incubator overnight. After the cells adhered, the test compounds were added to a 96-well plate at final concentrations of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, and 0 nM (the final DMSO concentration was 0.5%). After incubation at 37°C for 96 h, 50 μL of Cell-titer GLO working solution was added to each well. After shaking to mix, the plates were incubated at room temperature for 10 min. Luminescence values were read on a multifunctional enzyme labeler and the luminescence data were converted into inhibition percentages. The percentage of cell proliferation inhibition was calculated according to the following formula: Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100 ("maximum value" comes from the 0.5% DMSO control well, "Blank" comes from the blank control well, and "measured value" comes from the compound-treated well).

Use GraphPad Prism software to perform curve fitting and obtain IC ₅₀ values.

Table 1 Compound name AGS IC ₅₀ (nM) Compound name AGS IC ₅₀ (nM) D1 3.6 97 160 1 0.9 100 17 2 3.1 101 180 3 1.9 102 15 5 0.7 103 17.7 6 1.3 104 632 7 0.6 109 4.5 8 2.8 110 2.9 9 1.5 120 3.5 39 14.7 121 18 55 1.5 122 24.9 75 6.5 123 2.3 85 8.5 124 300 86 57 125 19.1 87 3.2 126 571 88 5.6 127 663 89 15 131 7 90 5.6 134 456 91 8.5 136 465 92 67 141 6.5 93 twenty three 143 11 94 182 180 1.3 95 520 181 7.0 96 41.6 214 0.3

Pharmacological experiments 2 : cell p-ERK Detection test

KRAS G12D mutant tumor cells AGS (ATCC ^® CRL-1739™) were spread in a 96-well plate at a cell density of 4×10 ⁴ /well and placed in a cell culture incubator for overnight culture. After the cells are adhered, the compound to be tested is added to the 96-well plate at a final concentration of 3000 nM, 600 nM, 120 nM, 24 nM, 4.8 nM, 0.96 nM, 0.19 nM, and 0.5% DMSO. After culturing for 3 hours, pERK is used to The lysis buffer in the HTRF Kit (Cisbio) is used to lyse each treated cell sample (40ul/well) in the 96-well plate. After full lysis is completed, 16ul/well of protein solution and 4ul of premixed pERK are added to the HTRF detection 96-well plate. -d2 antibody and pERK-Eu Cryptate antibody. After overnight culture at 4°C, read the ratio signal value of 665nM/620nM on a multifunctional microplate reader and collect raw data. And calculate the p-ERK inhibition percentage according to the following formula: Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100 ("Maximum value" comes from the 0.5% DMSO control well, "Blank" comes from the blank control wells, "measured values" are from compound-treated wells).

Use GraphPad Prism software to perform curve fitting and obtain IC ₅₀ values.

Table 2 Compound name AGS-pERK IC ₅₀ (nM) D1 1.2 1 0.6 7 0.5 86 37 87 0.5 88 1.7 89 2.6 110 3.6 214 0.3

Pharmacological experiments 3: Different cell proliferation experiments

KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were spread in a low-adsorption 96-well plate at a cell density of 1×10 ³ /well and placed in a cell culture incubator for overnight culture. After the cells adhere to the wall, add the compound to be tested into the 96-well plate according to the final concentration of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025, 0nM (the final DMSO concentration is 0.5%), and culture at 37°C. After 96 hours, add 50 μL Cell-titer GLO working solution to each well, shake and mix, and incubate at room temperature for 10 minutes. Read the Luminescence value on a multifunctional microplate reader, and calculate and convert the luminescence value data into an inhibition percentage. And calculate the cell proliferation inhibition percentage according to the following formula: Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100 ("Maximum value" comes from the 0.5% DMSO control well, "Blank" comes from the blank control well , “measured values” are from compound-treated wells).

