Compounds targeting pan-KRAS protein degraders and uses thereof

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to compounds targeting KRAS protein degraders and their uses. The present invention provides a compound having an FLM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein F is a KRAS protein-binding fragment, L is a linking unit connecting F and M, and M is a VHL-binding fragment. The compound can be used to treat diseases caused by KRAS mutation or amplification.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to compounds that target KRAS protein degraders and uses thereof. [Background technology]

[0002] PROTACs are heterobifunctional molecules, with one end of the molecule acting as a ligand that binds to the target protein, the other as a ligand for the E3 ligase, and the middle connected by an appropriate chain. Target protein degradation by PROTACs is achieved by the ubiquitin proteasome system (UPS), and the process is roughly as follows: the PROTAC molecule binds to the target protein (POI) and E3 ligase to form a ternary complex, tagging the target protein with a ubiquitin molecule, and the ubiquitinated protein is recognized and degraded by the intracellular proteasome 26S.

[0003] Traditional small molecules and antibodies exert their therapeutic effects against diseases by inhibiting the function of target proteins through an "occupancy-driven" mode of action. This mode of action requires relatively high concentrations of inhibitors or monoclonal antibodies to occupy the target's active site and block downstream signaling pathways. In contrast, PROTACs are "event-driven" and mediate the degradation of pathogenic target proteins rather than affecting protein function. PROTACs mediate the formation of ternary complexes and attach ubiquitination tags to target proteins, theoretically allowing for repeated use and therefore achieving efficacy at catalytic levels. They boast a broad spectrum of action, high activity, the ability to target "undruggable" targets, improved selectivity, activity, and safety, and the ability to overcome drug resistance.

[0004] KRAS activity is switched by binding either GDP or GTP, becoming inactive when bound to GDP and active when bound to GTP. Mutant KRAS proteins maintain a persistently activated GTP-bound state because GAP cannot bind to GTP, inhibiting hydrolysis. Mutant KRAS exhibits high affinity for guanosine triphosphate (GTP), and its small catalytic site and smooth protein surface make targeting difficult, making the development of small molecule inhibitors challenging and resulting in KRAS's "undruggability." On the one hand, KRAS binds GDP / GTP with picomolar affinity, significantly hindering the development of nucleotide-competitive inhibitors. On the other hand, the KRAS protein structure lacks an ideal small molecule binding pocket, making it difficult to design high-affinity allosteric inhibitors.

[0005] Cancers caused by RAS mutations account for 25% to 30% of all human cancers. Among these, KRAS mutations account for 86% of the three types of RAS mutations. All KRAS mutations include multiple mutations, such as G12D (35%), G12V (29%), G12C (21%), G13D (6.7%), G12R (4.3%), and G12A (4.1%). Simultaneous targeting of these different KRAS mutations would significantly meet clinical needs and have great commercial value.

[0006] However, current KRAS inhibitors face the problems of limited efficacy and susceptibility to resistance in clinical practice. Taking advantage of the resistance-overcoming and high efficacy features of PROTACs, we aim to develop novel pan-KRAS inhibitors for the treatment of diseases caused by KRAS mutations or amplifications. The development of PROTAC degrading drugs would be of great social and commercial significance. Summary of the Invention

[0007] The present invention provides novel pan-KRAS PROTAC degraders for treating diseases caused by KRAS mutations or amplifications.

[0008] On the one hand, the present invention provides a compound having an FLM structure, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

[0009] wherein F is a KRAS protein-binding fragment represented by general formula (A), [ka] The X is —O— or [ka] is selected from The aforementioned [ka] are independently selected from a single bond or a double bond; X4 is CR8, C(R8)2, O, N or NR8, and each R8 is independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, -SC 1-6 Alkyl group, -C 0-3 Alkylene-C 2-4 Alkenyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group or C 3-14 cycloalkyl groups, wherein C 3-14 Cycloalkyl groups, C 1-6 The alkyl group may optionally be one or more R a may be further substituted with X5 is selected from C, CH or N; The X6 is CR 14 , C(R 14 )2, O, N or NR 14 Selected from R 14are each independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, -SC 1-6 Alkyl group, -C 0-3 Alkylene-C 2-4 Alkenyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group or C 3-14 cycloalkyl groups, wherein C 3-14 Cycloalkyl groups, C 1-6 The alkyl group may optionally be one or more R a may be further substituted with R6 is absent or C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 Cycloalkyl group or 3-14 membered heterocyclyl The group may optionally be one or more R a may be further substituted with R9 is H, an amino group, a substituted amino group, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen, C 2-6 Alkenyl group, or C 3-6 cycloalkyl groups, wherein C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-6 The cycloalkyl group may optionally be one or more R a may be further substituted with R 10 is absent, -O-, or -NR 11 - selected from R 11 is H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group or C 1-6 aminoalkyl groups, The R7 is C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 an aryl group or a 5- to 18-membered heteroaryl group,3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 The aryl group or 5- to 18-membered heteroaryl group may optionally be one or more R a may be further substituted with The K is C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or 3- to 14-membered heterocyclyl group may be a single ring, a fused ring, a spiro ring, or a bridged ring, and may optionally be one or more R a and the 3- to 14-membered heterocyclyl group is [ka] Instead, wherein m and n are each independently selected from 0, 1, 2, 3, 4, or 5; L is a linking unit that links F and M, The L is [ka] is selected from where: The G ring or the D ring each independently represents C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14 The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with Each E is independently selected from -O-, -NH-, or -NCH3-; The Y1 and Y2 each independently represent either nothing, -O-, -NH-, a 3- to 6-membered nitrogen-containing heterocyclyl group, or C 1-6 Alkylene group, carbonyl group, ethynyl group or C 3-6 cycloalkyl groups, n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4;

[0010] wherein M is selected from VHL binding fragments of general formula (III) or (IV): [ka] wherein X1 is selected from C, CH or N; wherein X2 is selected from C, CH or N; X3 is selected from N, NH, O or S; The R1 is H, C 1-6 selected from alkyl groups, halogens, or cyano groups, preferably methyl groups, ethyl groups, F, or cyano groups; R2 is H or C 1-6 alkyl groups, preferably H or methyl groups; The R3 is H, C 1-6 Alkyl group, C 1-6 hydroxyalkyl group or -(CH2)n-CO-NH-(CH2)n-CH3, wherein n is selected from 0, 1, 2 or 3, and R3 is preferably H, a methyl group, a hydroxymethyl group, [ka] or -CH2-CO-NH-CH3, The R4 is [ka] or -NH-, The R5 is H, C 1-6 Alkyl group or C 1-6 haloalkyl groups, R 12 teeth, [ka] is selected from

[0011] R a are each independently H, a hydroxy group, an amino group, an oxo group, a cyano group, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -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)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 groups, [ka] C 2-6 Alkynyl group, -C 0-3 Alkylene-C 3-14 Cycloalkyl groups, -C 0-3 Alkylene-(3- to 14-membered heterocyclyl group), -C 0-3 Alkylene-C 6-18 Aryl group or -C 0-3 alkylene-(5- to 18-membered heteroaryl group), 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6Alkynyl group, -C 0-3 Alkylene-C 3-14 Cycloalkyl groups, -C 0-3 Alkylene-(3- to 14-membered heterocyclyl group), -C 0-3 Alkylene-C 6-18 Aryl group or -C 0-3 The alkylene-(5- to 18-membered heteroaryl group) may optionally be one or more R b may be further substituted with Each R b are each independently H, halogen, hydroxyl group, cyano group, or C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 an aryl group or a 5- to 18-membered heteroaryl group, 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 The aryl group or 5- to 18-membered heteroaryl group may optionally contain one or more halogen atoms, C 1-6 Alkyl group or C 1-6 may be further substituted with a haloalkyl group, or Two R's bonded to one atom b together with the atoms to which they are both bonded, form C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 An aryl group or a 5- to 18-membered heteroaryl group is formed, and 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 The aryl group or the 5- to 18-membered heteroaryl group may optionally contain one or more of a halogen, an amino group, a hydroxy group, a cyano group, a C 1-6 Alkyl group, C 3-6 Cycloalkyl group or C 1-6 It may be further substituted with a haloalkyl group.

[0012] In some embodiments of the present invention, L is [ka] is selected from where: The G ring or the D ring each independently represents C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14 The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with Each E is independently selected from -O-, -NH-, or -NCH3-; n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4; wherein M is selected from VHL binding fragments of general formula (V) or (IV): [ka] wherein X1 is selected from C, CH or N; wherein X2 is selected from C, CH or N; X3 is selected from N, NH, O or S; The R1 is H, C 1-6 selected from alkyl groups, halogens, or cyano groups, preferably methyl groups, ethyl groups, F, or cyano groups; R2 is H or C 1-6 alkyl groups, preferably H or methyl groups; The R3 is H, C 1-6 Alkyl group or C 1-6 hydroxyalkyl groups, preferably H, methyl or hydroxymethyl groups; The R4 is [ka] or -NH-, R 12 teeth, [ka] is selected from.

[0013] In some embodiments of the present invention, L is [ka] [ka] is selected from The G ring or the D ring each independently represents C 6-14 an aryl group, a 5- to 14-membered heteroaryl group, or a 3- to 14-membered heterocyclyl group, 6-14 The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with Each E is independently selected from -O-, -NH-, or -NCH3-; n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4; wherein M is selected from VHL binding fragments of general formula (V) or (IV): [ka] wherein X1 is selected from C, CH or N; wherein X2 is selected from C, CH or N; X3 is selected from N, NH, O or S; The R1 is H, C 1-6 selected from alkyl groups, halogens, or cyano groups, preferably methyl groups, ethyl groups, F, or cyano groups; R2 is H or C 1-6 alkyl groups, preferably H or methyl groups; The R3 is H, C 1-6 Alkyl group or C 1-6 hydroxyalkyl groups, preferably H, methyl or hydroxymethyl groups; The R4 is [ka] or -NH-, R 12 teeth, [ka] is selected from.

[0014] R a are independently H, hydroxyl group, amino group, oxo group, cyano group, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, -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)R b , -C 0-3 Alkylene-SR b , -C 0-3 Alkire N-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 2-6Alkenyl group, C 2-6 Alkynyl group, -C 0-3 Alkylene-C 3-14 Cycloalkyl groups, -C 0-3 Alkylene-(3- to 14-membered heterocyclyl group), -C 0-3 Alkylene-C 6-18 Aryl group or -C 0-3 alkylene-(5- to 18-membered heteroaryl group), 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, -C 0-3 Alkylene-C 3-14 Cycloalkyl groups, -C 0-3 Alkylene-(3- to 14-membered heterocyclyl group), -C 0-3 Alkylene-C 6-18 Aryl group or -C 0-3 The alkylene-(5- to 18-membered heteroaryl group) may optionally be one or more R b may be further substituted with Each R b are independently H, halogen, hydroxyl group, cyano group, C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 an aryl group or a 5- to 18-membered heteroaryl group, 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 1-6 Haloalkyl group, C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 The aryl group or 5- to 18-membered heteroaryl group may optionally contain one or more halogen atoms, C 1-6 Alkyl group or C 1-6 may be further substituted with a haloalkyl group, or Two R's bonded to one atom b together with the atoms to which they are both bonded, form C 3-14Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 An aryl group or a 5- to 18-membered heteroaryl group is formed, and 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 The aryl group or the 5- to 18-membered heteroaryl group may optionally contain one or more of a halogen, an amino group, a hydroxy group, a cyano group, a C 1-6 Alkyl group, C 3-6 Cycloalkyl group or C 1-6 It may be further substituted with a haloalkyl group.

[0015] In some embodiments of the present invention, F is a KRAS protein-binding fragment represented by general formula (I) or (II), [ka] The aforementioned [ka] are independently selected from a single bond or a double bond; X4 is CR8, C(R8)2, O, N or NR8, and each R8 is independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, -SC 1-6 Alkyl group, -C 0-3 Alkylene-C 2-4 Alkenyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group or C 3-14 cycloalkyl groups, wherein C 3-14 Cycloalkyl groups, C 1-6 The alkyl group may optionally be one or more R a may be further substituted with X5 is selected from C, CH or N; The X6 is CR 14 , C(R 14 )2, O, N or NR 14Selected from R 14 are each independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, or C 1-6 Alkyl group, C 1-6 Haloalkyl group, -SC 1-6 Alkyl group, -C 0-3 Alkylene-C 2-4 Alkenyl group, C 1-6 Alkoxy group, C 1-6 haloalkoxy group or C 3-14 cycloalkyl groups, wherein C 3-14 Cycloalkyl groups, C 1-6 The alkyl group may optionally be one or more R a may be further substituted with R6 is absent or C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or the 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with R9 is H, an amino group, a substituted amino group, a cyano group, C 1-6 Alkyl group, C 1-6 Alkoxy group, halogen, C 2-6 Alkenyl group, or C 3-6 cycloalkyl groups, wherein C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-6 The cycloalkyl group may optionally be one or more R a may be further substituted with R 10 is absent, -O-, or -NR 11 - selected from R 11 is H, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Hydroxyalkyl group or C 1-6 aminoalkyl groups, The R7 is C 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18an aryl group or a 5- to 18-membered heteroaryl group, 3-14 Cycloalkyl groups, 3- to 14-membered heterocyclyl groups, C 6-18 The aryl group or 5- to 18-membered heteroaryl group may optionally be one or more R a may be further substituted with The K is C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or 3- to 14-membered heterocyclyl group may be a single ring, a fused ring, a spiro ring, or a bridged ring, and may optionally be one or more R a and the 3- to 14-membered heterocyclyl group is [ka] Instead, The m and n are each independently selected from 0, 1, 2, 3, 4, and 5.

[0016] In some embodiments of the invention, R4 is [ka] or —NH—.

[0017] In some embodiments of the invention, R4 is [ka] is selected from.

[0018] In some embodiments of the present invention, K is C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or the 3- to 14-membered heterocyclyl group is monocyclic and optionally has one or more R a It may be further substituted with.

[0019] Furthermore, the K is [ka] is selected from.

[0020] In some embodiments of the present invention, K is C 3-14 is a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or the 3- to 14-membered heterocyclyl group is a spirocyclic ring and optionally contains one or more R a It may be further substituted with.

[0021] Furthermore, the K is [ka] is selected from.

[0022] In some embodiments of the present invention, K is C 3-14 is a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or 3- to 14-membered heterocyclyl group is a fused ring and optionally has one or more R a It is further substituted with That's fine.

[0023] Furthermore, the K is [ka] is selected from.

[0024] In some embodiments of the present invention, K is C 3-14 is a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 3-14 The cycloalkyl group or the 3- to 14-membered heterocyclyl group is a bridged ring and optionally has one or more R a It may be further substituted with.

[0025] Furthermore, the K is [ka] is selected from.

[0026] In some embodiments of the present invention, K is [ka] is selected from.

[0027] In some embodiments of the present invention, R7 is C 6-18 an aryl group or a 5- to 18-membered heteroaryl group, 6-18 The aryl group or 5- to 18-membered heteroaryl group may optionally be one or more R a may be further substituted with, a are each independently H, a halogen, a hydroxy group, an amino group, a cyano group, or C 2-6 Alkynyl group, C 1-6 Alkyl group, C 1-6 Haloalkyl group or C 2-6 alkenyl groups.

[0028] In some embodiments of the invention, R7 is [ka] The aforementioned [ka] optionally one or more R a may be further substituted with, a are each independently H, a halogen, a hydroxy group, an amino group, a cyano group, or C 2-6 Alkynyl group, C 1-6 Alkyl group, C 1-6 Haloalkyl group or C 2-6 alkenyl groups.

[0029] In some embodiments of the invention, R7 is [ka] is selected from.

[0030] In some embodiments of the invention, F is [ka] is selected from Here, R7, R9, R8, R 11 , R 14 is defined as in the above general formula (I) or (II), and K is [ka] is selected from.

[0031] In some embodiments of the present invention, K is [ka] is selected from.

[0032] In some embodiments of the invention, F is [ka] [ka] is selected from.

[0033] In some embodiments of the invention, F is [ka] is selected from.

[0034] In some embodiments of the present invention, the G or D ring in L is independently C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 The cycloalkyl group or the 3- to 14-membered heterocyclyl group may optionally be halogen or C 1-3 may be further substituted with an alkyl group, Said C 6-14 The aryl group is preferably [ka] and

[0035] The 5- to 14-membered heteroaryl group is preferably [ka] is selected from The 3- to 14-membered heterocyclyl group is preferably [ka] is selected from Said C 3-14 The cycloalkyl group is preferably [ka] is selected from.

[0036] In some embodiments of the present invention, the G or D ring in L is independently C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14Aryl group, 5- to 14-membered heteroaryl group, C 3-14 A cycloalkyl group or a 3- to 14-membered heterocyclyl group is , optionally halogen or C 1-3 may be further substituted with an alkyl group, Said C 6-14 The aryl group is preferably [ka] and The 5- to 14-membered heteroaryl group is preferably [ka] is selected from The 3- to 14-membered heterocyclyl group is preferably [ka] is selected from Said C 3-14 The cycloalkyl group is preferably [ka] is selected from.

[0037] In some embodiments of the present invention, the G or D ring in L is independently C 6-14 an aryl group, a 5- to 14-membered heteroaryl group, or a 3- to 14-membered heterocyclyl group, 6-14 The aryl group, 5- to 14-membered heteroaryl group or 3- to 14-membered heterocyclyl group may optionally be halogen or C 1-3 may be further substituted with an alkyl group, Said C 6-14 The aryl group is preferably [ka] and The 5- to 14-membered heteroaryl group is preferably [ka] is selected from The 3- to 14-membered heterocyclyl group is preferably [ka] is selected from.

[0038] In some embodiments of the present invention, L is [ka] is selected from where: The G ring or the D ring each independently represents C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14 The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with, a are independently H, hydroxyl group, amino group, oxo group, cyano group, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group or C 1-6 is selected from.

[0039] The Y1 and Y2 each independently represent either no group, -O-, -NH-, or a group containing 3 to 6 members. Nitrogen heterocyclyl groups, C 1-6 Alkylene group, carbonyl group, ethynyl group or C 3-6 cycloalkyl groups, Each E is independently selected from -O-, -NH-, or -NCH3-; The n1, n2, and n3 are each independently selected from integers of 0 to 10, and are preferably 0, 1, 2, 3, or 4.

[0040] In some embodiments of the present invention, L is selected from the structures shown below: [ka] [ka] [ka] [ka]

[0041] Here, n1 and n2 are each independently selected from integers of 0 to 10, and are preferably 0, 1, 2, or 3.

[0042] In some embodiments of the present invention, L is selected from the structures shown below: [ka] [ka]

[0043] In some embodiments of the present invention, M is [ka] is selected from.

[0044] In some embodiments of the present invention, M is [ka] is selected from.

[0045] In some embodiments of the present invention, L is [ka] is selected from wherein the G ring is C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14 The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with, a are each independently H, a hydroxy group, an amino group, an oxo group, a cyano group, a halogen, or C 1-6 Alkyl group, C 1-6 Haloalkyl group or C 1-6 alkoxy groups, The ring D is a 5- to 6-membered nitrogen-containing heteroaryl group, preferably [ka] is.

[0046] The Y1 and Y2 each independently represent either nothing, -O-, -NH-, a 3- to 6-membered nitrogen-containing heterocyclyl group, or C 1-6 Alkylene group, carbonyl group, ethynyl group or C 3-6 cycloalkyl groups, The n1 and n2 are each independently 0, 1, 2, 3, or 4.

[0047] In some embodiments of the present invention, L is [ka] is selected from.

[0048] In some embodiments of the invention, F is [ka] is selected from.

[0049] The L is selected from the structures shown below. [ka]

[0050] where: The G ring or the D ring each independently represents C 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 a cycloalkyl group or a 3- to 14-membered heterocyclyl group, 6-14 Aryl group, 5- to 14-membered heteroaryl group, C 3-14 The cycloalkyl group or the 3- to 14-membered heterocyclyl group may optionally be one or more R a may be further substituted with The Y1 and Y2 each independently represent either nothing, -O-, -NH-, a 3- to 6-membered nitrogen-containing heterocyclyl group, or C 1-6 Alkylene group, carbonyl group, ethynyl group or C 3-6 cycloalkyl groups, Each E is independently selected from -O-, -NH-, or -NCH3-; The n1, n2, and n3 are each independently selected from integers of 0 to 10, and are preferably 0, 1, 2, 3, or 4.

[0051] wherein M is selected from the VHL binding fragments of general formula (III): [ka] wherein X1 is selected from C, CH or N; wherein X2 is selected from C, CH or N; X3 is selected from N, NH, O or S; The R1 is H, C 1-6 selected from alkyl groups, halogens, or cyano groups, preferably methyl groups, ethyl groups, F, or cyano groups; R2 is H or C 1-6 alkyl groups, preferably H or methyl groups; The R3 is H, C 1-6 Alkyl group, C 1-6 hydroxyalkyl groups or -(CH2)n-CO-NH-(CH2)n-CH3, where n is selected from 0, 1, 2 or 3, and R3 is preferably H, a methyl group, a hydroxymethyl group, [ka] or -CH2-CO-NH-CH3, The R4 is [ka] or -NH-, The R5 is H, C 1-6 Alkyl group or C 1-6 haloalkyl groups, R a are independently H, hydroxyl group, amino group, oxo group, cyano group, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group or C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0052] In some embodiments of the present invention, the compound of FLM structure is selected from the following compounds: [ka] [ka] [ka]

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[0053] Through extensive research, the present inventors have found that the linking chain of the compounds of the present invention significantly affects the compound's ability to degrade KRAS and its cell growth inhibitory activity. Introducing a 5- to 6-membered nitrogen-containing heteroaryl group, particularly a pyrazine ring or pyridyl ring, into the linking chain located on the VHL ligand side significantly improves the compound's ability to degrade KRAS and its cell growth inhibitory activity. The inventors speculate that the unique spatial position of the nitrogen-containing heteroaromatic ring allows for interactions such as hydrogen bonding with the VHL protein, increasing the binding strength between the compound and VHL, thereby enhancing the compound's ability to degrade KRAS. Research has shown that directly binding the nitrogen-containing heteroaromatic ring to the VHL ligand is an important factor in enhancing the compound's degrading activity. Furthermore, compounds with such nitrogen-containing heteroaromatic rings have excellent in vivo pharmacokinetic properties and are highly promising candidates for drug discovery.

[0054] In another aspect, the present invention provides a pharmaceutical composition, which contains a compound of the present invention represented by any of the general formulas having an FLM structure described above, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0055] The present invention further provides use of a compound represented by any of the above general formulas having an FLM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of them, in the manufacture of a pharmaceutical for regulating the ubiquitination and degradation of KRAS protein in a subject.

[0056] The present invention further provides use of a compound represented by any of the above general formulas having an FLM structure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the manufacture of a medicament for treating and / or preventing a KRAS-mediated or dependent disease, wherein the KRAS-mediated disease is preferably selected from tumors.

[0057] In certain embodiments, 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 carcinoma, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, intrahepatic cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

[0058] The general chemical terms used in the general structural formula above have their usual meaning unless otherwise specified. Have.

[0059] For example, the term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine, unless otherwise specified.

[0060] In the present invention, the order of linking groups is not particularly limited, and they may be linked from left to right or from right to left.

[0061] In the present invention, unless otherwise specified, the term "alkyl group" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6The "1-6" in "alkyl group" refers to groups containing 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain.

[0062] The term "alkoxy group" refers to the oxy ether form of the above-mentioned straight or branched chain alkyl groups, i.e., -O-alkyl groups.

[0063] The term "alkylene group" refers to a divalent alkyl linking group. An alkylene group formally refers to an alkane in which two C—H bonds replace the points of attachment of the alkylene group to the rest of the compound. Similarly, C 1-3 "C" in the alkylene group 1-3 " means an alkylene group containing 1, 2 or 3 carbon atoms, including, but not limited to, a methylene group, a 1,2-ethylene group, a 1,3-propylene group, or a 1,2-isopropylene group.

[0064] The term "haloalkyl group" refers to an alkyl group in which one or more H has been replaced with a halogen atom.

[0065] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent that forms a carbonyl group when attached to C, or a sulfinyl or sulfonyl group or an N-oxide group when attached to a heteroatom.

[0066] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "heteroaromatic ring" refers to a polyunsaturated carbocyclic or heterocyclic ring having aromatic properties (having (4n+2) delocalized π electrons, where n is an integer).

[0067] In the present invention, the term "aryl group" refers to an unsubstituted or substituted, monocyclic or fused-ring aromatic group containing carbon ring atoms, unless otherwise specified. 6-18 is an aryl group, more preferably the aryl group is C 6-10The aryl ring is a monocyclic or bicyclic aromatic ring group. Preferably, it is a phenyl group or a naphthyl group, and most preferably, it is a naphthyl group. The aryl ring may be fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl group, and the ring attached to the parent structure is an aryl ring, and non-limiting examples include, but are not limited to, a benzocyclopentyl group.

[0068] The term "heterocyclyl group" refers to a ring system of a cyclized alkyl group or a cyclized alkenyl group containing at least one heteroatom selected from N, O, and / or S. The heterocyclyl group may contain a single ring or multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclyl group may be bonded to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. 3- to 14-membered heterocyclyl groups are preferred, and the "3- to 14-membered" in a 3- to 14-membered heterocyclyl group refers to 3-14 C, N, or C-membered heterocyclyl groups. , O, or S ring-forming atoms, wherein the nitrogen or sulfur heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Examples of such heterocyclyl groups include: [ka] Heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinylsulfinyl, thiomorpholinylsulfonyl, and tetrahydrooxadiazolyl. The heterocyclyl groups may be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring attached to the parent structure is a heterocyclyl group.

[0069] In the present invention, unless otherwise specified, the term "heteroaryl group" refers to a monocyclic or polycyclic (e.g., 2, 3, or 4 fused, spiro, or bridged) aromatic heterocycle having at least one heteroatom. The heteroatom is selected from N, O, and / or S, and the nitrogen or sulfur heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. A 5- to 18-membered heteroaryl group is preferred, and the "5- to 18-membered" in the 5- to 18-membered heteroaryl group refers to a heteroaryl group consisting of 5 to 18 ring-forming atoms of C, N, O, or S. A 5- to 10-membered heteroaryl group is more preferred, and a 5- to 6-membered heteroaryl group is even more preferred. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to a ring of an aryl, heterocyclyl, or cycloalkyl group, and the ring attached to the parent structure is a heteroaryl ring.

[0070] The term "cycloalkyl group" refers to a ring system having at least one cyclized alkyl group. 3-14 Cycloalkyl groups are preferred, and "C 3-14" means that the cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring-forming atoms. Cycloalkyl groups can include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused, spiro, bridged, etc.) rings. In some examples, cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like. The cycloalkyl group can be fused to the ring of an aryl, heterocyclyl, or heteroaryl group, where the ring attached to the parent structure is the cycloalkyl group.

[0071] The term "substituted" refers to the replacement of one or more hydrogen atoms of a group with a similar or different substituent, respectively. Typical substituents include halogen (F, Cl, Br, or I), C 1-8 Alkyl group, C 3-12 Cycloalkyl groups, -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 group, nitro group, -S(O)2R 1 , -OS(O2)OR 1 , -OS(O)2R 1 , -OP(O)(OR 1 )(OR 2 ), including, but not limited to, where R 1 and R 2 are independently -H, C 1-6 Alkyl group, C 1-6 Haloalkyl group or C 3-6In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, -SCH, -SCH, formaldehyde, -C(OCH), cyano, nitro, -CF, -OCF, amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0072] When the number of one linking group is 0, for example, -(CH2)0- represents that the linking group is a bond.

[0073] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

[0074] When the compound provided by the present invention is an acid, the corresponding salt may be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper (high and low valence), ferric, ferrous, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc, and the like salts. Among these, ammonium, calcium, magnesium, potassium, and sodium salts are preferred. Pharmaceutically acceptable non-toxic organic bases capable of forming salts include primary, secondary, and tertiary amines, including cyclic amines and substituted amines. The substituted amines include, for example, naturally occurring and synthetically derived substituted amines. Other pharmaceutically acceptable organic non-toxic bases which can form salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometamol, and the like.

[0075] When the compounds provided by the present invention are bases, the corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic 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, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid. Citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid are more preferred. More preferred are formic acid and hydrochloric acid.

[0076] Prodrugs of the compounds according to the present invention are included in the scope of protection of the present invention. A prodrug is a functional derivative that is readily converted in vivo into a desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound according to the invention can directly or indirectly provide a compound of the invention, or a pharmacologically active metabolite, or residue thereof, after administration to a subject.

[0077] The compounds according to the present invention may contain one or more asymmetric centers, thereby giving rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0078] Unless otherwise specified, the compounds of formula (I) may exist in the form of tautomers, and the present invention includes all possible tautomers and pharmaceutically acceptable salts thereof, as well as mixtures thereof.

[0079] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or pharmaceutically acceptable salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present invention to an organism.

[0080] As used herein, the terms "a," "one," "the," "at least one," and "one or more" can be used interchangeably. Thus, for example, a description of a mixture containing "one" pharmaceutically acceptable excipient can be interpreted as the pharmaceutical composition containing "one or more" pharmaceutically acceptable excipients.

[0081] The term "pharmaceutically acceptable excipient" refers to an excipient that does not have a significant irritating effect on the living body and does not impair the biological activity and properties 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.

[0082] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, and can be formulated as solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gelling agents, microspheres and aerosols.

[0083] 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, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0084] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect, which may partially or completely stabilize or cure a disease and / or its side effects, and the effect may be curative. As used herein, "treatment" includes any treatment of a patient's disease, including (a) inhibiting (i.e., preventing the onset of) a symptom of the disease, or (b) alleviating (i.e., causing regression of the disease or symptom).

[0085] The term "effective amount" refers to the amount of a compound of the present invention to (i) treat or prevent a particular disease, condition, or disorder, (ii) reduce, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present invention to achieve a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal being treated, but will be within the scope of the present invention. Those skilled in the art can make routine determinations based on their own knowledge and the contents of this disclosure. [Brief explanation of the drawings]

[0086] [Figure 1] FIG. 1 shows the degrading effect of Compound 2 on different KRAS in biological experiments. [Figure 2] FIG. 2 shows the results of Western blotting experiments of Compound 135 on KRAS proteolysis in different cell lines in biological experiments. [Figure 3] FIG. 3 is a graph showing the efficacy of Compound 135 in a mouse xenograft tumor model in a biological experiment. [Figure 4] FIG. 4 is a graph showing the efficacy of Compound 144 in a mouse xenograft tumor model in a biological experiment. [Figure 5]FIG. 5 shows the results of Western blotting experiments of Compound 144 on KRAS proteolysis in different cell lines in biological experiments. DETAILED DESCRIPTION OF THE INVENTION

[0087] In order to make the contents of the present invention clearer and more precise, the technical solutions of the present invention will be further described with reference to the following examples. The following examples are merely for explaining the modes for carrying out the invention so that those skilled in the art can understand the present invention, and are not intended to limit the scope of protection of the present invention. In the modes for carrying out the invention of the present invention, technical means or methods etc. not specifically described are conventional technical means or methods in this field.

[0088] Unless otherwise stated, all temperatures in this invention are in degrees Celsius.

[0089] In the examples, the following abbreviations are used: DMF: N,N-dimethylformamide, NIS: N-iodosuccinimide, THF: tetrahydrofuran; EA: ethyl acetate; PE: petroleum ether; DCM: dichloromethane, MeOH: methanol, TBDPSCl: tert-butylchlorodiphenylsilane, DPPA: diphenylphosphoryl azide; CDI: N,N'-carbonyldiimidazole; DIPEA: N,N-diisopropylethylamine, CataCXium A Pd G3: [di(1-adamantyl)-n-butylphosphine]-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate, LAH / LiAlH4: Lithium aluminum hydride, POCl3: phosphoryl chloride, DMSO: dimethyl sulfoxide; DMF-DMA: N,N-dimethylformamide dimethyl acetal, TosMIC: p-toluenesulfonylmethyl isocyanide; DCE: 1,2-dichloroethane; DMAP: 4-dimethylaminopyridine; PhN(Tf)2: phenylbis(trifluoromethanesulfonate)imide, PBS: phosphate buffer solution; Selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), TsOH: p-toluenesulfonic acid, (Boc)2O: di-tert-butyl dicarbonate, TMSCl: chlorotrimethylsilane, Pd2(dba)3: trisdibenzylideneacetonedipalladium, HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, TFA: trifluoroacetic acid; DABCO: Triethylenediamine, DIBAL-H: diisobutylaluminum hydride; TMSCN: trimethylsilyl cyanide; TMSOTf: trimethylsilyl trifluoromethanesulfonate; LiHMDS: lithium bistrimethylsilylamide; NaBH3CN: sodium cyanoborohydride, TBAF: tetrabutylammonium fluoride; NADPH: reduced nicotinamide adenine dinucleotide phosphate; UDPGA: uridine diphosphate glucuronic acid; UGT: uridine diphosphate glucuronosyltransferase; TEA: Triethylamine.

[0090] Synthesis of intermediate M1: [ka]

[0091] (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1 g) was dissolved in THF (10 mL) and acetonitrile (10 mL). TEA (1.88 mL) was added. A solution of 2-azido-1,3-dimethylimidazolium hexafluorophosphate (0.64 g) in acetonitrile (2 mL) was added dropwise in an ice bath and stirred for 2 hours. The reaction mixture was added with 20.0 mL of water and extracted three times with EA (20 mL each time). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give intermediate M1 (0.8 g).

[0092] ESI-MS m / z: 471 [M+H] + .

[0093] Synthesis of intermediate M2: [ka]

[0094] Step 1: Synthesis of compound M2-1 At room temperature, 2-chloro-3-fluoropyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butanol (390.00 mL), triethylamine (128.27 mL), and powdered 4A molecular sieves (90.00 mL) (pre-activated) were sequentially added and refluxed for 30 minutes under nitrogen gas protection (internal temperature 87 °C). After natural cooling to room temperature, DPPA (99.44 mL) was added, and the temperature was raised to reflux and allowed to react for 5 hours while maintaining the temperature. The reaction mixture was cooled to below 40 °C, diluted with EA (500 mL), further cooled to room temperature, and the added molecular sieves were removed by filtration using diatomaceous earth. The filter cake was washed several times with EA (1500 mL), sucked dry, and the filtrate was collected and washed with 700 mL of water and 700 mL of saturated brine, followed by separation. The organic phase was then dried over anhydrous sodium sulfate, filtered, the drying agent was removed, and concentrated. The concentrate was separated and purified by column chromatography (PE / EA = 30:1 to 20:1), and the eluate was concentrated to finally obtain product M2-1 (68.2 g, yield 89.88%).

[0095] ESI-MS m / z: 247.1 [M+H] + .

