Pan-KRAS protein targeted degrader compound and use thereof

Abstract

The present invention relates to a pan-KRAS protein targeted modulator compound and the use thereof. Specifically, the present invention relates to a pan-KRAS protein targeted modulator compound as shown in general formula (A), a preparation method therefor, and the pharmaceutical use thereof.

Description

A compound targeting pan-KRAS protein degrader and its application Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a compound that is a targeted KRAS protein degrader and applications thereof. Background Art

[0002] PROTAC is a heterobifunctional molecule with a ligand that binds to the target protein at one end and a ligand for the E3 ligase at the other end, connected in the middle by a suitable linker. PROTAC degradation of target proteins is achieved through the ubiquitin proteasome system (UPS). The general process is as follows: PROTAC molecules bind to the target protein (POI) and the E3 ligase to form a ternary complex, marking the target protein with a ubiquitin molecule. The ubiquitinated protein is recognized and degraded by the proteasome 26S in the cell.

[0003] Compared with traditional small molecules and antibodies, which inhibit the function of target proteins and play a role in treating diseases through an "occupancy-driven" mode of action, this mode of action requires a high concentration of inhibitors or monoclonal antibodies to occupy the active site of the target and block the transduction of downstream signaling pathways. PROTAC is "event-driven" and does not affect the function of the protein, but rather mediates the degradation of pathogenic target proteins. As long as PROTAC mediates the formation of a ternary complex and tags the target protein with ubiquitination, it can theoretically be recycled and reused, so the catalytic amount can play a role. It has the characteristics of a wider range of action, higher activity, and the ability to target "undruggable" targets; improve selectivity, activity and safety; and overcome drug resistance.

[0004] The activity of KRAS switches depending on the binding transition between GDP and GTP. It is inactive when bound to GDP and activated when bound to GTP. In mutated KRAS proteins, GAP access to GTP is restricted, preventing hydrolysis and forming a persistently activated GTP-bound state. Because mutant KRAS has a high affinity for guanosine triphosphate (GTP), and has difficult-to-target factors such as a small catalytic site and a smooth protein surface, the development of small molecule inhibitors has been challenging, making KRAS "undruggable." On the one hand, KRAS binds to GDP and GTP with an affinity of picomolar concentrations, which seriously hinders the development of nucleotide competitive inhibitors; on the other hand, the KRAS protein 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%-30% of all human cancers. KRAS mutations account for 86% of the three RAS mutations. Among all KRAS mutations, there are G12D (35%), G12V (29%), G12C (21%), G13D (6.7%), G12R (4.3%), G12A (4.1%) and other mutations. If these different KRAS mutations can be targeted simultaneously, it will have huge commercial value while greatly meeting clinical needs.

[0006] However, current KRAS inhibitors face the dilemma of limited efficacy and high drug resistance in clinical practice. If the anti-resistance and high efficacy of PROTAC can be combined to develop a new pan-KRAS PROTAC degrader drug for the treatment of diseases caused by KRAS mutation or amplification, it will have great social significance and commercial value.

[0007] Summary of the Invention

[0008] The present invention provides a novel pan-KRAS PROTAC degrader that can be used to treat diseases caused by KRAS mutation or amplification.

[0009] In one aspect, the present invention provides a compound having the structure of FLM, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0010] Said F is a KRAS protein binding fragment represented by general formula (A);

[0011] The X is selected from -O- or

[0012] described Indicates whether the bonds in the ring are single or double bonds;

[0013] The X4 is CR8, C(R8)2, O, N or NR8; R8 are each independently selected from H, hydroxyl, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4Alkenyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-14 The cycloalkyl group is optionally further substituted with one or more R a replace;

[0014] Said X5 is selected from C, CH or N;

[0015] The X6 is selected from CR 14 、C(R 14 )2, O, N or NR 14 ; R 14 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-14 The cycloalkyl group is optionally further substituted with one or more R a replace;

[0016] The R6 is absent or selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace;

[0017] The R9 is selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a replace;

[0018] The R 10 Not present or selected from -O- or -NR 11 -;R11 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl;

[0019] The R7 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a replace;

[0020] The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, condensed, spirocyclic or bridged ring, optionally further substituted by one or more R a Substituted, and the 3-14 membered heterocyclic group is not

[0021] m, n are each independently selected from 0, 1, 2, 3, 4 or 5;

[0022] The L is a connecting unit connecting F and M;

[0023] The L is selected from

[0024] in,

[0025] The G ring or D ring are each independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted by one or more R a replace;

[0026] The E's are each independently absent or selected from -O-, -NH-, or -NCH3-;

[0027] The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; wherein the 3-7 membered N-containing heterocyclic groups are optionally further substituted by one or more R a replace;

[0028] The R 15 、R 16Each independently selected from H, halogen, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0029] Or, R 15 、R 16 Together with the atoms it is connected to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace;

[0030] Said n1, n2, n3, n4 are each independently selected from an integer of 0-10; preferably 0, 1, 2, 3 or 4;

[0031] The M is selected from the VHL binding fragment represented by general formula (III), (IV) or (V);

[0032] Said X1 is selected from C, CH or N;

[0033] Said X2 is selected from C, CH or N;

[0034] Said X3 is selected from N, NH, O or S;

[0035] Said R1 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen or cyano; preferably methyl, ethyl, F or cyano;

[0036] R2 is selected from H or C 1-6 Alkyl; preferably H or methyl;

[0037] Said R3 is selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) n5 N(R 17 )2、-(CH2) n5 -CO-OR 17 or -(CH2) n5 -CO-N(R 17 )2, the R 17 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6Halogenated alkoxy; n5 is selected from 0, 1, 2 or 3; R3 is preferably H, methyl or hydroxymethyl;

[0038] The R4 is selected from or -NH-;

[0039] R5 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 haloalkoxy;

[0040] The R 12 Selected from

[0041] The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 0-3 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0042] Each R b are independently H, halogen, hydroxy, amino, oxo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 substituted by a haloalkyl group; or two R b Together with its common atoms, it forms C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl C 1-6 Haloalkoxy or C 1-6 Haloalkyl substitution.

[0043] In some embodiments of the present invention, in the aforementioned compound having an FLM structure, F is a KRAS protein binding fragment represented by general formula (A);

[0044] The X is selected from -O- or

[0045] described Indicates whether the bonds in the ring are single or double bonds;

[0046] The X4 is CR8, C(R8)2, O, N or NR8; R8 are each independently selected from H, hydroxyl, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace;

[0047] Said X5 is selected from C, CH or N;

[0048] The X6 is selected from CR 14 、C(R 14 )2, O, N or NR 14 ; R 14 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace;

[0049] The R6 is absent or selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace;

[0050] The R9 is selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C3-6 Cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a replace;

[0051] The R 10 Not present or selected from -O- or -NR 11 -;R 11 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl;

[0052] The R7 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a replace;

[0053] The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, condensed, spirocyclic or bridged ring, optionally further substituted by one or more R a Substituted, and the 3-14 membered heterocyclic group is not

[0054] m, n are each independently selected from 0, 1, 2, 3, 4 or 5;

[0055] The L is a connecting unit connecting F and M;

[0056] The L is selected from

[0057] in,

[0058] The G ring or D ring are each independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted by one or more R a replace;

[0059] Each of the E's is independently selected from -O-, -NH- or -NCH3-;

[0060] Said n1, n2, n3 are each independently selected from an integer of 0-10, preferably 0, 1, 2, 3 or 4;

[0061] The M is selected from the VHL binding fragment represented by general formula (III) or (IV);

[0062] Said X1 is selected from C, CH or N;

[0063] Said X2 is selected from C, CH or N;

[0064] Said X3 is selected from N, NH, O or S;

[0065] Said R1 is selected from H, C 1-6 Alkyl, halogen or cyano; preferably methyl, ethyl, F or cyano;

[0066] R2 is selected from H or C 1-6 Alkyl; preferably H or methyl;

[0067] Said R3 is selected from H, C 1-6 Alkyl or C 1-6 Hydroxyalkyl; preferably H, methyl or hydroxymethyl;

[0068] The R4 is selected from or -NH-;

[0069] The R 12 Selected from

[0070] The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b)5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0071] Each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 substituted by a haloalkyl group; or two R b The atoms connected to them form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

[0072] In some embodiments of the present invention, in the aforementioned compound having an FLM structure, F is a KRAS protein binding fragment represented by general formula (I) or (II);

[0073] described Indicates whether the bonds in the ring are single or double bonds;

[0074] The X4 is CR8, C(R8)2, O, N or NR8; R8 are each independently selected from H, hydroxyl, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace;

[0075] Said X5 is selected from C, CH or N;

[0076] The X6 is selected from CR 14 、C(R 14 )2, O, N or NR 14 ; R 14 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace;

[0077] The R6 is absent or selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; said C3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace;

[0078] The R9 is selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a replace;

[0079] The R 10 Not present or selected from -O- or -NR 11 -;R 11 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl;

[0080] The R7 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a replace;

[0081] The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, condensed, spirocyclic or bridged ring, optionally further substituted by one or more R a Substituted, and the 3-14 membered heterocyclic group is not

[0082] m, n are each independently selected from 0, 1, 2, 3, 4 or 5;

[0083] The L is a connecting unit connecting F and M;

[0084] The L is selected from

[0085] in,

[0086] The G ring or D ring are each independently selected from C 6-14Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 6-14 Aryl, 5-14 membered heteroaryl or 3-14 membered heterocyclic group is optionally further substituted by one or more R a replace;

[0087] The E is independently selected from -O-, -NH- or -NCH3-;

[0088] Said n1, n2, n3 are each independently selected from an integer of 0-10, preferably 0, 1, 2, 3 or 4;

[0089] The M is selected from the VHL binding fragment represented by general formula (III) or (IV);

[0090] Said X1 is selected from C, CH or N;

[0091] Said X2 is selected from C, CH or N;

[0092] Said X3 is selected from N, NH, O or S;

[0093] Said R1 is selected from H, C 1-6 Alkyl, halogen or cyano, preferably methyl, ethyl, F or cyano;

[0094] R2 is selected from H or C 1-6 Alkyl, preferably H or methyl;

[0095] Said R3 is selected from H, C 1-6 Alkyl or C 1-6 Hydroxyalkyl, preferably H, methyl or hydroxymethyl;

[0096] The R4 is selected from or -NH-;

[0097] The R 12 Selected from

[0098] The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0099] Each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C1-6 substituted by a haloalkyl group; or two R b The atoms connected to them form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

[0100] In some embodiments of the present invention, the R4 is selected from or -NH-.