GraphPad Prism software was used to fit the curves and obtain the _IC50 values. The results are shown in Table 3.

table 3 Cell proliferation inhibitory activity (IC ₅₀ , nM) KRAS G12D Mutant Cells D1 214 HPAC – Pancreatic Cancer 7 1.1 A427 – Lung Cancer 72 1.4 Aspc1 – Pancreatic Cancer twenty four 1.2 LS180 – Colon Cancer 12 0.6 Panc 04.03 – Pancreatic Cancer 19 1.5

The results showed that compound 214 had significantly higher activity in inhibiting cell proliferation in KRAS G12D mutant cells of the other five different cancer types tested.

Pharmacological experiments 4 : different cells p-ERK Testing

KRAS G12D mutant tumor cells HPAC, A427, Aspc-1, LS180, and Panc04.03 were plated in a 96-well plate at a cell density of 4×10 ⁴ /well and cultured in a cell culture incubator overnight. After the cells adhered to the wall, the test compounds were added to the 96-well plate at final concentrations of 3000 nM, 600 nM, 120 nM, 24 nM, 4.8 nM, 0.96 nM, 0.19 nM, and 0.5% DMSO. After 3 h of incubation, the treated cell samples in the 96-well plate were lysed using the lysis buffer in the pERK HTRF Kit (Cisbio) (40ul/well). After sufficient lysis, 16ul/well of protein solution and 4ul of premixed pERK-d2 antibody and pERK-Eu Cryptate antibody were added to the HTRF detection 96-well plate. After overnight incubation at 4°C, the ratio signal value of 665nM/620nM was read on the multifunctional enzyme labeler to collect the raw data. The p-ERK inhibition percentage was calculated according to the following formula: Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100 ("maximum value" comes from the 0.5% DMSO control well, "Blank" comes from the blank control well, and "measured value" comes from the compound-treated well).

Use GraphPad Prism software to perform curve fitting and obtain IC ₅₀ values. The results are shown in Table 4.

Table 4 pERK inhibitory activity (IC ₅₀ , nM) KRAS G12D Mutant Cells D1 214 HPAC – Pancreatic Cancer 2.6 0.9 A427 – Lung Cancer 2.1 0.4 Aspc1 – Pancreatic Cancer 2.2 0.8 LS180 – Colon Cancer 7.2 2.8 Panc 04.03 – Pancreatic Cancer 12 2.7

The results showed that compound 214 had significantly higher activity in inhibiting downstream pERK levels in KRAS G12D mutant cells of the other five different cancer types tested.

Pharmacological experiments 5 : compound in mice PK Investigation

Intravenous administration investigation: Mix the compound with the solvent 10% DMSO/5% Solutol/85% normal saline, vortex and sonicate to prepare a 0.2 mg/ml clear intravenous injection solution. Balbc female mice aged 6 to 7 weeks were selected and administered intravenously with compounds 7, 110, 141 and D1, and whole blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. . The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The dosage and experimental protocol are shown in Table 5 below, and the results are shown in Table 6.

table 5 Group Test substance How to give medicine Dosage (mg/kg) Dosage volume (ml/kg) Dosage concentration (mg/ml) Solvent G1 7 IV 1 5 0.2 10%DMSO/5%Solutol/85%Normal saline G2 D1 IV 1 5 0.2 10%DMSO/5%Solutol/85%Normal saline G3 110 IV 1 5 0.2 10%DMSO/5%Solutol/85%Normal saline G4 141 IV 1 5 0.2 10%DMSO/5%Solutol/85%Normal saline

The tested mouse PK data are as follows in Table 6:

Table 6 Group Test substance IV administration whole blood AUC (h*ng/ml) Cl clearance rate (ml/min/kg) G1 7 839 15 G2 D1 545 26 G3 110 795 19 G4 141 927 16

The results showed that, after intravenous administration, compounds 7, 110, and 141 had higher whole blood exposure and lower clearance in mice than the control compound D1.