[0096] Step 2: Synthesis of compound M2-2 Compound M2-1 (65.00 g) was dissolved in CH3CN (82.00 mL) at room temperature and cooled in a water bath. 4 M hydrogen chloride (dioxane solution, 264 mL) was slowly added. The mixture was stirred at room temperature for approximately 16 hours, during which a white solid precipitated and became suspended. The reaction mixture was filtered, and the filter cake was washed with a small amount of acetonitrile and dried by suction. The filtrate was discarded. The filter cake was collected and added to a mixture of 700 mL of saturated aqueous sodium bicarbonate and 700 mL of ethyl acetate to alkalize, extract, and separate. The aqueous phase was then extracted with 350 mL of ethyl acetate, separated, and the combined ethyl acetate layers were washed with 300 mL of saturated aqueous sodium chloride and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, the drying agent was removed, and concentrated to give product M2-2 (36.3 g, 94.0% yield).

[0097] ESI-MS m / z: 147.1 [M+H] + .

[0098] Step 3: Synthesis of compound M2-3 Compound M2-2 (36.00 g) was dissolved in acetonitrile (180.00 mL) at room temperature, and NIS (66.32 g) and p-toluenesulfonic acid (2.12 g) were added. The mixture was heated to 70 °C under nitrogen gas protection and allowed to react while maintaining the temperature. The reaction mixture was cooled to 50 °C, and 900 mL of water was added. A pink-white solid powder precipitated, and the mixture was triturated for 30 minutes. The mixture was then filtered, washed with water, and dried under suction. The filter cake was collected and completely dissolved in 1200 mL of ethyl acetate. It was then washed with 350 mL of saturated aqueous sodium sulfite solution twice, followed by 350 mL of saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give product M2-3 (63.2 g, 94.43% yield).

[0099] ESI-MS m / z: 272.9 [M+H] + .

[0100] Step 4: Synthesis of compound M2-4 Compound M2-3 (57.50 g) was dissolved in DMF (22.00 mL) at room temperature, and zinc cyanide (32.22 g), tetrakis(triphenylphosphine)palladium (12.19 g), and powdered 4 Å molecular sieves (20.00 mL) were added. The mixture was heated to 100 °C under a nitrogen atmosphere and allowed to react for approximately 7 hours while maintaining the temperature. The oil bath was removed, and the mixture was allowed to cool to room temperature before proceeding to workup. The reaction mixture was filtered using diatomaceous earth and dried under suction. The filtrate was collected and concentrated at 60-70 °C to obtain a pale yellow crude solid product. The filter cake was washed with 500 mL of ethyl acetate and dried under vacuum. The washes were collected, combined with the crude product, and reconcentrated until no distillate remained. The solid crude product obtained after concentration was then dissolved in 700 mL of ethyl acetate, washed three times with 250 mL of saturated brine, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid. 160 mL of a 3:1 PE / EA mixture was added, triturated for 30 minutes, filtered, and dried under vacuum. The filter cake was collected, concentrated in a water bath at 45 °C, and then dried under vacuum under a high-vacuum oil pump until the weight remained constant, finally affording product M2-4 (36.1 g, 99.7% yield).

[0101] ESI-MS m / z: 172.0 [M+H] + .

[0102] Step 5: Synthesis of compound M2-5 Concentrated sulfuric acid (61.37 mL) was added to a 500 mL single-neck flask at room temperature, cooled to below 10 °C in an ice-water bath, and compound M2-4 (39.30 g) was added in portions. After the addition was complete, the mixture was stirred for 10 minutes and then allowed to react for approximately 1 hour under a nitrogen atmosphere, maintaining the temperature at 60 °C in an oil bath. The reaction mixture was then cooled to room temperature and carefully added to 1100 mL of ice-water mixture, diluted, and quenched, resulting in the precipitation of a small amount of yellow solid. After stirring for 10 minutes, the mixture was filtered, the filter cake was collected, and triturated with 50 mL of saturated aqueous sodium bicarbonate solution for 20 minutes. The mixture was then filtered again, and the two filtrates were collected and combined. Solid sodium carbonate was then slowly added to adjust the pH to approximately 7, resulting in the precipitation of an off-white solid. The mixture was stirred for 30 minutes, filtered, and dried by suction. The filter cake was washed twice, each time with 100 mL of water, and dried by suction. The filter cake was collected and placed in a vacuum oven and dried at 55° C. until the weight remained constant to give product M2-5 (33.6 g, 77.37% yield). ESI-MS m / z: 190.0 [M+H] + .

[0103] Step 6: Synthesis of compound M2-6 Tetrahydrofuran (470.00 mL) was added at room temperature, and the mixture was purged with nitrogen gas. Under the protection of a slight nitrogen gas flow, sodium hydride (10.00 g) was added and heated in an oil bath, maintaining the temperature at 40-45 °C for 15 minutes while stirring. Compound M2-5 (18.95 g) was then added in portions. After the addition was complete, the mixture was mechanically stirred for 20 minutes while maintaining the temperature. CDI (24.31 g) was then carefully added in portions. After the addition was complete, the mixture was stirred for 15 minutes, then heated in an oil bath to reflux, and the reaction was continued while maintaining the temperature. The reaction mixture was cooled to below 10 °C in an ice-water bath. 500 mL of saturated aqueous ammonium chloride solution was added, resulting in the precipitation of a pale yellow solid. 1000 mL of water was then added. The mixture was then transferred to a 5 L beaker, 3000 mL of water was added, stirred for 1 hour, filtered, and suction dried. The filter cake was collected and placed in a vacuum oven and dried at 50-55 °C until the weight remained constant, yielding product M2-6 (18.3 g, 84.93% yield).

[0104] ESI-MS m / z: 216.0 [M+H] + .

[0105] Step 7: Synthesis of compound M2 At room temperature, compound M2-6 (18.00 g) and DIPEA (36.00 mL) were dissolved in POCl (180.00 mL), heated to 100 °C under a nitrogen gas atmosphere, and reacted for about 2.5 hours while maintaining the temperature. The mixture was concentrated under reduced pressure to remove phosphoryl chloride, and DCM The concentrate was washed twice with 100 mL of dichloromethane. The concentrated residue was then dissolved in 400 mL of dichloromethane, added dropwise to 500 mL of saturated aqueous sodium bicarbonate, cooled with ice water, stirred for 15 minutes, and then separated. The aqueous phase was further extracted with 300 mL of dichloromethane, separated, and the combined dichloromethane layers were washed with 300 mL of saturated aqueous sodium chloride, and then separated. The extract was then dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified on a silica gel column (PE / EA = 90 / 10 to 75 / 25) to obtain product M2 (10.95 g, yield 51.94%).

[0106] ESI-MS m / z: 251.9 [M+H] + .

[0107] Synthesis of intermediate M3: [ka]

[0108] Step 1: Synthesis of compound M3-1 tert-Butyl 4-ethynylpiperidine-1-carboxylate (147 mg), tert-butyl 4-(1-(((S)-1-((2S,4R)-4-hydroxy-2-((((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (330 mg) ) was dissolved in a mixed solvent of 6 mL of THF, 6 mL of HO, and 6 mL of tert-butanol, followed by the addition of sodium ascorbate (360 mg) and anhydrous copper sulfate (100 mg) in that order, and the mixture was allowed to react at room temperature for 3 hours. 20 mL of water was added to the reaction mixture, which was then extracted three times with EA (20 mL each time). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound M3-1 (420 mg).

[0109] ESI-MS m / z: 680 [M+H] + .

[0110] Step 2: Synthesis of compound M3 M3-1 (420 mg) was dissolved in 10 mL of DCM, followed by the addition of 3 mL of TFA and the reaction mixture at room temperature for 30 minutes. The reaction mixture was then added with 1 M aqueous NaOH to liberate the acid. The mixture was then extracted three times with DCM (10 mL each time). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure to give compound M3 (365 mg).

[0111] ESI-MS m / z: 580 [M+H] + .

[0112] Synthesis of intermediate M4: [ka]

[0113] N-tert-Butoxycarbonyl-3-methyl-3-hydroxypiperidine (1.0 g) was added to a 25 mL one-neck flask, 3 mL of acetonitrile was added, and 3 mL of hydrochloric acid (4 M / Dioxane) was added at 0° C. The reaction was allowed to proceed for 0.5 hours at 0° C. After completion of the reaction, the reaction solution was concentrated to give intermediate M4 (0.7 g, 99% yield), which was used directly in the next step.

[0114] Synthesis of intermediate M5: [ka]

[0115] Step 1: Synthesis of compound M5-1 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl (1.0 g) of (1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane was added to a 50 mL single-neck flask, followed by 6 mL of DMF, followed by 5.9 g of cesium fluoride, and the mixture was stirred at room temperature for 1 hour. After monitoring the complete reaction of the raw materials by TLC, the reaction mixture was slowly added dropwise to 20 mL of water. A white solid precipitated, which was filtered, and the filter cake was collected and dried to obtain 0.65 g of compound M5-1, a white solid.

[0116] Step 2: Synthesis of compound M5 Compound M5-1 (0.65 g) was added to a 50 mL single-neck flask, 6 mL of MeOH, and Pd / C (600 mg, 10% purity) were added, and the mixture was reacted at room temperature for 20 minutes under a hydrogen atmosphere. After the reaction was complete, the mixture was filtered, the filtrate was collected, concentrated, and the concentrate was purified by column chromatography to give compound M5 (496 mg, 75.5% yield).

[0117] 1H NMR(500MHz,Methanol-d4)δ7.56(dd,J=8.9,5.8Hz,1H),7.39(d,J=2.7Hz,1H),7.36(d,J=2.7Hz,1H),7.20( t,J=9.2Hz,1H),5.27(s,2H),3.50(s,3H),3.12(qd,J=7.5,2.5Hz,2H),1.44(s,12H),1.26(t,J=7.5Hz,3H).

[0118] Synthesis of intermediate M6: [ka]

[0119] Intermediate M5 (1.0 g) was placed in a 50 mL one-neck flask and 10 mL of 4 M hydrogen chloride in dioxane was added. After reacting at room temperature for 30 minutes, the reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted twice with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM:ammonia / methanol = 10:1) to give Intermediate M6 (0.82 g). 1 H NMR(500MHz,CDCl3)δ7.46(dd,J=8.9,5.8Hz,1H),7.27(d,J=2.7Hz,1H),7.17(dd,J=12. 5,5.9Hz,1H),7.12(d,J=2.7Hz,1H),3.17-3.07(m,2H),1.45(s,12H),1.29-1.25(m,3H).

[0120] Synthesis of intermediate M7: [ka]

[0121] Step 1: Synthesis of compound M7-1 4-Amino-2,6-dichloropyridine (63 g) was placed in a 1 L three-neck flask, followed by 440 mL of ACN and 180 mL of water. The temperature was raised to 45 °C, and selectfluor (164 g) was added. The reaction became exothermic, and the mixture was allowed to cool naturally in the air. After 10 minutes of reaction, the reaction was quenched by adding saturated sodium sulfite solution in an ice bath, followed by extraction three times with EA. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 10:1) to give compound M7-1 (42.6 g).

[0122] ESI-MS m / z: 163.9 [M+H] + .

[0123] Step 2: Synthesis of compound M7-2 Compound M7-1 (54 g) was added to a 1 L three-neck flask, 500 mL of ACN was added, and NIS (80 g) and TsOH (5.1 g) were added. The mixture was heated to 70 °C and reacted for 1 hour. 2.5 L of water was added dropwise, filtered, and the filter cake was dissolved in EA. After separation, the organic phase was concentrated to give compound M7-2 (94 g). ESI-MS m / z: 307.2 [M+H] + .

[0124] Step 3: Synthesis of compound M7-3 Compound M7-2 (88 g) was added to a 1 L three-neck flask, followed by 500 mL of DMF and CuCN (31 g). The mixture was heated to 125 °C and reacted for 16 hours. 2 L of water was added dropwise, followed by 2 L of water. The mixture was filtered, the filter cake was washed with water, and dissolved in EA. The aqueous phase was extracted twice with EA. The organic phases were collected, combined, and concentrated to give compound M7-3 (55.4 g).

[0125] ESI-MS m / z: 207.0 [M] - .

[0126] Step 4: Synthesis of compound M7-4 Compound M7-3 (88 g) was placed in a 250 mL three-neck flask, and 83 mL of concentrated sulfuric acid and 9 mL of water were added. After reacting at 60 °C for 16 hours, 70 mL of concentrated sulfuric acid and 5 mL of water were added, and the reaction was continued for another 24 hours. After cooling to 0 °C, the reaction solution was slowly poured into 2 L of ice water, filtered, and the filter cake was washed with water and then dissolved in EA. The filtrate was extracted twice with EA, and the organic phases were collected, combined, concentrated, and triturated with PE:EA = 1:1. Filtration gave compound M7-4 (59 g).

[0127] ESI-MS m / z: 224.1 [M+H] + .

[0128] Step 5: Synthesis of compound M7-5 Compound M7-4 (58 g) was placed in a 1 L three-neck flask, 650 mL of THF was added, and the mixture was heated to 40 °C. NaH (16 g) was then added slowly in portions. After stirring for 10 minutes, the mixture was heated to 60 °C and N,N'-thiocarbonyldiimidazole (69 g) was slowly added. After reacting for 1 hour, the reaction was quenched by adding saturated ammonium chloride solution, and the pH was adjusted to 4-5 by dropwise addition of dilute hydrochloric acid. THF was then removed by rotary evaporation. After filtration, the filter cake was washed with water and dissolved in methanol. The organic phase was concentrated to obtain crude product M7-5 (85 g).

[0129] ESI-MS m / z: 267.0 [M+H] + .

[0130] Step 6: Synthesis of compound M7 Compound M7-5 (74 g) was added to a 1 L three-neck flask, and 750 mL of ACN, iodomethane (22 mL), and an aqueous solution (100 mL) of sodium methoxide (23 g) were added. After reacting at room temperature for 15 minutes, the reaction solution was added to 3.5 L of water, and diluted hydrochloric acid was added to adjust the pH to 4-5. The mixture was filtered, and the filter cake was triturated using a 2:1 PE:EA mixed solvent. The filtered cake was compound M7 (42.2 g).

[0131] ESI-MS m / z: 281.2 [M+H] + .

[0132] Synthesis of intermediate M8: [ka]

[0133] Step 1: Synthesis of compound M8-1 Potassium carbonate (4.78 g) was added to a suspension of compound 1H-1,2,4-triazole-5-carboxylate (4.00 g) and N-tert-butoxycarbonyl-3-aminopropyl bromide (7.49 g) in acetonitrile (40 mL) at room temperature, and the mixture was stirred in an oil bath at 80 °C. After reacting for 1 hour, ethyl acetate and water were added to the reaction mixture for extraction and separation. The aqueous phase was further extracted once with ethyl acetate. The organic phase was washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product M8-1 (8.90 g, 99% yield). ESI-MS m / z = 285.2 [M+H] + .

[0134] Step 2: Synthesis of compound M8-2 Compound M8-1 (8.90 g) was dissolved in 40 mL of 4N HCl in dioxane at room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was dried on a rotary evaporator to give M8-2 (5.60 g, 97% yield), which was used directly in the next step. ESI-MS m / z = 185.1 [M+H] + .

[0135] Step 3: Synthesis of compound M8-3 Compound M8-2 (5.60 g) and sodium carbonate (9.96 g) were added to 100 mL of water at room temperature, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was neutralized with dilute hydrochloric acid and then concentrated to remove water. The resulting solid residue was washed with organic solvent (DCM:MeOH = 20:1) on a short silica gel column. The filtrate was concentrated to give compound M8-3 (1.32 g, 28% yield). ESI-MS m / z = 153.2 [M+H] + .

[0136] Step 4: Synthesis of compound M8 Compound M8-3 (1.20 g) was added to a suspension of LiAlH4 (0.75 g) in THF (24 mL) at room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was cooled to 0 °C, and water (0.75 mL), 15% sodium hydroxide solution (0.75 mL), and water (2.25 mL) were added sequentially. The reaction mixture was then allowed to warm to room temperature and stirred for 10 minutes. After that, an appropriate amount of anhydrous magnesium sulfate was added and stirred for another 10 minutes. The mixture was then filtered. The residue was washed with an appropriate amount of organic solvent (DCM:MeOH = 10:1). The resulting filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography (MeOH:DCM = 0-10%) to obtain product M8 (0.62 g, 57% yield). ESI-MS m / z = 139.2 [M+H] + .

[0137] Synthesis of intermediate M9: [ka]

[0138] Step 1: Synthesis of compound M9-1 4-Ethynylaniline (1 g) was dissolved in 10 mL of THF, (Boc)2O (2.24 g) was added, and the mixture was allowed to react at 55 °C for 24 hours. 20 mL of water was added to the reaction mixture, and the mixture was extracted with EA three times, each time with 20 mL of water. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound M9-1 (1.78 g). ESI-MS m / z: 218 [M+H] + .

[0139] Step 2: Synthesis of compound M9-2 M9-1 (152 mg) and M1 (330 mg) were dissolved in a mixture of 6 mL of THF, 6 mL of HO, and 6 mL of tert-butanol. Sodium ascorbate (360 mg) and anhydrous copper sulfate (100 mg) were then added sequentially and the mixture was allowed to react at room temperature for 3 hours. 20 mL of water was added to the reaction mixture, which was then extracted three times with EA (20 mL each time). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound M9-2 (450 mg). ESI-MS m / z: 688 [M+H] + .

[0140] Step 3: Synthesis of compound M9 M9-2 (450 mg) was dissolved in 10 mL of DCM, followed by the addition of 3 mL of TFA and the reaction mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was adjusted to pH 7 with 1 M aqueous NaOH and extracted three times with 10 mL of DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound M9 (320 mg). ESI-MS m / z: 588 [M+H] + .

[0141] Synthesis of intermediate M10: [ka]

[0142] Compound M10-1 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10 g) was added to a 100 mL one-neck flask, and 30 mL of 4 M hydrogen chloride in dioxane was added. After reacting at room temperature for 30 minutes, the reaction mixture was neutralized by adding saturated sodium bicarbonate solution in an ice bath, filtered, and the filter cake was washed twice with water. It was dissolved in EA, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 82:18) to obtain intermediate M10 (9.1 g).

[0143] Synthesis of intermediate M11: [ka]

[0144] The synthesis of Steps 1 to 3 was carried out in accordance with the synthesis of Intermediate M8.

[0145] Step 4: Synthesis of compound M11-4 Compound M11-3 (3.4 g) was added to a 250 mL three-necked flask, 100 mL of THF was added, and NaBH4 (3.1 g) was added in portions. Next, boron trifluoride diethyl etherate (14 mL) was slowly added dropwise at 0°C under a N2 atmosphere. After the addition was completed, the reaction solution was allowed to warm to room temperature and reacted overnight. After the reaction was completed, the reaction mixture was quenched by slowly adding ethanol (50 mL) under ice bath and concentrated under reduced pressure to remove THF and ethanol. The residue was then added with ethanol (70 mL), water (20 mL), and 10% hydrochloric acid solution (10 mL). The mixture was stirred at room temperature for 4 hours, concentrated under reduced pressure, and the remaining mother liquor was adjusted to pH 8 with saturated NaHCO3 solution. It was then extracted three times with DCM / MeOH (10:1), each time with 40 mL of DCM / MeOH. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried on a rotary evaporator to obtain the crude product (2.8 g) M11-4, which was used directly in the next step. ESI-MS m / z: 196.1 [M+H] + .

[0146] Step 5: Synthesis of compound M11-5 Compound M11-4 (2.8 g) was added to a 100 mL single-neck flask, 25 mL of DCM, DIPEA (5.9 mL) were added, and (Boc)2O (5.0 g) was added in an ice bath. The mixture was then warmed to room temperature and reacted for 3 hours. After completion of the reaction, the reaction mixture was added to saturated ammonium chloride solution, extracted with DCM, and the organic phase was collected. The aqueous phase was extracted twice with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (PE:EA = 3:1) to give 3.0 g of compound M11-5. ESI-MS m / z: 296.2 [M+H]+ .

[0147] Step 6: Synthesis of compound M11-6 Compound M11-5 (2.5 g) was added to a 100 mL one-neck flask, and 12 mL of MeOH and 12 mL of THF were added. Lithium hydroxide monohydrate (1.8 g, dissolved in 12 mL of HO) was then added and stirred at room temperature for 0.5 h. After the reaction was complete, water (12 mL) was added to dilute the reaction mixture, which was then concentrated under reduced pressure. The aqueous phase was adjusted to pH 5-6 with acetic acid and then extracted three times with DCM / MeOH (10:1), each time with 40 mL of DCM / MeOH. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product (3.1 g), which was used directly in the next step. ESI-MS m / z: 282.2 [M+H] + .

[0148] Step 7: Synthesis of compound M11-7 Compound M11-6 (1.4 g) was added to a 100 mL single-neck flask, 10 mL of DMF was added, followed by tetrahydropyrrole (0.71 g), DIPEA (3.29 mL), and HATU (2.84 g) in sequence. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted with EA and water. The organic phase was collected, and the aqueous phase was extracted twice with EA. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (DCM:EA = 3:1) to give 1.5 g of compound M11-7. ESI-MS m / z: 335.2 [M+H] + .

[0149] Step 8: Synthesis of compound M11 Compound M11-7 (1.5 g) was added to a 50 mL single-neck flask, 5 mL of CH3CN was added, and 5 mL of hydrochloric acid (4 M / Dioxane) was added. The mixture was stirred at room temperature for 0.5 hours to react. After completion of the reaction, the reaction mixture was concentrated to give intermediate M11 (0.98 g). ESI-MS m / z: 235.3 [M+H] + .

[0150] Synthesis of intermediate M12: [ka]

[0151] Intermediate M2 (500 mg) was added to a 25 mL single-neck flask, and intermediate M4 (275 mg) and N,N-diisopropylethylamine (1.0 g) were added at -40 °C. The reaction was continued for 0.5 hours at -40 °C. After the reaction was completed, the reaction mixture was extracted with dichloromethane and water. The organic phase was collected and the aqueous phase was extracted twice with dichloromethane. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 3:2) to give compound M12 (385 mg, 64.6% yield). ESI-MS m / z: 331.3 [M+H] + .

[0152] Synthesis of intermediate M13: [ka]

[0153] Step 1: Synthesis of compound M13-1 (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (304 mg), 2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptane-6-carboxylic acid (150 mg), and HATU (284 mg) were dissolved in 5 mL of DMF, followed by the addition of DIPEA (0.31 mL) and the reaction mixture was allowed to react at room temperature for 30 minutes. 20 mL of water was added to the reaction mixture, followed by extraction with EA three times (20 mL each time). The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound M13-1 (400 mg). ESI-MS m / z: 668 [M+H] + .

[0154] Step 2: Synthesis of compound M13 M13-1 (135 mg) was dissolved in 3 mL of DCM, followed by the addition of 1 mL of TFA and the reaction mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was adjusted to pH 7 with 1 M aqueous NaOH. The mixture was extracted three times with chloroform:isopropanol (3:1), each time using 5 mL of the chloroform:isopropanol mixture. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give M13 (110 mg). ESI-MS m / z: 568 [M+H] + . Synthesis of intermediate M14: [ka]

[0155] Step 1: Synthesis of compound M14-1 At room temperature, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g) was dissolved in DCM (50 mL), and then triethylamine (9.68 mL) and p-toluenesulfonyl chloride (5.31 g) were added sequentially. The mixture was reacted at room temperature for 15 hours. The reaction mixture was quenched by adding an appropriate amount of water, and then extracted with an appropriate amount of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure to obtain 8.02 g of the product, compound M14-1, which was used directly in the next step.

[0156] Step 2: Synthesis of compound M14-2 Compound M14-1 (7.0 g) and methyl 4-hydroxybenzoate (2.6 g) were dissolved in DMF (30.0 mL), potassium carbonate (4.72 g) was added, and the mixture was reacted at 60 °C for 10 hours. The reaction mixture was quenched by adding an appropriate amount of water, followed by extraction with an appropriate amount of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography to obtain 4.02 g of the product compound M14-2. ESI-MS m / z: 350 [M+H] + .

[0157] Step 3: Synthesis of compound M14 M14-2 (3.5 g) was dissolved in DCM (30.0 mL), trifluoroacetic acid (10.0 mL) was added, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction was monitored for completion by LC-MS, and the reaction mixture was directly concentrated, redissolved in 30.0 mL of DCM, and then concentrated again to obtain 2.5 g of the trifluoroacetic acid salt of the product, i.e., compound M14, which was used directly in the next step. ESI-MS m / z: 250 [M+H] + .

[0158] Synthesis of intermediate M15: [ka]

[0159] Step 1: Synthesis of compound M15-1 7-tert-Butoxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (200.0 mg), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300.0 mg) was dissolved in 5.00 mL of DMF, and then N,N-diisopropylethylamine (0.35 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (310.0 mg) were added and reacted at room temperature for 30 minutes. The reaction completion was monitored by LCMS. 100.0 mL of water was added to the reaction mixture, and the mixture was filtered to obtain a solid precipitated in the system. The solid was separated and purified by column chromatography to obtain 400.0 mg of a pale yellow solid, i.e., compound M15-1. ESI-MS m / z: 696 [M+H] + .

[0160] Step 2: Synthesis of compound M15 M15-1 (400.0 mg) was dissolved in 5.00 mL of DCM, then 2.00 mL of TFA was added, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was added dropwise to saturated sodium bicarbonate solution, and extracted with an appropriate amount of DCM / MeOH=10 / 1 solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M15. ESI-MS m / z: 596 [M+H] + .

[0161] Synthesis of intermediate M16: [ka]

[0162] Step 1: Synthesis of compound M16-1 7-tert-Butoxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (500.0 mg) was dissolved in 5.0 mL of THF, and borane-tetrahydrofuran solution (4.64 mL, 1 mol / L) was added. The mixture was allowed to react at room temperature for 1 hour. 5 mL of HCl / MeOH solution was slowly added to the reaction mixture, and the mixture was stirred until no more bubbles were generated. After that, 1 mol / L NaOH solution was added to adjust the pH to alkaline. Then, an appropriate amount of ethyl acetate was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M16-1 (450.0 mg). ESI-MS m / z: 200 [M+H-56]. + .

[0163] Step 2: Synthesis of compound M16-2 M16-1 (250.0 mg) was dissolved in 5.0 mL of DCM, Dess-Martin reagent (387.0 mg) was added, and the mixture was allowed to react at room temperature for 1 hour. An appropriate amount of ethyl acetate was added to the reaction mixture, and the precipitated solid was removed by filtration. The filtrate was adjusted to alkaline pH with 1 mol / L NaOH solution, and the organic phase was collected by extraction and separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M16-2 (180.0 mg). ESI-MS m / z: 198 [M+H-56]. + .

[0164] Step 3: Synthesis of compound M16-3 Under N2 protection, compound M16-2 (180 mg) was dissolved in 3.0 mL of anhydrous methanol, and anhydrous potassium carbonate (167 mg) and dimethyl (1-diazo-2-oxopropyl)phosphonate (174 mg) were added. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was extracted with an appropriate amount of water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M16-3 (110 mg). ESI-MS m / z: 194 [M+H-56]. + .

[0165] Step 4: Synthesis of compound M16-4 Compound M16-3 (110 mg), (2S,4R)-1-((S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (229 mg), anhydrous copper sulfate (63.3 mg), and sodium ascorbate (227 mg) were dissolved in a mixture of 4.0 mL of tert-butanol, 4.0 mL of water, and 4.0 mL of THF and reacted at room temperature for 2 hours. The reaction mixture was extracted with an appropriate amount of water and a 10:1 DCM / MeOH solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give compound M16-4 (250 mg). ESI-MS m / z: 664 [M+H-56]. + .

[0166] Step 5: Synthesis of compound M16 Under N2 protection, compound M16-4 (250 mg) was dissolved in 5.00 mL of DCM, then 2.00 mL of TFA was added, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was added dropwise to saturated sodium bicarbonate solution, and extracted with an appropriate amount of DCM / MeOH = 10 / 1 solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M16 (150.0 mg). ESI-MS m / z: 620 [M + H] + .

[0167] Synthesis of intermediate M17: [ka]

[0168] Step 1: Synthesis of compound M17-1 M16-4 (100.0 mg) was dissolved in DCM (2.0 mL) in an ice bath, and triethylamine (0.046 mL), 4-dimethylaminopyridine (1.7 mg), and acetyl chloride (0.019 mL) were added sequentially. The mixture was allowed to react in an ice bath for 1 hour. The reaction mixture was extracted with an appropriate amount of water and DCM. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography to give 80 mg of compound M17-1. ESI-MS m / z: 762 [M+H] + .

[0169] Step 2: Synthesis of compound M17 M17-1 (80.0 mg) was dissolved in DCM (2.0 mL) in an ice bath, 1.00 mL of TFA was added, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was then directly concentrated, redissolved in 5.00 mL of DCM, and concentrated again to give 80 mg of the trifluoroacetate salt of the product, i.e., compound M17, which was used directly in the next step. ESI-MS m / z: 662 [M+H] + .

[0170] Synthesis of intermediate M18: [ka]

[0171] Step 1: Synthesis of compound M18-1 Methyl 4-fluorobenzoate (0.15 g) was added to a 25 mL one-neck flask and dissolved in DMSO (3 mL). tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate and DIPEA (0.48 mL) were added, and the mixture was heated to 100 ° C. and reacted overnight. After cooling to room temperature, 10 mL of water was added to the reaction mixture, and a solid precipitated. The solid was filtered, washed with water, and dried to obtain 0.2 g of compound M18-1.

[0172] Step 2: Synthesis of compound M18-2 Compound M18-1 (0.2 g) was placed in a 25 mL single-neck flask and dissolved in THF (1 mL). 4 M NaOH solution (1 mL) and MeOH (1 mL) were added, and the mixture was heated to 40°C and reacted for 3 hours. After cooling to room temperature, the reaction mixture was directly concentrated, 5 mL of water was added to the reaction mixture, and the pH of the solution was adjusted to 3-4 with 1 M HCl solution. A solid precipitated, which was then filtered. The filter cake was washed with water and dried to obtain 0.17 g of compound M18-2.

[0173] Step 3: Synthesis of compound M18-3 Compound M18-2 (140.0 mg) was added to a 25 mL single-neck flask and dissolved in DMF (3 mL). (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide hydrochloride (180.0 mg), DIPEA (0.13 mL), and HATU (231.0 mg) were added and reacted at room temperature for 2 hours. Saturated brine (5 mL) was added to the reaction mixture, followed by extraction with EA. The organic phase was dried over anhydrous sodium sulfate, and the product was separated by column chromatography (DCM:MeOH = 12:1) to obtain 276.0 mg of compound M18-3.

[0174] Step 4: Synthesis of compound M18 Compound M18-3 (276.0 mg) was placed in a 25 mL single-neck flask, dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was then evaporated to dryness, 5 mL of DCM was added, and the pH of the mixture was adjusted to 8-9 with 1 M NaOH solution. The mixture was extracted three times with DCM. The organic phase was washed with water and saturated brine, and evaporated to dryness to give 214.0 mg of compound M18.

[0175] Synthesis of intermediate M19: [ka]

[0176] The synthesis steps of M19 were prepared with reference to M18.

[0177] Synthesis of intermediate M20: [ka]

[0178] The synthesis steps of M20 were prepared with reference to M18.

[0179] Synthesis of intermediate M21: [ka]

[0180] Step 1: Synthesis of compound M21-1 The compound (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-N-((R)-1-(4-(1-ethyl-1H-pyrazol-5-yl)phenyl)-2-hydroxyethyl)-4-hydroxypyrrolidine-2-carboxamide (0.08 g), 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate tert-butyl (0.044 g) was added to tert-butanol (1 mL) and THF (1 mL), copper sulfate (28 mg), an aqueous solution of sodium ascorbate (105 mg) (1 mL) was added, and the mixture was allowed to react at 20 ° C. for 1 hour. The reaction mixture was poured into 15 mL of water, 15 mL of EA was added, the organic phase was separated, dried, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was purified by prep-TLC (MeOH:DCM=1:20) to give 78 mg of compound M21-1. ESI-MS m / z: 719.40 [M+H] + .

[0181] Step 2: Synthesis of compound M21 Compound M21-1 (78 mg) in DCM (2.0 mL) was added with trifluoroacetic acid (0.4 mL) and reacted at 20°C for 0.5 hours. The reaction mixture was added to 20 mL of saturated sodium bicarbonate, extracted with chloroform / isopropanol = 3:1, and the organic phase was separated. The organic phase was dried, filtered, and concentrated to obtain 65 mg of compound M21. This was directly used in the next step. ESI-MS m / z: 619.40 [M+H] + .

[0182] Synthesis of intermediate M22: [ka]

[0183] Step 1: Synthesis of compound M22-1 To a solution of 2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (0.1 g), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.178 g) in DMF (5 mL), HATU (169 mg), and DIPEA (145 mg) were added and the mixture was allowed to react at 20°C for 1 hour. The reaction mixture was added to 20 mL of water, and 15 mL of EA and 1 mL of methanol were added. The organic phase was separated, dried, filtered, and the filtrate was concentrated under reduced pressure to give 0.22 g of compound M22-1. This was directly used in the next step. ESI-MS m / z: 696.40 [M+H] + .

[0184] Step 2: Synthesis of compound M22 Compound M22-1 (240 mg) in DCM (6.0 mL) was added with trifluoroacetic acid (1.2 mL) and reacted at 20°C for 0.5 hours. The reaction mixture was added to 20 mL of saturated sodium bicarbonate, extracted with chloroform / isopropanol = 3:1, and the organic phase was separated. The organic phase was dried, filtered, and concentrated to obtain 200 mg of compound M22. This was directly used in the next step. ESI-MS m / z: 596.40 [M+H] + .

[0185] Synthesis of intermediate M23: [ka]

[0186] Step 1: Synthesis of compound M23-1 2-Chloro-5-iodopyridine (1 g) was added to a 50 mL three-neck flask, and 10 mL of TEA was added under N2 protection. Trimethylsilylacetylene (1.03 g), cuprous iodide (80 mg), and PdCl2(PPh3)2 (146 mg) were added, and the mixture was heated to 50 °C and reacted for 3 hours. The reaction mixture was filtered, and the filtrate was collected and directly concentrated. The concentrate was purified by column chromatography (PE:EA = 10:1) to obtain 0.85 g of compound M23-1. ESI-MS m / z: 210 [M+H] + .

[0187] Step 2: Synthesis of compound M23 Compound M23-1 (500 mg) was added to a 50 mL one-neck flask, dissolved in 5 mL of MeOH, and then anhydrous potassium carbonate (658 mg) was added and stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was collected and directly concentrated. The concentrate was purified by column chromatography (PE:EA = 20:1) to obtain 240 mg of compound M23. ESI-MS m / z: 138 [M+H] + .