[0101] In some embodiments of the present invention, the R4 is selected from

[0102] In some embodiments of the present invention, the K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic ring, and is optionally further substituted by one or more R a replace.

[0103] In some embodiments of the present invention, the K is selected from

[0104] In some embodiments of the present invention, K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a spiro ring and is optionally further substituted by one or more R a replace.

[0105] In some embodiments of the present invention, the K is selected from

[0106] In some embodiments of the present invention, K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a fused ring, and is optionally further substituted by one or more R a replace.

[0107] In some embodiments of the present invention, the K is selected from

[0108] In some embodiments of the present invention, K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a bridged ring, and is optionally further substituted by one or more R a replace.

[0109] In some embodiments of the present invention, the K is selected from

[0110] In some embodiments of the present invention, the K is selected from

[0111] In some embodiments of the present invention, the R7 is selected from C 6-18 Aryl or 5-18 membered heteroaryl, the C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more R a Substituted; said R a Each independently selected from H, halogen, hydroxy, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Olefins.

[0112] In some embodiments of the present invention, the R7 is selected from described Optionally further comprised of one or more a Substituted; said R a Each independently selected from H, halogen, hydroxy, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Olefins.

[0113] In some embodiments of the present invention, the R7 is selected from

[0114] In some embodiments of the present invention, the F is selected from

[0115] Among them, R7, R9, R8, R 11 , R 14 is as defined above;

[0116] The K is selected from Further, in some embodiments of the present invention, the K is selected from

[0117] Further, in some embodiments of the present invention, the F is selected from

[0118] In some embodiments of the present invention, the F is selected from

[0119] In some embodiments of the present invention, the G ring or D ring in L is independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with halogen or C 1-3 Alkyl substitution;

[0120] The C 6-14 The aryl group is preferably

[0121] The 5-14 membered heteroaryl group is preferably selected from

[0122] The 3-14 membered heterocyclic group is preferably selected from

[0123] The C 3-14 The cycloalkyl group is preferably selected from In some embodiments of the present invention, L is selected from the following structures: Wherein, n1 and n2 are each independently selected from an integer of 0-10, preferably 0, 1, 2 or 3.

[0124] In some embodiments of the present invention, the M is selected from

[0125] In some embodiments of the present invention, in the aforementioned compound having an FLM structure, F is a KRAS protein binding fragment represented by formula (VI);

[0126] The R 14 selected from halogen;

[0127] The L is a connecting unit connecting F and M; the L is selected from

[0128] in,

[0129] The G ring and the D ring are each independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted by one or more R a replace;

[0130] The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; the 3-7 membered N-containing heterocyclic groups are optionally further substituted by one or more R a replace;

[0131] The E's are each independently absent or selected from -O-, -NH-, or -NCH3-;

[0132] The R 15 、R 16 Each independently selected from H, halogen, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0133] Or, R 15 、R 16 Together with the atoms it is connected to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace;

[0134] Said n1, n2, n3, n4 are each independently selected from an integer of 0-10, preferably 0, 1, 2, 3 or 4;

[0135] The M is selected from the VHL binding fragment represented by the general formula (V);

[0136] wherein X1 is selected from C, CH or N;

[0137] Said X2 is selected from C, CH or N;

[0138] Said X3 is selected from N, NH, O or S;

[0139] Said R1 is selected from H, C 1-6Alkyl, halogen or cyano; preferably methyl, ethyl, F or cyano;

[0140] R2 is selected from H or C 1-6 Alkyl; preferably H or methyl;

[0141] Said R3 is selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) n5 N(R 17 )2、-(CH2) n5 -CO-OR 17 or -(CH2) n5 -CO-N(R 17 )2, the R 17 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0142] Said n5 is selected from 0, 1, 2 or 3;

[0143] The R4 is selected from or -NH-;

[0144] R5 is selected from H, C 1-6 Alkyl or C 1-6 alkyl halide;

[0145] The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R 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 、-C0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace;

[0146] Each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 substituted by a haloalkyl group; or two R b The atoms connected to them form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6Cycloalkyl or C 1-6 Haloalkyl substitution.

[0147] In some embodiments of the present invention, the R4 is

[0148] In some embodiments of the present invention, the R4 is

[0149] In some embodiments of the present invention, said R4 is -NH-.

[0150] In some embodiments of the present invention, the D ring is independently selected from a 5-6 membered nitrogen-containing heteroaryl group; wherein the 5-6 membered nitrogen-containing heteroaryl group is optionally further substituted by one or more R a replace;

[0151] The G rings are each independently selected from 3-14 membered heterocyclic groups; wherein the 3-14 membered heterocyclic groups are optionally further substituted by one or more R a replace;

[0152] The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; wherein the 3-7 membered N-containing heterocyclic groups are optionally further substituted by one or more R a replace;

[0153] The E's are each independently absent or selected from -O-, -NH-, or -NCH3-;

[0154] The R 15 、R 16 Each independently selected from H, halogen, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 alkoxy;

[0155] Alternatively, the R 15 、R 16 Together with the atoms it is connected to form C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace;

[0156] Said n1, n2, n3 and n4 are each independently selected from integers of 0-10, preferably 0, 1, 2, 3 or 4.

[0157] In some embodiments of the present invention, the D rings are each independently selected from a 5-6 membered nitrogen-containing heteroaryl group, and the 5-6 membered nitrogen-containing heteroaryl group is selected from The 5-6 membered nitrogen-containing heteroaryl group is optionally further substituted with one or more R a Substituted; said R a Selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

[0158] In some embodiments of the present invention, the G rings are each independently selected from 3-14 membered heterocyclic groups, wherein the 3-14 membered heterocyclic groups are optionally further substituted by one or more R a replace;

[0159] The 3-14 membered heterocyclic group is preferably selected from

[0160] The R a Selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

[0161] In some embodiments of the present invention, the A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; wherein the 3-7 membered N-containing heterocyclic groups are optionally further substituted with one or more halogens or C 1-3 Alkyl substitution.

[0162] In some embodiments of the present invention, the 3-7 membered N-containing heterocyclic group is selected from

[0163] In some embodiments of the present invention, E is -O-.

[0164] In some embodiments of the present invention, E is -NH-.

[0165] In some embodiments of the present invention, E is -NCH3-.

[0166] In some embodiments of the present invention, E is

[0167] In some embodiments of the present invention, E is

[0168] In some embodiments of the present invention, R3 is selected from H, methyl, hydroxymethyl, -CH2-CO-O-CH3, -CH2-N(CH3)2 or -CH2-CO-NH-CH3.

[0169] In some embodiments of the present invention, the L is selected from

[0170] In some embodiments of the present invention, the L is selected from

[0171] In some embodiments of the present invention, the M is selected from

[0172] In some embodiments of the present invention, the compound of FLM structure is selected from the following compounds:

[0173] On the other hand, the present invention provides a pharmaceutical composition, which contains any compound represented by the general formula having an FLM structure of the present invention, its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0174] The present invention further provides the use of any of the above-mentioned compounds represented by the general formula having an FLM structure, its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of a medicament for regulating the ubiquitination and degradation of KRAS protein in a subject.

[0175] The present disclosure further provides the use of any of the above-mentioned compounds having the general structural formula FLM or its tautomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing KRAS-mediated or dependent diseases, wherein the KRAS-mediated disease is preferably selected from tumors.

[0176] 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 lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, hepatobiliary carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

[0177] In preferred embodiments, the subject is a human. The active compound can be formulated for administration by any suitable route, preferably in a unit dosage form, or in a form that allows a patient to self-administer a single dose. A unit dosage form of the disclosed compounds or compositions can be in the form of tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstituted powders, or liquid formulations.

[0178] Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

[0179] For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

[0180] Unless otherwise specified, when the linking group involved in the present invention does not specify its connection direction, its connection direction is arbitrary. For example, when the L of the linking group in the FLM compound is selected from When L is connected from left to right, F and M can be connected to form You can also connect F and M from right to left to form

[0181] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" in 1-6 ” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain.

[0182] The term "alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

[0183] The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two C—H bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, C1-3 The "C" in the alkylene 1-3 ” refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

[0184] The term "haloalkyl" refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.

[0185] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.

[0186] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0187] The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group containing carbon ring atoms. 6-18 Aryl, more preferably C 6-10 A monocyclic or bicyclic aromatic ring group. Phenyl or naphthyl is preferred; naphthyl is most preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl group, wherein the ring connecting to the parent structure is an aryl ring. Non-limiting examples include, but are not limited to, benzocyclopentyl.

[0188] The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom, wherein the heteroatom is selected from N, O and / or S. The heterocyclyl may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, the heterocyclyl is 3-14 members, and the "3-14 members" in the 3-14 membered heterocyclyl refers to a heterocyclyl consisting of 3-14 C, N, O or S ring atoms; wherein the nitrogen or sulfur heteroatom can be selectively oxidized, and the nitrogen heteroatom can be selectively quaternized. More preferred is a 3-10 membered heterocyclyl; even more preferred is a 5-10 membered heterocyclyl. Examples of these heterocyclyls include, but are not limited to Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydrooxadiazolyl. The heterocyclic group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group.

[0189] The term "heteroaryl" as used herein, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., 2, 3, or 4 fused, spiro, or bridged) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. A 5- to 18-membered heteroaryl is preferred, wherein the "5- to 18-membered" in the 5- to 18-membered heteroaryl refers to a heteroaryl group consisting of 5 to 18 ring atoms of C, N, O, or S. A 5- to 10-membered heteroaryl is more preferred; a 5- to 6-membered heteroaryl 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, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0190] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 3-14 Cycloalkyl, where "C 3-14 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. More preferred is a 3-10 membered cycloalkyl group; even more preferred is a 3-8 membered cycloalkyl group or a 5-6 membered cycloalkyl group. Cycloalkyl groups may include monocyclic and polycyclic rings (for example, having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). In some embodiments, cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group may also be fused to an aryl, heterocyclic or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0191] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -OR 1 、-SR 1 , =O, =S, -C(O)R 1 、-C(S)R 1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2, cyano, nitro, -S(O)2R 1 、-OS(O2)OR 1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0192] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0193] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

[0194] When the compound provided by the present invention is an acid, its corresponding salt can be easily prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0195] When compound provided by the invention is a base, it is possible to conveniently prepare its corresponding salt from pharmaceutically acceptable nontoxic acid, including inorganic and organic acids. Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, tamoxifen, 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 etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0196] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, such prodrugs are functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of the compounds of the present invention, which, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues.