Oral administration investigation: Mix compounds 110 and 109 with the solvent 10% DMSO/5% Solutol/85% normal saline, vortex and sonicate to prepare a 1 mg/ml clear solution; D1 and the solvent 10% DMSO/10% Solutol Mix with 80% normal saline, vortex and sonicate to prepare a 2 mg/ml clear solution. Balbc female mice aged 6 to 7 weeks were selected, and the compound was administered orally without fasting. Whole blood was collected for a certain period of time, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetics were calculated using Phoenix WinNolin software (Pharsight Company, USA). parameters, and the results are shown in Table 7.

Table 7 Mode of administration (PO) D1 109 110 Dosage (mg/kg) 20 10 10 gender female female female t _1/2 (h) 10.7 6.8 10.1 t _max (h) 2 2 2 C _max (ng/mL) 43 208 60 AUClast (h*ng/mL) 240 782 502 F(%) 2.6 24.7 6.3

The results showed that in mice, the oral exposure (AUC) and oral bioavailability (F%) of compound 110 were higher than those of compound D1; the oral exposure (AUC) and oral bioavailability (F%) of compound 109 were higher than those of compound D1.

Pharmacological experiments 6 ：Compounds in rats PK inspection

Compounds 7, 110, 141, 214 and the solvent 10% DMSO/5% Solutol/85% physiological saline were mixed, and the comparative compound D1 was mixed with the solvent 10% DMSO/5% Solutol/85% glucose, vortexed and sonicated to prepare a 0.5 mg/ml clear solution. 6-7 week old SD male rats were selected, fasted overnight, and intravenously injected with compounds 7, 110, 141, 214 and comparative compound D1. Whole blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight, USA). The dosage and experimental scheme are shown in Table 8 below, and the results are shown in Table 9.

Table 8 Group Test substance How to give medicine Dosage (mg/kg) Dosage volume (ml/kg) Dosage concentration (mg/ml) Solvent G1 7 IV 1 2 0.5 10%DMSO/5%Solutol/85%Normal saline G2 D1 IV 1 2 0.5 10%DMSO/5%Solutol/85%Glucose G3 110 IV 1 2 0.5 10%DMSO/5%Solutol/85%Normal saline G4 141 IV 1 2 0.5 10%DMSO/5%Solutol/85%Normal saline G5 214 IV 1 2 0.5 10%DMSO/5%Solutol/85%Normal saline

The measured rat PK data are shown in Table 9:

Table 9 Group test substance IV administration whole blood AUC (h*ng/ml) Cl clearance rate (ml/min/kg) t _1/2 half-life (h) Vss apparent volume of distribution (L/Kg) G1 7 2361 6 10 4.2 G2 D1 1417 7.7 11 10 G3 110 656 26 14 twenty three G4 141 1320 11 twenty one 13 G5 214 2276 4.7 20 6.6

The results showed that compound 7 had higher whole blood exposure and lower clearance rate in rats compared with comparative compound D1. Compounds 110 and 141 had higher apparent distribution volumes in rats than comparative compound D1, and compounds 110 and 141 had longer half-lives in rats than comparative compound D1. Compound 214 had higher whole blood exposure, lower clearance rate, and longer half-life in rats compared with comparative compound D1.

Pharmacological experiments 7 : Compound in beagle dogs PK inspection

Intravenous administration study: Compounds 7, 110, and 141 were mixed with a solvent of 10% DMSO/5% Solutol/85% saline, and the comparative compound D1 was mixed with a solvent of 10% DMSO/5% Solutol/85% glucose, vortexed, and sonicated to prepare a 0.5 mg/ml clear intravenous injection solution. Female beagle dogs were selected and whole blood samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight, USA). The dosage and experimental scheme are shown in Table 10 below, and the results are shown in Table 11.