[0188] Synthesis of intermediate M24: [ka]

[0189] Step 1: Synthesis of compound M24-1 Zinc powder (880 mg) and 80 mL of anhydrous tetrahydrofuran were added to a 250 mL three-necked flask, and under nitrogen gas protection, dibromomethane (200 mg) was added at room temperature, the temperature was raised to 65°C, and the reaction was carried out for 1 hour. After cooling to room temperature, TMSCl (115 mg) was added and the reaction was carried out for 1 hour at room temperature. tert-Butyl 3-iodoazetidine-1-carboxylate (3.0 g) was added and the reaction was carried out at 40°C for 1 hour, and the flask was sealed to obtain M24-1.

[0190] Step 2: Synthesis of compound M24-2 To the above M24-1 solution, methyl 4-bromobenzoate (1.1 g), Pd2(dba)3 (235 mg), and Johnphos (153 mg) were added in that order, and the mixture was reacted under nitrogen gas protection at 40°C for 2 hours. After completion of the reaction, the reaction was quenched with ammonium chloride, extracted with EA, washed with brine, dried over sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 10:1) to obtain compound M24-2 (660 mg).

[0191] Step 3: Synthesis of compound M24-3 Compound M24-2 (660 mg) was added to a 50 mL one-neck flask, and 10 mL of MeOH and 2 mL of water were added. Sodium hydroxide (410 mg) was added at room temperature, and the mixture was heated to 60° C. and reacted for 2 hours. After completion of the reaction, water was added to the reaction solution to adjust the pH to 6, extracted twice with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound M24-3 (550 mg).

[0192] Step 4: Synthesis of compound M24-4 Compound M24-3 (150 mg) was added to a 50 mL one-neck flask, 3 mL of DMF and HATU (250 mg) were added, and under nitrogen gas protection, DIPEA (350 mg) was added at 0 °C and the reaction was continued for 0.5 hours. (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (290 mg) was added, and the temperature was raised to room temperature and the reaction was continued for 1 hour. After completion of the reaction, the reaction was quenched with ammonium chloride, extracted twice with EA, washed with brine, dried over sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM:methanol = 10:1) to obtain compound M24-4 (340 mg). ESI-MS m / z: 704.3 [M+H] + .

[0193] Step 5: Synthesis of compound M24 Compound M24-4 (340 mg) was added to a 50 mL single-neck flask, 5 mL of DCM, and 1 mL of TFA were added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated, diluted with DCM, poured into sodium bicarbonate solution, extracted three times with DCM:MeOH (10:1), washed with brine, dried over anhydrous sodium sulfate, and concentrated to give compound M24 (250 mg). ESI-MS m / z: 604.3 [M+H] + .

[0194] Synthesis of intermediate M25: [ka]

[0195] Step 1: Synthesis of compound M25-1 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (100.0 mg), 4-(1-(((S)-1-((2S,4R)-4-hydroxy-2-((((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylic acid tert 174.0 mg of butyl ether and 149.4 mg of HATU were dissolved in 2 mL of DMF, 0.27 mL of DIPEA was added, and the mixture was allowed to react at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. 10 mL of DCM was added to the reaction mixture, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 231.0 mg of compound M25-1. ESI-MS m / z: 732 [M+H] + .

[0196] Step 2: Synthesis of compound M25 M25-1 (231.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, 1M NaOH (2 mL) was added, stirred at room temperature for 5 minutes, and filtered under vacuum to give 181.0 mg of a pale yellow solid, i.e., compound M25. ESI-MS m / z: 632 [M+H] + .

[0197] Synthesis of intermediate M26: [ka]

[0198] Step 1: Synthesis of intermediate M26-1 At room temperature, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g) was dissolved in DCM (50 mL), and then triethylamine (9.68 mL) and p-toluenesulfonyl chloride (5.31 g) were added successively. The mixture was reacted at room temperature for 15 hours. The reaction mixture was quenched by adding an appropriate amount of water, and then extracted with an appropriate amount of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8.02 g of the product, compound M26-1, which was used directly in the next step.

[0199] Step 2: Synthesis of intermediate M26-2 Intermediate M26-1 (7.0 g) and methyl 4-hydroxybenzoate (2.6 g) were dissolved in DMF (30.0 mL), potassium carbonate (4.72 g) was added, and the mixture was reacted at 60° C. for 10 hours. The reaction mixture was quenched by adding an appropriate amount of water, and then extracted with an appropriate amount of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain 4.02 g of the product, compound M26-2.

[0200] ESI-MS m / z: 350 [M+H] + .

[0201] Step 3: Synthesis of intermediate M26-3 Compound M26-2 (4.0 g) was dissolved in a mixed solution of THF (40.00 mL) and MeOH (40.00 mL), and sodium hydroxide (2.29 g) in water (20.0 mL) was added and reacted at 40°C for 1 hour. The reaction solution was cooled to room temperature, and then acidified with 1 M sulfuric acid. An appropriate amount of DCM / MeOH was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3.50 g of product intermediate M26-3.

[0202] ESI-MS m / z: 336 [M+H] + .

[0203] Step 4: Synthesis of intermediate M26-4 Intermediate M26-3 (1.00 g), (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.59 g) were dissolved in 15.00 mL of DMF, followed by N,N-diisopropylethylamine (1.56 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.36 g). The reaction mixture was reacted at room temperature for 30 minutes and monitored for completion by LCMS. 100.0 mL of water was added to the reaction mixture, and the solid precipitated in the system was filtered. This solid was purified by column chromatography to give 1.95 g of intermediate M26-4.

[0204] ESI-MS m / z: 762 [M+H] + .

[0205] Step 5: Synthesis of intermediate M26 Intermediate M26-4 (1.50 g) was dissolved in 20.00 mL of DCM, and 5.00 mL of TFA was added. The mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was added dropwise to saturated sodium bicarbonate solution, and extracted with an appropriate amount of DCM / MeOH=10 / 1 solution. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1.20 g of intermediate M26.

[0206] ESI-MS m / z: 662 [M+H] + .

[0207] Synthesis of intermediate M27: [ka]

[0208] Step 1: Synthesis of compound M27-1 To a solution of compound M11-6 (600 mg) in DMF (15 mL), dimethylamine (191 mg), DIPEA (1.76 mL), and HATU (973 mg) were added sequentially and stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was extracted with EA and water. The organic phase was collected, extracted twice with EA, combined, and washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM:EA = 3:1) to give 580 mg of compound M27-1.

[0209] ESI-MS m / z: 309.3 [M+H] + .

[0210] Step 2: Synthesis of compound M27 M27-1 (580 mg) was dissolved in HCl / dioxane (4N, 5 mL) and stirred at room temperature for 0.5 hours. After completion of the reaction, the reaction solution was concentrated to give intermediate M27 (390 mg). ESI-MS m / z: 209.3 [M+H] + .

[0211] Synthesis of intermediate M28: (R)-1-(((7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde [ka]

[0212] Step 1: Synthesis of compound M28-1 Intermediate M2 (5.0 g) was dissolved in DCM (20 mL) and cooled to approximately -40 °C. DIPEA (7.7 g) was added and stirred at low temperature for 30 minutes. (3R)-3-Methylpiperidin-3-ol hydrochloride (4.2 g) was slowly added and the reaction was continued with stirring for 1.0 hour. After the reaction was complete, the mixture was extracted with DCM and HO, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried by rotary evaporation, and purified by column chromatography (EA:DCM 10%) to give compound M28-1 (5.3 g).

[0213] ESI-MS m / z: 331.3 [M+H] + .

[0214] Step 2: Synthesis of compound M28-2 Compound M28-1 (5.3 g), cesium carbonate (10.4 g), DABCO (0.4 g), and 1,1-cyclopropane dimethanol (3.3 g) were dissolved in DMF (20 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with EA and HO, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and purified by rotary evaporation. Compound M28-2 (5.0 g) was obtained by column chromatography (EA:DCM 18%).

[0215] ESI-MS m / z: 397.1 [M+H] + .

[0216] Step 3: Synthesis of compound M28-3 Compound M28-2 (5.0 g), M5 (9.0 g), 3.5 g of potassium carbonate, and CataCxium A Pd G3 (1.3 g) were dissolved in 1,4-dioxane (24 mL) and HO (4 mL) and reacted at 90 °C for 1 hour under a nitrogen gas protective atmosphere. After the reaction was complete, the reaction mixture was diluted with EA and HO, extracted once with EA, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (dichloromethane:ammonia / methanol) to give M28-3 (6.0 g, 85% purity), which was used directly in the next step. ESI-MS m / z: 595.2 [M+H] + .

[0217] Step 4: Synthesis of compound M28 To a solution of compound M28-3 (6.0 g) in DCM (50 mL), DMP (6.4 g) was added in portions and stirred at room temperature for 3.0 hours. After the reaction was complete, the mixture was quenched with saturated sodium sulfite, extracted with DCM and HO, and the aqueous phase was further extracted twice with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and purified by rotary evaporation. Compound M28 (3.4 g) was obtained by column chromatography (PE:EA 50%).

[0218] ESI-MS m / z: 593.4 [M+H] + .

[0219] Synthesis of intermediate M29: Synthesis of the compound (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0220] Step 1: Synthesis of compound M29-1 (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylamine (12.7 g), Boc-L-hydroxyproline (13.5 g), and HATU (23.2 g) were dissolved in DMF (100 mL), DIPEA (38.5 mL) was added, and the reaction was allowed to proceed at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. EA (100 mL) and saturated brine (100 mL) were added to the reaction mixture, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 22.0 g of a white solid, i.e., compound M29-1.

[0221] ESI-MS m / z: 432 [M+H] + .

[0222] Step 2: Synthesis of compound M29-2 M29-1 (22.0 g) was added to DCM (100 mL), and a solution of hydrochloric acid in dioxane (100 mL) was added under ice-water bath conditions. The reaction was allowed to proceed at room temperature for 60 minutes, and the completion of the reaction was monitored by LCMS. The reaction mixture was directly concentrated, and 1 M NaOH solution was added until the reaction mixture reached pH 8. DCM (100 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 16.8 g of a white solid, i.e., compound M29-2.

[0223] ESI-MS m / z: 332 [M+H] + .

[0224] Step 3: Synthesis of compound M29-3 M29-2 (19.0 g), Boc-L-valine (12.5 g), and HATU (22.9 g) were dissolved in DMF (100 mL), DIPEA (28.4 mL) was added, and the mixture was allowed to react at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. EA (100 mL) and saturated brine (100 mL) were added to the reaction mixture, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 25.0 g of a white solid, i.e., compound M29-3.

[0225] ESI-MS m / z: 531 [M+H] + .

[0226] Step 4: Synthesis of compound M29-4 M29-3 (25.0 g) was added to DCM (100 mL), and a solution of hydrochloric acid in dioxane (100 mL) was added under ice-water bath conditions. The reaction was allowed to proceed at room temperature for 60 minutes, and the completion of the reaction was monitored by LCMS. The reaction mixture was directly concentrated, and 1 M NaOH solution was added until the reaction mixture reached pH 8. DCM (100 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 17.0 g of a white solid, i.e., compound M29-4.

[0227] ESI-MS m / z: 431 [M+H] + .

[0228] Step 5: Synthesis of compound M29 M29-4 (17.0 g) and TEA (32.9 mL) were dissolved in ACN (100 mL) and THF (130 mL). 2-Azido-1,3-dimethylimidazolium hexafluorophosphate (22.5 g) was dissolved in ACN (30 mL) and slowly added to the mixture under ice-water bath. The temperature was maintained for 3 hours, and the reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and DCM (100 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 15.3 g of a pale yellow powder, i.e., compound M29.

[0229] ESI-MS m / z: 457 [M+H] + .

[0230] 1H NMR(500MHz,MeOD)δ8.87(s,1H),7.46-7.40(m,4H),7.94(q,J=7.0Hz,1H),4.64-4.60(m,1H),4.45-4.44(m,1H),3.75(d,J= 8.0Hz,1H),3.71-3.64(m,2H),2.48(s,3H),2.26-2.15(m,2H),1.96-1.91(m,1H),1.52(d,J=7.0Hz,3H),1.09-0.98(m,6H).

[0231] Synthesis of intermediate M30 [ka]

[0232] Step 1: Synthesis of compound M30-1 Under a nitrogen atmosphere, 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20 g) in DCM (300 mL) was added dropwise with stirring at -78 °C for 30 min. The mixture was then warmed to room temperature and stirred for 2 h. After confirming the disappearance of the starting material by TLC, the mixture was cooled to 0 °C, MeOH (300 mL) and 1 M HCl (200 mL) were added, and the mixture was stirred at room temperature for 2 h. Completion of the reaction was confirmed by TLC. After completion of the reaction, the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated. Purification by column chromatography afforded a pale yellow liquid (13.9 g), i.e., compound M30-1.

[0233] Step 2: Synthesis of compound M30-2 M30-1 (13.9 g) was dissolved in 140 mL of DMF, and imidazole (4.5 g) was added at 0 °C. TBDPSCl (17.2 mL) was then added dropwise. After the addition was complete, the mixture was cooled to room temperature and stirred for 3 h. The reaction was monitored for completion by TLC. After the reaction was complete, 100 mL of water was added to the reaction mixture, and the mixture was extracted with EA three times, each time with 200 mL of water. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound M30-2 (21.09 g), a pale yellow liquid.

[0234] Step 3: Synthesis of compound M30-3 M30-2 (21.09 g) was dissolved in 140 mL of DCM, the reaction mixture was cooled to -35°C, TMSCN (7.48 mL) was added, and the mixture was stirred at -35°C for 15 minutes. TMSOTf (0.14 mL) was added dropwise, and the mixture was stirred at -35°C for 10 minutes. After monitoring the completion of the reaction by TLC, saturated sodium bicarbonate:water (15 mL:90 mL) was added, and the mixture was stirred for 15 minutes. The mixture was extracted with EA (200 mL each time) three times. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 16.2 g of a yellow liquid, i.e., compound M30-3.

[0235] Step 4: Synthesis of compound M30-4 M30-3 (16.2 g) and K2CO3 (7.55 g) were mixed in MeOH (120 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was acidified with 1 M aqueous HCl to pH = 2, and the resulting mixture was stirred at room temperature for 3 hours, after which TLC confirmed the completion of the reaction. The mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by column chromatography to give a yellow liquid (8.5 g), namely compound M30-4.

[0236] Step 5: Synthesis of compound M30-5 M30-4 (8.5 g) was dissolved in THF (85 mL) and a solution of LiHMDS in tetrahydrofuran (34.16 mL) was added dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 10 minutes, and then 3-chloro-2-(chloromethyl)propene (3.95 mL) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours, and the completion of the reaction was monitored by LC-MS. The mixture was quenched with water at 0° C. and then extracted with EA. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to give a yellow liquid (5 g), i.e., compound M30-5.

[0237] Step 6: Synthesis of compound M30-6 To a solution of M30-5 (5 g) in DCM (40 mL) was added TFA (20 mL) dropwise, and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and evaporated with DCM. The residue was dissolved in MeOH (40 mL), and K2CO3 (10 g) was added. The mixture was stirred at room temperature for 40 minutes, and after the completion of the reaction was confirmed by LC-MS, it was quenched with water at room temperature. The mixture Extracted with EA, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated and purified by column chromatography to give a yellow liquid (3.04 g), compound M30-6.

[0238] Step 7: Synthesis of compound M30 A 1 M solution of LiAlH4 in THF (6.8 mL) was added dropwise to a solution of M30-6 (3.04 g) in THF (30 mL) under a nitrogen atmosphere at -20 °C. The resulting mixture was stirred at 0 °C for 20 min, and the completion of the reaction was confirmed by LC-MS. Sodium sulfate decahydrate was then added at 0 °C and stirred for 30 min. The mixture was filtered, washed with EA, concentrated, and purified by neutral alumina column chromatography to give a yellow liquid (2 g), i.e., compound M30.

[0239] Intermediate M31: Synthesis of compound (R)-1-(7-(8-ethyl-7-fluoro-3-methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-((5S,7aS)-5-hydroxymethyl-2-methylenetetrahydro-1H-pyrrolidine-7a(5H)-methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol [ka]

[0240] Step 1: Synthesis of compound M31-1 In a 100 mL single-neck flask, M28-2 (2.90 g) was dissolved in tetrahydrofuran (30.0 mL), sodium hydride (1.40 g) was added, and the mixture was stirred for 10 minutes. M30 (4.43 g) was added, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction mixture was quenched by adding an appropriate amount of saturated aqueous ammonium chloride solution, extracted three times with dichloromethane, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was evaporated, and the product was separated by column chromatography to obtain 5.30 g of a yellow solid, compound M31-1.

[0241] Step 2: Synthesis of compound M31-2 Compound M31-1 (5.0 g), M5 (2.62 g), CataCXium A Pd G3 (0.40 g), and potassium phosphate (3.56 g) were added in this order to a 100 mL single-neck flask, dissolved in 1,4-dioxane (50.0 mL) and water (5.0 mL), purged with nitrogen gas two to three times, and reacted at 100 °C for three hours. An appropriate amount of water was added to the reaction solution, which was then extracted three times with ethyl acetate. The organic phase was collected and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the product was separated by column chromatography to obtain 4.5 g of a yellow solid, compound M31-2.

[0242] Step 3: Synthesis of intermediate M31 Compound M31-2 (4.50 g) was placed in a 100 mL single-neck flask and dissolved in dichloromethane (50 mL). Triethylamine hydrofluoride (10 mL) was added and the mixture was allowed to react for 0.5 hours in an ice bath. The reaction mixture was extracted three times with 5 mL of methanol and 50 mL of water, washed with saturated brine, and the organic phase was collected and evaporated to dryness. The product was separated by column chromatography to obtain 2.3 g of intermediate M31 as a yellow solid.

[0243] Intermediate M32: Synthesis of compound ((3S,7aS)-7a-((7-(8-ethyl-7-fluoro-3-methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methyl(4-nitrophenyl)carbonate [ka]

[0244] Step 1: Synthesis of compound M32 Compound M31 (100.0 mg), triethylamine (30.0 mg), DMAP (5.0 mg), and p-nitrophenyl chloroformate were added to a 10 mL one-neck flask, and tetrahydrofuran (4.00 mL) was added. The mixture was stirred at 20°C for 18 hours. The disappearance of the raw materials was monitored by LCMS, and the reaction was completed. The reaction mixture M32 was used directly in the next reaction.

[0245] Intermediate M33: Synthesis of compound (R)-2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)acetaldehyde [ka]

[0246] Step 1: Synthesis of compound M33-1 Compound M28-2 (2.50 g), acetonitrile (40.00 mL), 2,2-dimethoxyethanol (1.20 g), cesium carbonate (3.20 g), and triethylenediamine (0.08 g) were added to a reaction flask and reacted at room temperature for 2 hours. The solvent was first concentrated, diluted with water, extracted with EA, dried, and concentrated. The product was separated by column chromatography (DCM:EA = 3:1) to obtain yellow oily substance M33-1 (2.3 g). ESI-MS m / z: 401.28 [M+H] + .

[0247] Step 2: Synthesis of compound M33-2 A reaction flask was charged with 2-[8-ethyl-7-fluoro-3-methoxymethoxynaphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.24 g), compound M33-2 (2.25 g), [di(1-adamantyl)-n-butylphosphine]-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate (0.61 g), potassium phosphate (2.98 g), and 1,4-dioxane (36.00 mL). The atmosphere was purged with nitrogen gas, and the reaction was carried out at 100 °C for 3 hours under nitrogen gas protection. The mixture was diluted with water, extracted with EA, dried, and concentrated. The product was separated by column chromatography (DCM:EA = 3:1) to give a yellow oil, M33-2 (3.3 g). ESI-MS m / z: 599.45 [M+H] + .

[0248] Step 3: Synthesis of compound M33 Compound M33-2 (2.50 g), 1,4-dioxane (15.00 mL), and concentrated hydrochloric acid (9.00 mL) were added to a reaction flask and reacted at room temperature for 1 hour. The pH was adjusted to 8 with aqueous sodium bicarbonate in an ice bath, extracted with EA and THF, dried, and concentrated to give a yellow solid, M33 (2.15 g). ESI-MS m / z: 509.19 [M+H]. + .

[0249] Synthesis of intermediate M34 [ka]

[0250] Step 1: Synthesis of compound M34-1 3-Butyn-1-ol (140 g) and potassium bicarbonate (150 g) were added to a 3L single-neck flask containing ethyl acetate / water (1000 / 100 mL) with stirring. Then, 1,1-dibromoformaldoxime (100 g) was dissolved in ethyl acetate (250 mL) and added dropwise to the 3L single-neck flask. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water. The organic phase was separated and collected. The aqueous phase was extracted once with ethyl acetate. The organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 5:1) to give compound M34-1 (93 g, 97% yield). ESI-MS m / z: 191.9 [M+H]. + .

[0251] Step 2: Synthesis of compound M34-2 Compound M34-1 (93 g) was added to a 3 L single-neck flask, and acetone (1100 mL) was added. Jones reagent (450 mL) was then added dropwise to the reaction mixture at 0 °C. The mixture was then warmed to room temperature and stirred for 12 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected and extracted once with ethyl acetate. The organic phases were collected, combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated to give compound M34-2 (60 g, 60% yield) as a yellow oil. ESI-MS m / z: 205.9 [M+H] + .

[0252] Step 3: Synthesis of compound M34-3 Compound M34-2 (60 g) was added to a 1 L single-neck flask, methanol (500 mL) was added, and 5 mL of concentrated sulfuric acid was slowly added dropwise in an ice bath. The mixture was heated to 70 °C and reacted for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The organic phases were collected and combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 10:1) to give compound M34-3 (49 g, 76% yield). ESI-MS m / z: 219.9 [M+H] + .

[0253] Step 4: Synthesis of compound M34-4 Compound M34-3 (49 g) was added to a 1 L single-neck flask, and tetrahydrofuran (500 mL) was added. Potassium tert-butoxide (45 g) was then added. 2-iodopropane (49 g) was added dropwise in an ice bath, and the mixture was allowed to warm to room temperature and react for 16 hours. After the reaction was complete, the mixture was quenched with an ice-water mixture, followed by extraction with ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The organic phases were collected and combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 100:1) to give compound M34-4 (32 g, 55% yield). ESI-MS m / z: 262.0 [M+H] + .

[0254] Step 5: Synthesis of compound M34-5 Compound M34-4 (32 g) was added to a 1 L single-neck flask, and methanol (250 mL) and potassium hydroxide (73 g) were added. Potassium tert-butoxide (45 g) was then added and the mixture was refluxed and stirred for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, adjusted to pH 5 with 1N HCl solution, concentrated, and purified by reverse-phase column chromatography (5%-40% ACN / water (0.1% trifluoroacetic acid)) to obtain compound M34-5 (21 g, 86% yield). ESI-MS m / z: 200.1 [M+H]+.

[0255] Step 6: Synthesis of compound M34-6 Compound M34-5 (21 g) was added to a 500 mL one-neck flask, and acetic acid (150 mL) and 33% aqueous hydrogen bromide solution (150 mL) were added. The mixture was heated to 60 °C and stirred for 10 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure. The concentrate was dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated to give compound M34-6 (15 g, 77% yield). SI-MS m / z: 186.0 [M+H]+.

[0256] Step 7: Synthesis of compound M34-7 Compound M34-6 (15 g) was added to a 500 mL single-neck flask, methanol (150 mL) was added, and thionyl chloride (75 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic phase was collected and extracted once with ethyl acetate. The organic phases were collected and combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM:MeOH = 100:1) to give compound M34-7 (11 g, 69% yield). ESI-MS m / z: 200.1 [M+H] + .

[0257] Step 8: Synthesis of compound M34 Compound M34-7 (7 g) was added to a 500 mL single-neck flask, acetonitrile (75 mL) was added, potassium carbonate (10 g) was added in portions, and perfluorobutanesulfonyl fluoride (14 g) was slowly added dropwise. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected and extracted once with ethyl acetate. The organic phases were combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:THF = 100:1) to give compound M34 (14.5 g, 80% yield).

[0258] ESI-MS m / z: 482.0 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ7.02(s,1H),4.01(d,J=7.9Hz,1H),3.69(s,3H),2.37(dq,J=13.6,6.8Hz,1H),0.93(d,J=6.7Hz,3H),0.85(d,J=6.7Hz,3H).

[0259] Synthesis of intermediate M35 [ka]

[0260] Step 1: Synthesis of compound M35-1 Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (450.0 mg), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (1.57 g), and potassium carbonate (936.7 mg) were dissolved in DMF (10 mL) and reacted at 50 °C for 5 hours. Completion of the reaction was monitored by LCMS, and DCM (10 mL) was added to the reaction mixture, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 237.1 mg of a white solid, i.e., compound M35-1. ESI-MS m / z: 341.5 [M+H] + .

[0261] Step 2: Synthesis of compound M35-2 M35-1 (237.1 mg) was added to methanol (4 mL) and water (1 mL), and lithium hydroxide monohydrate (125.4 mg) was added. The reaction was allowed to proceed at room temperature for 1 hour, and the completion of the reaction was monitored by LCMS. The pH of the reaction mixture was adjusted to acidic, EA (20 mL) was added, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 200.0 mg of a white solid, i.e., compound M35-2. ESI-MS m / z: 283.5 [M+H] + .

[0262] Step 3: Synthesis of compound M35-3 M35-2 (200.0 mg), M29-2 (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (218.4 mg), and HATU (250.5 mg) were dissolved in DMF (5 mL), DIPEA (0.45 mL) was added, and the reaction was allowed to proceed at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. EA (20 mL) and saturated brine (20 mL) were added to the reaction mixture, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 300.0 mg of a white solid, i.e., compound M35-3. ESI-MS m / z: 696.9 [M+H] + .

[0263] Step 4: Synthesis of compound M35-4 M35-3 (300.0 mg) was separated by SFC and concentrated to give 135.0 mg of a white solid, i.e., compound M35-4. ESI-MS m / z: 696.9 [M+H] + .

[0264] Step 5: Synthesis of compound M35 M35-4 (135.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 109.0 mg of a white solid, i.e., compound M35. ESI-MS m / z: 596.9 [M+H] + .

[0265] Synthesis of intermediate M36 [ka]

[0266] Step 1: Synthesis of compound M36-1 Compound tert-butyl piperazine-1-carboxylate (2.55 g) was added to N,N-dimethylacetamide (150 mL), followed by triethylamine (5.2 mL). The reaction was heated to 145°C and stirred for 0.5 h. Finally, M34 (6.0 g) was added. The mixture was stirred at 145°C for 5 h. The reaction was monitored for completion by LCMS. After dilution with H2O, the mixture was extracted twice with EA. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded a pale yellow solid (4.2 g), which was identified as compound M36-1. ESI-MS m / z: 368.1 [M+H] + .

[0267] Step 2: Synthesis of compound M36-2 To compound M36-1 (4.2 g), tetrahydrofuran (5 mL), methanol (5 mL), water (5 mL), and lithium hydroxide monohydrate (1.0 g) were added. The mixture was stirred at 20°C for 1 hour. The completion of the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, adjusted to pH 5 with dilute hydrochloric acid, and extracted twice with dichloromethane / isopropanol = 5 / 1. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was used directly in the next step. A pale yellow solid (3.6 g) was obtained, which was compound M36-2. ESI-MS m / z: 354.3 [M+H] + .

[0268] Step 3: Synthesis of compound M36-4 Compounds M36-2 (3.5 g) and M29-2 (3.3 g) were added to a 25 mL one-neck flask, and N,N-dimethylacetamide (30.00 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (7.6 g), and N,N-diisopropylethylamine (4.9 mL) were added. The mixture was stirred at 20 °C for 0.5 h. The reaction was monitored for completion by LCMS. The mixture was diluted with HO and extracted twice with EA. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. The crude product M36-3 was separated by SFC to give a pale yellow solid (3.4 g), i.e., compound M36-4. ESI-MS m / z: 667.2 [M+H] + .

[0269] Step 4: Synthesis of compound M36 Compound M36-4 (80.0 mg) was added to a 10 mL one-neck flask, and dichloromethane (2.00 mL) and hydrochloric acid (4 M in dioxane) (1.00 mL) were added. The mixture was stirred at 20 °C for 0.5 hours. The completion of the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO3 solution, extracted twice with dichloromethane / isopropanol = 5 / 1, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was used directly in the next step. A pale yellow solid (73.0 mg) was obtained, which was compound M36. ESI-MS m / z: 567.3 [M+H] + .

[0270] Synthesis of intermediate M37 [ka]

[0271] Step 1: Synthesis of compound M37-1 A 50 mL flask was charged with 5-ethynyl-2-fluoropyridine (500 mg), 1-tert-butoxycarbonyl-piperazine (922 mg), acetone (5 mL), and DIPEA (1.6 g), and the mixture was heated to 60°C for 5 hours. After the solvent was distilled off, EA was added to dissolve the residue, washed with water, washed with brine, dried over sodium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound M37-1 (1.02 g).

[0272] Step 2: Synthesis of compound M37-2 A 50 mL flask was charged with M37-1 (200 mg), M29 (250 mg), sodium ascorbate (226 mg), copper sulfate (108 mg), tert-butanol 3 mL, THF 3 mL, and water 3 mL, and the mixture was reacted at room temperature for 1 hour. Completion of the reaction was detected, and EA was added for extraction. The organic phase was washed with water, washed with brine, dried over sodium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain compound M37-2 (198 mg).

[0273] Step 3: Synthesis of compound M37 M37-2 (198 mg) and 4 M hydrogen chloride in dioxane (5 mL) were placed in a 50 mL flask and reacted at room temperature for 1 hour, and the solvent was distilled off under reduced pressure to obtain about 200 mg of crude product M37.

[0274] Synthesis of intermediate M38 [ka]

[0275] Step 1: Synthesis of compound M38-1 7-tert-Butoxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (500.0 mg) was dissolved in 5.0 mL of THF, and borane tetrahydrofuran solution (4.64 mL, 1 mol / L) was added. The mixture was allowed to react at room temperature for 1 hour. 5 mL of HCl / MeOH solution was slowly added to the reaction mixture, and the mixture was stirred until no more bubbles were generated. After that, 1 mol / L NaOH solution was added to adjust the pH to alkaline. Then, an appropriate amount of ethyl acetate was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M38-1 (450.0 mg). ESI-MS m / z: 200 [M+H-56]. + .

[0276] Step 2: Synthesis of compound M38-2 M38-1 (250.0 mg) was dissolved in 5.0 mL of DCM, Dess-Martin reagent (387.0 mg) was added, and the mixture was allowed to react at room temperature for 1 hour. An appropriate amount of ethyl acetate was added to the reaction mixture, and the precipitated solid was removed by filtration. The filtrate was adjusted to alkaline pH with 1 mol / L NaOH solution, extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M38-2 (180.0 mg). ESI-MS m / z: 198 [M+H-56]. + .

[0277] Step 3: Synthesis of compound M38-3 Under N2 protection, compound M38-2 (180 mg) was dissolved in 3.0 mL of anhydrous methanol, and anhydrous potassium carbonate (167 mg) and dimethyl (1-diazo-2-oxopropyl)phosphonate (174 mg) were added. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was extracted with an appropriate amount of water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound M38-3 (110 mg). ESI-MS m / z: 194 [M+H-56]. + .

[0278] Step 4: Synthesis of compound M38-4 Compound M29 (200 mg) and compound M38-3 (131 mg) were dissolved in a mixed solvent of tert-butanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Anhydrous copper sulfate (63 mg) and sodium ascorbate (226 mg) were added and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was dried using a rotary evaporator, extracted with DCM and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated. The mixture was then purified by column chromatography (DCM / MeOH = 15:1) to give compound M38-4 (295 mg). ESI-MS m / z: 706 [M+H] + .

[0279] Step 5: Synthesis of compound M38 Compound M38-4 (295 mg) was dissolved in 6 mL of DCM and 3 mL of hydrogen chloride in dioxane (4 mol / L) and reacted at room temperature for 0.5 hours. The reaction mixture was dried on a rotary evaporator, extracted with DCM / isopropanol (3:1) and saturated sodium bicarbonate solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound M38 (240 mg). ESI-MS m / z: 606 [M+H] + .

[0280] Intermediate M39 was prepared by referring to the preparation method of 176-4 in Example 176 of WO2023138524A1. [ka]

[0281] Synthesis of intermediate M40 [ka]

[0282] Step 1: Synthesis of compound M40-1 Compound (S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)propionic acid (1.5 g) was added to a 50 mL one-neck flask and dissolved in DMF (15 mL). Iodomethane (0.74 g) and potassium carbonate (1.2 g) were added, and the mixture was allowed to react at room temperature for 2 hours. Saturated brine (5 mL) was added to the reaction solution, followed by extraction with EA. The organic phase was dried over anhydrous sodium sulfate to obtain 1.4 g of a yellow solid, compound M40-1.

[0283] Step 2: Synthesis of compound M40-2 Compound M40-1 (1.4 g) was placed in a 50 mL one-neck flask and dissolved in DMF (20 mL). 4-methylthiazole (1.2 g), potassium acetate (1.2 g), and palladium acetate (0.1 g) were added, and the mixture was heated to 80°C under nitrogen gas protection for 5 hours. Saturated brine (5 mL) was added to the reaction solution, which was then extracted with EA. The organic phase was dried over anhydrous sodium sulfate, and the product was separated by column chromatography (PE:EA = 4:1) to obtain 0.82 g of a yellow solid, compound M40-2.

[0284] Step 3: Synthesis of compound M40 Compound M40-2 (0.82 g) was placed in a 25 mL one-neck flask, dissolved in 4 M hydrogen chloride dioxane solution (20 mL), and methanol (1 mL) was added, followed by reaction at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 0.55 g of compound M40 as a yellow solid.

[0285] Synthesis of intermediate M42 [ka]

[0286] Step 1: Synthesis of compound M42-1 Compound tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.00 g, 23.22 mmol), TEA (6.46 mL, 46.45 mmol), and TsCl (6.64 g, 34.84 mmol) were added to DCM (50.00 mL) in that order and reacted at room temperature for 16 hours. 80 mL of ice water was added to the reaction mixture, which was then extracted twice with DCM (100.00 mL), washed twice with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (PE:EA = 85%:15%) to obtain compound M42-1 (8.00 g, 93.23%).

[0287] ESI-MS m / z: 270.16 [M+H] + .