[0197] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0198] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0199] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0200] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0201] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0202] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0203] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0204] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0205] The term "effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0206] The compounds of the present invention have excellent performance in biological activities such as KRAS degradation ability, cell proliferation inhibition activity, and in vivo pharmacokinetic properties, and have high drugability. In addition, through research, it was found that the connecting chain of the compound of the present invention has a great influence on the KRAS degradation ability and cell proliferation inhibition activity of the compound. When a 5-6-membered N-containing heteroaryl group (especially a pyrazine ring and a pyridine ring) is added to the connecting chain, close to the VHL ligand side, the compound's ability to degrade KRAS is enhanced, while the compound's cell proliferation inhibition activity is increased, achieving unexpected results. We speculate that the N-containing heteroaromatic ring is in a special spatial position, and it will interact with the VHL protein through hydrogen bonds and other interactions, thereby increasing the binding force between the compound and VHL, thereby increasing the compound's ability to degrade the KRAS protein. In particular, the use of a specific connecting chain The compound of the present invention formed when the pyrazine end is bonded to the VHL ligand has better KRAS degradation ability and cell proliferation inhibition activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0207] Figure 1 shows the degradation effect of compound 2 on different KRAS in biological experiments.

[0208] Figure 2 shows the Western Blotting results of KRAS protein degradation by some compounds in different cell lines in biological experiments. DETAILED DESCRIPTION

[0209] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0210] Unless otherwise stated, all temperatures herein are in degrees Celsius.

[0211] The following abbreviations are used in the examples:

[0212] DMF: N,N-dimethylformamide;

[0213] NIS: N-iodosuccinimide;

[0214] THF: tetrahydrofuran;

[0215] EA: ethyl acetate;

[0216] PE: petroleum ether;

[0217] DCM: dichloromethane;

[0218] MeOH: methanol;

[0219] TBDPSCl: tert-butyldiphenylchlorosilane;

[0220] DPPA: diphenylphosphoryl azide;

[0221] CDI: N,N'-carbonyldiimidazole;

[0222] DIEA: N,N-diisopropylethylamine;

[0223] CataCXium A Pd G3: [n-butyldi(1-adamantyl)phosphine](2-amino-1,1′-biphenyl-2-yl)palladium(II) methanesulfonate;

[0224] LAH / LiAlH4: lithium aluminum tetrahydride;

[0225] POCl3: phosphorus oxychloride;

[0226] DMSO: dimethyl sulfoxide;

[0227] DMF-DMA: N,N-dimethylformamide dimethyl acetal;

[0228] TosMIC: p-Toluenesulfonylmethyl isocyanide;

[0229] DCE: 1,2-dichloroethane;

[0230] DMAP: 4-dimethylaminopyridine;

[0231] PhN(Tf)2: phenylbis(trifluoromethanesulfonyl)imide;

[0232] PBS: phosphate buffered saline;

[0233] Selectfluor:1-Chloromethyl-4-fluoro-1,4-diazacyclo[2.2.2]octane bis(tetrafluoroborate)

[0234] TsOH: p-Toluenesulfonic acid

[0235] (Boc)2O: Di-tert-butyl dicarbonate

[0236] TMSCl: trimethylchlorosilane

[0237] Pd2(dba)3: Trisdibenzylideneacetone dipalladium

[0238] HATU: 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0239] TFA: trifluoroacetic acid

[0240] DABCO: triethylenediamine

[0241] DIBAL-H: Diisobutylaluminum hydride

[0242] TMSCN: trimethylsilyl cyanide

[0243] TMSOTf: trimethylsilyl trifluoromethanesulfonate

[0244] LiHMDS: lithium bis(trimethylsilyl)amide

[0245] NaBH3CN: sodium cyanoborohydride

[0246] TBAF:Tetrabutylammonium fluoride

[0247] NADPH: Nicotinamide adenine dinucleotide phosphate (reduced)

[0248] UDPGA: uridine diphosphate glucuronic acid

[0249] UGT: Uridine diphosphate glucuronosyltransferase

[0250] TEA:Triethylamine

[0251] Synthesis of intermediate M1:

[0252] (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 under ice-cooling. The mixture was stirred on ice for 2 h. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with EA (3 times, 20 mL each). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by column chromatography to obtain the target intermediate M1 (0.8 g).

[0253] ESI-MS m / z:471[M+H] + .

[0254] Synthesis of intermediate M2:

[0255] Step 1: Synthesis of compound M2-1

[0256] At room temperature, 2-chloro-3-fluoro-pyridine-4-carboxylic acid (54.00 g), toluene (390.00 mL), tert-butyl alcohol (390.00 mL), triethylamine (128.27 mL), and powdered 4A molecular sieves (90.00 mL) (preactivated) were added in sequence. Under nitrogen protection, the mixture was refluxed for half an hour (internal temperature 87°C). The mixture was then naturally cooled to room temperature, and DPPA (99.44 mL) was added. The temperature was raised to reflux and the reaction was maintained for 5 hours. The reaction mixture was cooled to below 40°C, and then 500 mL of EA was added to dilute it; the reaction mixture was further cooled to room temperature, and the added molecular sieves were removed by filtration using diatomaceous earth as the filter aid; the filter residue was rinsed with 1500 mL of EA several times and dried; the filtrate was collected, washed with 700 mL of water and 700 mL of saturated brine in sequence, and the liquids were separated; the organic phase was dried over anhydrous sodium sulfate; filtered, the desiccant was removed, and the concentrate was 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 the product M2-1 (68.2 g, yield 89.88%).

[0257] ESI-MS m / z:247.1[M+H] + .

[0258] Step 2: Synthesis of compound M2-2

[0259] Compound M2-1 (65.00 g) was dissolved in CH3CN (82.00 mL) at room temperature, cooled in a water bath, and hydrochloric acid (4M / dioxane) (264 mL) was slowly added. The reaction was stirred at room temperature for approximately 16 hours, during which time a white solid precipitated and became suspended. The reaction mixture was filtered, and the filter cake was rinsed with a small amount of acetonitrile, drained, and the filtrate discarded. The filter cake was collected and added to a mixture of 700 mL of saturated aqueous sodium bicarbonate solution and 700 mL of ethyl acetate, alkalized, extracted, and separated. The aqueous phase was further extracted with 350 mL of ethyl acetate and separated. The ethyl acetate phases were combined, washed with 300 mL of saturated aqueous sodium chloride solution, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, the desiccant was removed, and concentrated to obtain product M2-2 (36.3 g, 94.0% yield).

[0260] ESI-MS m / z:147.1[M+H] + .

[0261] Step 3: Synthesis of Compound M2-3

[0262] 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. The reaction mixture was cooled to 50°C, and 900 mL of water was added. A white solid precipitated and was slurried for half an hour. The mixture was filtered, and the filter cake was rinsed with water and dried. The filter cake was collected and completely dissolved in 1200 mL of ethyl acetate. The mixture was then washed twice with 350 mL of saturated sodium sulfite solution and then with 350 mL of saturated brine. The mixture was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to yield product M2-3 (63.2 g, 94.43% yield).

[0263] ESI-MS m / z:272.9[M+H] + .

[0264] Step 4: Synthesis of Compound M2-4

[0265] At room temperature, compound M2-3 (57.50 g) was dissolved in DMF (22.00 mL), zinc cyanide (32.22 g), tetrakistriphenylphosphine palladium (12.19 g) and powdered Molecular sieves (20.00 mL) were added, and the mixture was heated to 100°C under a nitrogen atmosphere for approximately 7 hours. The oil bath was removed, and the mixture was allowed to cool naturally to room temperature for post-processing. The reaction mixture was filtered through diatomaceous earth and drained. The filtrate was collected and concentrated at 60-70°C to obtain a pale yellow solid crude product. The filter residue was rinsed with 500 mL of ethyl acetate and drained. The rinse was collected and added to the crude product, and the product was concentrated again until no liquid was distilled out. The concentrated crude solid product was dissolved in 700 mL of ethyl acetate, and then washed three times with 250 mL of saturated sodium chloride, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a pale yellow solid. 160 mL of a 3 / 1 PE / EA mixture was added, and the mixture was slurried for half an hour, filtered, and drained. The filter cake was collected, concentrated in a 45°C water bath, and then pumped to constant weight with a high vacuum oil pump. The product M2-4 (36.1 g, 99.7% yield) was finally obtained.

[0266] ESI-MS m / z:172.0[M+H] + .

[0267] Step 5: Synthesis of Compound M2-5

[0268] At room temperature, concentrated sulfuric acid (61.37 mL) was added to a 500 mL single-necked flask. The mixture was cooled to below 10°C in an ice-water bath. Compound M2-4 (39.30 g) was added portionwise. After addition, the mixture was stirred for 10 minutes. The mixture was then kept at 60°C in an oil bath under a nitrogen atmosphere and allowed to react for approximately 1 hour. The reaction mixture was cooled to room temperature and then carefully added to 1100 mL of ice-water mixture to dilute and quench the mixture. A small amount of yellow solid precipitated. After stirring for 10 minutes, the mixture was filtered. The filter cake was collected and slurried with 50 mL of saturated sodium bicarbonate aqueous solution for 20 minutes. The filtrates were collected again and combined. Solid sodium carbonate was then slowly added to adjust the pH to approximately 7. An off-white solid powder precipitated. The mixture was stirred for half an hour, filtered, and drained. The filter cake was rinsed with 100 mL of water each time and drained, for a total of two rinses. The filter cake was collected and dried in a vacuum oven at 55°C to constant weight to obtain product M2-5 (33.6 g, 77.37% yield).

[0269] ESI-MS m / z:190.0[M+H] + .

[0270] Step 6: Synthesis of Compound M2-6

[0271] At room temperature, tetrahydrofuran (470.00 mL) was added. After nitrogen replacement, sodium hydride (10.00 g) was added under a slight nitrogen flow. The mixture was heated in an oil bath at 40-45°C and stirred for 15 minutes. Compound M2-5 (18.95 g) was then added in portions. After addition, the mixture was mechanically stirred for 20 minutes. CDI (24.31 g) was then carefully added in portions. After addition, the mixture was stirred for 15 minutes, and the mixture was heated in an oil bath and refluxed. The reaction mixture was cooled to below 10°C in an ice-water bath. 500 mL of saturated aqueous ammonium chloride was then added. A light yellow solid precipitated. 1000 mL of water was added. The mixture was then transferred to a 5 L beaker and 3000 mL of water was added. The mixture was stirred for 1 hour, filtered, and drained. The filter cake was collected and dried in a vacuum oven at 50-55°C to constant weight to obtain product M2-6 (18.3 g, 84.93% yield).