Table 10 Group test substance Dosing method Dosage (mg/kg) Dosing volume (ml/kg) Dosing concentration (mg/ml) solvent G1 7 IV 1 2 0.5 10%DMSO/5%Solutol/85% saline G2 D1 IV 1 2 0.5 10%DMSO/5%Solutol/85%glucose G3 110 IV 1 2 0.5 10%DMSO/5%Solutol/85% saline G4 141 IV 1 2 0.5 10%DMSO/5%Solutol/85% saline

The tested beagle PK data are shown in Table 11:

Table 11 Group test substance IV administration whole blood AUC (h*ng/ml) Cl clearance rate (ml/min/kg) t _1/2 half-life (h) Vss apparent volume of distribution (L/Kg) G1 7 1926 6.1 32.0 13 G2 D1 2527 5.4 23.8 7.9 G3 110 2024 7.1 21.0 8.7 G4 141 2074 6.4 24.0 10.4

The results showed that compounds 7, 110, and 141 had higher apparent distribution volumes in beagle dogs than compound D1, and compounds 7 and 141 had longer half-lives.

Pharmacological experiments 8 ：Compounds in NCI-H1975 in tumor tissues of tumor-bearing mice PK Investigation

A Balbc nude nude mouse model of subcutaneous xenograft tumor of human lung adenocarcinoma cell NCI-H1975 was constructed. After the tumor volume reached 200 ^mm , 21 tumor-bearing mice were selected and administered Compound 7 and D1 1mpk IV Cassette. The solvent was 10% DMSO/5% Solutol/85% saline. Mouse whole blood samples and tumor tissue samples were collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated using Phoenix WinNolin software (Pharsight Company, USA). The results are shown in Table 12.

Table 12 Tumor tissue AUC (h*ng/ml) Ratio (Tumor/Blood) Tumor tissue t _1/2 D1 6551 2.04-25.8 26.6 7 13096 2.23-40.8 47.7

Tumor tissue was collected at 0.5h, 4h, 7h, 24h, 48h, 72h, and 96h after administration, and the concentrations of compound 7 and D1 in the tumor tissue were detected. The detection results are shown in Figure 3 below.

The results showed that in the tumor tissue of the mouse tumor-bearing model, Compound 7 had significantly higher tumor tissue exposure, significantly longer tumor tissue t _1/2 and higher Tumor/Blood Ratio than the comparative compound D1.

Although the present invention has been fully described by its implementation mode, it is worth noting that various changes and modifications are obvious to those skilled in the art. Such changes and modifications should be included in the scope of the appended claims of the present invention.

without

Figure 1 is a bulk polarizing microscope image of a single crystal sample of compound M13-1.

Figure 2 is an analytical diagram of the single crystal structure of compound M13-1.

Figure 3 shows the distribution of the compound in the tumor tissue of NCI-H1975 tumor-bearing mice.

Claims (36)