[0288] Step 2: Synthesis of compound M42-2 Compound M42-1 (8000.00 mg, 21.65 mmol), p-hydroxybenzaldehyde (2908.62 mg, 23.82 mmol), and cesium carbonate (21164.30 mg, 64.96 mmol) were added to DMF (80.00 mL) and reacted at 80 °C for 2 hours. Water was added to the reaction mixture, and the product precipitated. The product was filtered, washed with water, and dried to obtain compound M42-2 (6100.00 mg, 88.21%). ESI-MS m / z: 220.15 [M+H] + .

[0289] Step 3: Synthesis of compound M42-3 Compound M42-2 (3.00 g, 9.39 mmol) and potassium carbonate (2.60 g, 18.79 mmol) were added to methanol (30.00 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.83 mL, 12.21 mmol) was added with stirring. The mixture was allowed to react at room temperature for 6 hours. The reaction mixture was concentrated, 50 mL of water was added, and the mixture was extracted twice with EA (100.00 mL). The extract was dried over anhydrous sodium sulfate and separated by column chromatography (PE:EA = 90%:10%) to give compound M42-3 (2.30 g, 77.64%).

[0290] ESI-MS m / z: 216.19 [M+H]+ .

[0291] Step 4: Synthesis of compound M42-4 Compound M42-3 (276.36 mg, 0.88 mmol), M29 (200.00 mg, 0.44 mmol), copper sulfate (62.93 mg, 0.39 mmol), sodium ascorbate (225.66 mg, 1.14 mmol), water (2.00 mL), and tert-butanol (2.00 mL) were added sequentially to tetrahydrofuran (2.00 mL) and reacted at room temperature for 2 hours. The reaction mixture was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM (80.00 mL), dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 95%:5%) to give compound M42-4 (300.00 mg, 88.71%).

[0292] ESI-MS m / z: 772.52 [M+H] + .

[0293] Step 5: Synthesis of compound M42 Compound M42-4 (300.00 mg, 0.39 mmol) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) in that order and reacted at room temperature for 1 hour. The reaction mixture was adjusted to alkaline by adding saturated aqueous sodium bicarbonate, extracted twice with DCM (80.00 mL), dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 93%:7%) to obtain compound M42 (130.00 mg, 49.79%).

[0294] ESI-MS m / z: 672.72 [M+H] + .

[0295] Synthesis of intermediate M43 [ka]

[0296] Step 1: Synthesis of compound M43-1 Compound M28-3 (16.5 g) was dissolved in DCM (200 mL), and DMP (18.4 g) was added slowly in portions at 0 ° C. The mixture was allowed to warm to room temperature and react for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with DCM, and the organic phase was washed with saturated saline and purified by column chromatography to give compound M43-1 (9.5 g). ESI-MS m / z: 395.2 [M+H] + .

[0297] Step 2: Synthesis of compound M43 Compound M43-1 (9.5 g), M6 (15.21 g), [di(1-adamantyl)-n-butylphosphine]-2-(2'-amino-1,1'-biphenyl)palladium (3.50 g), and potassium phosphate (15.3 g) were added to 1,4-dioxane (100.00 mL) and water (25 mL). The mixture was reacted at 90 °C for 1.5 hours under nitrogen gas protection. After the reaction was completed, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and purified by column chromatography to obtain compound M43 (8.5 g). ESI-MS m / z: 549.1 [M+H] + .

[0298] Synthesis of intermediate M44 [ka]

[0299] Step 1: Synthesis of compound M44-1 A reaction flask was charged with commercially available tert-butyl N-((1R)-1-(4-bromophenyl)-2-hydroxyethyl)carbamate (2.50 g), 4-methylthiazole (1.57 g), palladium acetate (0.18 g), potassium acetate (1.55 g, 15.81 mmol), and N,N-dimethylacetamide (40.00 mL). The mixture was purged with nitrogen gas and reacted at 100 °C for 10 h under nitrogen gas protection. The mixture was diluted with HO (100 mL) and extracted twice with EA (80 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (DCM:ammonia / methanol = 20:1) to give compound M44-1 (2.01 g) as a yellow solid. ESI-MS m / z: 335.29 [M+H] + .

[0300] Step 2: Synthesis of compound M44-2 Compound M44-1 (2.01 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (10.00 mL) was added while stirring at 0°C. The mixture was allowed to react at room temperature for 1 hour, and the solvent was concentrated to give crude yellow solid product M44-2 (1.85 g). ESI-MS m / z: 218.21 [M-OH] + .

[0301] Step 3: Synthesis of compound M44-3 Compound M44-2 (1.50 g), commercially available (2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid (1.48 g), N,N-dimethylformamide (25.00 mL), and N,N-diisopropylethylamine (3.17 mL) were added to a reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.16 g) was added with stirring and reacted at room temperature for 0.5 h. The mixture was diluted with saturated brine and extracted with EA. The aqueous phase was extracted with EA:isopropanol = 9:1. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was isolated by column chromatography (DCM:ammonia / methanol = 15:1) to give yellow solid M44-3 (2.02 g). ESI-MS m / z: 448.20 [M+H] + .

[0302] Step 4: Synthesis of compound M44-4 Compound M44-3 (2.02 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (10.00 mL) was added while stirring at 0°C. The mixture was allowed to react at room temperature for 1 hour, and the solvent was concentrated to give crude yellow solid product M44-4 (1.86 g). ESI-MS m / z: 348.18 [M+H] + .

[0303] Step 5: Synthesis of compound M44-5 Compound M44-4 (1.55 g), commercially available (2S)-3-methyl-2-((2-methylpropan-2-yl)oxycarbonylamino)butanoic acid (1.07 g), N,N-dimethylformamide (20.00 mL), and N,N-diisopropylethylamine (2.21 mL) were added to a reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.21 g) was added with stirring and reacted at room temperature for 0.5 h. The mixture was diluted with saturated brine and extracted with EA. The aqueous phase was extracted with EA:isopropanol = 9:1. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was isolated by column chromatography (DCM:ammonia / methanol = 15:1) to give yellow solid M44-5 (2.01 g). ESI-MS m / z: 547.30 [M+H] + .

[0304] Step 6: Synthesis of compound M44-6 Compound M44-5 (2.01 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (10.00 mL) was added while stirring at 0 °C. The mixture was allowed to react at room temperature for 1 hour, the solvent was concentrated, and the pH was adjusted to 8 with aqueous sodium bicarbonate in an ice bath. The mixture was purified using a reverse-phase column (MeOH / HO = 95%:5%) to obtain a pale yellow solid, M44-6 (1.5 g). ESI-MS m / z: 447.30 [M+H] + .

[0305] Step 7: Synthesis of compound M44 Compound M44-6 (1.50 g), tetrahydrofuran (15.00 mL), acetonitrile (7.50 mL), and triethylamine (1.87 mL) were added to a reaction flask and cooled to 0 °C. 2-Azido-1,3-dimethylimidazolium hexafluorophosphate (1.91 g, 6.72 mmol) was dissolved in acetonitrile (7.50 mL) and slowly added to the reaction mixture. After the addition was complete, the mixture was allowed to react at this temperature for 1 hour. An appropriate amount of saturated brine was added to the reaction mixture, and the mixture was extracted with EA. The aqueous phase was further extracted with EA:isopropanol = 9:1. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was isolated by column chromatography (7% ammonia in MeOH / DCM) to obtain a pale yellow solid, M44 (0.92 g). ESI-MS m / z: 473.20 [M+H]. + .

[0306] Synthesis of intermediate M45 [ka]

[0307] Step 1: Synthesis of compound M45-1 A reaction flask was charged with commercially available 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.83 g), tert-butyl N-((1R)-1-(4-bromophenyl)-2-hydroxyethyl)carbamate (2.00 g), potassium carbonate (1.75 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.52 g), 1,4-dioxane (35.00 mL), and water (7.00 mL). The mixture was purged with nitrogen gas and reacted at 100 °C for 2 hours under nitrogen gas protection. Sampling indicated complete reaction of the starting materials. The mixture was then diluted with water, extracted with EA, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The product was separated by column chromatography (DCM:EA=3:1) to obtain a yellow solid, compound M45-1 (1.7 g). ESI-MS m / z: 332.29 [M+H] + .

[0308] Step 2: Synthesis of compound M45-2 Compound M45-1 (1.7 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (10.00 mL) was added while stirring at 0°C. The mixture was allowed to react at room temperature for 1 hour, and the solvent was concentrated to give crude product M45-2 (1.35 g) as a yellow solid. ESI-MS m / z: 215.21 [M-OH] + .

[0309] Step 3: Synthesis of compound M45-3 Compound M45-2 (1.30 g), commercially available (2S)-3-methyl-2-((2-methylpropan-2-yl)oxycarbonylamino)butanoic acid (0.82 g), N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (1.25 mL) were added to a reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.87 g) was added with stirring and reacted at room temperature for 0.5 h. The mixture was diluted with saturated brine and extracted with EA. The aqueous phase was extracted with EA:isopropanol = 9:1. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was isolated by column chromatography (DCM:ammonia / methanol = 20:1) to obtain a yellow solid, M45-3 (1.75 g). ESI-MS m / z: 445.20 [M+H] + .

[0310] Step 4: Synthesis of compound M45-4 Compound M45-3 (1.75 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (10.00 mL) was added while stirring at 0°C. The mixture was allowed to react at room temperature for 1 hour, and the solvent was concentrated to give crude yellow solid product M45-4 (1.66 g). ESI-MS m / z: 345.18 [M+H] + .

[0311] Step 5: Synthesis of compound M45-5 Compound M45-4 (1.30 g), commercially available (2S)-3-methyl-2-((2-methylpropan-2-yl)oxycarbonylamino)butanoic acid (0.82 g), N,N-dimethylformamide (1.00 mL), and N,N-diisopropylethylamine (1.25 mL) were added to a reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.87 g) was added with stirring and reacted at room temperature for 0.5 h. The mixture was diluted with saturated brine and extracted with EA. The aqueous phase was extracted with EA:isopropanol = 9:1. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was isolated by column chromatography (DCM:ammonia / methanol = 20:1) to give yellow solid M45-5 (1.8 g). ESI-MS m / z: 544.30 [M+H] + .

[0312] Step 6: Synthesis of compound M45-6 Compound M45-5 (1.8 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (10.00 mL) was added while stirring at 0 °C. The mixture was allowed to react at room temperature for 1 hour, the solvent was concentrated, and the pH was adjusted to 8 with aqueous sodium bicarbonate in an ice bath. The mixture was then purified using a reverse-phase column to give pale yellow solid M45-6 (1.12 g). ESI-MS m / z: 444.30 [M+H] + .

[0313] Step 7: Synthesis of compound M45 Compound M45-6 (1.10 g), tetrahydrofuran (10.00 mL), acetonitrile (5.00 mL), and triethylamine (1.38 mL) were added to a reaction flask and cooled to 0 °C. 2-Azido-1,3-dimethylimidazolium hexafluorophosphate (1.41 g, 4.96 mmol) was dissolved in acetonitrile (5.00 mL) and then added to the reaction mixture. After the addition was complete, the reaction mixture was allowed to react at this temperature for 1 hour. The reaction mixture was diluted with an appropriate amount of saturated brine, extracted with EA, and the aqueous phase was further extracted with EA:isopropanol = 9:1. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the product was isolated by column chromatography to obtain a pale yellow solid, M45 (0.8 g). ESI-MS m / z: 470.20 [M+H] + .

[0314] Synthesis of intermediate M46 [ka]

[0315] Step 1: Synthesis of compound M46-1 2-Chloro-5-iodopyrazine (1 g), trimethylsilylacetylene (0.88 mL), bis(triphenylphosphine)palladium dichloride (0.36 g), and cuprous iodide (0.1 g) were dissolved in 10 mL of tetrahydrofuran, triethylamine (2.16 mL) was added, and the mixture was purged with nitrogen three times. The mixture was incubated at 80 °C for 2 hours and monitored for completion by LCMS. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with DCM:MeOH. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 0.5 g of a white solid, i.e., M46-1. ESI-MS m / z: 211 [M+H] + .

[0316] Step 2: Synthesis of compound M46 M46-1 (0.5 g) was dissolved in 2 mL of ACN, and 5 M aqueous potassium hydroxide solution (1.25 mL) was added dropwise in an ice bath. The mixture was stirred for 15 minutes while maintaining the temperature. The reaction was monitored for completion by LCMS. Extraction was performed three times with EA (10 mL each time). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 0.17 g of a white solid, i.e., M46. ESI-MS m / z: 139 [M+H] + .

[0317] Synthesis of intermediate M47 [ka]

[0318] Step 1: Synthesis of compound M47-1 ((2-Fluoro-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1 g) was dissolved in 10 mL of DMF, and then cesium fluoride (3.36 g) was added and reacted at 25 °C for 5 hours. The reaction was monitored for completion by TLC. Diluted with water and extracted three times with EA, the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to give 0.65 g of a white solid, i.e., M47-1. The obtained crude product was used directly in the next step without purification. ESI-MS m / z: 297 [M+H] + .

[0319] Step 2: Synthesis of compound M47 M47-1 (0.65 g) was dissolved in 10 mL of THF, followed by the addition of 10% Pd / C (0.4 g). The mixture was purged with hydrogen gas three times and stirred at 25°C for 12 hours. The reaction was monitored for completion by TLC. After filtration through diatomaceous earth, the organic phase was concentrated and purified by column chromatography to give 0.48 g of a white solid, i.e., M47. ESI-MS m / z: 301 [M+H] + .

[0320] Synthesis of intermediate M48 [ka]

[0321] Step 1: Synthesis of compound M48-1 Compound M46 (0.83 g) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.63 g) were dissolved in 15.0 mL of 1,4-dioxane, triethylamine (2.5 mL) was added, and the mixture was heated to 80 °C under a N2 atmosphere and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE / EA = 65:35) to obtain compound M48-1 (1.6 g). ESI-MS m / z: 329.1 [M+H] + .

[0322] Step 2: Synthesis of compound M48-2 Compound M48-1 (300 mg) and compound M29 (459 mg) were dissolved in tert-butanol (5 mL), tetrahydrofuran (5 mL), and water (5 mL). Anhydrous copper sulfate (131 mg) and sodium ascorbate (470 mg) were added and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was dried on a rotary evaporator, extracted with DCM / MeOH (10:1) and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure. The filtrate was purified by column chromatography (DCM / MeOH = 10:1) to give compound M48-2 (646 mg). ESI-MS m / z: 785.3 [M+H] + .

[0323] Step 3: Synthesis of intermediate M48 Compound M48-2 (600 mg) was dissolved in 8 mL of DCM and 8 mL of 4 M hydrogen chloride dioxane solution and reacted at room temperature for 0.5 hours. After the reaction was completed, the reaction mixture was dried on a rotary evaporator, diluted with water, extracted with EA, the aqueous phase was collected, the pH of the aqueous phase was adjusted to alkaline with anhydrous sodium carbonate, and extracted with DCM / isopropanol (3:1). The organic phases were collected and combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound M48 (498 mg). ESI-MS m / z: 685.3 [M+H] + .

[0324] Example 1 Synthesis of compound (2S,4R)-1-((2S)-2-(4-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)benzamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0325] Step 1: Synthesis of Compound 1-1 Compound M1 (0.25 g) was added to a 50 mL single-neck flask and dissolved in DMF (5 mL) and THF (5 mL). 1,1-cyclopropane dimethanol (0.31 g), cesium carbonate (0.738 g), and DABCO (8.47 mg) were added and reacted under N2 protection at 40 °C for 5 hours. After cooling to room temperature, an appropriate amount of water was added to the reaction mixture, followed by separation. The aqueous phase was extracted with DCM, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, and the product was isolated by column chromatography (DCM:MeOH = 10:1) to obtain 0.278 g of a pale yellow solid, compound 1-1.

[0326] Step 2: Synthesis of Compound 1-2 Compound 1-1 (200.0 mg) was placed in a 25 mL single-neck flask and dissolved in THF (10 mL) and water (2 mL). M5 (379.3 mg), KPO (321.0 mg), and CataCXium A Pd G3 (36.7 mg) were added and reacted at 75 °C for 2 hours under N2 protection. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (DCM:MeOH = 10:1) yielded 210.5 mg of a yellow solid, compound 1-2.

[0327] Step 3: Synthesis of Compounds 1-3 Compound 1-2 (210.0 mg) was placed in a 25 mL single-neck flask, dissolved in DCM (10 mL), and DMP (299.5 mg) was added. The mixture was allowed to react at room temperature for 4 hours. The reaction mixture was quenched by adding sodium thiosulfate solution, extracted three times with DCM, and the organic phase was washed with water and saturated brine, evaporated to dryness, and the product was separated by column chromatography ((DCM:MeOH=10:1)) to obtain 192 gm of a pale yellow solid, Compound 1-3.

[0328] Step 4: Synthesis of Compounds 1-4 Compound 1-3 (100 mg) was placed in a 25 mL single-neck flask and dissolved in MeOH (3 mL). M26 (167.5 mg) and 1 M ZnCl / THF solution (0.1 mL) were added, heated to 40 °C, and reacted for 2 hours. NaBHCN (53.1 mg) was then added and reacted overnight. The reaction solution was directly evaporated to dryness. Purification by column chromatography (DCM:MeOH = 8:1) yielded 84.0 mg of a pale yellow solid, compound 1-4.

[0329] Step 5: Synthesis of Compound 1 Compound 1-4 (84.0 mg) was placed in a 25 mL single-neck flask, dissolved in DCM (2 mL), and TFA (1 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was evaporated to dryness, and the product was isolated by reverse-phase column chromatography (CHCN / HO = 30% to 55%) to obtain 30.6 mg of a white solid, i.e., Compound 1 (purity 99.14%).

[0330] LCMS: 1 / 2 [M+2H] + =598.31

[0331] 1H NMR(500MHz,MeOD)δ9.31(s,1H),8.98(s,1H),7.78(d,J=8.6Hz,2H),7.71-7.62(m,2H),7.49-7.37(m,4H),7.33(s,1H),7.25(t,J =9.3Hz,1H),7.07(s,1H),6.96(d,J=7.6Hz,2H),5.03(dd,J=12.9,6.2Hz,2H),4.70-4.59(m,2H),4.57-4.45(m,3H),4.37(t,J=14 .8Hz,2H),4.05-3.94(m,5H),3.86-3.76(m,1H),3.66-3.51(m,2H),3.47-3.35(m,2H),3.04(t,J=12.4Hz,2H),2.51-2.39(m,4H), 2.28-2.09(m,7H),1.92-1.80(m,3H),1.77-1.68(m,2H),1.52(d,J=6.8Hz,3H),1.27(d,J=8.3Hz,3H),1.17-1.06(m,9H),1.06-0. 98(m,2H),0.92-0.86(m,2H),0.82(q,J=7.6Hz,3H).

[0332] Example 2 Synthesis of compound ((3R,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl 2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka]

[0333] Step 1: Synthesis of Compound 2-1 A 25 mL single-neck flask was charged with ((3R,7aR)-3-((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (100.0 mg), dissolved in THF (5 mL), added with NaH (38.7 mg), and reacted at room temperature for 0.5 hours. Compound M12 (82.0 mg) was then added and reacted at room temperature for 2 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution, extracted three times with EA, and the organic phase was washed with water, washed with saturated brine, and concentrated under reduced pressure. The product ((DCM:MeOH = 10:1)) was separated by column chromatography to obtain 104.0 mg of a pale yellow solid, Compound 2-1.

[0334] Step 2: Synthesis of compound 2-2 Compound 2-1 (104.0 mg) was placed in a 25 mL single-neck flask and dissolved in THF (10 mL) and water (2 mL). M5 (124.0 mg), KPO (109.8 mg), and CataCXium AP d G3 (12.5 mg) were added and reacted under N protection at 75 °C for 2 hours. The reaction solution was concentrated under reduced pressure and then purified by column chromatography (DCM:MeOH = 10:1) to obtain 106.0 mg of a yellow solid, compound 2-2.

[0335] Step 3: Synthesis of Compound 2-3 Compound 2-2 (106.0 mg) was placed in a 25 mL single-neck flask, dissolved in THF (3 mL), and then a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (2 mL) was added and reacted at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (DCM:MeOH = 10:1) to obtain 67.0 mg of a yellow solid, Compound 2-3.

[0336] Step 4: Synthesis of Compounds 2-4 Compound 2-3 (67.0 mg) was added to a 25 mL one-neck flask and dissolved in THF (4 mL). CDI (24.6 mg) was added and the mixture was heated to 40°C and reacted for 2 hours. Compound M15 (300.6 mg) was then added and the mixture was heated to 80°C and reacted overnight. The reaction solution was concentrated under reduced pressure and then purified by column chromatography (DCM:MeOH = 10:1) to obtain 62.0 mg of a pale yellow solid, compound 2-4.

[0337] Step 5: Synthesis of Compound 2 Compound 2-4 (62.0 mg) was placed in a 25 mL single-neck flask, dissolved in DCM (2 mL), and TFA (1 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the product was separated by reverse-phase column chromatography (CHCN / HO = 30% to 55%) to obtain 18.5 mg of a white solid, i.e., compound 2 (purity 96.48%).

[0338] LCMS: 1 / 2 [M+2H] + =621.93

[0339] 1 H NMR(500MHz,Methanol-d4)δ9.30(s,1H),8.92(s,1H),7.69(dd,J=8.9,5.9Hz,1H),7.43(q,J=8.3Hz,4H),7.32(d,J=2.5Hz,1H),7.26(t,J =9.3Hz,1H),7.07(t,J=2.8Hz,1H),5.00(dd,J=13.8,6.9Hz,2H),4.73(dd,J=12.3,4.5Hz,1H),4.68-4.60(m,3H),4.57-4.23(m,7H),3.87 (d,J=10.9Hz,1H),3.75(dd,J=10.9,3.7Hz,1H),3.70-3.53(m,3H),3.50-3.36(m,6H),3.24-3.13(m,1H),2.49(s,3H),2.45-2.30(m,3H), 2.27-1.92(m,14H),1.90-1.75(m,3H),1.66-1.56(m,3H),1.54-1.47 (m,4H),1.31(d,J=10.8Hz,3H),1.07-0.99(s,9H),0.84-0.78(m,3H).

[0340] Example 67 Synthesis of compound (2S,4R)-1-(S)-2-(4-(1-(2-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)ethyl)piperidin-4-yl)methoxy)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0341] Step 1: Synthesis of compound 67 Compound M42 (80.00 mg), compound M33 (78.96 mg), and acetic acid (0.05 mL) were added to dichloromethane (2.00 mL) and isopropanol (0.50 mL), and the mixture was allowed to react at room temperature for 0.5 hours. 2-Picoline borane (38.22 mg) was then added and the mixture was allowed to react at room temperature for an additional 2 hours. 30 mL of saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted three times with DCM. The organic phases were combined, concentrated, and purified by pre-HPLC to give compound 67 (42.4 mg, 29.43%).

[0342] ESI-MS m / z: 583.27 1 / 2 [M+2H] + .

[0343] 1H NMR(500MHz,Methanol-d4)δ9.21(d,J=4.1Hz,1H),8.87(s,1H),8.35(s,1H),7.73(d,J=8.6Hz,2 H),7.67(dd,J=8.8,5.9Hz,1H),7.47-7.36(m,4H),7.30(d,J=2.4Hz,1H),7.24(t,J=9.3Hz,1H), 7.06(s,1H),6.97(d,J=8.6Hz,2H),5.32(d,J=10.3Hz,1H),5.04(q,J=6.9Hz,1H),4.68(t,J=5.4 Hz,2H),4.53(t,J=8.3Hz,2H),4.47(s,1H),4.28(t,J=13.0Hz,1H),3.93-3.84(m,4H),3.64(d,J= 13.3Hz,1H),3.58(d,J=13.5Hz,1H),3.45(dd,J=20.6,9.8Hz,1H),3.18(d,J=10.9Hz,2H),2.93( d,J=4.8Hz,2H),2.68-2.57(m,1H),2.48(s,3H),2.45(s,1H),2.29(t,J=11.2Hz,2H),2.24-2.13 (m,3H),2.03(s,1H),2.01-1.94(m,1H),1.87(t,J=14.3Hz,4H),1.77(t,J=9.4Hz,2H),1.51(dd, J=18.2,9.6Hz,5H),1.29(d,J=3.5Hz,3H),1.27(s,1H),1.15(t,J=7.7Hz,3H),0.84-0.78(m,6H).

[0344] Example 69 (2S,4R)-1-((S)-2-(4-(4-(1-(1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methoxy)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0345] Step 1: Synthesis of compound 69-1 Compound M42 (62.35 mg, 0.09 mmol), intermediate compound M28 (50.00 mg, 0.08 mmol), and a solution of zinc chloride in tetrahydrofuran (0.08 mL, 1.00 mol / L, 0.08 mmol) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL) and reacted at 40 °C for 1 hour. Sodium cyanoborohydride (53.04 mg, 0.84 mmol) was added and reacted at 40 °C for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM (80.00 mL), dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 90%:10%) to give compound 69-1 (80.00 mg, 75.92%).

[0346] ESI-MS m / z: 625.35, 1 / 2 [M+2H] + .

[0347] Step 2: Synthesis of compound 69 Compound 69-1 (80.00 mg, 0.06 mmol) and TFA / trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 hour. The reaction mixture was concentrated and purified by pre-HPLC to give compound 69 (19.00 mg, 23.75%).

[0348] ESI-MS m / z: 603.18, 1 / 2 [M+2H] + .

[0349] 1H NMR(500MHz,MeOD)δ9.19(d,J=1.8Hz,1H),8.86(d,J=7.8Hz,1H),8.34(d,J=4.2Hz,1H ),7.72(dd,J=8.8,1.4Hz,2H),7.66(dd,J=9.0,5.8Hz,1H),7.46-7.37(m,4H),7.29(d ,J=2.5Hz,1H),7.23(t,J=8.9Hz,1H),7.06(t,J=2.6Hz,1H),6.96(d,J=7.9Hz,2H),5. 32(d,J=10.3Hz,1H),5.05(q,J=7.0Hz,1H),4.55-4.42(m,5H),4.24(t,J=14.2Hz,1H) ,3.88(ddd,J=23.4,11.5,4.7Hz,4H),3.62(dd,J=34.4,13.3Hz,1H),3.50-3.41(m,1H ),3.14(dd,J=20.3,7.1Hz,2H),2.67-2.58(m,1H),2.54-2.37(m,7H),2.24-2.13(m,3 H),2.04-1.94(m,4H),1.89-1.72(m,7H),1.53(d,J=7.0Hz,3H),1.45-1.37(m,2H),1. 34(s,2H),1.15(dd,J=10.8,4.8Hz,4H),0.84-0.78(m,7H),0.72(s,2H),0.51(s,2H).

[0350] Example 71 Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0351] Step 1: Synthesis of compound 71-1 Compound M29 (200.00 mg) and M16-3 (142.00 mg) were added to a mixed solvent of tetrahydrofuran (4.00 mL), tert-butanol (2.00 mL), and water (2.00 mL). Copper sulfate (62.93 mg) and sodium ascorbate (225.67 mg) were then added. The mixture was stirred at 20°C for 6 hours. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure and purified by column chromatography to give a pale yellow solid (291.00 mg, 94.10% yield), identified as compound 71-1.

[0352] Step 2: Synthesis of compound 71-2 Compound 71-2 (291.00 mg) was added to a 25 mL one-neck flask, and dichloromethane (5.00 mL) and a solution of hydrogen chloride in dioxane (2.00 mL) were added. The mixture was stirred at 20 °C for 0.5 h. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO3 solution, extracted twice with dichloromethane / isopropanol = 5 / 1, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was used directly in the next step. A pale yellow solid (290.00 mg) was obtained, i.e., compound 71-2.

[0353] Step 3: Synthesis of compound 71-3 Compound M28 (80.00 mg) and 71-2 (98.14 mg) were added to a 25 mL one-neck flask, followed by methanol (2.00 mL) and zinc chloride (0.20 mL, 1.00 mol / L). The reaction mixture was heated to 40 °C and stirred for 2 h. Finally, sodium cyanoborohydride (29.69 mg) was added, and the mixture was stirred at 40 °C for 12 h. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure and purified by column chromatography to give a pale yellow solid (130.00 mg, 81.44% yield), identified as compound 71-3.

[0354] Step 4: Synthesis of compound 71 Compound 71-3 (130.00 mg) was added to a 25 mL one-neck flask, followed by dichloromethane (4.00 mL) and trifluoroacetic acid (2.00 mL). The mixture was stirred at 20 °C for 0.5 h. The reaction was monitored for completion by LCMS. After concentration under reduced pressure, the crude product was purified by HPLC to give the pure product as a pale yellow solid (50.00 mg, 37.47% yield), i.e., compound 71.

[0355] ESI-MS m / z: 570.23 1 / 2 [M+2H] +

[0356] 1 H NMR(500MHz,Methanol-d4)δ9.11(s,1H),8.77(s,1H),7.81(d,J=8.4Hz,1H),7.57(t,J=7.5Hz,1H),7.33(q,J=8.1Hz,4H),7.23-7.10(m,2H),6.96(s,1H) ),5.15(d,J=10.3Hz,1H),4.94(d,J=6.9Hz,1H),4.52-4.29(m,6H),4.16(t, J=13.9Hz,1H),3.83-3.68(m,2H),3.59-3.43(m,2H),3.35(q,J=11.7,11.3H z,1H),2.55(s,3H),2.45(s,1H),2.38(s,4H),2.18(d,J=10.9Hz,2H),2.09( s,2H),1.88(d,J=12.2Hz,3H),1.77-1.73(m,2H),1.71-1.66(m,2H),1.61(s ,2H),1.42(d,J=7.0Hz,3H),1.28(d,J=23.5Hz,2H),1.02(d,J=6.8Hz,3H),0 .82-0.75(m,5H),0.70(t,J=9.4Hz,5H),0.65(d,J=6.7Hz,3H),0.49(s,2H).

[0357] Example 73 Compound (2S,4R)-1-((S)-2-(4-(7-((1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro- Synthesis of 4-(((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-7-azaspiro[3.5]nonan-2-yl)oxy)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0358] Step 1: Synthesis of compound 73-1 7-tert-Butoxycarbonyl-7-azaspiro[3.5]-2-nonanol (500 mg) was dissolved in 6 mL of DCM, followed by the addition of triethylamine (0.58 mL) and methanesulfonyl chloride (0.19 mL) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water in an ice bath. The mixture was extracted once with EA and once with DCM. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and concentrated to give crude product 73-1 (660 mg). ESI-MS m / z: 320.1 [M+H] + .

[0359] Step 2: Synthesis of compound 73-2 Compound 73-1 (660 mg) was added to a 50 mL one-neck flask, followed by 10 mL of DMF, 4-((trimethylsilyl)ethynyl)phenol (511 mg), and cesium carbonate (2.01 g). The mixture was allowed to react at 60 °C for 3 hours. 50 mL of water was added dropwise to the reaction mixture, and the mixture was filtered. The filter cake was washed with water. The filter cake was dissolved in DCM and washed with saturated brine. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to give compound 73-2 (330 mg). ESI-MS m / z: 413.3 [M+H] + .

[0360] Step 3: Synthesis of compound 73-3 73-2 (330 mg) was added to a 10 mL one-neck flask, 3 mL of DMF was added, and cesium fluoride (500 mg) was added. The mixture was stirred at room temperature for 3 hours. 20 mL of water was added dropwise to the reaction mixture, filtered, and the filter cake was washed with water and dried to give compound 73-3 (300 mg). ESI-MS m / z: 342.2 [M+H] + .

[0361] Step 4: Synthesis of compound 73-4 73-3 (300 mg) was added to a 50 mL single-neck flask, followed by 3 mL of tetrahydrofuran, 3 mL of tert-butanol, and 3 mL of water. M29 (269 mg), copper sulfate (95 mg), and sodium ascorbate (338 mg) were added and the mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with EA. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography to give compound 73-4 (280 mg). ESI-MS m / z: 798.4 [M+H] + .

[0362] Step 5: Synthesis of compound 73-5 Compound 73-4 (280 mg) was added to a 10 mL one-neck flask, and 4 M hydrogen chloride in dioxane (3 mL) was added. The mixture was allowed to react at room temperature for 30 minutes. Saturated sodium bicarbonate solution was added to neutralize the reaction mixture, and the mixture was extracted twice with EA. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and concentrated to give crude product 73-5 (220 mg). ESI-MS m / z: 698.4 [M+H]. + .

[0363] Step 6: Synthesis of compound 73-6 M28 (80 mg) was added to a 10 mL one-neck flask, 1 mL of methanol was added, 73-5 (94 mg) was added, and 1 M zinc chloride in tetrahydrofuran (0.2 mL) was added and stirred at room temperature for 3 hours. Sodium cyanoborohydride (25 mg) was added and stirred at room temperature for 16 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with EA. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and concentrated to give crude product 73-6 (100 mg). ESI-MS m / z: 638.7 1 / 2 [M+2H] + .

[0364] Step 7: Synthesis of Compound 73 73-6 (100 mg) was added to a 10 mL single-neck flask, and 2 mL of DCM and 2 mL of trifluoroacetic acid were added. The mixture was allowed to react at room temperature for 1 hour. After drying by rotary evaporation, the mixture was purified by pre-HPLC to give compound 73 (51.4 mg).

[0365] ESI-MS m / z: 616.4 1 / 2 [M+2H] + .

[0366] 1H NMR(500MHz,DMSO-d6)δ9.21(s,1H),8.99(s,1H),8.57(s,1H),8.53-8.48(m,1H) ,7.80-7.72(m,3H),7.45(d,J=8.4Hz,2H),7.37(d,J=8.2Hz,2H),7.32(d,J=2.8H z,1H),7.03(d,J=2.5Hz,1H),6.88(d,J=8.8Hz,2H),5.31(t,J=8.3Hz,1H),5.22- 5.10(m,1H),4.93(t,J=7.2Hz,1H),4.74(t,J=6.7Hz,2H),4.40(t,J=8.1Hz,1H), 4.36-4.23(m,4H),4.04(dd,J=27.4,13.5Hz,1H),3.81-3.69(m,1H),3.70-3.49( m,1H),2.45(d,J=3.9Hz,3H),2.40-2.21(m,9H),2.19-1.93(m,5H),1.81-1.64(m ,6H),1.59-1.47(m,5H),1.38(d,J=7.0Hz,3H),1.17(d,J=12.1Hz,4H),1.08(d,J =6.5Hz,3H),0.85(t,J=6.9Hz,1H),0.76-0.70(m,6H),0.64(s,2H),0.40(s,2H).

[0367] Example 75 Synthesis of compound (2S,4R)-1-((S)-2-(4-(4-(7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0368] Step 1: Synthesis of compound 75-1 tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (3.00 g), ((4-bromophenyl)ethynyl)trimethylsilane (5.03 g), tris(dibenzylideneacetone)dipalladium (2.43 g), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (3.30 g), and cesium carbonate (12.96 g) were added to toluene (30.00 mL), purged with nitrogen gas, and reacted at 90 °C for 7 hours. The reaction mixture was filtered, the filter cake was washed with DCM, and the filtrate was concentrated and separated by column chromatography (PE:EA = 93%:7%) to give compound 75-1 (1.40 g, 26.50%).