[0272] ESI-MS m / z:216.0[M+H] + .

[0273] Step 7: Synthesis of Compound M2

[0274] Compound M2-6 (18.00 g) and DIEA (36.00 mL) were dissolved in POCl3 (180.00 mL) at room temperature and heated to 100°C under a nitrogen atmosphere for approximately 2.5 hours. The mixture was concentrated under reduced pressure to remove phosphorus oxychloride and rinsed twice with 100 mL of DCM. The residue was dissolved in 400 mL of dichloromethane and then added dropwise to 500 mL of saturated aqueous sodium bicarbonate solution, cooled with ice water. After stirring for 15 minutes, the mixture was separated. The aqueous phase was extracted with 300 mL of dichloromethane and separated. The combined dichloromethane phases were washed with 300 mL of saturated aqueous sodium chloride solution and separated. The product was 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, 51.94% yield).

[0275] ESI-MS m / z:251.9[M+H] + .

[0276] Synthesis of intermediate M3:

[0277] Step 1: Synthesis of Compound M3-1

[0278] 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) were dissolved in 6 mL of THF and 6 mL of water. HO was added to 6 mL of tert-butanol, followed by the addition of sodium ascorbate (360 mg) and anhydrous copper sulfate (100 mg). The mixture was allowed to react at room temperature for 3 hours. 20.0 mL of water was added to the reaction solution, and the mixture was extracted three times with 20 mL of EA each time. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The organic phase was then separated and purified by column chromatography to obtain compound M3-1 (420 mg).

[0279] ESI-MS m / z:680[M+H] + .

[0280] Step 2: Synthesis of Compound M3

[0281] M3-1 (420 mg) was dissolved in 10 mL of DCM, followed by the addition of 3 mL of TFA and allowed to react at room temperature for 30 min. A 1 M aqueous NaOH solution was added to the reaction mixture to free the acid. The mixture was then extracted with DCM three times, 10 mL each time. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to yield compound M3 (365 mg).

[0282] ESI-MS m / z:580[M+H] + .

[0283] Synthesis of intermediate M4:

[0284] N-Boc-3-methyl-3-hydroxypiperidine (1.0 g) was added to a 25 mL single-necked flask, along with 3 mL of acetonitrile and 3 mL of 4M hydrochloric acid (Dioxane) at 0°C. The mixture was allowed to react at 0°C for 0.5 h. After completion of the reaction, the reaction solution was concentrated to afford intermediate M4 (0.7 g, 99% yield), which was used directly in the next step.

[0285] Synthesis of intermediate M5:

[0286] Step 1: Synthesis of compound M5-1

[0287] ((2-Fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.0 g) was added to a 50 mL single-necked flask, followed by 6 mL of DMF and cesium fluoride (5.9 g). The mixture was stirred at room temperature for 1 h. TLC confirmed the complete reaction of the starting material. The reaction solution was slowly added dropwise to water (20 mL), resulting in the precipitation of a white solid. The filter cake was collected by filtration and dried to obtain 0.65 g of a white solid, compound M5-1.

[0288] Step 2: Synthesis of Compound M5

[0289] Compound M5-1 (0.65 g) was added to a 50 mL single-necked vial, along with 6 mL of MeOH and Pd / C (600 mg, 10% purity). The mixture was reacted at room temperature under a hydrogen atmosphere for 20 min. After the reaction was complete, the filtrate was filtered, collected, and concentrated. The concentrate was purified by column chromatography to yield the target compound M5 (496 mg, 75.5% yield).

[0290] 1 H 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).

[0291] Synthesis of intermediate M6:

[0292] Intermediate M5 (1.0 g) was added to a 50 mL single-necked bottle, followed by 10 mL of hydrochloric acid (4 M / Dioxane). After reacting at room temperature for half an hour, the reaction mixture was neutralized by adding saturated sodium bicarbonate solution and extracted twice with EA. The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (DCM:ammonia methanol = 10:1) to obtain the target 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).

[0293] Synthesis of intermediate M7:

[0294] Step 1: Synthesis of compound M7-1

[0295] 4-Amino-2,6-dichloropyridine (63 g) was added to a 1 L three-necked flask, along with 440 mL of ACN and 180 mL of water. Selectfluor (164 g) was added while the temperature was raised to 45°C. The reaction was exothermic and allowed to cool naturally in air. After 10 minutes of reaction, the reaction was quenched by the addition of saturated sodium sulfite solution in an ice bath. The product was extracted three times with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 10:1) to obtain the target compound M7-1 (42.6 g).

[0296] ESI-MS m / z:163.9[M+H] + .

[0297] Step 2: Synthesis of compound M7-2

[0298] Compound M7-1 (54 g) was added to a 1 L three-necked flask, along with 500 mL of ACN, NIS (80 g), and TsOH (5.1 g). The mixture was heated to 70°C and reacted for 1 h. Then, 2.5 L of water was added dropwise, the mixture was filtered, and the filter cake was dissolved in EA. After separation, the organic phase was concentrated to obtain the target compound M7-2 (94 g). ESI-MS m / z: 307.2 [M+H] + .

[0299] Step 3: Synthesis of Compound M7-3

[0300] Compound M7-2 (88 g) was added to a 1 L three-necked flask, along with 500 mL of DMF and 31 g of CuCN. The mixture was heated to 125°C and reacted for 16 h. After 2 L of water was added dropwise, the mixture was added to 2 L of water and 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 yield the desired product, M7-3 (55.4 g).

[0301] ESI-MS m / z:207.0[M] - .

[0302] Step 4: Synthesis of Compound M7-4

[0303] Compound M7-3 (88 g) was added to a 250 mL three-necked flask, along with 83 mL of concentrated sulfuric acid and 9 mL of water. After reacting at 60°C for 16 h, 70 mL of concentrated sulfuric acid and 5 mL of water were added and the reaction continued for 24 h. The temperature was lowered to 0°C, and the reaction solution was slowly poured into 2 L of ice water. The filter cake was washed with water and then dissolved in EA. The filtrate was extracted twice with EA. The organic phases were collected and combined, concentrated, and slurried in a 1:1 ratio of PE to EA. Filtering afforded the desired product, M7-4 (59 g).

[0304] ESI-MS m / z:224.1[M+H] + .

[0305] Step 5: Synthesis of Compound M7-5

[0306] Compound M7-4 (58 g) was added to a 1 L three-necked flask, along with 650 mL of THF. After heating to 40°C, NaH (16 g) was slowly added in portions. After stirring for 10 min, the temperature was raised to 60°C, and N,N'-thiocarbonyldiimidazole (69 g) was slowly added. After reacting for 1 h, saturated ammonium chloride solution was added to quench the reaction. Dilute hydrochloric acid was added dropwise to adjust the pH to 4-5, and the THF was removed by vortexing. Filter, wash the filter cake with water, dissolve it in methanol, and concentrate the organic phase to obtain crude product M7-5 (85 g).

[0307] ESI-MS m / z:267.0[M+H] + .

[0308] Step 6: Synthesis of Compound M7

[0309] Compound M7-5 (74 g) was added to a 1 L three-necked flask, followed by 750 mL of ACN, 22 mL of iodomethane, and 100 mL of an aqueous solution of sodium methoxide (23 g). After reacting at room temperature for 15 min, the reaction solution was added to 3.5 L of water, and the pH was adjusted to 4-5 with dilute hydrochloric acid. The mixture was filtered, and the filter cake was slurried with a 2:1 PE:EA mixture. The filter cake was filtered to obtain the desired product, M7 (42.2 g).

[0310] ESI-MS m / z:281.2[M+H] + .

[0311] Synthesis of intermediate M8:

[0312] Step 1: Synthesis of compound M8-1

[0313] Potassium carbonate (4.78 g) was added to a suspension of 1H-1,2,4-triazole-5-carboxylic acid methyl ester (4.00 g) and N-Boc-3-aminopropyl bromide (7.49 g) in acetonitrile (40 mL) at room temperature, and the mixture was stirred in an 80°C oil bath. After reacting for 1 hour, ethyl acetate and water were added to the reaction system for extraction and separation, and the aqueous phase was 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 obtain the crude product M8-1 (8.90 g, 99% yield). ESI-MS m / z = 285.2 [M+H] + .

[0314] Step 2: Synthesis of compound M8-2

[0315] Compound M8-1 (8.90 g) was dissolved in 4N HCl in dioxane (40 mL) at room temperature and stirred for 1 hour. After the reaction, the solution was dried 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] + .

[0316] Step 3: Synthesis of compound M8-3

[0317] Compound M8-2 (5.60 g) and sodium carbonate (9.96 g) were added to 100 ml of water (100 mL) at room temperature, and the reaction system was stirred at room temperature for 5 hours. After the reaction, the reaction solution was adjusted to neutrality with dilute hydrochloric acid and then concentrated to remove water, resulting in a solid residue. The solid residue was washed with an organic solvent (DCM:MeOH = 20:1) on a short silica gel column, and the filtrate was concentrated to obtain the product M8-3 (1.32 g, 28% yield). ESI-MS m / z = 153.2 [M+H] + .

[0318] Step 4: Synthesis of Compound M8

[0319] At room temperature, compound M8-3 (1.20 g) was added to a suspension of LiAlH4 (0.75 g) in THF (24 mL), and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction was cooled to 0 degrees Celsius, and water (0.75 mL), 15% sodium hydroxide solution (0.75 mL), and water (2.25 mL) were added in sequence. The reaction was then returned to room temperature and stirred for 10 minutes. An appropriate amount of anhydrous magnesium sulfate was added, and the mixture was stirred for another 10 minutes before filtering. The filter residue was rinsed with an appropriate amount of organic solvent (DCM:MeOH=10:1), and 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] + .