A compound represented by the general formula (I), or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof, (I) wherein X is selected from a bond, NR _a , O or S; is selected from a single bond or a double bond; L is selected from a bond, -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene-; the -C _1-3 alkylene-, -C _3-14 cycloalkyl-C _0-3 alkylene- or -3-14 membered heterocyclic group-C _0-3 alkylene- is optionally further substituted with one or more halogens, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; Ring A is selected from C _5-14 cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl; the C _5-14 membered cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro, hydroxyl, replaced by; Selected from or ;in, or The two _R6 in the above-mentioned group may form a _C3-8 cycloalkyl group or a 3-8 membered heterocyclic group together with the atoms to which they are connected, and the _C3-8 cycloalkyl group or the 3-8 membered heterocyclic group may be further substituted by one or more _Ra ; _R2 is selected from _C3-14 cycloalkyl group, a 3-14 membered heterocyclic group, a _C6-18 aryl group or a 5-18 membered heteroaryl group; the _C3-14 cycloalkyl group, the 3-14 membered heterocyclic group, the _C6-18 aryl group or the 5-18 membered heteroaryl group may be further substituted by one or more _Ra ; _R3 is independently selected from _C1-6 alkoxy, _C3-14 cycloalkyl-O- or _C1-6 halogenated alkoxy; the _C1-6 alkoxy, C wherein the C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl, C 1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, cyano, amino, nitro or hydroxyl groups; R ₄ is independently selected from H, halogen, cyano, amino, -NHR _a , -N(R _a ) ₂ , nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy group or hydroxyl group; the C _1-6 alkyl, C 1-6 alkoxy, C 3-14 cycloalkyl-O-, C _1-6 halogenated alkyl or C 1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C 1-6 alkyl, C 1-6 alkoxy, C _3-14 cycloalkyl-O-, C _1-6 halogenated alkyl or C _1-6 halogenated alkoxy group is optionally further substituted by one or more halogen, C _R5 is selected from H, halogen, _{-C0-3 alkylene cyano, C1-6 alkyl} , _C1-6 alkoxy or _C1-6 halogenated alkyl; _R6 is selected from H, halogen, hydroxyl, cyano, _C1-6 alkyl, _C1-6 halogenated alkyl, _C3-14 cycloalkyl, _3-14 membered heterocyclic group, C6-18 aryl or 5-18 membered heteroaryl; the C1-6 alkyl, _C1-6 halogenated alkyl, _C3-14 cycloalkyl, 3-14 membered heterocyclic group, _C6-18 aryl or 5-18 membered heteroaryl group is selected from H, halogen, _-C0-3 alkylene cyano, _C1-6 alkyl, _C1-6 alkoxy or C1-6 halogenated alkyl; The _6-18 membered aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy groups; R _{a is} each independently selected from H, hydroxyl, cyano, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, -C _0-3 alkylene-OR _b , -OC(═O)C _1-6 alkyl, -C _0-3 alkylene-SR _b , -C _0-3 alkylene-N(R _b ) ₂ , -C _0-3 alkylene-S(═O)R _b , -C _0-3 alkylene-S(═O) ₂ R _b , -C _0-3 alkylene-SR _b , -C _0-3 alkylene-S(R _b ) ₅ , -C -C _0-3 alkylene-C (= O) R _b , -C _0-3 alkylene-C (= O) OR _b , -C _0-3 alkylene-C (= O) N (R _b ) ₂ , C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclic group), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl); the C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclic group), -C -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5-18 membered heteroaryl) is optionally further substituted by one or more R _b ; each R _b is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 halogenated alkyl, -C (= O) C _1-6 alkyl or -C (= O) O C _1-6 alkyl; m is selected from 0, 1, 2, 3 or 4. The compound of claim 1, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein each R _b is independently H, halogen, hydroxyl, cyano, C _{1 -6} alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl. The compound as claimed in claim 1, or a stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt thereof, wherein: X is selected from a bond, NH, O or S; Ring A is selected from C _5-14 cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl, the C _5-14 cycloalkyl or 5-14 membered heterocyclic group is selected from a monocyclic ring, a fused ring, a spirocyclic ring or a bridged ring, and the C _5-14 cycloalkyl, 5-14 membered heterocyclic group, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogens, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl groups; Selected from or ,in, For double keys, _R3 is independently selected from _C1-6 alkoxy, _C3-14 cycloalkyl-O- or _C1-6 halogenated alkoxy, wherein the _C1-6 alkoxy or _C3-14 cycloalkyl-O- is further substituted by one or more halogen, C1-6 alkyl, _C1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; _R4 is selected from H, halogen, cyano, amino, nitro, _C1-6 alkyl, C1-6 alkoxy, C3-14 cycloalkyl-O-, _{C1-6 halogenated alkyl, C1-6 halogenated alkoxy, hydroxyl or hydroxylalkyl, wherein the C1-6} alkyl, _C1-6 alkoxy, _C3-14 cycloalkyl-O- is _further substituted by one or more halogen, _C1-6 alkyl, _C1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or _hydroxyl . _3-14 cycloalkyl-O-, halogenated alkyl or hydroxyalkyl is optionally further substituted with one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated alkyl, cyano, amino, nitro or hydroxyl; each R _b is independently H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 halogenated alkyl. The compound as described in any one of claims 1 to 3, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein X is O. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein said L is selected from -C _1-3 alkylene- or -C _3-14 cycloalkyl-C _0-3 alkylene-. The compound as described in any one of claims 1 to 5, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the ring A is selected from C _5-14 cycloalkyl or 5-14 membered heterocyclyl. The compound as described in claim 6, or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, wherein the 5-14 membered heterocyclic group is a fused ring. The compound of claim 7, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the fused ring is selected from , , , , , , , , , , , , , or . The compound as described in any one of claims 1 to 8, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein said Selected from or . The compound of claim 9, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein said R ₆ is independently selected from H, halogen, C _1-6 alkyl, C _{3 -14} cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl; the C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6- The ₁₈ -aryl or 5-18-membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro or C _1-6 alkyl. The compound as described in any one of claims 1 to 10, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein said Selected from or ; said or may optionally be further substituted by one or more halogens, C _1-6 alkyl or replaced. The compound as claimed in claim 11, or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, wherein the Selected from or ; or Optionally further one or more replaced. The compound described in claim 12, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein said Selected from , , , , , , , , , or ;in, Indicates Z configuration or E configuration. The compound described in claim 13, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein: Selected from , , , or . The compound as described in any one of claims 1 to 14, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R ₂ is selected from C _6-18 aryl or 5-18 Member heteroaryl; the C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R _a , R _{a is} independently selected from H, hydroxyl, cyano, amino, halogen , C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl or -C _0-3 alkylene-C _3-14 cycloalkyl. The compound as described in any one of claims 1 to 15, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the R ₂ is selected from , , , , , , , , , or ; Among them, the , , , , , , , , , ,or Optionally further substituted by one or more _Ra independently selected from H, hydroxy, cyano, amino, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl or -C _0-3 alkylene -C _3-14 cycloalkyl. The compound as described in any one of claims 1 to 16, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein R ₂ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound as described in any one of claims 1 to 17, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein R ₃ is selected from C _1-6 alkoxy or C _3-14 cycloalkyl-O-. The compound as described in any one of claims 1 to 18, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein R ₃ is selected from methoxy, , , or . The compound as described in any one of claims 1 to 19, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein R ₄ is selected from H, halogen, C _1-6 alkoxy or C _1-6 halogenated alkoxy; preferably F. The compound as described in any one of claims 1 to 20, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein R ₅ is H. The compound as described in any one of claims 1 to 21, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein the compound represented by formula (I) is selected from formula (IA) or (IB): (IA) (IB) wherein the ring A, X, L, R ₂ , R ₃ , R ₄ and R ₆ are as defined in any one of claims 1 to 21. The compound described in any one of claims 1 to 22, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the compound represented by formula (I) is selected from the group consisting of formula ( IA-1) or (IB-1): (IA-1) (IB-1) Wherein, the definitions of X, L, R ₂ , R ₃ , R ₄ and R ₆ are as described in any one of claims 1 to 21. The compound as described in any one of claims 1 to 23, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, wherein the compound represented by formula (I) is selected from formula (IA-1') or (IB-1'): (IA-1′) (IB-1′) wherein X, L, R ₂ , R ₃ , R ₄ , R ₆ and _Ra are as defined in any one of claims 1 to 21. The compound as described in claim 23 or 24, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the