[0369] ESI-MS m / z: 398.28 [M+H] + .

[0370] Step 2: Synthesis of compound 75-2 Compound 75-1 (1,400 mg) and potassium carbonate (1,456.26 mg) were added to methanol (20 mL) and reacted at room temperature for 16 hours. The reaction mixture was concentrated, diluted with DCM, filtered, the filter cake was washed with DCM, and the filtrate was concentrated and separated by column chromatography (PE:EA = 90%:10%) to give compound 75-2 (650 mg, 56.69%).

[0371] ESI-MS m / z: 327.25 [M+H] + .

[0372] Step 3: Synthesis of compound 75-3 Compound M29 (200.00 mg), compound 75-2 (286.02 mg), sodium ascorbate (216.98 mg), and copper sulfate (69.93 mg) were added to tetrahydrofuran (2.00 mL), water (2.00 mL), and tert-butanol (2.00 mL) and reacted at room temperature for 3 hours. 50 mL of water was added to the reaction mixture, which was then extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 95%:5%) to give compound 75-3 (230 mg, 67.05%).

[0373] ESI-MS m / z: 783.59 [M+H] + .

[0374] Step 4: Synthesis of compound 75-4 Compound 75-3 (230.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) in that order and allowed to react at room temperature for 1 hour. The reaction mixture was adjusted to alkaline by adding 40 mL of saturated aqueous sodium bicarbonate solution, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 90%:10%) to give compound 75-4 (129.00 mg, 64.32%).

[0375] ESI-MS m / z: 683.49 [M+H] + .

[0376] Step 5: Synthesis of compound 75-5 Compound 75-4 (120.00 mg), compound M28 (104.13 mg), and a 1.0 M zinc chloride solution in tetrahydrofuran (0.35 mL) were added to methanol (3.00 mL) and 1,2-dichloroethane (3.00 mL) and reacted at 40° C. for 2 hours. Sodium cyanoborohydride (55.20 mg) was then added and reacted at 40° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to give compound 75-5 (110.00 mg, 49.71%).

[0377] ESI-MS m / z: 630.71 1 / 2 [M+2H] + .

[0378] Step 6: Synthesis of compound 75-6 Compound 75-5 (110.00 mg) and trifluoroacetic acid (1.50 mL) were added to dichloromethane (3.00 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated and then purified by pre-HPLC to give compound 75 (26.10 mg, 23.43%).

[0379] ESI-MS m / z: 608.68 1 / 2 [M+2H] + .

[0380] 1 H NMR(500MHz,Methanol-d4)δ9.21(d,J=5.5Hz,1H),8.87(d,J=6.9Hz,1H),8.25(s,1H),7.67(dd,J=9.0,5.8Hz,1H),7.62(d,J=8.5Hz,2H),7.49-7.35(m,4H) ),7.30(d,J=2.6Hz,1H),7.24(t,J=9.3Hz,1H),7.06(t,J=2.4Hz,1H),6.51(d ,J=8.7Hz,2H),5.30(d,J=10.4Hz,1H),5.05(q,J=7.0Hz,1H),4.56-4.40(m,5H ),4.25(t,J=14.4Hz,1H),3.92(dd,J=11.0,3.9Hz,1H),3.85(d,J=11.1Hz,1H ),3.69-3.52(m,5H),3.51-3.41(m,1H),2.67-2.36(m,11H),2.25-2.13(m,3H) ,2.10-1.94(m,2H),1.89-1.74(m,7H),1.53(d,J=7.0Hz,2H),1.35-1.24(m,8 H),1.14(dd,J=15.1,6.5Hz,3H),0.83-0.79(m,5H),0.73(s,2H),0.52(s,2H).

[0381] Example 79 Synthesis of compound (2S,4R)-1-((R)-2-(3-(2-(1-(2-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R-)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)ethyl)piperidin-4-yl)ethoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0382] Step 1: Synthesis of compound 79-1 Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (500 mg), N-BOC-4-(2-bromoethyl)piperidine (1.03 g), and potassium carbonate (1.04 g) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 50 °C for 2 hours. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed three times with saturated brine. Compound 79-1 (920 mg) was obtained by column chromatography (petroleum ether / ethyl acetate). ESI-MS m / z: 433.22 [M+Na] + .

[0383] Step 2: Synthesis of compound 79-2 Compound 79-1 (920 mg) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide (268 mg) was added. The mixture was allowed to react at 25°C for 1 hour. After the reaction was completed, citric acid was added to adjust the pH to 4, and the mixture was extracted three times with dichloromethane / isopropanol (10:1), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 79-2 (883 mg). ESI-MS m / z: 297.31 [M+H-100] + .

[0384] Step 3: Synthesis of compound 79-3 Compound 79-2 (883 mg), M29-2 (775 mg), HATU (1.27 g), and N,N-diisopropylethylamine (1.1 mL) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 25 °C for 1 hour. After the reaction was complete, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated saline, purified by column chromatography (dichloromethane / methanol), and separated on a chiral column to give compound 79-3 (263 mg). ESI-MS m / z: 710.53 [M+H] + .

[0385] Step 4: Synthesis of compound 79-4 Compound 79-3 (263 mg) was dissolved in dichloromethane (5 mL), and 4 M hydrogen chloride in dioxane (1 mL) was added. The mixture was allowed to react at 25° C. for 20 minutes. After the reaction was completed, water was added to dissolve the mixture, and the mixture was neutralized with sodium bicarbonate solution. The mixture was extracted with dichloromethane / isopropanol (10:1), dried, and concentrated to give compound 79-4 (203 mg). ESI-MS m / z: 610.41 [M+H] + .

[0386] Step 5: Synthesis of Compound 79 Compound 79-4 (100 mg), M33 (83 mg), and glacial acetic acid (49 mg) were dissolved in dichloromethane (5 mL) and isopropanol (0.5 mL) and reacted at 25°C for 20 minutes. 2-Methylpyridine-N-borane (87 mg) was added and reacted at 25°C for 1 hour. After the reaction was completed, the mixture was quenched by adding sodium bicarbonate solution, extracted with dichloromethane / isopropanol (10:1), concentrated, and purified by column chromatography (dichloromethane / methanol) and pre-TLC to obtain compound 79 (32.5 mg).

[0387] ESI-MS m / z: 552.18 1 / 2 [M+2H] + .

[0388] 1 H NMR(500MHz,DMSO-d6)δ10.00(s,1H),9.26(s,1H),8.99(d,J=2.7Hz,1H),8.43(d,J=7.4Hz,1H),7.77(dd, J=9.1,6.0Hz,1H),7.48-7.41(m,2H),7.39-7.32(m,4H),7.29(s,1H),7.05(s,1H),6.68(s,1H),6.07(s,1 H),5.15-5.13(m,1H),4.91(p,J=7.2Hz,1H),4.82-4.65(m,3H),4.43-4.31(m,2H),4.30-4.25(m,1H),4.2 1-4.17(m,2H),4.10(dd,J=25.0,13.4Hz,1H),3.70(dd,J=10.6,4.4Hz,1H),3.64(d,J=10.0Hz,2H),3.58- 3.50(m,2H),3.49-3.39(m,2H),3.10-2.95(m,2H),2.46(s,3H),2.39-2.29(m,1H),2.2 8-2.08(m,3H),2.05-1.97(m,3H),1.92-1.85(m,2H),1.81-1.77(m,1H),1.76(s,3H),1 .72-1.63(m,6H),1.45(d,J=7.0Hz,1H),1.37(d,J=7.0Hz,3H),1.17(d,J=11.6Hz,3H), 0.95(d,J=6.5Hz,3H),0.86-0.80(m,1H),0.79(d,J=6.7Hz,2H),0.74(q,J=7.7Hz,3H).

[0389] Example 80 Synthesis of compound (2S,4R)-1-(R)-2-(3-(1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)ethyl)piperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0390] In a reaction flask, intermediate M33 (30 mg), intermediate M35 (35.15 mg), and Dichloromethane (1.00 mL), isopropanol (0.10 mL), and acetic acid (0.02 mL) were added and reacted at room temperature for 10 minutes. Dimethylpyridineborane (31.27 mg) was then added and reacted at room temperature for 1 hour. The pH was adjusted to 8 with aqueous sodium bicarbonate, extracted with DCM, dried, and concentrated. Compound 80 (12 mg) was obtained by pre-HPLC separation. ESI-MS m / z: 545.19 1 / 2 [M+2H] + .

[0391] 1H NMR(500MHz,Methanol-d4)δ8.99(t,J=75.2Hz,1H),8.66(s,1H),7.92(d,J=6.7Hz,1H),7.61-7.46(m,1H),7.35(s, 4H),7.28(s,1H),7.18(m,2H),5.73(d,J=8.0Hz,1H),5.05(td,J=7.1,2.3Hz,1H),4.76-4.37(m,5H),4.35-4.18(m, 2H),3.99(m,3H),3.65(d,J=8.8Hz,1H),3.45-3.34(m,2H),3.28-3.05(m,5H),2.85(s,2H),2.49(s,3H),2.38-2.07 (m,8H),2.01(d,J=4.5Hz,5H),1.70(d,J=12.7Hz,4H),1.52-1.46(m,4H),0.99(d,J=6.3Hz,3H),0.87-0.74(m,6H).

[0392] Example 88 Synthesis of compound ((3R,7aR)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl 2-(((S)-1-((2S,4R)-4-hydroxy-2-((((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka]

[0393] Step 1: Synthesis of compound 88-1 (R)-1-(2,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (300 mg) was dissolved in 2 mL of THF. Under nitrogen gas protection, NaH (72 mg) was added, followed by a solution of ((3R,7aR)-3-((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (259 mg) in THF (1 mL). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored for completion by LC-MS. The reaction mixture was quenched by slowly adding 10 mL of saturated ammonium chloride solution and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 315 mg of a pale yellow solid, i.e., compound 88-1.

[0394] ESI-MS m / z: 580 [M+H] + .

[0395] Step 2: Synthesis of compound 88-2 Compound 88-1 (315 mg), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (187 mg), potassium phosphate (340 mg), and CataCXium A Pd G3 (39 mg) were dissolved in 5 mL of dioxane and 1 mL of water, purged with nitrogen, and reacted at 90 °C for 3 h. Completion was monitored by LCMS. 20.0 mL of water was added to the reaction mixture, which was then extracted three times with EA (30 mL each time). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 146 mg of a pale yellow solid, i.e., compound 88-2. ESI-MS m / z: 778 [M+H] + .

[0396] Step 3: Synthesis of compound 88-3 Compound 88-2 (146 mg) was dissolved in 3 mL of DCM, and then 1.5 mL of triethylamine trihydrofluoride was added. The reaction was allowed to proceed at room temperature for 2 hours. The reaction was monitored for completion by LCMS. 10.0 mL of water was added to the reaction mixture, and the mixture was extracted with DCM:MeOH (10:1). The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 80 mg of a pale yellow solid, i.e., compound 88-3.

[0397] Step 4: Synthesis of compound 88-4 Compound 88-3 (43 mg) was dissolved in 3 mL of THF, then 14 mg of CDI was added, and the mixture was reacted at 40 °C for 1 hour. The intermediate was monitored by LC-MS. M15 (58 mg) was then added, and the mixture was stirred at 80 °C for 12 hours. The completion of the reaction was monitored by LC-MS. The mixture was quenched by adding 5.00 mL of methanol, and the organic phase was concentrated and purified by column chromatography to obtain 29 mg of a pale yellow solid, i.e., compound 88-4.

[0398] ESI-MS m / z: 643 1 / 2 [M+2H] + .

[0399] Step 5: Synthesis of Compound 88 Compound 88-4 (29 mg) was dissolved in 3 mL of DCM, and then 1 mL of TFA was added. The reaction was allowed to proceed at room temperature for 30 minutes, and the reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to obtain 13.6 mg of a pale yellow powder, i.e., compound 88.

[0400] ESI-MS m / z: 621 1 / 2 [M+2H] + . 1 H NMR(500MHz,Methanol-d4)δ9.29(s,1H),8.92(s,1H),7.70-7.67(m,1H),7.4 3(q,J=8.2Hz,4H),7.32-7.24(m,2H),7.06-7.05(m,1H),5.03-4.98(m,1H),4 .73(d,J=12.2Hz,1H),4.67-4.60(m,3H),4.57-4.48(m,2H),4.43(s,1H),4.39-4.28(m,3H), 3.87(d,J=10.9Hz,1H),3.76-3.73(m,1H),3.67-3.53(m,2H),3.45-3.40(m,3H),3.17-3.16( m,1H),2.48-2.35(m,6H),2.24-2.17(m,5H),2.14-2.01(m,7H),1.99-1.86(m,4H),1.82-1.8 0(m,3H),1.61(s,3H),1.51-1.49(m,5H),1.33-1.29(m,7H),1.02(s,9H),0.84-0.78(m,3H).

[0401] Example 89 Synthesis of compound 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-(1-(4-(4-((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)phenoxy)methyl)piperidin-1-yl)methylcyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazole[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0402] Step 1: Synthesis of compound 89-1 To a solution of intermediate compound M27 (270 mg) in DCM (5 mL) was added DIPEA (0.83 mL) and 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (255 mg) at -40 °C, and the reaction was stirred at the same temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and the concentrate was purified by column chromatography (0-4% MeOH / DCM) to give compound 89-1 (416 mg).

[0403] ESI-MS m / z: 424.3 [M+H] + .

[0404] Step 2: Synthesis of compound 89-2 To a solution of compound 89-1 (416 mg) in DMF (5 mL) was added 1,1-cyclopropane dimethanol (150 mg), CsCO (639 mg), and DABCO (22 mg) at room temperature. The reaction mixture was stirred at the same temperature for 12 hours. After completion of the reaction, EA and water were added to the reaction mixture. The aqueous phase was further extracted twice with EA. The organic phases were combined and washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (0-6% MeOH / DCM) to give compound 89-2 (220 mg).

[0405] ESI-MS m / z: 490.3 [M+H] + .

[0406] Step 3: Synthesis of compound 89-3 Compound 89-2 (220 mg), M10 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (335 mg), cataCXium A Pd G3 (33 mg), and K3PO4 (286 mg) were added to a 50 mL one-neck flask at room temperature. THF (5 mL) and HO (1 mL) were then added. The system was purged with nitrogen gas and stirred at 70 °C for 1 h. After completion of the reaction, EA and saturated brine were added to the reaction system. The aqueous phase was further extracted once with EA. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative thin-layer chromatography (8% MeOH / DCM) to give compound 89-3 (196 mg).

[0407] ESI-MS m / z: 840.7 [M+H] + .

[0408] Step 4: Synthesis of compound 89-4 To a solution of compound 89-3 (196 mg) in DCM (5 mL) was added DMP (148 mg) at room temperature, and the reaction was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction was quenched by adding saturated sodium sulfite solution to the reaction system, followed by extraction and separation with an appropriate amount of DCM. The aqueous phase was further extracted twice with DCM, and the organic phases were combined. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (0-5% MeOH / DCM) to give compound 89-4 (180 mg).

[0409] ESI-MS m / z: 838.7 [M+H] + .

[0410] Step 5: Synthesis of compound 89-5 To a solution of compound 89-4 (180 mg) and M26 (156 mg) in MeOH (5 mL) was added ZnCl (0.2 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. NaBHCN (67 mg) was then added, and the reaction was stirred at 40 °C overnight. After completion of the reaction, the reaction was quenched by adding saturated sodium bicarbonate solution. The mixture was then extracted with a mixed solvent (DCM / MeOH = 9:1) and separated. The aqueous phase was further extracted twice with the mixed solvent. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by preparative thin-layer chromatography (10% MeOH / DCM) to give compound 89-5 (23 mg).

[0411] ESI-MS m / z: 742.5 1 / 2 [M+2H] + .

[0412] Step 6: Synthesis of compound 89-6 To a solution of compound 89-5 (23 mg) in DCM (1 mL) was added CsF (47 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After the reaction was completed, EA and saturated brine were added to the reaction system, followed by extraction and separation. The organic phase was further washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by preparative thin-layer chromatography (11% MeOH / DCM) to give compound 89-6 (17 mg).

[0413] ESI-MS m / z: 664.3 1 / 2 [M+2H] + .

[0414] Step 7: Synthesis of Compound 89 To a solution of compound 89-6 (17 mg) in DCM (2 mL) was added boron trifluoride diethyl etherate (0.4 mL) at room temperature and stirred at the same temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into a cooled saturated sodium carbonate solution, extracted three times with a mixed solvent (DCM / MeOH = 9:1), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and then concentrated. The concentrate was purified by preparative thin-layer chromatography (12% MeOH / DCM) to give compound 89 (7 mg).

[0415] ESI-MS m / z: 642.8 1 / 2 [M+2H] + .

[0416] 1 H NMR(500MHz,Methanol-d4)δ9.12(s,1H),8.93-8.83(m,1H),7.85(dd,J=9.1,5.7Hz,1H),7.79-7.75(m,2H),7.46-7.36(m,4H),7.36-7.33(m,1 H),7.31(t,J=8.9Hz,1H),7.22-7.19(m,1H),6.97-6.92(m,2H),6.74(s ,1H),5.36-5.28(m,1H),5.20(d,J=16.1Hz,1H),5.02(q,J=6.8Hz,1H),4 .63-4.53(m,3H),4.51-4.32(m,5H),3.95(d,J=10.9Hz,1H),3.88-3.77 (m,3H),3.32(s,3H),3.06(s,3H),2.48(s,3H),2.44-2.38(m,2H),2.20( dd,J=19.4,12.0Hz,2H),2.06-1.94(m,2H),1.91-1.81(m,3H),1.52(d, J=7.0Hz,3H),1.31-1.27(m,9H),1.11(s,9H),0.77(s,2H),0.57(s,2H).

[0417] Example 90 Synthesis of compound (3R,7aR)-7a-((7-(8-ethynyl-7-fluoro)-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(1,4-oxolan-4-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)hexahydro-1H-pyrrolidin-3-yl)methyl 2-(((S)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamoyl)-7-azaspiro[3.5]nonane-7-carboxylate [ka]

[0418] Step 1: Synthesis of compound 90-1 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1 g) was dissolved in 10 mL of DCM, DIPEA (1.96 mL) was added, and the mixture was placed in an ice bath. A solution of homomorpholine hydrochloride (1 g) in DCM (3 mL) was then added dropwise, and a nitrogen balloon was inserted. The mixture was stirred at 0 °C for 0.5 h. The reaction was monitored for completion by LC-MS. 10 mL of water was added to the reaction mixture, and the mixture was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 1.26 g of a pale yellow solid, i.e., compound 90-1.

[0419] ESI-MS m / z: 317 [M+H] + .

[0420] Step 2: Synthesis of compound 90-2 ((3R,7aR)-3-((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (1.08 g) was dissolved in 4 mL of THF. Under nitrogen gas protection, NaH (230 mg) was added and the mixture was stirred at room temperature for 0.5 hours. After that, a solution of compound 90-1 (600 mg) in THF (2 mL) was added and the mixture was stirred at room temperature for 0.5 hours. The reaction was monitored for completion by LC-MS. The reaction mixture was quenched by slowly adding 10 mL of saturated ammonium chloride solution and extracted three times with EA. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 790 mg of a pale yellow solid, i.e., compound 90-2.

[0421] ESI-MS m / z: 566 [M+H] + .

[0422] Step 3: Synthesis of compound 90-3 Compound 90-2 (790 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (537 mg), potassium phosphate (887 mg), and CataCXium A Pd G3 (51 mg) were dissolved in 8 mL of dioxane and 1.6 mL of water, purged with nitrogen, and reacted at 90 °C for 3 h. Completion was monitored by LCMS. 20 mL of water was added to the reaction mixture, which was then extracted three times with EA (30 mL each time). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 620 mg of a pale yellow solid, i.e., compound 90-3.

[0423] ESI-MS m / z: 916 [M+H] + .

[0424] Step 4: Synthesis of compound 90-4 Compound 90-3 (620 mg) was dissolved in 6 mL of DCM, followed by the addition of 3 mL of triethylamine trihydrofluoride. The mixture was allowed to react at room temperature for 2 hours, and the reaction was monitored for completion by LCMS. 20.0 mL of water was added to the reaction mixture, and the mixture was extracted with a 10:1 mixture of DCM and MeOH. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 500 mg of a pale yellow solid, i.e., compound 90-4.

[0425] Step 5: Synthesis of compound 90-5 Compound 90-4 (89 mg) was dissolved in 3 mL of THF, then 23 mg of CDI was added, and the mixture was stirred at 40 °C for 1 hour. The intermediate was monitored by LC-MS. Then, intermediate compound M15 (99 mg) was added, and the mixture was stirred at 80 °C for 12 hours. The completion of the reaction was monitored by LC-MS. The mixture was quenched by adding 5.00 mL of methanol, and the organic phase was concentrated and purified by column chromatography to obtain 101 mg of a pale yellow solid, i.e., compound 90-5.

[0426] ESI-MS m / z: 712 1 / 2 [M+2H] + .

[0427] Step 6: Synthesis of compound 90-6 Compound 90-5 (101 mg) was dissolved in 3 mL of DMF, and then CsF (108 mg) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction was monitored for completion by LCMS. After extraction with water and ethyl acetate, the organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography to give 70 mg of a pale yellow solid, compound 90-6.

[0428] ESI-MS m / z: 634 1 / 2[M+2H] + ;

[0429] Step 7: Synthesis of Compound 90 Compound 90-6 (70 mg) was dissolved in 3 mL of DCM, followed by the addition of 1.5 mL of boron trifluoride diethyl ether solution. The reaction was allowed to proceed at room temperature for 30 minutes, and the reaction was monitored for completion by LCMS. The reaction mixture was added dropwise to an aqueous sodium carbonate solution, extracted with DCM:isopropanol = 10:1, and the combined organic phases were dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid chromatography to obtain 33.2 mg of a yellow powder, i.e., compound 90.

[0430] ESI-MS m / z: 612 1 / 2 [M+2H] + .

[0431] 1 H NMR(500MHz,Methanol-d4)δ9.18(d,J=5.3Hz,1H),8.93(s,1H),7.90-7.87(m,1H),7.45-7.33(m,6H),7.25(d,J=2.6Hz) ,1H),4.99(q,J=6.9Hz,1H),4.76-4.71(m,2H),4.64-4.54(m,3H),4.48-4.43(m,2H),4.36-4.26(m,6H),4.07(t,J=4.9H z,2H),3.89-3.86(m,3H),3.77-3.74(m,1H),3.56(d,J=11.9Hz,1H),3.46-3.41(m,4H),3.16(s,1H),2.48(s,3H),2.42- 2.34(m,2H),2.22-2.11(m,5H),2.09-1.93(m,10H),1.60(s,3H),1.50(d,J=7.4Hz,5H),1.33-1.28(m,2H),1.01(s,9H).

[0432] Example 92 Synthesis of compound (2S,4R)-1-((R)-2-(3-((4-((1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl)azetidin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0433] Step 1: Synthesis of compound 92-1 Benzyl 3-(hydroxymethyl)azetidine-1-carboxylate (2 g) was dissolved in 20 mL of DCM, and Dess-Martin periodinane (4.6 g) was added in portions in an ice bath. After returning to room temperature and stirring for 3 hours, the reaction mixture was filtered, the filtrate was washed with an appropriate amount of saturated sodium bicarbonate solution, and extracted once with DCM. The organic phases were collected and combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude compound 92-1 (2.3 g). ESI-MS m / z: 220.1 [M+H] + .

[0434] Step 2: Synthesis of compound 92-2 Compound 92-1 (2.3 g) was added to a 100 mL one-neck flask, followed by 30 mL of toluene, tert-butyl piperazine-1-carboxylate (5.86 g), and tetraisopropyl titanate (2.98 g). The mixture was allowed to react at 60 °C for 1 hour. Then, sodium cyanoborohydride (1.32 g) was added to the reaction mixture, and the mixture was allowed to react for 5 hours. After the reaction was complete, silica gel was added to the reaction mixture, which was then concentrated. The concentrate was purified by column chromatography to obtain compound 92-2 (1.6 g). ESI-MS m / z: 390.2 [M+H] + .

[0435] Step 3: Synthesis of compound 92-3 Compound 92-2 (1.6 g) was added to a 100 mL one-neck flask, 15 mL of methanol was added, and palladium hydroxide (1 g) was added. A hydrogen gas atmosphere was generated, and the mixture was stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was collected and concentrated to give compound 92-3 (850 mg). ESI-MS m / z: 256.2 [M+H] + .

[0436] Step 4: Synthesis of compound 92-4 Compound 92-3 (850 mg) was added to a 50 mL one-neck flask, followed by intermediate M34 (1.4 g), DMA (15 mL), and DIPEA (1.55 mL) dropwise. The mixture was reacted at 140 °C for 2 hours. The reaction mixture was diluted with water and extracted twice with EA. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography to give compound 92-4 (205 mg). ESI-MS m / z: 437.3 [M+H]. + .

[0437] Step 5: Synthesis of compound 92-5 Compound 92-4 (205 mg) was added to a 25 mL single-neck flask, and 1 mL of methanol, 1 mL of tetrahydrofuran, and 1 mL of water were added. Lithium hydroxide (24 mg) was then added and the mixture was allowed to react at room temperature for 30 minutes. The reaction mixture was concentrated, diluted with water, adjusted to pH 5 with saturated sodium bicarbonate solution, and extracted twice with dichloromethane:isopropanol (5:1). The organic phases were collected, combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound 92-5 (150 mg). ESI-MS m / z: 423.3 [M+H] + .

[0438] Step 6: Synthesis of compound 92-6 Compound 92-5 (150 mg), M29-2 (140 mg), HATU (200 mg), and N,N-diisopropylethylamine (0.37 mL) were dissolved in N,N-dimethylformamide (5.00 mL) and reacted at 25 °C for 1 hour. After the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was washed with saturated saline, purified by column chromatography (dichloromethane / methanol), and separated using a chiral column to obtain compound 92-6 (47 mg). ESI-MS m / z: 736.4 [M+H] + .

[0439] Step 7: Synthesis of compound 92-7 Compound 92-6 (43 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at 25° C. for 20 minutes. After the reaction was completed, the mixture was concentrated, diluted with water, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethanol (10:1), dried over anhydrous sodium sulfate, and concentrated to give compound 92-7 (35 mg). ESI-MS m / z: 636.3 [M+H] + .

[0440] Step 8: Synthesis of compound 92-8 Compound 92-7 (35 mg) was added to a 25 mL one-neck flask, followed by 1 mL of methanol, M28 (50 mg), and 0.1 mL of zinc chloride (1 mol / L in THF). The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (25 mg) was added, and the mixture was stirred at 50 °C for 3 hours. The mixture was quenched with saturated ammonium chloride solution and extracted twice with EA. The organic phases were collected, combined, dried over anhydrous sodium sulfate, and concentrated to give compound 92-8 (100 mg). ESI-MS m / z: 607.8 1 / 2 [M+2H] + .

[0441] Step 9: Synthesis of Compound 92 92-8 (100 mg) was added to a 10 mL single-neck flask, 2 mL of DCM, and 1 mL of trifluoroacetic acid were added, and the mixture was allowed to react at room temperature for 1 hour. After drying on a rotary evaporator, the mixture was purified by pre-HPLC to give 92 (18.3 mg). ESI-MS m / z: 585.3 1 / 2 [M+2H] + .

[0442] Example 93: Synthesis of compound (2S,4R)-1-((S)-2-(4-((1-((1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)methyl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0443] Step 1: Synthesis of compound 93-1 Compound N-tert-butoxycarbonyl-4-hydroxypiperidine (300.00 mg) and 1-(bromomethyl)-4-ethynylbenzene (377.98 mg) were added to tetrahydrofuran (5.00 mL), and sodium hydride (149.06 mg, 60%) was added in portions at 0 °C. The reaction was heated to 50 °C and stirred for 3 h. Completion of the reaction was monitored by LCMS. The mixture was diluted with HO and extracted twice with EA. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded a pale yellow solid (249.00 mg, 52.96% yield), i.e., compound 93-1.

[0444] Step 2: Synthesis of compound 93-2 Compound M29 (280.00 mg) and 93-1 (251.47 mg) were added to a mixed solvent of tetrahydrofuran (6.00 mL), tert-butanol (3.00 mL), and water (3.00 mL). Copper sulfate (88.10 mg) and sodium ascorbate (315.91 mg) were then added. The mixture was stirred at 20°C for 4 hours. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure and purified by column chromatography to give a pale yellow solid (306.00 mg, 64.63% yield), i.e., compound 93-2.

[0445] Step 3: Synthesis of compound 93-3 Compound 93-2 (306.00 mg) was added to a 25 mL one-neck flask, and dichloromethane (5.00 mL) and a solution of hydrogen chloride in dioxane (2.00 mL) were added. The mixture was stirred at 20 °C for 0.5 h. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO3 solution, extracted twice with dichloromethane / isopropanol = 5 / 1, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was used directly in the next step. A pale yellow solid (278.00 mg) was obtained, i.e., compound 93-3.

[0446] Step 4: Synthesis of compound 93-4 Compound M28 (80.00 mg) and 93-3 (108.84 mg) were added to a 25 mL one-neck flask, and methanol (2.00 mL) and zinc chloride (0.20 mL, 1.00 mol / L) were added. The reaction mixture was heated to 40 °C and stirred for 2 h. Finally, sodium cyanoborohydride (29.69 mg) was added, and the mixture was stirred at 40 °C for 12 h. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure and purified by column chromatography to give a pale yellow solid (77.00 mg, 45.68% yield), identified as compound 93-4.

[0447] Step 5: Synthesis of Compound 93 Compound 93-4 (77.00 mg) was added to a 25 mL one-neck flask, followed by dichloromethane (3.00 mL) and trifluoroacetic acid (1.50 mL). The mixture was stirred at 20 °C for 0.5 hours. The reaction was monitored for completion by LCMS. The crude product was concentrated under reduced pressure and purified by pre-HPLC to give the pure product as a white solid (33.00 mg, 42.19% yield), i.e., compound 93.

[0448] ESI-MS m / z: 603.18 1 / 2 [M+2H] +

[0449] 1 H NMR(500MHz,Methanol-d4)δ9.12(d,J=4.0Hz,1H),8.79(d,J=8.0Hz,1H),8.39(s,1H),7.73(d,J=7.8Hz,2H),7.59(dd,J=9.1,5.8Hz,1H),7. 34(h,J=8.2Hz,6H),7.22(d,J=2.7Hz,1H),7.16(t,J=9.3Hz,1H),6.99(t,J=2.8Hz,1H),5.28(d,J=10.3Hz,1H),4.97(d,J=7.0Hz,2H),4.48( d,J=9.5Hz,3H),4.40(s,2H),4.36(s,2H),4.16(t,J=14.8Hz,1H),3.87-3.78(m,2H),3.60-3.48(m,1H),3.39(t,J=11.4Hz,2 H),2.85(d,J=11.4Hz,2H),2.56(dq,J=10.2,6.7Hz,1H),2.39(d,J=11.6Hz,4H),2.34(dd,J=12.9,5.7Hz,1H),2.16-2.08(m, 4H),1.93-1.89(m,1H),1.89-1.83(m,2H),1.77(d,J=12.6Hz,1H),1.69(q,J=10.9,7.5Hz,2H),1.61-1.49(m,3H),1.45(d,J= 7.0Hz,2H),1.28-1.24(m,1H),1.20(d,J=14.1Hz,4H),1.09(d,J=6.8Hz,3H),0.74(t,J=8.0Hz,5H),0.64(s,2H),0.42(s,2H).

[0450] Example 100: Synthesis of compound (2S,4R)-1-((R)-2-(3-((1-(1-((((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(((R-)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-4-fluoropiperidin-4-yl)methoxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0451] Step 1: Synthesis of Compound 100-1 Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (500 mg), tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (585 mg), triphenylphosphine (1.32 g), and DIAD (1.02 g) were dissolved in tetrahydrofuran (10 mL) and reacted at 60 °C for 1 hour. After the reaction was completed, the mixture was concentrated and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 100-1 (786 mg). ESI-MS m / z: 315.21 [M+H-100] + .

[0452] Step 2: Synthesis of Compound 100-2 Compound 100-1 (786 mg) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide (227 mg) was added. The mixture was allowed to react at 25°C for 1 hour. After the reaction was completed, citric acid was added to adjust the pH to 4, and the mixture was extracted three times with dichloromethane / isopropanol (10:1), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 100-2 (683 mg). ESI-MS m / z: 301.22 [M+H-100] + .

[0453] Step 3: Synthesis of compound 100-3 Compound 100-2 (300 mg), M29-2 (248 mg), HATU (427 mg), and N,N-diisopropylethylamine (0.37 mL) were dissolved in N,N-dimethylformamide (5.00 mL) and reacted at 25 °C for 1 hour. After the reaction was completed, the mixture was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated saline, purified by column chromatography (dichloromethane / methanol), and separated using a chiral column to obtain compound 100-3 (170 mg). ESI-MS m / z: 714.54 [M+H] + .

[0454] Step 4: Synthesis of compound 100-4 Compound 100-3 (170 mg) was dissolved in dichloromethane (5 mL), and 4 M hydrogen chloride in dioxane (1 mL) was added. The mixture was allowed to react at 25° C. for 20 minutes. After the reaction was complete, the mixture was neutralized with sodium bicarbonate solution, extracted with dichloromethane / isopropanol (10:1), dried, and concentrated to give compound 100-4 (118 mg). ESI-MS m / z: 614.50 [M+H] + .

[0455] Step 5: Synthesis of Compound 100-5 Compound 100-4 (118 mg), M28 (114 mg), and zinc chloride (0.18 mL, 1.00 mol / L) were dissolved in methanol (10 mL) and reacted at 40°C for 2 hours. Sodium cyanoborohydride (18 mg) was added, and the reaction was continued at 40°C for 8 hours. After the reaction was completed, the mixture was quenched by adding ammonium chloride solution, concentrated, and purified by column chromatography (dichloromethane / methanol) to obtain compound 100-5 (177 mg). ESI-MS m / z: 596.27 1 / 2 [M+2H] + .

[0456] Step 6: Synthesis of Compound 100 Compound 100-5 (177 mg) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted for 1 hour at 25° C. After the reaction was completed, the mixture was concentrated and separated and purified by Pre-HPLC (C18 column, A: 0.05% trifluoroacetic acid aqueous solution, B: acetonitrile, concentration gradient: 20% B to 75% B, 11 minutes, flow rate: 15 mL / min, 254 nm), concentrated, neutralized with sodium bicarbonate solution, and the product precipitated. This was filtered to obtain compound 100 (29.9 mg).