[0320] Synthesis of intermediate M9:

[0321] Step 1: Synthesis of compound M9-1

[0322] 4-Ethynylaniline (1 g) was dissolved in 10 mL of THF, followed by the addition of (Boc)2O (2.24 g) and the reaction mixture was allowed to react at 55°C for 24 hours. 20.0 mL of water was added to the reaction solution, and the mixture was extracted three times with 20 mL of EA each time. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The organic phase was then purified by column chromatography to obtain compound M9-1 (1.78 g). ESI-MS m / z: 218 [M+H] + Step 2: Synthesis of Compound M9-2

[0323] M9-1 (152 mg) and M1 (330 mg) were dissolved in 6 mL THF, 6 mL H2O, and 6 mL tert-butanol, followed by the addition of sodium ascorbate (360 mg) and anhydrous copper sulfate (100 mg). The mixture was reacted at room temperature for 3 hours. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with EA three times, 20 mL each time. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by column chromatography to obtain compound M9-2 (450 mg). ESI-MS m / z: 688 [M+H] + .

[0324] Step 3: Synthesis of Compound M9

[0325] 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 min. A 1 M aqueous NaOH solution was added to the reaction mixture to adjust the pH to 7, and the mixture was extracted with DCM three times, 10 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield compound M9 (320 mg). ESI-MS m / z: 588 [M+H]+ .

[0326] Synthesis of intermediate M10:

[0327] Compound M10-1 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (10 g) was added to a 100 mL single-necked flask, followed by 30 mL of hydrochloric acid (4 M / Dioxane). After reacting at room temperature for half an hour, the reaction mixture was neutralized by adding saturated sodium bicarbonate solution under ice-cooling. The mixture was filtered, and the filter cake was washed twice with water, dissolved with EA, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 82:18) to obtain the target intermediate M10 (9.1 g).

[0328] Synthesis of intermediate M11:

[0329] The synthesis of steps 1 to 3 refers to the synthesis of intermediate M8.

[0330] Step 4: Synthesis of compound M11-4

[0331] Compound M11-3 (3.4 g) was added to a 250 mL three-necked flask, followed by 100 mL of THF and portionwise addition of NaBH4 (3.1 g). Boron trifluoride etherate (14 mL) was then slowly added dropwise under a nitrogen atmosphere at 0°C. After the addition was complete, the reaction solution was allowed to warm to room temperature and allowed to react overnight. After completion of the reaction, ethanol (50 mL) was slowly added to the reaction solution under an ice bath to quench the reaction. The THF and ethanol were then concentrated under reduced pressure to remove the THF and ethanol. Ethanol (70 mL), water (20 mL), and 10% hydrochloric acid solution (10 mL) were then added to the residue. Stirring was continued at room temperature for 4 h, followed by concentration under reduced pressure. The remaining mother liquor was adjusted to pH 8 with saturated NaHCO3 solution and extracted three times with 40 mL of DCM / MeOH (10:1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried 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] + .

[0332] Step 2: Synthesis of compound M11-5

[0333] Compound M11-4 (2.8 g) was added to a 100 mL single-necked flask, followed by 25 mL of DCM and DIEA (5.9 mL). (Boc)2O (5.0 g) was added under an ice bath, and the mixture was allowed to react at room temperature for 3 h. After completion of the reaction, the reaction solution was added to a 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 obtain 3.0 g of compound M11-5. ESI-MS m / z: 296.2 [M+H] + .

[0334] Step 3: Synthesis of compound M11-6

[0335] Compound M11-5 (2.5 g) was added to a 100 mL single-necked flask, along with 12 mL of MeOH and 12 mL of THF, followed by lithium hydroxide monohydrate (1.8 g dissolved in 12 mL of H₂O). The reaction was stirred at room temperature for 0.5 h. After completion, the reaction solution was diluted with water (12 mL) and concentrated under reduced pressure. The aqueous phase was adjusted to pH 5-6 with acetic acid and then extracted three times with 40 mL of DCM / MeOH (10:1). The organic phases were combined, filtered, and concentrated to yield the crude product (3.1 g), which was used directly in the next step. ESI-MS m / z: 282.2 [M+H] + .

[0336] Step 4: Synthesis of Compound M11-7

[0337] Compound M11-6 (1.4 g) was added to a 100 mL single-necked flask, followed by 10 mL of DMF, followed by tetrahydropyrrole (0.71 g), DIEA (3.29 mL), and HATU (2.84 g). The mixture was stirred at room temperature for 1 h. After the reaction, EA and water were added to the reaction solution for extraction. 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 obtain 1.5 g of compound M11-7.

[0338] ESI-MS m / z:335.2[M+H] + .

[0339] Step 5: Synthesis of Compound M11

[0340] Compound M11-7 (1.5 g) was added to a 50 mL single-necked flask, followed by 5 mL of CH3CN and 5 mL of hydrochloric acid (4M / Dioxane). The mixture was stirred at room temperature for 0.5 h. After the reaction, the reaction solution was directly concentrated to obtain intermediate M11 (0.98 g). ESI-MS m / z: 235.3 [M+H] + .

[0341] Synthesis of intermediate M12:

[0342] Intermediate M2 (500 mg) was added to a 25 mL single-necked flask. Intermediate M4 (275 mg) and N,N-diisopropylethylamine (1.0 g) were added at -40°C, and the reaction was continued at -40°C for 0.5 h. After the reaction, dichloromethane and water were added to the reaction solution for extraction. 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 obtain the target compound M12 (385 mg, 64.6% yield). ESI-MS m / z: 331.3 [M+H] + .

[0343] Synthesis of intermediate M13:

[0344] Step 1: Synthesis of compound M13-1

[0345] (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, and then DIEA (0.31 mL) was added and reacted at room temperature for 30 minutes. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with EA three times, 20 mL each time. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by column chromatography to obtain compound M13-1 (400 mg). ESI-MS m / z: 668 [M+H] + .

[0346] Step 2: Synthesis of compound M13

[0347] M13-1 (135 mg) was dissolved in 3 mL of DCM, followed by the addition of 1 mL of TFA and allowed to react at room temperature for 30 min. A 1 M aqueous NaOH solution was added to the reaction solution to adjust the pH to 7. The solution was then extracted three times with 5 mL of chloroform:isopropanol (3:1). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield M13 (110 mg). ESI-MS m / z: 568 [M+H] + . Synthesis of intermediate M14:

[0348] Step 1: Synthesis of compound M14-1

[0349] 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 in sequence. The reaction was allowed to react at room temperature for 15 h. The reaction solution was quenched with 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 the solvent was evaporated under reduced pressure to obtain 8.02 g of the product, i.e., compound M14-1, which was used directly in the next step.

[0350] Step 2: Synthesis of compound M14-2

[0351] 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 h. The reaction solution was quenched with an appropriate amount of water, then extracted with an appropriate amount of ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Column chromatography was used for purification to obtain 4.02 g of the product, compound M14-2, ESI-MS m / z: 350 [M+H] + .

[0352] Step 3: Synthesis of Compound M14

[0353] M14-2 (3.5 g) was dissolved in DCM (30.0 mL), trifluoroacetic acid (10.0 mL) was added, and the mixture was reacted at room temperature for 0.5 h. The reaction was monitored by LC-MS. The reaction solution was directly concentrated, redissolved in 30.0 mL of DCM, and concentrated again to obtain 2.5 g of the product trifluoroacetate, i.e., compound M14, which was used directly in the next step. ESI-MS m / z: 250 [M+H] +

[0354] Synthesis of intermediate M15:

[0355] Step 1: Synthesis of compound M15-1

[0356] 7-tert-Butyloxycarbonyl-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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300.0 mg) were dissolved in 5.00 mL of DMF, followed by the addition of N,N-diisopropylethylamine (0.35 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (310.0 mg). The mixture was reacted at room temperature for 30 minutes. LCMS monitored the reaction completion. 100.0 mL of water was added to the reaction solution, and the precipitated solid was filtered and purified by column chromatography to obtain 400.0 mg of a light yellow solid, i.e., compound M15-1. ESI-MS m / z:696[M+H] + .

[0357] Step 2: Synthesis of Compound M15

[0358] M15-1 (400.0 mg) was dissolved in 5.00 mL of DCM, followed by the addition of 2.00 mL of TFA. The reaction mixture was allowed to react at room temperature for 0.5 h. The reaction solution was added dropwise to a saturated sodium bicarbonate solution and extracted with an appropriate amount of a 10 / 1 DCM / MeOH solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound M15. ESI-MS m / z: 596 [M+H] + .

[0359] Synthesis of intermediate M16:

[0360] Step 1: Synthesis of compound M16-1

[0361] 7-tert-Butyloxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (500.0 mg) was dissolved in 5.0 mL of THF, and a borane tetrahydrofuran solution (4.64 mL, 1 mol / L) was added. The mixture was reacted at room temperature for 1 h. 5 mL of HCl / MeOH solution was slowly added to the reaction solution and stirred until no bubbles were generated. 1 mol / L NaOH solution was added to adjust the pH to alkaline. An appropriate amount of ethyl acetate was then added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M16-1 (450.0 mg). ESI-MS m / z: 200 [M+H-56] + .

[0362] Step 2: Synthesis of compound M16-2

[0363] M16-1 (250.0 mg) was dissolved in 5.0 mL of DCM, and Dess-Martin reagent (387.0 mg) was added. The mixture was allowed to react at room temperature for 1 h. An appropriate amount of ethyl acetate was added to the reaction solution, and the precipitated solid was removed by filtration. The filtrate was added with 1 mol / L NaOH solution to adjust the pH to alkaline. The organic phase was collected by extraction and separation, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M16-2 (180.0 mg). ESI-MS m / z: 198 [M+H-56] + .

[0364] Step 3: Synthesis of compound M16-3

[0365] 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 h. The reaction solution was extracted with appropriate amounts of water and ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M16-3 (110 mg). ESI-MS m / z: 194 [M+H-56] + .

[0366] Step 4: Synthesis of compound M16-4

[0367] Under N2 protection, compound M16-3 (110 mg), 2S,4R-1-(S)-2-azido-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(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 mixed solvent 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 h. The reaction solution was extracted with appropriate amounts of water and a DCM / MeOH = 10 / 1 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]. + .

[0368] Step 5: Synthesis of Compound M16

[0369] Under N2 protection, compound M16-4 (250 mg) was dissolved in 5.00 mL of DCM, followed by the addition of 2.00 mL of TFA. The mixture was allowed to react at room temperature for 0.5 h. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution and extracted with an appropriate amount of a DCM / MeOH = 10 / 1 solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound M16 (150.0 mg). ESI-MS m / z: 620 [M+H] + .