R ₂ is selected from C _6-18 aryl or 5-18 membered hetero Aryl; wherein, the C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more R _a , and the R _{a is} independently selected from H, hydroxyl, cyano, halogen , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -C _0-3 alkylene-C _3-14 Cycloalkyl, -C _0-3 alkylene-(3-14 membered heterocyclyl), -C _0-3 alkylene-C _6-18 aryl or -C _0-3 alkylene-(5 -18-membered heteroaryl); the R ₃ is selected from C _1-6 alkoxy, C _3-14 cycloalkyl-O- or C _1-6 haloalkoxy; wherein, the C _1-6 alkyl Oxygen, C _3-14 cycloalkyl-O- or C _1-6 haloalkoxy is optionally further substituted by one or more halogens, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Substituted by haloalkyl, cyano, amino, nitro or hydroxyl; R ₄ is selected from H, halogen, cyano, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-14 Cycloalkyl-O-, C _1-6 haloalkyl, C _1-6 haloalkoxy or hydroxyl; wherein, the C _1-6 alkyl, C _1-6 alkoxy, C _3-14 cycloalkyl -O-, C _1-6 haloalkyl or C _1-6 haloalkoxy is optionally further substituted by one or more halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, Substituted by cyano, amino, nitro or hydroxyl; The X is selected from bond, NH, O or S; The L is selected from bond or -C _1-3 alkylene-; The R ₆ is independently selected from H , halogen, C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl, the C _1-6 alkyl, C _3-14 cycloalkyl, 3-14 membered heterocyclyl, C _6-18 aryl or 5-18 membered heteroaryl is optionally further substituted by one or more halogen, hydroxyl, cyano, amino, nitro Or substituted by C _1-6 alkyl. The compound described in claim 23, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the compound represented by formula (I) is selected from formula (IA-1-1) or (IB-1-1): or The R ₂ is selected from , described Optionally further substituted by one or more _Ra independently selected from H, hydroxy, cyano, amino, halogen, C _{1-6 alkyl} , C _1-6 alkoxy, C _{2- 6} alkenyl, C _2-6 alkynyl or -C _0-3 alkylene-C _3-14 cycloalkyl; the R ₄ is selected from hydrogen or halogen; the R ₆ is selected from hydrogen or halogen; the R ₇ is selected from C _1-6 alkyl, C _1-6 haloalkyl or C _3-14 cycloalkyl; preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl. The compound as claimed in claim 24, or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts, wherein the compound represented by formula (I) is selected from (IA-1'-1) or (IB-1'-1): (IA-1'-1) or (IB-1'-1) wherein _R2 is selected from , Optionally further substituted by one or more _Ra , wherein _{Ra is} independently selected from H, hydroxyl, cyano, amino, halogen, _C1-6 alkyl, _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl or _-C0-3 alkylene- _C3-14 cycloalkyl; wherein _R4 is selected from hydrogen or halogen; wherein _R6 is selected from hydrogen or halogen; wherein _R7 is selected from _C1-6 alkyl, _C1-6 halogenated alkyl or _C3-14 cycloalkyl, preferably methyl, ethyl, isopropyl, trifluoroethyl or cyclopropyl. The compound described in any one of claims 1 to 27, or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, wherein the compound represented by formula (I) is selected from: . An intermediate compound, characterized in that the intermediate compound is selected from: , , , , , , , , or . A kind of preparation intermediate compound M13 The method is characterized in that it includes the following steps: converting racemate M9 It reacts with a chiral acid to form the corresponding salt, which is dissociated under alkaline conditions to obtain the S-configured free base M13. The method of claim 30, wherein the chiral acid is selected from the group consisting of L-(-)-dibenzoyltartaric acid, L-(-)-dibenzyltartaric acid or L-(-) -Di-p-methoxybenzoyl tartaric acid. The method as claimed in claim 30 or 31, wherein the method comprises the following steps: 1) reacting the racemate M9 with a chiral acid L-(-)-di-p-methylbenzoyltartaric acid (DPLT) to generate a corresponding compound M13-1; 2) ionizing under alkaline conditions to obtain an S-configuration free base M13; . A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound described in any one of claims 1 to 28, or its stereoisomer, tautomer, deuterated product or drug. Use salt. Use of the compound as described in any one of claims 1 to 28, or its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, or the pharmaceutical composition as described in claim 33 in the preparation of a medicament. The use as claimed in claim 34, wherein the use in preparing a medicament is the use in preparing a medicament for treating and/or preventing diseases mediated by KRAS G12D. The use as described in claim 35, wherein the disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, hepatocholangiocarcinoma, myeloproliferative syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann's cell carcinoma, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

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