[0457] ESI-MS m / z: 574.10 1 / 2 [M+2H] + . 1 H NMR(500MHz,Methanol-d4)δ9.21-9.19(m,1H),8.87-9.86(m,1H),7.68-7. 65(m,1H),7.46-7.35(m,4H),7.30-7.27(m,1H),7.26-7.22(m,1H),7.07-7. 04(m,1H),6.03(d,J=3.7Hz,1H),5.04-4.98(m,1H),4.52-4.40(m,5H),4.2 7-4.16(m,3H),3.82(dd,J=10.9,4.2Hz,1H),3.69-3.64(m,1H),3.63-3.57( m,1H),3.50-3.41(m,1H),2.93-2.83(m,2H),2.54-2.43(m,6H),2.39-2.28 (m,3H),2.25-2.09(m,3H),1.97-1.82(m,5H),1.81-1.72(m,4H),1.57(d,J= 7.0Hz,1H),1.51(d,J=7.0Hz,2H),1.29-1.25(m,3H),1.04(d,J=6.5Hz,3H), 0.91-0.87(m,3H),0.83-0.78(m,3H),0.74-0.70(m,2H),0.54-0.46(m,2H).

[0458] Example 104 Synthesis of compound (2S,4R)-1-((R)-2-(3-(1-((1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methyl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylpyrrolidine-2-carboxamide [ka]

[0459] Step 1: Synthesis of compound 104-1 M36 (80.0 mg) and 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (30.0 mg) were dissolved in dichloromethane (5 mL), and one drop of acetic acid was added. The mixture was allowed to react at room temperature for 1 hour. Sodium cyanoborohydride (17.8 mg) was then added and the mixture was allowed to react at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 73.0 mg of a white solid, i.e., compound 104-1. ESI-MS m / z: 764.3 [M+H] + .

[0460] Step 2: Synthesis of compound 104-2 104-1 (73.0 mg) was dissolved in DCM (1 mL) and TFA (1 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 55.0 mg of a white solid, i.e., compound 104-2. ESI-MS m / z: 664.1 [M+H]+ .

[0461] Step 3: Synthesis of compound 104-3 104-2 (55.0 mg) and M28 (61.6 mg) were dissolved in methanol (8 mL), and 1 M zinc chloride in ether (0.25 mL) was added. The mixture was allowed to react at 40 °C for 1 hour. Sodium cyanoborohydride (29.2 mg) was then added and the mixture was allowed to react at 60 °C for 8 hours. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 78.0 mg of a white solid, i.e., compound 104-3. ESI-MS m / z: 621.4 1 / 2[M+2H] + .

[0462] Step 4: Synthesis of Compound 104 104-3 (78.0 mg) was dissolved in DCM (2 mL) and TFA (1 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 15.3 mg of a white powder, i.e., compound 104.

[0463] ESI-MS m / z: 599.2 1 / 2 [M+2H] + .

[0464] Example 105: Synthesis of compound (2S,4R)-1-(R)-2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0465] Step 1: Synthesis of compound 105-1 A reaction flask was charged with commercially available tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (310.00 mg), intermediate M34 (791.14 mg), N,N-dimethylacetamide (6.00 mL), and N,N-diisopropylethylamine (0.68 mL). The mixture was reacted in a microwave oven at 150 °C for 1 hour. The mixture was extracted with EA and water, dried, and concentrated. The product was separated by column chromatography to give compound 105-1 (300 mg) as a yellow solid. ESI-MS m / z: 408.24 [M+H] + .

[0466] Step 2: Synthesis of compound 105-2 Compound 105-1 (300 mg), methanol (4.00 mL), water (1.00 mL), and lithium hydroxide monohydrate (185.35 mg) were added to a reaction flask and reacted at room temperature for 2 hours. After first concentrating the solvent, the mixture was adjusted to pH 3 with dilute hydrochloric acid, extracted with DCM and methanol, dried, and concentrated to give yellow oil 105-2 (270 mg). ESI-MS m / z: 394.23 [M+H] + .

[0467] Step 3: Synthesis of compound 105-3 Compound 105-2 (260 mg), M29-2 (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (241 mg), N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (0.33 mL) were added to a reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (301 mg) was added with stirring, and the mixture was allowed to react at room temperature for 0.5 hours. The mixture was diluted with water, extracted with EA, dried, concentrated, and the product was separated by column chromatography (DCM:MeOH=20:1) to give 310 mg of a yellow solid, which was then further separated by SFC to give single compound 105-3 (105 mg). ESI-MS m / z: 707.35 [M+H] + .

[0468] Step 4: Synthesis of compound 105-4 Compound 105-3 (105 mg) and dichloromethane (3 mL) were added to a reaction flask, and 4 M hydrogen chloride in dioxane (0.5 mL) was added with stirring. The mixture was allowed to react at room temperature for 0.2 hours, at which point a large amount of solid precipitated. The supernatant was discarded, and the solid was dissolved in methanol, diluted with DCM, and adjusted to pH 8 with aqueous sodium bicarbonate. The mixture was extracted, dried, and concentrated to give compound 105-4 (70 mg) as a yellow solid. ESI-MS m / z: 707.35 [M+H] + .

[0469] Step 5: Synthesis of compound 105-5 A reaction flask was charged with intermediate M28 (50 mg), compound 105-4 (56 mg), methanol (1.50 mL), 1,2-dichloroethane (1.50 mL), and 1M zinc chloride in ether (0.08 mL). The mixture was incubated at 40°C for 1 hour. Sodium cyanoborohydride (53.04 mg) was then added and the mixture was incubated at 40°C for 8 hours. The mixture was diluted with aqueous sodium bicarbonate, extracted with DCM, dried, concentrated, and separated by pre-TLC using a 15:1 mixture of DCM and ammonia in methanol to give 50 mg of a white solid, 105-5. ESI-MS m / z: 592.68 1 / 2 [M+2H] + .

[0470] Step 6: Synthesis of Compound 105 Compound 105-5 (50.00 mg), dichloromethane (1.50 mL), and trifluoroacetic acid (1.50 mL) were added to a reaction flask, and the mixture was reacted at room temperature for 0.5 hours. The mixture was concentrated and then separated by pre-HPLC to obtain compound 105 (21 mg).

[0471] ESI-MS m / z: 570.62 1 / 2 [M+2H] + . 1 H NMR(500MHz,CDCl3)δ9.32-9.01(m,1H),8.75-8.50(m,1 H),7.58-7.47(m,1H),7.33(dt,J=9.1,4.7Hz,2H),7.27(d,J=7.7Hz,4H),7.21-7.10(m,2H),6.85 (d,J=126.4Hz,1H),5.67(d,J=9.9Hz,1H),4.99-4.90(m,1H),4.76-4.68(m,1H),4.55(d,J=4.8Hz, 1H),4.36-4.12(m,3H),3.99-3.77(m,1H),3.66-3.42(m,7H),3.29-3.01(m,2H),2.53-2.34(m,8H ),2.24-1.96(m,5H),1.87-1.48(m,12H),1.39-1.21(m,9H),1.04-0.84(m,6H),0.83-0.74(m,3H).

[0472] Example 110 Synthesis of compound (3S,7aS)-7a-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methyl 4-(5-((R)-1-((2S,4R)-4-hydroxy-2-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)isoxazol-3-yl)piperazine-1-carboxylate [ka]

[0473] Step 1: Synthesis of compound 110-1 Compound M36 (73.0 mg) was added to the reaction solution of intermediate M32 and stirred at 20°C for 1 hour. Completion of the reaction was monitored by LCMS. The mixture was diluted with H2O and extracted twice with EA. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography gave a pale yellow solid (55.1 mg), which was compound 110-1. ESI-MS m / z: 635.2 1 / 2 [M+2H] +

[0474] Step 2: Synthesis of Compound 110 110-6 (55.1 mg) was added to DCM (2 mL) and TFA (1 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 22.2 mg of a white powder, i.e., compound 110.

[0475] ESI-MS m / z: 613.2 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.22(d,J=9.5Hz,1H),8.87(s,1H),7.88(s,1H),7.68-7.65(m,1H),7.44-7.38(m,4H),7.29(d,J=3.0Hz) ,1H),7.24(t,J=4.0Hz,1H),7.08-7.06(m,1H),6.11(d,J=10.5Hz,1H),5.03-5.01(m,1H),4.97-4.93(m,1H),4.85-4.80(m,1H),4.5 0-4.49(m,2H),4.19-4.08(m,2H),4.00-3.79(m,2H),3.79-3.38(m,12H),3.33-3.19(m,4H),3.10-3.00(m,1H),2.65-2.71(m,1H),2 .50-2.41(m,4H),2.40-2.30(m,2H),2.29-1.90(m,6H),1.89-1.72(m,5H),1.55-1.45(m,3H),1.40-1.20(m,2H),1.10-0.79(m,9H).

[0476] Example 111 Synthesis of compound (2S,4R)-1-(R)-2-(3-(4-(4-((1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0477] Step 1: Synthesis of compound 111-1 tert-Butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (400.00 mg), compound M34 (815.16 mg), and DIPEA (0.70 mL, 4.23 mmol) were added to DMA (3.00 mL) and reacted for 2 hours at 150 ° C. The mixture was diluted with 50 mL of water, extracted twice with EA, washed with saturated brine, and separated by column chromatography (PE:EA = 1:1) to obtain compound 111-1 (380.00 mg, 57.95%).

[0478] ESI-MS m / z: 465.33 [M+H] + .

[0479] Step 2: Synthesis of compound 111-2 Compound 111-1 (370.00 mg) and anhydrous lithium hydroxide (47.68 mg) were added to a mixed solvent of water (2.00 mL), methanol (2.00 mL), and tetrahydrofuran (2.00 mL) and reacted at room temperature for 1 hour. The mixture was diluted with water, adjusted to pH 3 with 1N aqueous hydrochloric acid, extracted three times with DCM, dried over anhydrous sodium sulfate, and concentrated to dryness to give compound 111-2 (350 mg, 97.54%).

[0480] ESI-MS m / z: 451.35 [M+H] + .

[0481] Step 3: Synthesis of compound 111-3 Compound 111-2 (340.00 mg), DIPEA (0.62 mL), HATU (373.01 mg), and compound M29-2 (250.10 mg) were added to dichloromethane (8.00 mL) in that order and reacted at room temperature for 2 hours. Water was added, and the mixture was extracted with DCM, washed with saturated brine, dried, and separated by column chromatography (DCM:MeOH = 91%:9%). Compound 111-3 (100 mg, 17.35%) was obtained by separation on a chiral column.

[0482] ESI-MS m / z: 764.55 [M+H] + .

[0483] Step 4: Synthesis of compound 111-4 Compound 111-3 (100.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 hour. The reaction mixture was adjusted to alkaline by adding 40 mL of saturated aqueous sodium bicarbonate solution, extracted twice with DCM, dried over anhydrous sodium sulfate, and concentrated to dryness to give compound 111-4 (80.00 mg, 92.06%).

[0484] ESI-MS m / z: 664.49 [M+H] + .

[0485] Step 5: Synthesis of compound 111-5 Compound 111-4 (80.00 mg), compound M28 (71.41 mg), and a 1.0 M zinc chloride solution in tetrahydrofuran (0.24 mL) were added to methanol (3.00 mL) and 1,2-dichloroethane (3.00 mL) and reacted at 40° C. for 2 hours. Sodium cyanoborohydride (75.72 mg) was then added and reacted at 40° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to give compound 111-5 (70.00 mg, 46.83%).

[0486] ESI-MS m / z: 621.24 1 / 2 [M+2H] + .

[0487] Step 6: Synthesis of Compound 111 Compound 111-5 (70.00 mg) and trifluoroacetic acid (1.00 mL) were dissolved in dichloromethane. The mixture was added to methane (2.00 mL) and reacted at room temperature for 1 hour. The reaction mixture was concentrated and purified by pre-HPLC to obtain Compound 111 (25.40 mg, 36.67%).

[0488] ESI-MS m / z: 599.17 1 / 2 [M+2H] + .

[0489] 1 H NMR(500MHz,Methanol-d4)δ9.20(d,J=8.0Hz,1H),8.87(s,1H),7.67(dd,J=8.8,5.9Hz,1H),7.46-7.36(m,4H),7.30(d,J=2.3Hz,1H),7.24(t,J=9.3H) z,1H),7.05(s,1H),6.08(s,1H),5.06-4.99(m,1H),4.49(dt,J=10.1,5.9H z,3H),4.45-4.38(m,2H),4.28-4.20(m,1H),3.84(dd,J=10.8,4.1Hz,1H),3 .68-3.42(m,8H),2.81(t,J=12.2Hz,2H),2.66-2.29(m,15H),2.18(t,J=11 .9Hz,6H),1.95(ddd,J=8.6,6.6,3.4Hz,1H),1.89-1.68(m,7H),1.58(d,J= 7.0Hz,1H),1.52(d,J=7.0Hz,3H),1.26-1.16(m,3H),1.04(d,J=6.5Hz,3H) ,0.92-0.86(m,4H),0.82(dd,J=16.2,7.6Hz,3H),0.72(s,2H),0.51(s,2H).

[0490] Example 112 Synthesis of compound (2S,4R)-1-(R)-2-(3-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0491] Step 1: Synthesis of compound 112-1 Compound M36 (50.00 mg), compound M28 (52.27 mg), and a 1.0 M zinc chloride solution in tetrahydrofuran (0.18 mL) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL) and reacted at 40° C. for 2 hours. Sodium cyanoborohydride (27.71 mg) was then added and reacted at 40° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to obtain compound 112-1 (15.00 mg, 14.87%).

[0492] ESI-MS m / z: 572.74 1 / 2 [M+2H] + .

[0493] Step 2: Synthesis of Compound 112 Compound 112-1 (15.00 mg) and trifluoroacetic acid (0.50 mL) were added to dichloromethane (1.00 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated and purified by pre-HPLC to give compound 112 (8.50 mg, 56.67%).

[0494] ESI-MS m / z: 550.57 1 / 2 [M+2H] + .

[0495] Example 113 Synthesis of compound (2S,4R)-1-(R)-2-(3-(3aR,6aS)-5-(1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0496] Step 1: Synthesis of compound 113-1 Compound (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (242.60 mg) was added to N,N-dimethylacetamide (2.50 mL), followed by triethylamine (0.72 mL). The reaction was heated to 120 °C and stirred for 0.5 h. Finally, M34 (500.00 mg) was added. The mixture was stirred at 120 °C for 5 h. The reaction was monitored for completion by LCMS. The mixture was diluted with HO and extracted twice with EA. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded a pale yellow solid (212.00 mg, 51.86% yield), identified as compound 113-1.

[0497] Step 2: Synthesis of compound 113-2 Compound 113-1 (212.00 mg) was added to a mixed solvent of tetrahydrofuran (2.00 mL), methanol (2.00 mL), and water (2.00 mL), followed by the addition of lithium hydroxide monohydrate (113.04 mg, 2.69 mmol). The mixture was stirred at 20°C for 1 hour. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure, adjusted to pH 5 with dilute hydrochloric acid, and extracted twice with dichloromethane / isopropanol = 5 / 1. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product was used directly in the next step. A pale yellow solid (209.00 mg) was obtained, i.e., compound 113-2.

[0498] Step 3: Synthesis of compound 113-3 Compound 113-2 (201.53 mg) and M29-2 (160.00 mg) were added to a 25 mL one-neck flask, and N,N-dimethylacetamide (3.00 mL), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (238.63 mg, 0.63 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.41 mmol) were added. The mixture was stirred at 20 °C for 0.5 h. The reaction was monitored for completion by LCMS. The mixture was diluted with HO and extracted twice with EA. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. The crude product was separated by SFC to give a pale yellow solid (96.00 mg), i.e., compound 113-3.

[0499] Step 4: Synthesis of compound 113-4 Compound 113-3 (96.00 mg) was added to a 25 mL one-neck flask, and dichloromethane (2.00 mL) and 4 M hydrogen chloride in dioxane (1.00 mL) were added. The mixture was stirred at 20 °C for 0.5 h. Completion of the reaction was monitored by LCMS. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO3 solution, extracted twice with dichloromethane / isopropanol = 5 / 1, washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was used directly in the next step. A pale yellow solid (84.00 mg) was obtained, i.e., compound 113-4.

[0500] Step 5: Synthesis of compound 113-5 Compound M28 (70.00 mg) and 113-4 (83.99 mg) were added to a 25 mL one-neck flask, and methanol (2.00 mL) and zinc chloride (0.18 mL, 1.00 mol / L) were added. The reaction mixture was heated to 40 °C and stirred for 2 h. Finally, sodium cyanoborohydride (25.98 mg, 0.41 mmol) was added, and the mixture was stirred at 50 °C for 12 h. The reaction was monitored for completion by LCMS. The mixture was concentrated under reduced pressure and purified by column chromatography to give a pale yellow solid (88.00 mg, 63.72% yield), identified as compound 113-5.

[0501] Step 6: Synthesis of Compound 113 Compound 113-5 (88.00 mg) was added to a 25 mL one-neck flask, and dichloromethane (4.00 mL) and trifluoroacetic acid (1.50 mL) were added. The mixture was stirred at room temperature for 0.5 hours. The reaction was monitored for completion by LCMS. After concentration under reduced pressure, the crude product was purified by HPLC to give the pure product as a white solid (42.20 mg, 48.01% yield), i.e., Compound 113.

[0502] ESI-MS m / z: 563.70 1 / 2 [M+2H] +

[0503] 1H NMR(500MHz,Methanol-d4)δ9.08(dd,J=7.3,2.6Hz,1H),8.77(d,J=6.3Hz,1H),7.57(dd,J=9.1,5 .7Hz,1H),7.39-7.23(m,5H),7.20(dt,J=4.3,2.6Hz,1H),7.14(td,J=9.3,4.7Hz,1H),7.01-6.95( m,1H),5.89-5.85(m,1H),4.92(d,J=7.0Hz,1H),4.50(s,2H),4.39(dt,J=11.7,4.1Hz,2H),4.35-4 .30(m,2H),4.19-4.09(m,1H),3.71(dt,J=10.7,3.8Hz,1H),3.58-3.48(m,2H),3.38-3.31(m,1H), 3.25(d,J=6.3Hz,2H),3.04(q,J=9.7,8.3Hz,2H),2.83(s,3H),2.49(d,J=31.0Hz,3H),2.37(d,J=2 .0Hz,3H),2.26(dt,J=9.7,6.6Hz,1H),2.12-2.02(m,3H),1.87-1.80(m,1H),1.77-1.72(m,1H),1. 67(dt,J=11.7,7.0Hz,2H),1.46(dd,J=7.0,3.7Hz,2H),1.40(d,J=7.0Hz,3H),0.93(dt,J=6.6,3.1 Hz,3H),0.80-0.77(m,4H),0.76(d,J=6.3Hz,3H),0.71(d,J=7.2Hz,2H),0.63(s,2H),0.45(s,2H).

[0504] Example 114 Synthesis of compound (2S,4R)-1-((R)-2-(3-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0505] Step 1: Synthesis of compound 114-1 Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (567.0 mg), tert-butyl 4-hydroxypiperidine-1-carboxylate (573.0 mg), and triphenylphosphine (1.12 g) were dissolved in THF (10 mL). Under nitrogen gas protection, diisopropyl azodicarboxylate (863 mg) was slowly added and the reaction mixture was allowed to react at 60 °C for 4 hours. Completion of the reaction was monitored by LCMS. EA (20 mL) was added to the reaction mixture, which was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 850.0 mg of a white solid, i.e., compound 114-1. ESI-MS m / z: 383.2 [M+H] + .

[0506] Step 2: Synthesis of compound 114-2 Compound 114-1 (850.0 mg) was added to methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (467.0 mg) was added. The reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored for completion by LCMS. The pH of the reaction mixture was adjusted to 3, EA (20 mL) was added, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 825.0 mg of a white solid, i.e., compound 114-2. ESI-MS m / z: 369.2 [M+H] + .

[0507] Step 3: Synthesis of compound 114-3 Compound 114-2 (825.0 mg), (2S,4R)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (821 mg), and HATU (1028 mg) were dissolved in DMF (10 mL), DIPEA (1.18 mL) was added, and the mixture was allowed to react at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. EA (20 mL) and saturated brine (20 mL) were added to the reaction mixture, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1291.0 mg of a white solid, i.e., compound 114-3. ESI-MS m / z: 682.3 [M+H] + .

[0508] Step 4: Synthesis of compound 114-4 Compound 114-3 (1291 mg) was separated by SFC and concentrated to give 502 mg of a white solid, i.e., compound 114-4. ESI-MS m / z: 682.3 [M+H] + .

[0509] Step 5: Synthesis of compound 114-5 114-4 (502.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 426 mg of a white solid, i.e., compound 114-5. ESI-MS m / z: 582.3 [M+H] + .

[0510] Step 6: Synthesis of compound 114-6 Compound 114-5 (200.0 mg) and M28 (207 mg) were dissolved in methanol (10 mL), and 1.0 M zinc chloride diethyl ether solution (0.52 mL) was added. The mixture was allowed to react at 40 °C for 1 hour. Sodium cyanoborohydride (64.8 mg) was then added and the mixture was allowed to react at 60 °C for 12 hours. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 310 mg of a white solid, i.e., compound 114-6. ESI-MS m / z: 579.8 1 / 2 [M+2H] + .

[0511] Step 7: Synthesis of Compound 114 114-6 (310 mg) was added to DCM (10 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 48.0 mg of a white powder, i.e., compound 114.

[0512] ESI-MS m / z: 558.1 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.19(d,J=8.4Hz,1H),8.86(s,1H),7.66(dd,J=9.0,5.9Hz,1H),7.47-7.35(m,4H),7.29(t,J=2.5Hz,1H),7.24( dd,J=12.5,6.2Hz,1H),7.07(t,J=2.4Hz,1H),5.98(d,J=1.8Hz,1H),5.08-4.96(m,1H),4.63-4.35(m,7H),4.24(t,J=13.8Hz,1H),3.86-3.78 (m,1H),3.67-3.39(m,4H),2.87(s,2H),2.57-2.29(m,9H),2.25-2.10(m,3H),2.02(d,J=5.6Hz,3H),1.95(ddd,J=13.2,8.7,4.7Hz,1H),1.82 (dd,J=35.3,10.7Hz,7H),1.51(d,J=7.0Hz,4H),1.27(s,2H),1.03(t,J=15.0Hz,4H),0.81(dd,J=16.3,7.5Hz,4H),0.72(s,3H),0.50(s,2H).

[0513] Example 115 Synthesis of compound (2S,4R)-1-(R)-2-(3-(4-(1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0514] Step 1: Synthesis of compound 115-1 Compound M36 (90.00 mg), tert-butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (63.28 mg), and 1.0 M zinc chloride in tetrahydrofuran (0.32 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL) and reacted at 40 ° C. for 2 hours. Sodium cyanoborohydride (49.90 mg) was added and reacted at 40 ° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 115-1 (87.00 mg, 73.35%).

[0515] ESI-MS m / z: 750.59 [M+H] + .

[0516] Step 2: Synthesis of compound 115-2 Compound 115-1 (87.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 hour. The reaction mixture was adjusted to alkaline by adding 40 mL of saturated aqueous sodium bicarbonate solution, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 90%:10%) to give compound 115-2 (60.00 mg, 79.59%).

[0517] ESI-MS m / z: 650.48 [M+H] + .

[0518] Step 3: Synthesis of compound 115-3 Compound 115-2 (50.00 mg), compound M28 (42.19 mg), and a 1.0 M zinc chloride solution in tetrahydrofuran (0.15 mL) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL) and reacted at 40° C. for 2 hours. Sodium cyanoborohydride (24.16 mg) was then added and reacted at 40° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to give compound 115-3 (35.00 mg, 38.49%).

[0519] ESI-MS m / z: 614.18 1 / 2 [M+2H] + .

[0520] Step 4: Synthesis of Compound 115 Compound 115-3 (35.00 mg) and trifluoroacetic acid (0.50 mL) were added to dichloromethane (1.00 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated and purified by pre-HPLC to give compound 115 (11.40 mg, 33.59%).

[0521] ESI-MS m / z: 592.27 1 / 2 [M+2H] + .

[0522] Example 116 Synthesis of compound (2S,4R)-1-(R)-2-(3-(4-(1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)azetidin-3-yl)piperazin-1-yl)isoxazol-5-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0523] Step 1: Synthesis of compound 116-1 Compound M36 (80.00 mg), tert-butyl 3-oxoazetidine-1-carboxylate (72.52 mg), and a 1.0 M solution of zinc chloride in tetrahydrofuran (0.28 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL) and reacted at 40° C. for 2 hours. Sodium cyanoborohydride (44.37 mg) was then added and reacted at 40° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to obtain compound 116-1 (60.00 mg, 58.56%).

[0524] ESI-MS m / z: 722.57 [M+H] + .

[0525] Step 2: Synthesis of compound 116-2 Compound 116-1 (60.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 hour. The reaction mixture was adjusted to alkaline by adding 40 mL of saturated aqueous sodium bicarbonate solution, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 90%:10%) to give compound 116-2 (40.00 mg, 77.41%).

[0526] ESI-MS m / z: 622.46 [M+H] + .

[0527] Step 3: Synthesis of compound 116-3 Compound 116-2 (40.00 mg), compound M28 (45.75 mg), and a 1.0 M zinc chloride solution in tetrahydrofuran (0.13 mL) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL) and reacted at 40° C. for 2 hours. Sodium cyanoborohydride (22.20 mg) was then added and reacted at 40° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to give compound 116-3 (30.00 mg, 38.93%).

[0528] ESI-MS m / z: 600.30 1 / 2 [M+2H] + .

[0529] Step 4: Synthesis of Compound 116 Compound 116-3 (30.00 mg) and trifluoroacetic acid (0.50 mL) were added to dichloromethane (1.00 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated and purified by pre-HPLC to give compound 116 (15.00 mg, 49.67%).

[0530] ESI-MS m / z: 578.14 1 / 2 [M+2H] + .

[0531] 1H NMR(500MHz,Methanol-d4)δ9.24(d,J=3.7Hz,1H),8.87(d,J=3.2Hz,1H),7.67(dt,J=9.1,5.5Hz,1H),7.46-7.38(m,4H),7.31-7.28(m,1H),7 .27-7.22(m,1H),7.06(t,J=2.6Hz,1H),6.10-6.00(m,1H),5.07-4.99 (m,1H),4.59-4.48(m,2H),4.45-4.35(m,3H),4.30(t,J=13.4Hz,1H),4 .16(s,2H),3.84(dd,J=10.8,4.2Hz,1H),3.62(dt,J=29.2,9.1Hz,3H),3.47(dd,J=17.9,8.2Hz,1H),2.50-2.29(m,10H),2.24-2.10(m,3H),2 .03(s,1H),2.00-1.92(m,2H),1.85(s,1H),1.82-1.74(m,2H),1.58(d d,J=7.0,2.9Hz,1H),1.52(d,J=7.0Hz,3H),1.31-1.26(m,10H),1.05(d ,J=6.5Hz,3H),0.85(ddd,J=24.4,15.5,7.1Hz,12H).

[0532] Example 117 Synthesis of compound (2S,4R)-1-((S)-2-(4-(5-(1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0533] Step 1: Synthesis of compound 117-1 A reaction flask was charged with tert-butyl 4-hydroxypiperidine-1-carboxylate (3.47 g), 6-bromopyridin-3-ol (2.00 g), tetrahydrofuran (50.00 mL), and triphenylphosphine (3.92 g). The mixture was cooled to 0°C, and diisopropyl azodicarboxylate (3.02 g) was slowly added. After the addition was complete, the mixture was returned to room temperature and reacted for 6 hours. The mixture was diluted with water, extracted with EA, dried, and concentrated. The product was separated by column chromatography (PE:EA = 4:1) to obtain colorless liquid compound 117-1 (3.3 g). ESI-MS m / z: 301.1 [M+Ht-Bu] + .

[0534] Step 2: Synthesis of compound 117-2 Compound 117-1 (1.00 g), bis(triphenylphosphine)palladium dichloride (0.10 g), triethylamine (4.67 mL), and tetrahydrofuran (5.00 mL) were added to a reaction flask. After purging with nitrogen gas, the mixture was allowed to react at room temperature for 10 minutes. Cuprous iodide (0.03 g) and ethynyltrimethylsilane (0.41 g) were added, and the mixture was allowed to react at room temperature for 2.5 hours. The reaction mixture was purified directly by column chromatography (PE:EA = 4:1) to give yellow solid 117-2 (930 mg). ESI-MS m / z: 375.2 [M+H] + .

[0535] Step 3: Synthesis of compound 117-3 Compound 117-2 (930.00 mg), methanol (3.00 mL), and potassium carbonate (686.35 mg) were added to a reaction flask and reacted at room temperature for 1 hour. The mixture was filtered, the filter cake was washed three times with EA, and the mother liquor was concentrated and purified by column chromatography (PE:EA = 2:1) to give yellow solid 117-3 (702 mg). ESI-MS m / z: 303.4 [M+H] + .

[0536] Step 4: Synthesis of compound 117-4 Compound 117-3 (99.33 mg), M29 (100.00 mg), copper sulfate (31.46 mg), sodium ascorbate (112.80 mg), tetrahydrofuran (1.50 mL), tert-butanol (1.50 mL), and water (1.50 mL) were added to a reaction flask and reacted at 60 °C for 2 hours. The mixture was concentrated, extracted with DCM, dried, and concentrated. Purification by column chromatography (DCM:ammonia / methanol = 25:1) afforded pale yellow solid 117-4 (91 mg). ESI-MS m / z: 759.4 [M+H] + .

[0537] Step 5: Synthesis of compound 117-5 A reaction flask was charged with 117-4 (91.00 mg), dichloromethane (3.00 mL), and 4M hydrogen chloride in dioxane (0.18 mL). The mixture was allowed to react at room temperature for 0.2 hours. A large amount of solid precipitated. The reaction mixture was decanted, the solid dissolved in methanol, diluted with DCM, and adjusted to pH 8 with aqueous sodium bicarbonate, extracted, dried, and concentrated. Compound 117-5 (72 mg) was obtained. ESI-MS m / z: 659.4 [M+H] + .

[0538] Step 6: Synthesis of compound 117-6 Compound 117-5 (61.14 mg), intermediate M28 (50.00 mg), methanol (1.00 mL), 1,2-dichloroethane (1.00 mL), and zinc chloride (11.50 mg) were added to a reaction flask and reacted at 40 °C for 1 hour. Sodium cyanoborohydride (53.04 mg) was then added and the reaction continued for 4 hours. The solvent was concentrated, diluted with water, extracted with DCM and MeOH, dried, and concentrated. Separation and purification by pre-TLC yielded yellow solid 117-6 (52 mg). ESI-MS m / z: 618.8 1 / 2 [M+2H] + .

[0539] Step 7: Synthesis of Compound 117 Compound 117-6 (51.00 mg), dichloromethane (1.00 mL), and trifluoroacetic acid (1.00 mL) were added to a reaction flask and reacted at room temperature for 0.6 hours. The mixture was concentrated, and then DCM was added to dissolve the mixture. The reaction mixture was added to ice-cooled aqueous sodium bicarbonate solution, adjusted to pH 8, extracted with DCM and methanol, dried, and concentrated. The mixture was purified by pre-TLC using a developing solvent of DCM:MeOH=11:1 to give compound 117 (24 mg).

[0540] ESI-MS m / z: 596.66 1 / 2 [M+2H] + . 1 H NMR(500MHz,CDCl3)δ9.12(d,J=12.6Hz,1H),8.65(s,1H),8.52-8.35(m,1H),8.11(d,J=27.8Hz,1H ),7.92-7.70(m,2H),7.53-7.39(m,1H),7.28(m,1H),7.23-7.03(m,6H),5.18-5.00(m,2H),4.38(m ,8H),3.70(m,2H),3.24(d,J=73.9Hz,3H),2.77(s,2H),2.49(m,8H),2.33(d,J=8.2Hz,4H),2.13-1 .84(m,7H),1.79-1.53(m,5H),1.45(t,J=9.8Hz,3H),1.34-1.17(m,5H),1.06(s,3H),0.75(s,6H).

[0541] Example 118 Synthesis of compound (2S,4R)-1-((S)-2-(4-(6-(7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0542] Step 1: Synthesis of compound 118-1 tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (280.00 mg), 5-ethynyl-2-fluoropyridine (224.76 mg), and cesium carbonate (1209.31 mg) were added to DMSO (3.00 mL) and reacted for 3 hours at 50° C. 40 mL of water was added to the reaction mixture, which was then extracted twice with EA, dried over anhydrous sodium sulfate, and separated by column chromatography (PE:EA = 75%:25%) to obtain compound 118-1 (290.00 mg, 71.59%).

[0543] ESI-MS m / z: 328.33 [M+H] + .

[0544] Step 2: Synthesis of compound 118-2 Compound 118-1 (121.90 mg), compound M29 (170.00 mg), sodium ascorbate (184.40 mg), and copper sulfate (59.42 mg) were added to THF / tetrahydrofuran (2.00 mL), water (2.00 mL), and tert-butanol (2.00 mL) and reacted at room temperature for 3 hours. 50 mL of water was added to the reaction mixture, which was then extracted twice with EA, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 93%:7%) to give compound 118-2 (230 mg, 78.80%).

[0545] ESI-MS m / z: 784.61 [M+H] + .

[0546] Step 3: Synthesis of compound 118-3 Compound 118-2 (230.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) in that order and reacted at room temperature for 1 hour. The reaction mixture was adjusted to alkaline by adding 40 mL of saturated aqueous sodium bicarbonate solution, extracted twice with DCM, dried over anhydrous sodium sulfate, and concentrated to dryness to give compound 118-3 (200.00 mg, 99.68%).

[0547] ESI-MS m / z: 684.50 [M+H] + .

[0548] Step 4: Synthesis of compound 118-4 Compound 118-3 (190.00 mg), compound M28 (164.63 mg), and a 1.0 M zinc chloride solution in tetrahydrofuran (0.56 mL, 1.00 mol / L) were added to methanol (3.00 mL) and 1,2-dichloroethane (3.00 mL) and reacted at 60° C. for 2 hours. Sodium cyanoborohydride (87.28 mg) was then added and reacted at 60° C. for 3 hours. The reaction mixture was concentrated, 30 mL of water was added, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to give compound 118-4 (100.00 mg, 28.56%).

[0549] ESI-MS m / z: 631.21 1 / 2 [M+2H] + .

[0550] Step 5: Synthesis of Compound 118 Compound 118-4 (100.00 mg) and TFA / trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 hour. The reaction mixture was concentrated and purified by pre-HPLC to give compound 118 (42.40 mg, 43.40%).