[0370] Synthesis of intermediate M17:

[0371] Step 1: Synthesis of compound M17-1

[0372] M16-4 (100.0 mg) was dissolved in DCM (2.0 mL) under ice-cooling, and triethylamine (0.046 mL), 4-dimethylaminopyridine (1.7 mg), and acetyl chloride (0.019 mL) were added sequentially. The mixture was reacted under ice-cooling for 1 h. An appropriate amount of water and DCM were added to the reaction solution for extraction. 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 obtain 80 mg of the compound M17-1, ESI-MS m / z: 762 [M+H]. + .

[0373] Step 2: Synthesis of compound M17

[0374] Under ice bath, M17-1 (80.0 mg) was dissolved in DCM (2.0 mL), 1.00 mL of TFA was added, and the mixture was reacted at room temperature for 0.5 h. The reaction solution was directly concentrated, redissolved in 5.00 mL of DCM, and concentrated again to obtain 80 mg of the product trifluoroacetate, i.e., compound M17, which was used directly in the next step. ESI-MS m / z: 662 [M+H] + .

[0375] Synthesis of intermediate M18:

[0376] Step 1: Synthesis of compound M18-1

[0377] Methyl 4-fluorobenzoate (0.15 g) was added to a 25 mL single-necked flask and dissolved in DMSO (3 mL). Tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate and DIEA (0.48 mL) were added. The mixture was heated to 100°C and allowed to react overnight. After cooling to room temperature, 10 mL of water was added to the reaction solution. Solids precipitated and were filtered. The filter cake was rinsed with water and dried to obtain 0.2 g of compound M18-1.

[0378] Step 2: Synthesis of compound M18-2

[0379] Compound M18-1 (0.2 g) was added to a 25 mL single-necked 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 for 3 h. After cooling to room temperature, the reaction solution was concentrated directly. 5 mL of water was added to the reaction solution, and the pH was adjusted to 3-4 with 1 M HCl solution. Solid precipitated and was filtered. The filter cake was rinsed with water and dried to obtain 0.17 g of compound M18-2.

[0380] Step 3: Synthesis of compound M18-3

[0381] Compound M18-2 (140.0 mg) was added to a 25 mL single-necked 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), DIEA (0.13 mL), and HATU (231.0 mg) were added and reacted at room temperature for 2 h. Saturated brine (5 mL) was added to the reaction solution, and the mixture was extracted 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.

[0382] Step 4: Synthesis of Compound M18

[0383] Compound M18-3 (276.0 mg) was added to a 25 mL single-necked flask and dissolved in DCM (2 mL). TFA (2 mL) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was evaporated to dryness, 5 mL of DCM was added, and the pH was adjusted to 8-9 with 1 M NaOH solution. The solution was extracted three times with DCM. The organic phase was washed with water and saturated brine and evaporated to dryness to obtain 214.0 mg of compound M18.

[0384] Synthesis of intermediate M19:

[0385] The synthesis steps of M19 were prepared by referring to M18.

[0386] Synthesis of intermediate M20:

[0387] The synthesis steps of M20 were prepared by referring to M18.

[0388] Synthesis of intermediate M21:

[0389] Step 1: Synthesis of compound M21-1

[0390] 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) and tert-butyl 2-ethynyl-7-azaspiro[3.5]nonane-7-carboxylate (0.044 g) were dissolved in tert-butanol (1 mL) and THF (1 mL). Copper sulfate (28 mg) and an aqueous solution (1 mL) of sodium ascorbate (105 mg) were added and the mixture was allowed to react at 20°C for 1 h. The reaction mixture was added to 15 mL of water and 15 mL of EA. The organic phase was separated, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by prep-TLC (MeOH:DCM = 1:20) to obtain 78 mg of compound M21-1. ESI-MS m / z:719.40[M+H] + .

[0391] Step 2: Synthesis of compound M21

[0392] Compound M21-1 (78 mg) was dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was allowed to react at 20°C for 0.5 h. The reaction mixture was added to 20 mL of saturated sodium bicarbonate and extracted with chloroform / isopropanol (3:1). The organic phase was separated and the aqueous phase, free of product, was discarded. The organic phase was dried, filtered, and concentrated to yield 65 mg of compound M21. This was used directly in the next step. ESI-MS m / z: 619.40 [M+H] + .

[0393] Synthesis of intermediate M22:

[0394] Step 1: Synthesis of compound M22-1

[0395] Compound 2-(tert-Butoxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (0.1 g) and (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) were dissolved 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 h. The reaction mixture was added to 20 mL of water, followed by 15 mL of EA and 1 mL of methanol. The organic phase was separated, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.22 g of compound M21-1. This was used directly in the next step. ESI-MS m / z: 696.40 [M+H] + .

[0396] Step 2: Synthesis of compound M22

[0397] Compound M22-1 (240 mg) was dissolved in DCM (6.0 mL) and trifluoroacetic acid (1.2 mL) was added. The mixture was allowed to react at 20°C for 0.5 h. The reaction mixture was added to 20 mL of saturated sodium bicarbonate and extracted with chloroform / isopropanol (3:1). The organic phase was separated, dried, filtered, and concentrated to yield 200 mg of compound M22. This was used directly in the next step. ESI-MS m / z: 596.40 [M+H] + .

[0398] Synthesis of intermediate M23:

[0399] Step 1: Synthesis of compound M23-1

[0400] 2-Chloro-5-iodopyridine (1 g) was added to a 50 mL three-necked flask. Under nitrogen protection, 10 mL of TEA was added, along with trimethylsilyl acetylene (1.03 g), cuprous iodide (80 mg), and PdCl2(PPh3)2 (146 mg). The reaction mixture was heated to 50°C and allowed to react for 3 h. The reaction solution was filtered, the filtrate 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] + .

[0401] Step 2: Synthesis of compound M23

[0402] Compound M23-1 (500 mg) was added to a 50 mL single-necked flask and dissolved in 5 mL of MeOH. Anhydrous potassium carbonate (658 mg) was added and stirred at room temperature for 2 h. The reaction mixture was filtered, the filtrate collected, and directly concentrated. The concentrate was separated and purified by column chromatography (PE:EA = 20:1) to obtain 240 mg of compound M23. ESI-MS m / z: 138 [M+H] + .

[0403] Synthesis of intermediate M24:

[0404] Step 1: Synthesis of compound M24-1

[0405] Zinc powder (880 mg) and 80 mL of anhydrous tetrahydrofuran were added to a 250 mL three-necked flask under nitrogen protection. Dibromomethane (200 mg) was added at room temperature, and the temperature was raised to 65°C for reaction for 1 h. After cooling to room temperature, TMSCl (115 mg) was added and the temperature was allowed to react for 1 h at room temperature. 3-iodoazetidine-1-carboxylic acid tert-butyl ester (3.0 g) was added and the temperature was allowed to react for 1 h at 40°C to obtain M24-1, which was sealed for later use.

[0406] Step 2: Synthesis of compound M24-2

[0407] To the above M24-1 solution, methyl 4-bromobenzoate (1.1 g), Pd2(dba)3 (235 mg), and Johnphos (153 mg) were added sequentially under nitrogen atmosphere at 40°C for 2 h. 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).

[0408] Step 3: Synthesis of compound M24-3

[0409] Compound M24-2 (660 mg) was added to a 50 mL single-necked flask, along with 10 mL of MeOH and 2 mL of water. Sodium hydroxide (410 mg) was added at room temperature, and the temperature was raised to 60°C for 2 h. After the reaction, water was added to the reaction solution to adjust the pH to 6. The solution was extracted twice with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield the target compound M24-3 (550 mg).

[0410] Step 4: Synthesis of Compound M24-4

[0411] Compound M24-3 (150 mg) was added to a 50 mL single-necked vial, followed by 3 mL of DMF and HATU (250 mg). Under nitrogen protection, DIEA (350 mg) was added at 0°C and allowed to react for 0.5 h. (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 then added and the mixture was allowed to react at room temperature for 1 h. 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 the target compound M24-4 (340 mg). ESI-MS m / z: 704.3 [M+H] + .

[0412] Step 5: Synthesis of Compound M24

[0413] Compound M24-4 (340 mg) was added to a 50 mL single-necked flask, followed by 5 mL of DCM and 1 mL of TFA. The mixture was allowed to react at room temperature for 1 h. After completion of the reaction, the mixture was concentrated, diluted with DCM, poured into a sodium bicarbonate solution, and extracted three times with DCM:MeOH (10:1). The mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield the target compound M24 (250 mg). ESI-MS m / z: 604.3 [M+H] + .

[0414] Synthesis of intermediate M25:

[0415] Step 1: Synthesis of compound M25-1

[0416] 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-butyl ester (174.0 mg) and HATU (149.4 mg) were dissolved in DMF (2 mL), and DIEA (0.27 mL) was added. The mixture was allowed to react at room temperature for 10 minutes, and the reaction was monitored for completion by LCMS. DCM (10 mL) was added to the reaction solution, and the mixture was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 231.0 mg of compound M25-1. ESI-MS m / z: 732 [M+H] + .

[0417] Step 2: Synthesis of compound M25

[0418] M25-1 (231.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. LCMS monitored the reaction to completion. The reaction solution was directly concentrated, 1 M NaOH (2 mL) was added, and the mixture was stirred at room temperature for 5 minutes. The mixture was filtered to obtain 181.0 mg of a light yellow solid, compound M25. ESI-MS m / z: 632 [M+H] + .

[0419] Synthesis of intermediate M26:

[0420] Step 1: Synthesis of intermediate M26-1

[0421] 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 in sequence. The reaction was allowed to react at room temperature for 15 h. An appropriate amount of water was added to the reaction solution for quenching, and 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 obtain 8.02 g of the product, i.e., compound M26-1, which was used directly in the next step.

[0422] Step 2: Synthesis of intermediate M26-2

[0423] 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 h. The reaction solution was quenched with water and then extracted with 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.

[0424] ESI-MS m / z:350[M+H] + .

[0425] Step 3: Synthesis of intermediate M26-3

[0426] Compound M26-2 (4.0 g) was dissolved in a mixed solution of THF (40.00 mL) and MeOH (40.00 mL), and a solution of sodium hydroxide (2.29 g) in water (20.0 mL) was added. The mixture was reacted at 40°C for 1 h. After the reaction solution was cooled to room temperature, 1 M sulfuric acid was added to adjust it to acidity. 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 the product, namely, intermediate M26-3.

[0427] ESI-MS m / z:336[M+H] + .

[0428] Step 4: Synthesis of intermediate M26-4

[0429] Intermediate M26-3 (1.00 g), 2S,4R-1-(S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(S)-1-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (1.59 g) were dissolved in 15.00 mL of DMF, followed by the addition of N,N-diisopropylethylamine (1.56 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (1.36 g). The reaction was allowed to react at room temperature for 30 minutes. LCMS monitored the reaction completion. 100.0 mL of water was added to the reaction solution, and the precipitated solid was filtered and purified by column chromatography to give 1.95 g of intermediate M26-4.

[0430] ESI-MS m / z:762[M+H] + .

[0431] Step 5: Synthesis of intermediate M26

[0432] Intermediate M26-4 (1.50 g) was dissolved in 20.00 mL of DCM, and then 5.00 mL of TFA was added. The mixture was reacted at room temperature for 0.5 h. The reaction solution was added dropwise to a 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 the solvent was evaporated under reduced pressure to obtain 1.20 g of intermediate M26.

[0433] ESI-MS m / z:662[M+H] + .

[0434] Synthesis of intermediate M27:

[0435] Step 1: Synthesis of compound M27-1

[0436] To a solution of compound M11-6 (600 mg) in DMF (15 mL) were added dimethylamine (191 mg), DIEA (1.76 mL), and HATU (973 mg) in sequence, and the mixture was stirred at room temperature for 1 h. After completion of the reaction, EA and water were added to the reaction solution for extraction. The organic phase was collected and the aqueous phase was extracted twice more with EA. The combined organic phases were 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 obtain 580 mg of compound M27-1.

[0437] ESI-MS m / z:309.3[M+H] + .

[0438] Step 5: Synthesis of Compound M27

[0439] M27-1 (580 mg) was dissolved in HCl / dioxane (4N, 5 mL) and stirred at room temperature for 0.5 h. After the reaction, the reaction solution was directly concentrated to obtain intermediate M27 (390 mg). ESI-MS m / z: 209.3 [M+H] + .

[0440] Synthesis of Intermediate M28: Synthesis of (R)-1-(7-(8-ethyl-7-fluoro-3-methoxymethoxy)naphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methylpiperidin-1-yl)pyridopyrimidin-2-yl)oxy)methyl)cyclopropane-1-carbaldehyde

[0441] Step 1: Synthesis of intermediate M28-1

[0442] The raw materials 7-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (30.0 g) and phosphorus oxychloride (120 mL) were added sequentially to a 500 mL reaction flask. DIPEA (50 mL) was slowly added dropwise at room temperature. A large amount of smoke was generated and the temperature increased. After the addition, the temperature was raised to 100°C and the reaction was stirred for 1.0 h. After the reaction was complete, the solvent was dried and the mixture was slowly poured into ice water. A large amount of solid precipitated. The mixture was stirred for 2.0 h, filtered, and the filter cake was dried to obtain compound M28-1 (31.6 g), which was directly carried out to the next step.

[0443] ESI-MS m / z:252.1[M+H] + .

[0444] Step 2: Synthesis of compound M28-2

[0445] Intermediate M28-1 (5.0 g) was dissolved in DCM (20 mL), cooled to approximately -40°C, and DIPEA (7.7 g) was added. The mixture was stirred at low temperature for 30 minutes, and (3R)-3-methylpiperidin-3-ol hydrochloride (4.2 g) was slowly added. The reaction was stirred for 1.0 hour. After the reaction was complete, the mixture was extracted with DCM and H2O, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (EA:DCM 10%) to afford compound M28-2 (5.3 g).

[0446] ESI-MS m / z:331.3[M+H] + .

[0447] Step 3: Synthesis of compound M28-3

[0448] Compound M28-2 (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 at room temperature overnight. Upon completion, the mixture was extracted with EA and H2O, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (EA:DCM 18%) to afford compound M28-3 (5.0 g).

[0449] ESI-MS m / z:397.1[M+H] + .

[0450] Step 4: Synthesis of compound M28-4

[0451] Compound M28-3 (5.0 g), M5 (9.0 g), 3.5 g potassium carbonate, and Cataxium A Pd G3 (1.3 g) were dissolved in 1,4-dioxane (24 mL) and H2O (4 mL). The mixture was reacted at 90°C under a nitrogen atmosphere for 1 h. After the reaction was complete, the reaction solution was diluted with EA and H2O, 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 obtain M28-4 (6.0 g, 85% purity), which was directly used in the next step. ESI-MS m / z: 595.2 [M+H] + .

[0452] Step 5: Synthesis of Compound M28

[0453] To a solution of compound M28-4 (6.0 g) in DCM (50 mL) was added DMP (6.4 g) portionwise, and the mixture was stirred at room temperature for 3.0 h. Upon completion of the reaction, the mixture was quenched with saturated sodium sulfite, extracted with DCM and H2O, and the aqueous phase was extracted twice more with DCM. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified by column chromatography (PE:EA 50%) to afford the target compound M28 (3.4 g).

[0454] ESI-MS m / z:593.4[M+H] + .

[0455] Synthesis of intermediate M29: Synthesis of compound (2S,4R)-1-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0456] Step 1: Synthesis of compound M29-1

[0457] (S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethanamine (12.7 g), Boc-L-hydroxyproline (13.5 g), and HATU (23.2 g) were dissolved in DMF (100 mL). DIEA (38.5 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 solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 22.0 g of a white solid, compound M29-1.

[0458] ESI-MS m / z:432[M+H] + .

[0459] Step 2: Synthesis of compound M29-2

[0460] M29-1 (22.0 g) was added to DCM (100 mL). A dioxane hydrochloride solution (100 mL) was added under an ice-water bath. The mixture was allowed to react at room temperature for 60 minutes. The reaction was monitored for completion by LCMS. The reaction solution was directly concentrated, and 1 M NaOH solution was added until the pH reached 8. DCM (100 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 16.8 g of a white solid, compound M29-2.

[0461] ESI-MS m / z:332[M+H] + .

[0462] Step 3: Synthesis of compound M29-3

[0463] M29-2 (19.0 g), Boc-L-valine (12.5 g), and HATU (22.9 g) were dissolved in DMF (100 mL). DIEA (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 solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 25.0 g of a white solid, compound M29-3.

[0464] ESI-MS m / z:531[M+H] + .

[0465] Step 4: Synthesis of compound M29-4

[0466] M29-3 (25.0 g) was added to DCM (100 mL). A dioxane hydrochloride solution (100 mL) was added under an ice-water bath. The mixture was allowed to react at room temperature for 60 minutes. The reaction was monitored for completion by LCMS. The reaction solution was concentrated directly, and 1 M NaOH solution was added until the pH reached 8. DCM (100 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 17.0 g of a white solid, compound M29-4.

[0467] ESI-MS m / z:431[M+H] + .

[0468] Step 5: Synthesis of Compound M29

[0469] 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) under an ice-water bath and slowly added to the system. The reaction was incubated for 3 hours, and the reaction was monitored for completion by LCMS. The reaction solution was directly concentrated, and DCM (100 mL) was added to the reaction solution. 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 light yellow powder, namely compound M29.

[0470] ESI-MS m / z:457[M+H] + .

[0471] 1 H 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).

[0472] Synthesis of intermediate M30:

[0473] Step 1: Synthesis of compound M30-1

[0474] To a stirred solution of 1-(tert-butyl)-2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (20 g) in DCM (300 mL) was added a 1.0 M solution of DIBAL-H in n-hexane (329 mL) dropwise under a nitrogen atmosphere at -78°C, and stirred at -78°C for 30 min. The mixture was then transferred to room temperature and stirred for 2 hours. TLC confirmed the disappearance of the starting material. After cooling to 0°C, MeOH (300 mL) and 1 M HCl (200 mL) were added, and the mixture was stirred at room temperature for 2 hours. TLC confirmed the end point of the reaction. After the reaction was completed, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to obtain a light yellow liquid (13.9 g), compound M30-1.

[0475] Step 2: Synthesis of compound M30-2

[0476] M30-1 (13.9 g) was dissolved in 140 mL of DMF, and imidazole (4.5 g) was added at 0°C, followed by the dropwise addition of TBDPSCl (17.2 mL). After completion of the dropwise addition, the mixture was transferred to room temperature and stirred for 3 h. The reaction endpoint was monitored by TLC. After completion of the reaction, 100.0 mL of water was added to the reaction solution, and the mixture was extracted with EA three times, 200 mL each time. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain a light yellow liquid (21.09 g), compound M30-2.

[0477] Step 3: Synthesis of compound M30-3

[0478] M30-2 (21.09 g) was dissolved in 140 mL of DCM, the reaction solution was cooled to -35°C, TMSCN (7.48 mL) was added, and the mixture was stirred at -35°C for 15 min. TMSOTf (0.14 mL) was added dropwise, and the mixture was stirred at -35°C for 10 min. After the reaction was completed as monitored by TLC, saturated sodium bicarbonate: water = 15 mL: 90 mL was added, and the mixture was stirred for 15 min. The mixture was extracted with EA three times, 200 mL each time. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and the organic phase was concentrated. The mixture was separated and purified by column chromatography to obtain 16.2 g of a yellow liquid, namely compound M30-3.

[0479] Step 4: Synthesis of compound M30-4

[0480] A mixture of M30-3 (16.2 g) and K2CO3 (7.55 g) in MeOH (120 mL) was stirred at room temperature for 3 h. The mixture was acidified to pH = 2 with 1 M aqueous HCl and stirred at room temperature for 3 h. TLC confirmed the reaction was complete. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to yield a yellow liquid (8.5 g), compound M30-4.

[0481] Step 5: Synthesis of compound M30-5

[0482] M30-4 (8.5 g) was dissolved in THF (85 mL) and LiHMDS (34.16 mL) in tetrahydrofuran was added dropwise at -78 ° C under a nitrogen atmosphere. The resulting mixture was stirred at -78 ° C for 10 min, 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. LC-MS confirmed that the reaction was complete. The mixture was quenched with water at 0 ° C, and the resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give a yellow liquid (5 g), compound M30-5.

[0483] Step 6: Synthesis of Compound M30-6

[0484] 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 h. The reaction mixture was concentrated under reduced pressure and evaporated from 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. LC-MS confirmed the reaction endpoint, and then the mixture was quenched with water at room temperature. The mixture was extracted with EA, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give a yellow liquid (3.04 g), compound M30-6.