[0551] ESI-MS m / z: 609.32 1 / 2 [M+2H] + .

[0552] 1 H NMR(500MHz,Methanol-d4)δ9.11(d,J=5.8Hz,1H),8.76(d,J=6.8Hz,1H),8.38(d,J=1.7Hz ,1H),8.28(d,J=2.7Hz,1H),7.83(dt,J=6.9,3.1Hz,1H),7.57(dd,J=9.0,5 .8Hz,1H),7.37-7.26(m,4H),7.20(d,J=2.6Hz,1H),7.14(t,J=9.3Hz,1H), 6.97(t,J=2.7Hz,1H),6.36(dd,J=8.8,3.3Hz,1H),5.23(d,J=10.3Hz,1H), 4.95(q,J=7.0Hz,1H),4.46-4.29(m,5H),4.15(t,J=13.4Hz,1H),3.80(dt,J =25.0,7.5Hz,2H),3.65(s,4H),3.55(dd,J=12.3,4.8Hz,1H),3.36(q,J=10 .5Hz,1H),2.60-2.30(m,11H),2.17-2.01(m,3H),1.93(s,1H),1.87(ddd,J= 19.5,9.9,5.3Hz,1H),1.79-1.65(m,7H),1.42(d,J=7.0Hz,3H),1.22-1.15 (m,6H),1.05(t,J=8.2Hz,3H),0.75-0.68(m,6H),0.64(s,2H),0.43(s,2H).

[0553] Example 119: Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)-3,3-dimethylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0554] Step 1: Synthesis of compound 119-1 M39 (0.155 g) and M28 (0.100 g) were dissolved in 4.00 mL of anhydrous methanol, and 1 M zinc chloride diethyl ether solution (0.337 mL) was added. The mixture was incubated at 40°C for 1 hour. Sodium cyanoborohydride (106 mg) was then added and the mixture was incubated at 40°C for 4 hours. The reaction mixture was quenched by adding 50 mL of saturated aqueous sodium bicarbonate and extracted three times with a 10:1 mixture of DCM / MeOH. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (10:1 DCM / MeOH) to give 0.150 g of a yellow solid product, compound 119-1. ESI-MS m / z: 617.3 1 / 2 [M+2H] + .

[0555] Step 2: Synthesis of Compound 119 119-1 (150 mg) was dissolved in 5.00 mL of dichloromethane at room temperature, and then 2.00 mL of trifluoroacetic acid was added and the mixture was allowed to react at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the mixture was redissolved in dichloromethane. The solvent was evaporated again, and the mixture was redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, and solid sodium carbonate was added and stirred for 20 minutes. Anhydrous sodium sulfate was then added for drying, filtered, concentrated under reduced pressure, and purified by pre-HPLC to give 66.5 mg of a white solid product, Compound 119.

[0556] ESI-MS m / z: 595.3 1 / 2 [M+2H] + ; 1H NMR(500MHz,Methanol-d4)δ9.22(s,1H),8.91-8.83(m,1H),8.57-8.46(m,1H),7.79-7.62(m,3H),7.43(td,J=13.1,12.4,8.2Hz,3H),7 .34-7.18(m,4H),7.05(dt,J=6.5,3.2Hz,1H),5.57(s,1H),5.05(p,J=6.5,6.0Hz,1H),4.60-4.37(m,5H),4.25(t,J=15.0Hz,1H),3.93-3 .77(m,2H),3.63(dd,J=34.6,13.4Hz,2H),3.48(t,J=11.2Hz,1H),3.22(dd,J=21.4,11.5Hz,3H),2.54(s,2H),2.47-2.39(m,2H),2.27- 2.01(m,5H),1.76(dd,J=23.1,11.4Hz,5H),1.55(dd,J=7.0,1.9Hz,2H),1.33-1.21(m,4H),1.12(s,3H),0.85-0.67(m,5H),0.53(s,2H).

[0557] Example 120: Synthesis of compound (2S,4R)-1-((S)-2-(5-(((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methoxy)methyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0558] Step 1: Synthesis of compound 120-1 M31 (100 mg) was dissolved in 3 mL of THF, NaH (12 mg) was added, and the mixture was stirred at room temperature for 30 minutes. 3-Bromopropyne (15 μL) was then added, and a nitrogen gas balloon was inserted. The mixture was stirred at 25°C for 2 hours. The reaction was monitored for completion by LC-MS. The reaction mixture was quenched by slowly adding 10 mL of saturated ammonium chloride solution, extracted three times with EA, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the mixture was purified by column chromatography to give 65 mg of a pale yellow solid, i.e., compound 120-1. ESI-MS m / z: 714 [M+H] + .

[0559] Step 2: Synthesis of compound 120-2 Compound 120-1 (65 mg) and M29 (50 mg) were dissolved in 2 mL of THF, 2 mL of HO, and 2 mL of tert-butanol. Sodium ascorbate (47 mg) and anhydrous copper sulfate (13 mg) were then added sequentially. The reaction was allowed to proceed at room temperature for 0.5 hours, and the reaction was monitored for completion by LCMS. 20.0 mL of water was added to the reaction mixture, and the mixture was extracted three times with DCM:MeOH = 4:1, each time with 20 mL of water. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give 54 mg of a pale yellow solid, i.e., compound 120-2. ESI-MS m / z: 586 1 / 2 [M+2H] + .

[0560] Step 3: Synthesis of Compound 120 120-2 (54 mg) was dissolved in 2 mL of DCM, and then 1 mL of TFA was added. The reaction was allowed to proceed at room temperature for 30 minutes, and the completion of the reaction was monitored by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to obtain 18.4 mg of a white powder, i.e., compound 120.

[0561] ESI-MS m / z: 564 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.21-9.20(m,1H),8.87(s,1H),8.14(s,1H),7.68-7.65(m,1H),7.44-7.39(m,4H),7.30-7.29(m,1H),7. 26-7.21(m,1H),7.07-7.06(m,1H),5.31(d,J=10.2Hz,1H),4.62-4.60(m,10H),4.54-4.45(m,4H),4.39-4.17(m,3H),3.90-3.80(m,2H) ),3.73-3.57(m,2H),3.51-3.39(m,3H),3.02-3.01(m,1H),2.57-2.51(m,1H),2.48-2.39(m,4H),2.29-2.04(m,6H),1.97-1.91(m,1H) ,1.89-1.85(m,1H),1.78-1.71(m,2H),1.69-1.62(m,2H),1.53-1.49(m,2H),1.30-1.27(m,5H),1.14-1.08(m,3H),0.83-0.73(m,6H).

[0562] Example 121 Synthesis of compound (2S,4R)-1-((S)-2-(4-(2-((3S,7aS)-7a-(((7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methoxy)pyridin-4-yl)-1H-1,2,3-triazol-1-yl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0563] Step 1: Synthesis of compound 121-1 Sodium hydride (26.6 mg) and M31 (150.0 mg) were dissolved in THF (5 mL) and stirred at room temperature for 0.5 hours. 4-Ethynyl-2-fluoropyridine (35.0 mg) was added to the reaction mixture and allowed to react at room temperature for 3 hours. Completion of the reaction was monitored by LCMS, and DCM (10 mL) was added to the reaction mixture, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 23.0 mg of a yellow solid, i.e., compound 121-1. ESI-MS m / z: 777.9 [M+H] + .

[0564] Step 2: Synthesis of compound 121-2 121-1 (23.0 mg), (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (13.5 mg), anhydrous copper sulfate (4.3 mg), and sodium ascorbate (15.3 mg) were dissolved in a THF / tert-butanol / water (1 / 1 / 1 mL) mixture and reacted at room temperature for 1 hour. Completion of the reaction was monitored by LCMS. DCM (10 mL) was added to the reaction mixture, washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 15.0 mg of a yellow solid, i.e., compound 121-2. ESI-MS m / z: 618.3 1 / 2 [M+2H] + .

[0565] Step 3: Synthesis of Compound 121 121-2 (15.0 mg) was added to DCM (2 mL) and TFA (1 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 5.7 mg of a white powder, i.e., compound 121.

[0566] ESI-MS m / z: 595.8 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.20(s,1H),8.87(s,1H),8.57(s,1H),8.47(s,1H),8.08-8.07(m,1H),7.68-7.66(m,1H),7.45-7.39(m,4H),7.29(s,1 H),7.26-7.22(m,1H),7.07(s,1H),6.81(d,J=10.0Hz,1H),5.37-5.35(d, J=10.0Hz,1H),5.06-5.02(m,3H),4.55-4.52(m,1H),4.46(s,2H),4.27-4 .21(m,1H),3.93-3.86(m,2H),3.58(s,1H),3.49-3.46(m,1H),2.91-2.88 (m,3H),2.66-2.62(m,1H),2.52-2.44(m,6H),2.35(s,2H),2.23-2.16(m, 3H),2.03-1.98(m,4H),1.81-1.76(m,5H),1.53-1.52(d,J=5.0Hz,3H),1. 31-1.27(d,J=15.0Hz,3H),1.17-1.16(d,J=5.0Hz,3H),0.83-0.79(m,6H).

[0567] Example 122 Synthesis of compound (2S,4R)-1-((S)-2-(4-(4-(((3S,7aS)-7a-((((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrrolopyrimidin-2-yl)oxy)methyl)-[4,3-d]pyrimidin-2-yl)butanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0568] Step 1: Synthesis of compound 122-1 In a 50 mL flask, 140 mg of (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((5S,7aS)-5-(hydroxymethyl)-2-methyltetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (M31) was added, and THF was added. 10 mL was added, cooled to 0°C, 41 mg of NaH was added, and the mixture was warmed to room temperature and reacted for 0.5 hours. 1-(bromomethyl)-4-ethynylbenzene (80 mg) was added, and the mixture was heated to 45°C and reacted for 1 hour. The mixture was cooled to 0°C, quenched with saturated ammonium chloride, extracted with EA, the organic phase was washed with water, washed with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain compound 122-1 (49 mg).

[0569] Step 2: Synthesis of compound 122-2 A 50 mL flask was charged with 122-1 (49 mg), (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (M29) (32 mg), sodium ascorbate (33 mg), copper sulfate (10 mg), tert-butanol 1 mL, THF 1 mL, and water 1 mL. The reaction was allowed to proceed at room temperature for 1 hour. The completion of the reaction was detected, and EA was added for extraction. The organic phase was washed with water, washed with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 122-2 (32 mg).

[0570] Step 3: Synthesis of Compound 122 A 50 mL flask was charged with 122-2 (32 mg), 3 mL of DCM, and 1 mL of TFA, and the mixture was reacted at room temperature for 0.5 hours. After detection, the solvent was evaporated under reduced pressure, DCM was added to dissolve the residue, and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The mixture was stirred, separated, washed with brine, dried over sodium sulfate, and filtered. The solvent was evaporated from the filtrate under reduced pressure to obtain a crude product, which was then purified by pre-HPLC to obtain compound 122 (13.3 mg).

[0571] ESI-MS m / z: 602.14 1 / 2 [M+2H] +

[0572] Example 123 Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-(((3S,7aS)-7a-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0573] Step 1: Synthesis of compound 123-1 A 10 mL flask was charged with M31 (100 mg), 2 mL of DCM, 75 mg of TEA, and 23 μL of methanesulfonyl chloride, and the mixture was reacted at room temperature for 2 hours. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate, separated, washed with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain compound 123-1 (45 mg).

[0574] Step 2: Synthesis of compound 123-2 A 10 mL flask was charged with 123-1 (45 mg), 2 mL of DMF, cesium carbonate (145 mg), and 4-ethynylpiperidine (43 mg), and the mixture was heated to 60° C. for 3 hours. The mixture was diluted with EA, washed with water, washed with brine, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give the crude product, which was then purified by column chromatography to give compound 123-2 (39 mg).

[0575] Step 3: Synthesis of compound 123-3 A 10 mL flask was charged with 123-2 (39 mg), M29 (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (32 mg), sodium ascorbate (33 mg), copper sulfate (10 mg), tert-butanol 1 mL, THF 1 mL, and water 1 mL. The reaction was allowed to proceed at room temperature for 1 hour. The completion of the reaction was detected, and EA was added for extraction. The organic phase was washed with water, washed with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain compound 123-3 (25 mg).

[0576] Step 4: Synthesis of Compound 123 A 10 mL flask was charged with 123-3 (25 mg), 3 mL of DCM, and 1 mL of TFA, and the mixture was reacted at room temperature for 0.5 hours. After detection, the solvent was evaporated under reduced pressure, DCM was added to dissolve the residue, and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The mixture was stirred, separated, washed with brine, dried over sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to obtain crude product 123, which was then purified by pre-HPLC to obtain compound 123 (1.7 mg).

[0577] ESI-MS m / z: 590.80 1 / 2 [M+2H] +

[0578] Example 124 Synthesis of compound (2S,4R)-1-((S)-2-(4-(6-(((3S,7aS))-7a-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methoxy)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0579] Step 1: Synthesis of compound 124-1 To M31 (150.00 mg, 0.22 mmol) in tetrahydrofuran (6.00 mL) was added sodium hydride (26.64 mg, 60%, 0.67 mmol), cooled in an ice-water bath, and incubated at 0°C for 0.5 hours under nitrogen gas protection. 5-Ethynyl-2-fluoropyridine (53.77 mg, 0.44 mmol) was added, followed by incubation at 20°C for 4 hours. The reaction mixture was poured into 20 mL of saturated ammonium chloride, 15 mL of EA was added, and the organic phase was separated. The aqueous phase was extracted once more with 5 mL of EA. The organic phases were combined, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to yield 85 mg of a yellow foamy solid, identified as compound 124-1. ESI-MS m / z: 777.30 [M+H] + .

[0580] Step 2: Synthesis of compound 124-2 To a solution of 124-1 (60.00 mg), M29 (35.25 mg), tert-butanol (1.50 mL), and tetrahydrofuran (1.50 mL) was added copper sulfate (12.32 mg), sodium ascorbate (45.88 mg), and water (0.75 mL). The mixture was allowed to react at 20 °C for 1 hour, and the reaction completion was monitored by LCMS. The reaction mixture was added to 20 mL of water, extracted with EA, dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (MEOH:DCM = 1% to 7%) to give 75.00 mg of a yellow foamy solid, namely, compound 124-2. ESI-MS m / z: 617.7 1 / 2 [M+2H] + .

[0581] Step 3: Synthesis of compound 124 Trifluoroacetic acid (0.96 mL) was added to 124-2 (80.00 mg) in dichloromethane (4.00 mL) and the mixture was allowed to react at 20°C for 0.5 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was directly concentrated without heating and purified by pre-HPLC to give 31.80 mg of a white powder, i.e., compound 124.

[0582] ESI-MS m / z: 595.4 1 / 2 [M+2H] +. 1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),9.21(s,1H),8.99(s,1H),8.72(s,1H),8.67(s,1H),8.54-8.52(m,1H),8.19-8.17(m,1H), 7.78-7.75(m,1H),7.46-7.44(m,2H),7.38-7.36(m,2H),7.03(s,1H),6.91-6.88(m,1H),5.34(s,1H),5.19-5.18(m,1H),4.94- 4.91(m,1H),4.77-4.75(s,1H),4.42-4.38(m,3H),4.23-4.20(m,1H),4.16-4.11(m,2H),4.03-3.96(m,2H),3.79-3.69(m,2H), 2.39-2.34(m,3H),2.12-1.99(m,8H),1.67-1.62(m,3H),1.39-1.34(m,5H),1.17(s,3H),1.15(s,3H),1.08(s,3H),0.72(s,6H).

[0583] Example 125 Synthesis of compound (3S,7aS)-7a-((7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methyl-4-(((5-(R)-1-(2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-isoxazol-3-yl)oxy)methyl)piperidine-1-carboxylic acid ester [ka]

[0584] Step 1: Synthesis of compound 125-1 M35 (30.0 mg) was dissolved in THF (2 mL), CDI (10.8 mg) was added, and the mixture was allowed to react at 40 °C for 1 hour. M31 (39.7 mg) was then added, and the mixture was allowed to react at 60 °C for 12 hours. The reaction completion was monitored by LCMS. Methanol (5.0 mL) was added to quench the reaction, and the reaction mixture was directly concentrated and purified by column chromatography to obtain 35.0 mg of a pale yellow solid, i.e., compound 125-1. ESI-MS m / z: 650.3 1 / 2 [M+2H] + .

[0585] Step 2: Synthesis of Compound 125 125-1 (35.0 mg) was added to DCM (5 mL) and TFA (2 mL), and the reaction was allowed to proceed at room temperature for 10 minutes. The reaction mixture was monitored for completion by LCMS. The reaction mixture was directly concentrated and purified by pre-HPLC to give 15.3 mg of a white powder, i.e., compound 125.

[0586] ESI-MS m / z: 627.8 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.21(d,J=7.0Hz,1H),8.87(s,1H),7.68-7.65(m,1H ),7.44-7.36(m,4H),7.29(d,J=2.5Hz,1H),7.24(t,J=4.5Hz,1H),7.09-7.06(m,1 H),5.98-5.92(m,1H),5.26(d,J=10.0Hz,1H),5.03(d,J=7.0Hz,1H),4.52-4.49( m,2H),4.43-4.40(m,1H),4.34-4.24(m,2H),4.17-4.13(m,2H),4.07-4.01(m,2H) ,3.96-3.92(m,1H),3.84-3.81(m,1H),3.70-3.57(m,4H),3.48-3.42(m,2H),3.0 7-3.04(m,1H),2.93-2.83(m,3H),2.71-2.68(m,1H),2.47(s,3H),2.43-2.35(m,2 H),2.23-2.15(m,5H),2.06-1.92(m,4H),1.85-1.77(m,6H),1.51(d,J=7.0Hz,2H ),1.33-1.23(m,6H),1.05(d,J=6.5Hz,3H),0.91-0.87(m,3H),0.83-0.79(m,3H).

[0587] Example 126 Synthesis of compound (7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methyl ((3-(1-((S)-1-(2S,4R)-4-hydroxy-2-(S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)bicyclo[1.1.1]pentan-1-yl)methyl)carbamate [ka]

[0588] Step 1: Synthesis of compound 126-1 At 0 °C, 3-(((tert-butoxycarbonyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.00 g) and dimethylhydroxylamine hydrochloride (0.510 g) were dissolved in 10.0 mL of DCM. N,N-Diisopropylethylamine (2.17 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.99 g) were then added sequentially. The reaction was allowed to proceed at room temperature for 3 hours. The reaction mixture was quenched by slowly adding 50 mL of saturated sodium bicarbonate solution, extracted three times with EA, and the combined organic phases were washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1.40 g of a colorless oily product, Compound 126-1. ESI-MS m / z: 285 [M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ4.51(s,1H),3.66(s,3H),3.18(s,3H),2.80(s,2H),2.02(s,6H),1.44(s,9H).

[0589] Step 2: Synthesis of compound 126-2 Compound 126-1 (1.40 g) was dissolved in 20.0 mL of THF and cooled to -40°C. Lithium aluminum hydride (0.330 g) was added and allowed to warm to room temperature for 2 hours. The reaction mixture was then cooled to 0°C. 0.33 mL of water, 0.33 mL of 15% NaOH solution, and 0.33 mL of water were added dropwise to the reaction mixture. The mixture was stirred for 30 minutes and then filtered through diatomaceous earth to remove insoluble impurities. The filter cake was eluted with 20.0 mL of EA three times. The filtrate was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.910 g of a pale yellow oily product, compound 126-2. 1 H NMR(500MHz,Chloroform-d)δ9.50(s,1H),4.50(s,1H),3.15(s,2H),1.88(s,6H),1.38(s,9H).

[0590] Step 3: Synthesis of compound 126-3 Under N2 protection, compound 126-2 (0.910 g) was dissolved in 10.0 mL of anhydrous methanol, followed by the addition of anhydrous potassium carbonate (0.920 g) and dimethyl (1-diazo-2-oxopropyl)phosphonate (0.960 g) in that order, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and then purified by column chromatography (PE / EA = 5 / 1) to obtain 0.480 g of a white solid, compound 126-3. 1 H NMR (500MHz, Chloroform-d) δ4.47(s,1H),3.16(s,2H),2.09(s,1H),1.97(s,6H),1.44(s,9H).

[0591] Step 4: Synthesis of compound 126-4 At room temperature, compound 126-3 (0.400 g), M29 (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (0.818 g), sodium ascorbate (0.838 g), and anhydrous copper sulfate (0.234 g) were dissolved in a mixed solvent of 4.00 mL of tert-butanol, 4.00 mL of tetrahydrofuran, and 4.00 mL of water, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was quenched by adding 50 mL of aqueous solution and extracted three times with a mixed solvent of DCM / MeOH = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to give 1.050 g of a yellow solid product, compound 126-4. ESI-MS m / z: 678 [M+H] + ;

[0592] Step 5: Synthesis of compound 126-5 At room temperature, compound 126-4 (0.800 g) was dissolved in 10.0 mL of dichloromethane, and then 3.00 mL of trifluoroacetic acid was added and reacted at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the mixture was redissolved in dichloromethane, the solvent was evaporated again, and the mixture was redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, solid sodium carbonate was added, and the mixture was stirred for 20 minutes. Anhydrous sodium sulfate was then added for drying, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 0.600 g of a yellow solid product, compound 126-5. ESI-MS m / z: 578 [M+H] + ;

[0593] Step 6: Synthesis of compound 126-6 M31 (100 mg) was dissolved in tetrahydrofuran (2.00 mL) at room temperature, and triethylamine (0.165 mL), phenyl p-nitrochloroformate (60.0 mg), and 4-dimethylaminopyridine (5.50 mg) were added sequentially. The mixture was allowed to react overnight at room temperature. Compound 126-5 (103 mg) was then added and reacted at room temperature for 0.5 hours. An appropriate amount of water was added to the reaction mixture, which was then extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 10 / 1) to give 150 mg of a yellow solid product, Compound 126-6. ESI-MS m / z: 640.7 1 / 2 [M+2H] + ;

[0594] Step 7: Synthesis of Compound 126 Compound 126-6 (150 mg) was dissolved in 5.00 mL of dichloromethane at room temperature, and then 2.00 mL of trifluoroacetic acid was added and reacted at room temperature for 1 hour. After concentration under reduced pressure, the mixture was redissolved in dichloromethane, the solvent was evaporated again, and the mixture was redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, solid sodium carbonate was added, and the mixture was stirred for 20 minutes. Anhydrous sodium sulfate was then added for drying, followed by filtration and concentration under reduced pressure. The mixture was then purified by pre-HPLC to give 25.1 mg of a white solid product, Compound 126.

[0595] ESI-MS m / z:618.8 1 / 2[M+2H] + ; 1 H NMR(500MHz,Methanol-d4)δ9.20(s,1H),8.87(d,J=3.1Hz,1H),7.90(d,J=11.8Hz,1H),7.66(dd,J=9.1,5.8Hz,1H),7.42(qd,J=8.4,7.6,2.8Hz,4H),7.29(d,J=2.7Hz,1H),7.23(t,J=9.3Hz,1H),7.06(dd,J=5.7,2.6Hz,1H),5.25(d,J=10.3Hz,1H),5.03(q,J=6.5,6.1Hz,1H),4.94(s,2H),4.55-4.40(m,3H),4.36-4.22(m,2H),4.17(d,J=10.6Hz,1H),4.03(d,J=11.3Hz,1H),3.93(dd,J=10.8,6.0Hz,1H),3.90-3.79(m,2H),3.68(dd,J=29.6,13.7Hz,2H),3.51-3.38(m,2H),3.23(s,2H),3.04(s,1H),2.84(s,1H),2.70(d,J=15.5Hz,1H),2.51(d,J=7.1Hz,2H),2.41(d,J=15.6Hz,2H),2.28-2.11(m,4H),2.08-1.92(m,8H),1.89-1.73(m,5H),1.51(d,J=7.0Hz,3H),1.28(d,J=13.8Hz,3H),1.10(t,J=6.9Hz,3H),0.81(q,J=7.2Hz,3H),0.73(d,J=6.7Hz,3H).

[0596] Example 127 Synthesis of compound ((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolidin-3-yl)methyl 2-(1-(S)-1-(2S,4R)-4-hydroxy-2-(S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethylcarbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate [ka]

[0597] Step 1: Synthesis of compound 127-1 7-tert-Butoxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (500.0 mg) was dissolved in 5.0 mL of THF, and borane tetrahydrofuran solution (4.64 mL, 1 mol / L) was added. The mixture was allowed to react at room temperature for 1 hour. 5 mL of HCl / MeOH solution was slowly added to the reaction mixture, and the mixture was stirred until no more bubbles were generated. After that, 1 mol / L NaOH solution was added to adjust the pH to alkaline. Then, an appropriate amount of ethyl acetate was added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 450.0 mg of a colorless oily product, i.e., compound 127-1. ESI-MS m / z: 200 [M+H-56] +

[0598] Step 2: Synthesis of compound 127-2 127-1 (250.0 mg) was dissolved in 5.0 mL of DCM, Dess-Martin reagent (387.0 mg) was added, and the mixture was allowed to react at room temperature for 1 hour. An appropriate amount of ethyl acetate was added to the reaction mixture, and the precipitated solid was removed by filtration. The filtrate was adjusted to alkaline pH with 1 mol / L NaOH solution, and the organic phase was collected by extraction and separation. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 180.0 mg of a colorless oily product, i.e., compound 127-2. ESI-MS m / z: 198 [M+H-56]. + .

[0599] Step 3: Synthesis of compound 127-3 Under N2 protection, compound 127-2 (180 mg) was dissolved in 3.0 mL of anhydrous methanol, and anhydrous potassium carbonate (167 mg) and dimethyl (1-diazo-2-oxopropyl)phosphonate (174 mg) were added. The mixture was allowed to react at room temperature for 3 hours. An appropriate amount of water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The mixture was purified by column chromatography to give 110 mg of a colorless oily product, i.e., compound 127-3. ESI-MS m / z: 194 [M+H-56] + .

[0600] Step 4: Synthesis of compound 127-4 At room temperature, 127-3 (120 mg), M29 (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (218 mg), sodium ascorbate (223 mg), and anhydrous copper sulfate (62.0 mg) were dissolved in a mixed solvent of 2.00 mL of tert-butanol, 2.00 mL of tetrahydrofuran, and 2.00 mL of water, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with 50 mL of aqueous solution and extracted three times with a mixed solvent of DCM / MeOH = 10 / 1. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography (DCM / MeOH = 10 / 1) to give 300 mg of a yellow solid product, compound 127-4. ESI-MS m / z: 706 [M+H] + .

[0601] Step 5: Synthesis of compound 127-5 127-4 (300 mg) was dissolved in 5.00 mL of dichloromethane at room temperature, followed by the addition of 2.00 mL of trifluoroacetic acid and the resulting mixture was allowed to react at room temperature for 1 hour. The solvent was evaporated under reduced pressure, redissolved in dichloromethane, evaporated again, and redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, solid sodium carbonate was added, and the mixture was stirred for 20 minutes. Anhydrous sodium sulfate was then added for drying, filtered, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography (DCM / MeOH = 10 / 1) to give 225 mg of a yellow solid product, compound 127-5. ESI-MS m / z: 606 [M+H] + .

[0602] Step 6: Synthesis of compound 127-6 At room temperature, M31 (100 mg) was dissolved in tetrahydrofuran (2.00 mL), and the solution was added with triethylamine (0.165 mL), phenyl p-nitrochloroformate (60.0 mg), 4-Dimethylaminopyridine (5.50 mg) was added sequentially and the mixture was allowed to react overnight at room temperature. Then, 127-5 (99.2 mg) was added and the mixture was allowed to react at room temperature for 0.5 hours. An appropriate amount of water was added to the reaction mixture, which was then extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 155 mg of a yellow solid product, compound 127-6. ESI-MS m / z: 654.8 1 / 2 [M+2H] + .

[0603] Step 7: Synthesis of Compound 127 127-6 (155 mg) was dissolved in 5.00 mL of dichloromethane at room temperature, followed by the addition of 2.00 mL of trifluoroacetic acid and the resulting mixture was allowed to react at room temperature for 1 hour. The solvent was evaporated under reduced pressure, the mixture was redissolved in dichloromethane, the solvent was evaporated again, and the mixture was redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, sodium carbonate was added, and the mixture was stirred for 20 minutes. Anhydrous sodium sulfate was added for drying, followed by filtration. The solvent was evaporated under reduced pressure, and the mixture was purified by pre-HPLC to give 26.8 mg of a white solid product, compound 127.

[0604] ESI-MS m / z: 632.9 1 / 2 [M+2H] + ; 1H NMR(500MHz,Methanol-d4)δ9.22(d,J=4.4Hz,1H),8.87(d,J=3.5Hz,1H),7.90(s,1H),7.66(dd,J=9. 1,5.8Hz,1H),7.42(q,J=8.6,7.8Hz,3H),7.34-7.22(m,2H),7.07(dd,J=10.1,2.6Hz,1H),5.25(d,J= 10.3Hz,1H),5.12-5.01(m,3H),4.94(s,5H),4.59(s,3H),4.52(t,J=8.5Hz,2H),4.43(d,J=25.9Hz,1 H),4.30(ddd,J=29.2,17.1,12.1Hz,2H),4.16(d,J=10.9Hz,1H),4.06(dd,J=10.5,4.9Hz,1H),3.97- 3.86(m,2H),3.83(s,1H),3.66(dd,J=24.0,13.8Hz,2H),3.61-3.55(m,1H),3.46(d,J=12.2Hz,2H),3 .40-3.36(m,1H),3.05(s,1H),2.70(d,J=15.4Hz,1H),2.55(dt,J=10.9,6.5Hz,1H),2.41(d,J=15.8H z,1H),2.31-2.14(m,5H),2.10-1.94(m,4H),1.85(s,1H),1.84-1.74(m,3H),1.69(d,J=5.6Hz,2H),1 .54(dd,J=25.8,6.3Hz,4H),1.30(dd,J=15.5,11.4Hz,5H),1.12(d,J=6.7Hz,3H),0.86-0.72(m,5H).

[0605] Example 128 Synthesis of compound (2S,4R)-1-((S)-2-(4-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0606] Step 1: Synthesis of compound 128-1 M29 (1000.0 mg), tert-butyl 3-ethynyl-1-azetidinecarboxylate (396.9 mg), anhydrous copper sulfate (314.6 mg), and sodium ascorbate (1128.2 mg) were dissolved in a THF / tert-butanol / water (10 / 10 / 10 mL) mixture and reacted at room temperature for 3 hours. Completion of the reaction was monitored by LCMS. DCM (30 mL) was added to the reaction mixture, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 628.0 mg of a yellow solid, i.e., compound 128-1. ESI-MS m / z: 638.3 [M+H] + .

[0607] Step 2: Synthesis of compound 128-2 128-1 (295.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 165.0 mg of a white solid, i.e., compound 128-2. ESI-MS m / z: 538.3 [M+H] + .

[0608] Step 3: Synthesis of compound 128-3 128-2 (165.0 mg) and N-tert-butoxycarbonyl-4-piperidone (61.2 mg) were dissolved in methanol (5 mL), 1 M zinc chloride diethyl ether solution (0.46 mL) was added, and the mixture was reacted at 40 °C for 1 hour. Sodium cyanoborohydride (57.9 mg) was added, and the mixture was reacted at 40 °C for 10 minutes. The reaction completion was monitored by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 120.0 mg of a white solid, i.e., compound 128-3. ESI-MS m / z: 721.3 [M+H] + .

[0609] Step 4: Synthesis of compound 128-4 128-3 (120.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 80.0 mg of a white solid, i.e., compound 128-4. ESI-MS m / z: 621.3 [M+H] + .

[0610] Step 5: Synthesis of compound 128-5 128-4 (80.0 mg) and M28 (76.4 mg) were dissolved in methanol (5 mL), 1 M zinc chloride diethyl ether solution (0.19 mL) was added, and the mixture was reacted at 40 °C for 1 hour. Sodium cyanoborohydride (24.3 mg) was then added, and the mixture was reacted at 60 °C for 12 hours. The reaction completion was monitored by LCMS. The reaction was then quenched by adding saturated sodium bicarbonate solution (5.0 mL), and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 84.0 mg of a white solid, i.e., compound 128-5. ESI-MS m / z: 600.3 1 / 2 [M+2H]+ .

[0611] Step 6: Synthesis of Compound 128 128-5 (84.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 28.9 mg of a white powder, i.e., compound 128.

[0612] ESI-MS m / z: 578.2 1 / 2 [M+2H] + . 1 H NMR(500MHz,Methanol-d4)δ9.20(d,J=2.5Hz,1H),8.87(s,1H),8.04(s,1H),7.68-7.65(m ,1H),7.45-7.39(m,4H),7.29(d,J=2.5Hz,1H),7.24(t,J=4.5Hz,1H),7.06(t,J=2.5Hz,1H) ,5.27(d,J=10.0Hz,1H),5.03(q,J=7.0Hz,1H),4.50(t,J=8.5Hz,2H),4.47-4.44(m,1H),4 .42-4.39(m,2H),4.25(t,J=14.5Hz,1H),3.90-3.87(m,1H),3.82-3.78(m,2H),3.75-3.71( m,2H),3.67-3.58(m,1H),3.49-3.43(m,1H),3.26(q,J=7.5Hz,2H),3.10-3.04(m,2H),2.5 9-2.56(m,1H),2.47(s,1H),2.43-2.39(m,1H),2.23-2.17(m,2H),2.01-1.93(m,2H),1.87- 1.85(m,1H),1.81-1.73(m,4H),1.51(d,J=7.0Hz,2H),1.30-1.27(m,6H),1.12(d,J=7.0Hz, 3H),0.90-0.86(m,2H),0.84-0.79(m,3H),0.75(d,J=6.5Hz,3H),0.71(s,2H),0.49(s,1H).

[0613] Example 129 Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)piperidin-4-yl)methyl)azetidin-3-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0614] Step 1: Synthesis of compound 129-1 128-2 (300.0 mg) and 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (119.0 mg) were dissolved in methanol (8 mL), 1 M zinc chloride diethyl ether solution (0.61 mL) was added, and the mixture was reacted at 40 °C for 1 hour. Sodium cyanoborohydride (105.2 mg) was added, and the mixture was reacted at 40 °C for 10 minutes. The reaction completion was monitored by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 267.0 mg of a white solid, i.e., compound 129-1. ESI-MS m / z: 735.4 [M+H] + .

[0615] Step 2: Synthesis of compound 129-2 129-1 (267.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 230.0 mg of a white solid, i.e., compound 129-2. ESI-MS m / z: 635.4 [M+H] + .

[0616] Step 3: Synthesis of compound 129-3 M28 (100 mg) and compound 129-2 (128.5 mg) were dissolved in methanol (8 mL), 1M zinc chloride diethyl ether solution (0.25 mL) was added, and the mixture was reacted at 40 °C for 1 hour. Sodium cyanoborohydride (31.8 mg) was then added, and the mixture was reacted at 60 °C for 12 hours. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 82.0 mg of a white solid, i.e., compound 129-3. ESI-MS m / z: 607.3 1 / 2 [M+2H] + .

[0617] Step 4: Synthesis of Compound 129 129-3 (82.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 37.6 mg of a white powder, i.e., compound 129.

[0618] ESI-MS m / z: 585.2 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.20(d,J=8.0Hz,1H),8.87(s,1H),8.03(d,J=4.0Hz,1H),7 .67-7.64(m,1H),7.44-7.39(m,4H),7.29(d,J=2.5Hz,1H),7.23(t,J=9.0Hz,1H),7.06(t ,J=2.5Hz,1H),5.27(d,J=10.5Hz,1H),5.03(q,J=7.0Hz,1H),4.52-4.39(m,5H),4.24(t, J=13.5Hz,1H),3.90-3.87(m,1H),3.82-3.78(m,2H),3.74-3.71(m,2H),3.66-3.56(m,1H ),3.49-3.41(m,1H),3.26(q,J=7.5Hz,2H),3.10-3.03(m,2H),2.57-2.53(m,1H),2.47(s ,1H),2.41-2.37(m,3H),2.21-2.16(m,2H),1.98-1.91(m,2H),1.86-1.84(m,1H),1.80-1 .74(m,2H),1.69-1.66(m,2H),1.51(d,J=7.0Hz,2H),1.29-1.27(m,6H),1.12(d,J=6.5Hz ,3H),0.91-0.86(m,2H),0.83-0.79(m,3H),0.75-0.74(m,3H),0.70(s,2H),0.49(s,1H).

[0619] Example 130 Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-((1-((1-(((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)methylpiperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0620] Step 1: Synthesis of compound 130-1 M29 (800.0 mg), 1-tert-butoxycarbonyl-4-ethynylpiperidine (476.7 mg), anhydrous copper sulfate (251.7 mg), and sodium ascorbate (902.5 mg) were dissolved in a mixed solvent of THF / tert-butanol / water (10 / 10 / 10 mL) and reacted at room temperature for 3 hours. Completion of the reaction was monitored by LCMS. DCM (30 mL) was added to the reaction mixture, washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 800.0 mg of a yellow solid, i.e., compound 130-1. ESI-MS m / z: 666.3 [M+H] + .

[0621] Step 2: Synthesis of compound 130-2 130-1 (800.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 577.0 mg of a white solid, i.e., compound 130-2. ESI-MS m / z: 566.3 [M+H] + .

[0622] Step 3: Synthesis of compound 130-3 130-2 (577.0 mg) and 1-tert-butoxycarbonylpiperidine-4-carbaldehyde (217.5 mg) were dissolved in methanol (10 mL), 1 M zinc chloride diethyl ether solution (1.53 mL) was added, and the mixture was reacted at 40 °C for 1 hour. Sodium cyanoborohydride (192.3 mg) was then added, and the mixture was reacted at 40 °C for 10 minutes. The reaction was monitored for completion by LCMS. The reaction was then quenched by adding saturated sodium bicarbonate solution (5.0 mL), and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 356.0 mg of a white solid, i.e., compound 130-1. ESI-MS m / z: 764.1 [M+H] + .

[0623] Step 4: Synthesis of compound 130-4 130-3 (356.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated, and 1M NaOH solution was added until the reaction mixture reached pH = 8. DCM (20 mL) was added to the reaction mixture, and the organic phase was collected. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 198.0 mg of a white solid, i.e., compound 130-4. ESI-MS m / z: 664.1 [M+H] + .

[0624] Step 5: Synthesis of compound 130-5 130-4 (100.0 mg) and M28 (134.2 mg) were dissolved in methanol (10 mL), 1 M zinc chloride diethyl ether solution (0.25 mL) was added, and the mixture was reacted at 40 °C for 1 hour. Sodium cyanoborohydride (31.8 mg) was then added, and the mixture was reacted at 60 °C for 12 hours. The reaction completion was monitored by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction, and DCM (20 mL) was added to the reaction mixture. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 90.0 mg of a white solid, i.e., compound 130-5. ESI-MS m / z: 621.3 1 / 2 [M+2H] + .

[0625] Step 6: Synthesis of Compound 130 130-5 (90.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored for completion by LCMS. The reaction mixture was directly concentrated and separated by preparative liquid chromatography to give 41.2 mg of a white powder, i.e., compound 130. Got it.

[0626] ESI-MS m / z: 599.2 1 / 2 [M+2H] + . 1H NMR(500MHz,Methanol-d4)δ9.20(d,J=8.0Hz,1H),8.87(s,1H),7.89(s,1H),7.67-7.64 (m,1H),7.44-7.39(m,4H),7.29(d,J=3.0Hz,1H),7.23(t,J=9.5Hz,1H),7.06(d,J=3.0Hz ,1H),5.25(d,J=10.0Hz,1H),5.04(q,J=6.5Hz,1H),4.53-4.39(m,5H),4.23(t,J=13.0H z,1H),3.90-3.87(m,1H),3.81(d,J=11.0Hz,1H),3.66-3.56(m,1H),3.49-3.41(m,1H),3 .08(q,J=11.5Hz,2H),2.93(d,J=11.5Hz,2H),2.75-2.69(m,1H),2.58-2.54(m,1H),2.4 7(s,1H),2.41-2.38(m,1H),2.22-2.14(m,4H),2.09-2.04(m,2H),1.99-1.93(m,4H),1.8 6-1.84(m,1H),1.79-1.70(m,6H),1.57-1.51(m,4H),1.29-1.26(m,6H),1.12(d,J=6.5Hz ,3H),0.89-0.86(m,2H),0.84-0.79(m,3H),0.74-0.73(m,3H),0.71(s,2H),0.50(s,1H).

[0627] Example 131 Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-((((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0628] Step 1: Synthesis of compound 131-1 Compound M29 (100.0 mg) was placed in a 25 mL single-neck flask and dissolved in THF (2 mL). 1-Boc-4-ethynylpiperidine (55.0 mg), copper sulfate (35.2 mg), water (2 mL), tert-butanol (2 mL), and sodium ascorbate (160.0 mg) were added and reacted at room temperature for 0.5 hours. The reaction mixture was directly evaporated to dryness. Purification by column chromatography (DCM:MeOH = 12:1) yielded 104.2 mg of a pale yellow solid, compound 131-1. ESI-MS m / z: 666 [M+H] +

[0629] Step 2: Synthesis of compound 131-2 Compound 131-1 (104.2 mg) was placed in a 25 mL single-neck flask and dissolved in 4 M hydrogen chloride in dioxane (5 mL). Methanol (1 mL) was added and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was evaporated directly to dryness, and 5 mL of saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7-8. The mixture was then extracted with a mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate to obtain 79.0 mg of a yellow solid, compound 131-2. ESI-MS m / z: 566 [M+H] +

[0630] Step 3: Synthesis of compound 131-3 Compound 13-2 (79.0 mg) was placed in a 25 mL single-neck flask and dissolved in MeOH (3 mL). M28 (100.0 mg) and 1 M zinc chloride tetrahydrofuran solution (0.1 mL) were added, heated to 40 °C, and reacted for 2 hours. NaBH3CN (35.2 mg) was then added and reacted overnight. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (DCM:MeOH = 10:1) yielded 108.2 mg of a pale yellow solid, compound 131-3. ESI-MS m / z: 572 1 / 2 [M+2H] +

[0631] Step 4: Synthesis of Compound 131 Compound 131-3 (108.2 mg) was placed in a 25 mL single-neck flask, dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was evaporated directly to dryness, and 5 mL of saturated sodium bicarbonate solution was added to the mixture to adjust the pH to 7-8. The mixture was then extracted with a mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate, and the product was separated by pre-HPLC (CH3CN / HO = 30%-55%) to obtain 67.6 mg of a white solid, i.e., compound 131.

[0632] ESI-MS m / z: 550.1 1 / 2 [M+2H] +

[0633] 1 H NMR(500MHz,Methanol-d4)δ9.27-9.19(m,1H),8.87(s,1H),7.87(t,J=9.3Hz,1H ),7.66(dd,J=8.9,5.9Hz,1H),7.46-7.35(m,4H),7.29(d,J=2.5Hz,1H),7.23(t,J =9.2Hz,1H),7.09-7.04(m,1H),5.25(d,J=10.2Hz,1H),5.08-4.99(m,1H),4.59-4 .41(m,5H),4.25(dd,J=28.6,13.2Hz,1H),3.88(dd,J=10.9,3.8Hz,1H),3.79(dd, J=19.9,9.0Hz,1H),3.70-3.58(m,1H),3.45(d,J=6.9Hz,1H),3.22-3.06(m,2H), 2.94(dd,J=14.3,7.1Hz,1H),2.68(d,J=29.7Hz,2H),2.59-2.35(m,8H),2.14(dd, J=22.5,11.5Hz,6H),1.99-1.83(m,4H),1.81-1.58(m,5H),1.54-1.46(m,3H),1.2 6(dd,J=17.7,10.1Hz,4H),1.11(t,J=8.2Hz,3H),0.85-0.68(m,9H),0.51(s,2H).

[0634] Example 132 Compound (2S,4R)-1-((S)-2-(4-((4-((1-(( Synthesis of (7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperazin-1-yl)methyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0635] Step 1: Synthesis of compound 132-1 Compound M1 (1.0 g) was placed in a 25 mL single-neck flask and dissolved in DCM (10.0 mL). DIPEA (1.4 mL) and 3-bromopropyne (0.7 g) were added and reacted at room temperature for 5 hours. The reaction solution was directly evaporated to dryness. The product was purified by column chromatography (PE:EA = 1:1) to obtain 1.05 g of a pale yellow solid, compound 132-1.

[0636] Step 2: Synthesis of compound 132-2 Compound M29 (100.0 mg) was placed in a 25 mL single-neck flask and dissolved in THF (2 mL). Compound 132-1 (55.0 mg), copper sulfate (35.2 mg), water (2 mL), tert-butanol (2 mL), and sodium ascorbate (160.0 mg) were added and reacted at room temperature for 0.5 hours. The reaction solution was directly evaporated to dryness. The product was purified by column chromatography (DCM:MeOH = 12:1) to obtain 105.7 mg of a pale yellow solid, compound 132-2.

[0637] Step 3: Synthesis of compound 132-3 Compound 132-2 (105.7 mg) was placed in a 25 mL single-neck flask, dissolved in 4 M hydrogen chloride in dioxane (5 mL), and then methanol (1 mL) was added and reacted at room temperature for 1 hour. The reaction mixture was evaporated directly to dryness, and 5 mL of saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7-8. The mixture was then extracted with dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate to obtain 83.2 mg of a yellow solid, compound 132-3.

[0638] Step 4: Synthesis of compound 132-4 Compound 132-3 (83.2 mg) was placed in a 25 mL single-neck flask and dissolved in MeOH (3 mL). M28 (100.0 mg) and 1 M zinc chloride tetrahydrofuran solution (0.1 mL) were added, heated to 40 °C, and reacted for 2 hours. NaBH3CN (35.2 mg) was then added and reacted overnight. The reaction solution was directly evaporated to dryness. Separation and purification by column chromatography (DCM:MeOH = 10:1) yielded 94.3 mg of a pale yellow solid, compound 132-4.

[0639] Step 5: Synthesis of Compound 132 Compound 132-4 (94.3 mg) was placed in a 25 mL single-neck flask, dissolved in DCM (2 mL), and TFA (2 mL) was added. The mixture was allowed to react at room temperature for 1 hour. The reaction mixture was evaporated directly to dryness, and 5 mL of saturated sodium bicarbonate solution was added to the mixture. The pH of the mixture was adjusted to 7-8. The mixture was then extracted with a mixture of dichloromethane and isopropanol. The organic phase was dried over anhydrous sodium sulfate, and the product (CH3CN / HO = 30%-55%) was separated by pre-HPLC to obtain 36.1 mg of a white solid, i.e., compound 132.

[0640] LCMS: 1 / 2 [M+2H] + =557.57

[0641] 1H NMR(500MHz,DMSO-d6)δ9.22(s,1H),8.98(s,1H),8.50(d,J=7.2Hz,1H),7.97(d,J=13.6Hz,1H),7.81-7.72(m,1H),7.44(d,J=7.9 Hz,2H),7.40-7.29(m,4H),7.03(s,1H),5.24(d,J=10.1Hz,1H),5.11(d,J=44.3Hz,1H),4.97-4.84(m,1H),4.75(d,J=5.7Hz,1H), 4.44-4.23(m,5H),4.04(dd,J=26.8,13.5Hz,1H),3.74(d,J=6.9Hz,1H),3.65(s,1H),3.52(d,J=15.4Hz,3H),2.41-2.27(m,9H),2 .09(d,J=48.3Hz,4H),1.83-1.59(m,5H),1.37(d,J=6.8Hz,3H),1.17(d,J=11.3Hz,3H),1.02(d,J=6.8Hz,6H),0.74(d,J=7.3Hz,3 H), 0.63(s,5H), 0.40(s,2H).

[0642] Example 133 Synthesis of compound (2S,4R)-1-((S)-2-(4-(1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)cyclopropyl)methyl)piperidin-4-yl)phenyl)-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide [ka]

[0643] Step 1: Synthesis of compound 133-1 M29 (380 mg) and tert-butyl 4-(4-ethynylphenyl)piperidine-1-carboxylate (310 mg) were dissolved in tert-butanol (4 mL), tetrahydrofuran (4 mL), and water (4 mL). Anhydrous copper sulfate (120 mg) and sodium ascorbate (429 mg) were added and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was dried on a rotary evaporator, extracted with DCM and water, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by column chromatography (DCM / MeOH = 15:1) to give compound 133-1 (560 mg). ESI-MS m / z: 742.3 [M+H] + .

[0644] Step 2: Synthesis of compound 133-2 Compound 133-1 (300 mg) was dissolved in 6 mL of DCM and 4 M hydrogen chloride in dioxane (3 mL) and reacted at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM / isopropanol (3:1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to give compound 133-2...

Claims

1. A compound having the structure F-L-M, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, F is a KRAS protein-binding fragment represented by general formula (A), 【Chemistry 1】 The X is —O— or 【Chemistry 2】 is selected from The aforementioned 【Transformation 3】 are independently selected from a single bond or a double bond; The X ４ is CR ８ , C(R ８ ) ２ , O, N or NR ８ and R ８ are each independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, or C １－６ Alkyl group, C １－６ Haloalkyl group, —S—C １－６ alkyl group, -C ０－３ Alkylene-C ２－４ Alkenyl group, C １－６ Alkoxy group, C １－６ haloalkoxy group or C ３－１４ cycloalkyl groups, wherein said C ３－１４ Cycloalkyl group, C １－６ The alkyl group may optionally be one or more R ａ may be further substituted with The X ５ is selected from C, CH or N; The X ６ is CR １４ , C(R １４ ) ２ , O, N or NR １４ and R １４ are each independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, or C １－６ Alkyl group, C １－６ Haloalkyl group, —S—C １－６ alkyl group, -C ０－３ Alkylene-C ２－４ Alkenyl group, C １－６ Alkoxy group, C １－６ haloalkoxy group or C ３－１４ cycloalkyl groups, wherein said C ３－１４ Cycloalkyl group, C １－６ The alkyl group may optionally be one or more R ａ may be further substituted with The R ６ does not exist or C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or the 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with The R ９ is H, an amino group, a substituted amino group, a cyano group, C １－６ Alkyl group, C １－６ Alkoxy group, halogen, C ２－６ alkenyl group, or C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－６ The cycloalkyl group may optionally be one or more R ａ may be further substituted with The R １０ is absent, -O- or -NR １１ -, and R １１ is H, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group or C １－６ aminoalkyl groups, The R ７ is C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ an aryl group or a 5- to 18-membered heteroaryl group, ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ The aryl group or 5- to 18-membered heteroaryl group may optionally be one or more R ａ may be further substituted with The K is C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group may be a single ring, a fused ring, a spiro ring, or a bridged ring, and may optionally be one or more R ａ and said 3- to 14-membered heterocyclyl group is 【Chemistry 4】 Instead, wherein m and n are each independently selected from 0, 1, 2, 3, 4, or 5; L is a linking unit that links F and M, The L is 【Transformation 5】 is selected from where: The G ring or the D ring each independently represents C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with Each of the E's is independently -O-, -NH- or -NCH ３ Selected from - The Y １ , Y ２ are each independently absent, —O—, —NH—, a 3- to 6-membered nitrogen-containing heterocyclyl group, C １－６ Alkylene group, carbonyl group, ethynyl group or C ３－６ cycloalkyl groups, n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4; M is selected from VHL-binding fragments represented by general formula (III) or (IV), 【Transformation 6】 The X １ is selected from C, CH or N; The X ２ is selected from C, CH or N; The X ３ is selected from N, NH, O or S; The R １ is H, C １－６ selected from alkyl groups, halogens or cyano groups, preferably methyl groups, ethyl groups, F or cyano groups; The R ２ is H or C １－６ alkyl groups, preferably H or methyl groups; The R ３ is H, C １－６ Alkyl group, C １－６ Hydroxyalkyl group, or -(CH ２ )n-CO-NH-(CH ２ ) n-CH ３ wherein n is selected from 0, 1, 2, or 3; ３ is preferably H, a methyl group, a hydroxymethyl group, 【Transformation 7】 or -CH ２ —CO—NH—CH ３ and The R ４ teeth, 【Transformation 8】 or —NH—, The R ５ is H, C １－６ Alkyl group or C １－６ haloalkyl groups, The R １２ teeth, 【Chemistry 9】 is selected from The R ａ are each independently H, a hydroxy group, an amino group, an oxo group, a cyano group, a halogen, or C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, —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 -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 groups, 【Chemistry 10】 , C ２－６ Alkynyl group, —C ０－３ Alkylene-C ３－１４ cycloalkyl group, -C ０－３ alkylene-(3- to 14-membered heterocyclyl group), —C ０－３ Alkylene-C ６－１８ Aryl group or —C ０－３ alkylene-(5- to 18-membered heteroaryl group), １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —C ０－３ Alkylene-C ３－１４ cycloalkyl group, -C ０－３ alkylene-(3- to 14-membered heterocyclyl group), —C ０－３ Alkylene-C ６－１８ Aryl group or —C ０－３ The alkylene-(5- to 18-membered heteroaryl group) may optionally be one or more R ｂ may be further substituted with Each R ｂ are each independently H, a halogen, a hydroxy group, a cyano group, or C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Haloalkyl group, C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ an aryl group or a 5- to 18-membered heteroaryl group, １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Haloalkyl group, C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ The aryl or 5- to 18-membered heteroaryl group may optionally contain one or more halogen, C １－６ Alkyl group or C １－６ may be further substituted with a haloalkyl group, or Two Rs bonded to one atom ｂ together with the atoms to which they are both attached, form C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ forming an aryl group or a 5- to 18-membered heteroaryl group, ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ The aryl group or 5- to 18-membered heteroaryl group may optionally contain one or more of a halogen, an amino group, a hydroxy group, a cyano group, a C １－６ Alkyl group, C ３－６ Cycloalkyl group or C １－６ optionally further substituted with a haloalkyl group; or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

2. The L is 【Chemistry 11】 is selected from where: The G ring or the D ring each independently represents C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with Each of the E's is independently -O-, -NH- or -NCH ３ - is selected from, n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4; M is selected from VHL-binding fragments represented by general formula (V) or (IV), 【Chemistry 12】 The X １ is selected from C, CH or N; The X ２ is selected from C, CH or N; The X ３ is selected from N, NH, O or S; The R １ is H, C １－６ selected from alkyl groups, halogens or cyano groups, preferably methyl groups, ethyl groups, F or cyano groups; The R ２ is H or C １－６ alkyl groups, preferably H or methyl groups; The R ３ is H, C １－６ Alkyl group or C １－６ hydroxyalkyl groups, preferably H, methyl or hydroxymethyl groups; The R ４ teeth, 【Chemistry 13】 or —NH—, The R １２ teeth, 【Chemistry 14】 Selected from:

2. A compound according to claim 1, in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The L is 【Chemistry 15】 【Chemistry 16】 is selected from The G ring or the D ring each independently represents C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, or a 3- to 14-membered heterocyclyl group; ６－１４ The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with Each of the E's is independently -O-, -NH- or -NCH ３ Selected from - n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4; M is selected from VHL-binding fragments represented by general formula (V) or (IV), 【Chemistry 17】 The X １ is selected from C, CH or N; The X ２ is selected from C, CH or N; The X ３ is selected from N, NH, O or S; The R １ is H, C １－６ selected from alkyl groups, halogens or cyano groups, preferably methyl groups, ethyl groups, F or cyano groups; The R ２ is H or C １－６ alkyl groups, preferably H or methyl groups; The R ３ is H, C １－６ Alkyl group or C １－６ hydroxyalkyl groups, preferably H, methyl or hydroxymethyl groups; The R ４ teeth, [Chemistry 18] or —NH—, The R １２ teeth, 【Chemistry 19】 is selected from The R ａ are independently H, a hydroxy group, an amino group, an oxo group, a cyano group, a halogen, or C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, —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 Alkire N-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 group, C ２－６ Alkynyl group, —C ０－３ Alkylene-C ３－１４ cycloalkyl group, -C ０－３ alkylene-(3- to 14-membered heterocyclyl group), —C ０－３ Alkylene-C ６－１８ Aryl group or —C ０－３ alkylene-(5- to 18-membered heteroaryl group), １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, —C ０－３ Alkylene-C ３－１４ cycloalkyl group, -C ０－３ alkylene-(3- to 14-membered heterocyclyl group), —C ０－３ Alkylene-C ６－１８ Aryl group or —C ０－３ The alkylene-(5- to 18-membered heteroaryl group) may optionally be one or more R ｂ may be further substituted with Each R ｂ are independently H, halogen, hydroxy group, cyano group, C １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Haloalkyl group, C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ an aryl group or a 5- to 18-membered heteroaryl group, １－６ Alkyl group, C ３－６ Cycloalkyl group, C １－６ Haloalkyl group, C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ The aryl or 5- to 18-membered heteroaryl group may optionally contain one or more halogen, C １－６ Alkyl group or C １－６ may be further substituted with a haloalkyl group, or Two Rs bonded to one atom ｂ together with the atoms to which they are both attached, form C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ forming an aryl group or a 5- to 18-membered heteroaryl group, ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ The aryl group or 5- to 18-membered heteroaryl group may optionally contain one or more of a halogen, an amino group, a hydroxy group, a cyano group, a C １－６ Alkyl group, C ３－６ Cycloalkyl group or C １－６ optionally further substituted with a haloalkyl group; 3. A compound according to claim 2, in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

4. F is a KRAS protein-binding fragment represented by general formula (I) or (II), 【Chemistry 20】 The aforementioned 【Chemistry 21】 are independently selected from a single bond or a double bond; The X ４ is CR ８ , C(R ８ ) ２ , O, N or NR ８ and R ８ are each independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, or C １－６ Alkyl group, C １－６ Haloalkyl group, —S—C １－６ alkyl group, -C ０－３ Alkylene-C ２－４ Alkenyl group, C １－６ Alkoxy group, C １－６ haloalkoxy group or C ３－１４ cycloalkyl groups, wherein said C ３－１４ Cycloalkyl group, C １－６ The alkyl group may optionally be one or more R ａ may be further substituted with The X ５ is selected from C, CH or N; The X ６ is CR １４ , C(R １４ ) ２ , O, N or NR １４ and R １４ are each independently H, a hydroxy group, an oxo group, a halogen atom, a cyano group, or C １－６ Alkyl group, C １－６ Haloalkyl group, —S—C １－６ alkyl group, -C ０－３ Alkylene-C ２－４ Alkenyl group, C １－６ Alkoxy group, C １－６ haloalkoxy group or C ３－１４ cycloalkyl groups, wherein said C ３－１４ Cycloalkyl group, C １－６ The alkyl group may optionally be one or more R ａ may be further substituted with The R ６ does not exist or C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or the 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with The R ９ is H, an amino group, a substituted amino group, a cyano group, C １－６ Alkyl group, C １－６ Alkoxy group, halogen, C ２－６ alkenyl group, or C ３－６ cycloalkyl groups, wherein said C １－６ Alkyl group, C ２－６ Alkenyl group, C ３－６ The cycloalkyl group may optionally be one or more R ａ may be further substituted with The R １０ is absent, -O- or -NR １１ -, and R １１ is H, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group or C １－６ aminoalkyl groups, The R ７ is C ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ an aryl group or a 5- to 18-membered heteroaryl group, ３－１４ Cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ The aryl group or 5- to 18-membered heteroaryl group may optionally be one or more R ａ may be further substituted with The K is C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group may be a single ring, a fused ring, a spiro ring, or a bridged ring, and may optionally be one or more R ａ and said 3- to 14-membered heterocyclyl group is 【Chemistry 22】 Instead, wherein m and n are each independently selected from 0, 1, 2, 3, 4, or 5; The compound according to any one of claims 1 to 3, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The R ４ teeth, 【Chemistry 23】 or —NH—; The compound according to any one of claims 1 to 4, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

6. The R ４ teeth, 【Chemistry 24】 Selected from: The compound according to any one of claims 1 to 4, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

7. The K is C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group is monocyclic and optionally has one or more R ａ and optionally further substituted with 7. The compound according to any one of claims 1 to 6, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

8. The K is 【Chemistry 25】 Selected from:

8. A compound according to claim 7, in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

9. The K is C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or the 3- to 14-membered heterocyclyl group is a spirocyclic ring and optionally has one or more R ａ and optionally further substituted with 7. The compound according to any one of claims 1 to 6, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

10. The K is 【Chemistry 26】 Selected from:

10. The compound according to claim 9, in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

11. The K is C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group is a fused ring and optionally has one or more R ａ and optionally further substituted with 7. The compound according to any one of claims 1 to 6, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

12. The K is 【Chemistry 27】 【Chemistry 28】 Selected from:

12. A compound according to claim 11, or in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

13. The K is C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group is a bridged ring and optionally has one or more R ａ and optionally further substituted with 7. The compound according to any one of claims 1 to 6, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

14. The K is 【Chemistry 29】 Selected from:

14. A compound according to claim 13, in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

15. The K is 【Transformation 30】 Selected from:

15. The compound according to any one of claims 1 to 14, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

16. The R ７ is C ６－１８ an aryl group or a 5- to 18-membered heteroaryl group, ６－１８ The aryl group or 5- to 18-membered heteroaryl group may optionally be one or more R ａ may be further substituted with, and the R ａ are each independently H, a halogen atom, a hydroxy group, an amino group, a cyano group, or C ２－６ Alkynyl group, C １－６ Alkyl group, C １－６ haloalkyl group or C ２－６ alkenyl groups, 16. The compound according to any one of claims 1 to 15, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

17. The R ７ teeth, 【Chemistry 31】 【Chemistry 32】 is selected from The aforementioned 【Transformation 33】 optionally one or more R ａ may be further substituted with, and the R ａ are each independently H, a halogen atom, a hydroxy group, an amino group, a cyano group, or C ２－６ Alkynyl group, C １－６ Alkyl group, C １－６ haloalkyl group or C ２－６ alkenyl groups, 17. The compound according to any one of claims 1 to 16, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

18. The R ７ teeth, 【Transformation 34】 Selected from:

18. The compound according to any one of claims 1 to 17, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

19. The F is 【Chemistry 35】 is selected from Here, the R ７ , R ９ , R ８ , R １１ , R １４ is defined as in claim 1, The K is 【Transformation 36】 Selected from:

19. The compound according to any one of claims 1 to 18, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

20. The K is 【Chemistry 37】 Selected from:

20. The compound according to any one of claims 1 to 19, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

21. The F is 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 Selected from:

21. The compound according to any one of claims 1 to 20, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

22. The F is 【Chemistry 42】 Selected from:

22. The compound according to any one of claims 1 to 21, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

23. The G ring or the D ring in the L is independently C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group may optionally be halogen or C １－３ may be further substituted with an alkyl group, Said C ６－１４ The aryl group is preferably 【Chemistry 43】 and The 5- to 14-membered heteroaryl group is preferably 【Chemistry 44】 is selected from The 3- to 14-membered heterocyclyl group is preferably 【Chemistry 45】 is selected from Said C ３－１４ The cycloalkyl group is preferably 【Chemistry 46】 Selected from:

23. The compound according to any one of claims 1 to 22, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

24. The G ring or the D ring in the L is independently C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ The cycloalkyl group or 3- to 14-membered heterocyclyl group may optionally be halogen or C １－３ may be further substituted with an alkyl group, Said C ６－１４ The aryl group is preferably 【Chemistry 47】 and The 5- to 14-membered heteroaryl group is preferably 【Chemistry 48】 is selected from The 3- to 14-membered heterocyclyl group is preferably 【Chemistry 49】 is selected from Said C ３－１４ The cycloalkyl group is preferably [Transformation 50] Selected from:

24. The compound according to any one of claims 1 to 23, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

25. The G ring or the D ring in the L is independently C ６－１４ an aryl group, a 5- to 14-membered heteroaryl group, or a 3- to 14-membered heterocyclyl group; ６－１４ a The aryl group, 5- to 14-membered heteroaryl group or 3- to 14-membered heterocyclyl group may optionally be halogen or C １－３ may be further substituted with an alkyl group, Said C ６－１４ The aryl group is preferably 【Chemistry 51】 and The 5- to 14-membered heteroaryl group is preferably 【Chemistry 52】 is selected from The 3- to 14-membered heterocyclyl group is preferably 【Chemistry 53】 Selected from:

25. The compound according to any one of claims 1 to 24, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

26. The L is 【Chemistry 54】 is selected from where: The G ring or the D ring each independently represents C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with, and the R ａ is independent H, hydroxy group, amino group, oxo group, cyano group, halogen, C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ alkoxy groups, The Y １ , Y ２ are each independently absent, —O—, —NH—, a 3- to 6-membered nitrogen-containing heterocyclyl group, C １－６ Alkylene group, carbonyl group, ethynyl group or C ３－６ cycloalkyl groups, Each of the E's is independently -O-, -NH- or -NCH ３ - is selected from, n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4.

26. The compound according to any one of claims 1 to 25, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

27. The L is 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Chemistry 58】 is selected from wherein n1 and n2 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, or 3.

27. The compound according to any one of claims 1 to 26, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

28. The L is 【Chemistry 59】 【Transformation 60】 Selected from:

30. The compound according to any one of claims 1 to 29, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

29. The M is 【Chemistry 61】 Selected from:

29. The compound according to any one of claims 1 to 28, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

30. The L is 【Transformation 62】 is selected from wherein the G ring is C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ The aryl group, 5- to 14-membered heteroaryl group, or 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with, and the R ａ are each independently H, a hydroxy group, an amino group, an oxo group, a cyano group, a halogen, or C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ alkoxy groups, The ring D is a 5- to 6-membered nitrogen-containing heteroaryl group, preferably 【Transformation 63】 and The Y １ , Y ２ are each independently absent, —O—, —NH—, a 3- to 6-membered nitrogen-containing heterocyclyl group, C １－６ Alkylene group, carbonyl group, ethynyl group or C ３－６ cycloalkyl groups, n1 and n2 each independently represent 0, 1, 2, 3, or 4; 30. The compound according to any one of claims 1 to 29, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

31. The L is 【Chemistry 64】 Selected from:

31. A compound according to claim 30, in the form of a tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof.

32. The F is 【Transformation 65】 is selected from The L is 【Chemical Formula 66】 is selected from where: The G ring or the D ring each independently represents C ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ a cycloalkyl group or a 3- to 14-membered heterocyclyl group, ６－１４ aryl group, 5- to 14-membered heteroaryl group, C ３－１４ The cycloalkyl group or the 3- to 14-membered heterocyclyl group may optionally be one or more R ａ may be further substituted with The Y １ , Y ２ are each independently absent, —O—, —NH—, a 3- to 6-membered nitrogen-containing heterocyclyl group, C １－６ Alkylene group, carbonyl group, ethynyl group or C ３－６ cycloalkyl groups, Each of the E's is independently —O—, —NH—, or —NCH ３ - is selected from, n1, n2, and n3 are each independently selected from integers of 0 to 10, and preferably 0, 1, 2, 3, or 4; M is selected from the VHL-binding fragments of general formula (III): 【Transformation 67】 Here, the X １ is selected from C, CH or N; The X ２ is selected from C, CH or N; The X ３ is selected from N, NH, O or S; The R １ is H, C １－６ selected from alkyl groups, halogens or cyano groups, preferably methyl groups, ethyl groups, F or cyano groups; The R ２ is H or C １－６ alkyl groups, preferably H or methyl groups; The R ３ is H, C １－６ Alkyl group, C １－６ Hydroxyalkyl group or -(CH ２ )n-CO-NH-(CH ２ ) n-CH ３ wherein n is selected from 0, 1, 2, or 3; ３ is preferably H, a methyl group, a hydroxymethyl group, 【Transformation 68】 or -CH ２ —CO—NH—CH ３ and The R ４ teeth, 【Transformation 69】 or —NH—, The R ５ is H, C １－６ Alkyl group or C １－６ haloalkyl groups, The R ａ are independently H, a hydroxy group, an amino group, an oxo group, a cyano group, a halogen, or C １－６ Alkyl group, C １－６ haloalkyl group or C １－６ alkoxy groups, 32. The compound according to any one of claims 1 to 31, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

33. The compound having the F-L-M structure is 【Transformation 70】 【Chemistry 71】 【Chemistry 72】 【Transformation 73】 【Chemistry 74】 【Chemistry 75】 【Transformation 76】 【Chemical 77】 【Transformation 78】 【Chemistry 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 【Chemistry 83】 【Chemical 84】 【Chemical 85】 【Chemical 86】 【Transformation 87】 【Chemical 88】 【Chemistry 89】 【Chemistry 90】 【Chemistry 91】 【Chemistry 92】 【Chemistry 93】 【Chemical 94】 【Chemical 95】 【Chemistry 96】 Selected from:

33. The compound according to any one of claims 1 to 32, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising the compound according to any one of claims 1 to 33, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

35. Use of a compound according to any one of claims 1 to 33, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33, in the manufacture of a medicament for modulating the ubiquitination and degradation of KRAS protein in a subject.

36. Use of a compound according to any one of claims 1 to 33, or in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 33, in the manufacture of a medicament for treating and / or preventing a disease mediated or dependent on a KRAS protein, The KRAS protein-mediated disease is preferably a tumor.

37. 37. The use according to claim 36, characterized in that 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 carcinoma, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, intrahepatic cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

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