[0485] Step 7: Synthesis of Compound M30

[0486] To a solution of M30-6 (3.04 g) in THF (30 mL) was added dropwise a 1 M solution of LiAlH4 in THF (6.8 mL) at -20°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 20 min. LC-MS confirmed the completion of the reaction. Sodium sulfate decahydrate was then added at 0°C and stirred for 30 min. The mixture was filtered, washed with EA, and concentrated. The residue was purified by column chromatography on neutral alumina to yield a yellow liquid (2 g), compound M30.

[0487] Synthesis of 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-pyrrolizine-7a(5H)-methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol

[0488] Step 1: Synthesis of compound M31-1

[0489] In a 100 mL single-necked flask, dissolve M28-2 (2.90 g) in tetrahydrofuran (30.0 mL). Add sodium hydride (1.40 g). Stir for 10 min, then add M30 (4.43 g). React at room temperature for 0.5 h. Quench the reaction mixture with an appropriate amount of saturated ammonium chloride solution. Extract three times with dichloromethane. Collect the organic phase, dry over anhydrous sodium sulfate, and evaporate the solvent. Isolate the product by column chromatography to obtain 5.30 g of a yellow solid, compound M31-1.

[0490] Step 2: Synthesis of compound M31-2

[0491] To a 100 mL single-necked flask, 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 sequence and dissolved in 1,4-dioxane (50.0 mL) and water (5.0 mL). The atmosphere was replaced with nitrogen 2-3 times and the reaction was carried out at 100°C for 3 h. An appropriate amount of water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was isolated by column chromatography to obtain 4.5 g of a yellow solid, compound M31-2.

[0492] Step 3: Synthesis of intermediate M31

[0493] Compound M31-2 (4.50 g) was added to a 100 mL single-necked flask under ice, dissolved in dichloromethane (50.0 mL), and triethylamine hydrofluoride (10.0 mL) was added. The mixture was allowed to react under ice for 0.5 h. 5.0 mL of methanol was added to the reaction solution, and the mixture was extracted three times with 50.0 mL of water. The organic phase was washed with saturated brine, collected, and evaporated to dryness. The product was isolated by column chromatography to obtain 2.3 g of a yellow solid, intermediate M31.

[0494] Synthesis of 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-pyrrolizin-3-yl)methyl(4-nitrophenyl)carbonate

[0495] Step 1: Synthesis of compound M32

[0496] Compound M31 (100.0 mg), triethylamine (30.0 mg), DMAP (5.0 mg), and p-nitrophenyl chloroformate were added to a 10 mL single-necked vial, followed by tetrahydrofuran (4.00 mL). Stirring was performed at 20°C for 18 hours. LCMS monitoring indicated the disappearance of the starting material, indicating the reaction was complete. Reaction solution M32 was used directly in the next step.

[0497] Synthesis of 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

[0498] Step 1: Synthesis of compound M33-1

[0499] To a reaction flask, intermediate M2 (5 g), dichloromethane (70.00 mL), and N,N-diisopropylethylamine (9.82 mL, 59.42 mmol) were added. The temperature was lowered to -40°C, and (3R)-3-methylpiperidin-3-ol (2.51 g, 21.79 mmol) was added. The reaction was allowed to proceed at this temperature for 0.5 h. The mixture was extracted twice with DCM (100 mL) and H2O (100 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (PE:EA = 3:2) to obtain compound M33-1 (5.75 g) as a yellow solid. ESI-MS m / z: 331.18 [M+H] + .

[0500] Step 2: Synthesis of compound M33-2

[0501] Compound M33-1 (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 allowed to react at room temperature for 2 h. The solvent was concentrated, extracted with EA and water, dried, and concentrated. The product was separated by column chromatography (DCM:EA = 3:1) to obtain M33-2 (2.3 g) as a yellow oil. ESI-MS m / z: 401.28 [M+H] + .

[0502] Step 3: Synthesis of compound M33-3

[0503] To a reaction flask were added 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), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (0.61 g), potassium phosphate (2.98 g), and 1,4-dioxane (36.00 mL). After nitrogen replacement, the reaction was incubated at 100°C under nitrogen protection for 3 h. The mixture was then extracted with water and EA, dried, and concentrated. The product was separated by column chromatography (DCM:EA = 3:1) to give M33-3 (3.3 g) as a yellow oil. ESI-MS m / z: 599.45 [M+H] + .

[0504] Step 4: Synthesis of Compound M33

[0505] Compound M33-3 (2.50 g), 1,4-dioxane (15.00 mL), and concentrated hydrochloric acid (9.00 mL) were added to the reaction flask and reacted at room temperature for 1 h. Under ice bath, sodium bicarbonate aqueous solution was added to adjust the pH to 8. The mixture was extracted with EA and THF, dried, and concentrated to obtain a yellow solid M33 (2.15 g). ESI-MS m / z: 509.19 [M+H] + .

[0506] Synthesis of intermediate M34:

[0507] Step 1: Synthesis of compound M34-1

[0508] 3-Butyn-1-ol (140 g) and potassium bicarbonate (150 g) were added to a 3 L single-necked flask filled with ethyl acetate / water (1000 / 100 mL) while stirring. 1,1-Dibromoformaldehyde oxime (100 g) was then dissolved in ethyl acetate (250 mL) and added dropwise to the 3 L single-necked flask. The mixture was stirred at room temperature for 16 hours. After the reaction, water was added to dilute the reaction mixture. The organic phase was separated and collected, and the aqueous phase was extracted once more 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 = 5:1) to obtain the target compound M34-1 (93 g, 97% yield). ESI-MS m / z: 191.9 [M+H] + .

[0509] Step 2: Synthesis of compound M34-2

[0510] Compound M34-1 (93 g) was added to a 3 L single-necked flask, along with acetone (1100 mL). Jones reagent (450 mL) was then added dropwise to the reaction mixture at 0°C. The mixture was heated to room temperature and stirred for 12 h. After the reaction, water was added to dilute the mixture, followed by extraction with ethyl acetate. The organic phase was collected and the aqueous phase was extracted once more with ethyl acetate. The organic phases were collected and combined, washed once with brine, dried over anhydrous sodium sulfate, and concentrated to yield compound M34-2 (60 g, 60% yield) as a yellow oil. ESI-MS m / z: 205.9 [M+H] + .

[0511] Step 3: Synthesis of compound M34-3

[0512] Compound M34-2 (60 g) was added to a 1 L single-necked flask, followed by methanol (500 mL). 5 mL of concentrated sulfuric acid was slowly added dropwise under an ice bath, and the temperature was raised to 70°C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The aqueous phase was extracted twice more 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 obtain the target compound M34-3 (49 g, 76% yield).

[0513] ESI-MS m / z:219.9[M+H] + .

[0514] Step 4: Synthesis of compound M34-4

[0515] Compound M34-3 (49 g) was added to a 1L single-necked flask, followed by tetrahydrofuran (500 mL) and potassium tert-butoxide (45 g). 2-Iodopropane (49 g) was added dropwise under an ice bath and allowed to react at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with ice-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 = 100:1) to obtain the target compound M34-4 (32 g, 55% yield). ESI-MS m / z: 262.0 [M+H] + .

[0516] Step 5: Synthesis of Compound M34-5

[0517] Compound M34-4 (32 g) was added to a 1 L single-necked flask, followed by methanol (250 mL) and potassium hydroxide (73 g), followed by potassium tert-butoxide (45 g). The mixture was stirred under reflux for 4 h. After completion of the reaction, the mixture was cooled to room temperature and the pH was adjusted to 5 with 1N HCl solution. The reaction solution was concentrated and the concentrate was purified by reverse-phase column chromatography (5%-40% ACN / water (0.1% trifluoroacetic acid)) to afford the target compound M34-5 (21 g, 86% yield). ESI-MS m / z: 200.1 [M+H]+.

[0518] Step 6: Synthesis of Compound M34-6

[0519] Compound M34-5 (21 g) was added to a 500 mL single-necked flask, followed by acetic acid (150 mL) and 33% aqueous hydrogen bromide (150 mL). The temperature was raised to 60°C and stirred for 10 h. 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 afford compound M34-6 (15 g, 77% yield). ESI-MS m / z: 186.0 [M+H]+.

[0520] Step 7: Synthesis of Compound M34-7

[0521] Compound M34-6 (15 g) was added to a 500 mL single-necked flask, followed by methanol (150 mL). Thionyl chloride (75 mL) was added dropwise under an ice bath and stirred at room temperature for 1.5 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic phase was collected and the aqueous phase was extracted once more 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 obtain the target compound M34-7 (11 g, 69% yield). ESI-MS m / z: 200.1 [M+H] + .

[0522] Step 8: Synthesis of Compound M34

[0523] Compound M34-7 (7 g) was added to a 500 mL single-necked flask, followed by acetonitrile (75 mL) and potassium carbonate (10 g) in portions. Perfluorobutylsulfonyl fluoride (14 g) was then slowly added dropwise and stirred at room temperature for 2 h. After the reaction, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was collected and the aqueous phase was extracted once more 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:THF = 100:1) to obtain the target compound M34 (14.5 g, 80% yield).

[0524] ESI-MS m / z:482.0[M+H] + . 1 H NMR (500MHz, DMSO) 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).

[0525] Synthesis of intermediate M35:

[0526] Step 1: Synthesis of compound M35-1

[0527] 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. LCMS monitored the reaction completion. DCM (10 mL) was added to the reaction solution, and the mixture was washed once with saturated brine. 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, compound M35-1. ESI-MS m / z: 341.5 [M+H] + .

[0528] Step 2: Synthesis of compound M35-2

[0529] 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 react at room temperature for 1 hour. LCMS monitored the reaction to completion. The pH of the reaction solution was adjusted to acidic, and EA (20 mL) was added. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 200.0 mg of a white solid, compound M35-2. ESI-MS m / z: 283.5 [M+H] + .

[0530] Step 3: Synthesis of compound M35-3

[0531] 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), DIEA (0.45 mL) was added, and the mixture was reacted at room temperature for 10 minutes. The reaction was monitored by LCMS to be complete. EA (20 mL) and saturated brine (20 mL) were added to the reaction solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 300.0 mg of a white solid, i.e., compound M35-3. ESI-MS m / z: 696.9 [M + H] + .

[0532] Step 4: Synthesis of compound M35-4

[0533] M35-3 (300.0 mg) was separated by SFC and concentrated to obtain 135.0 mg of a white solid, namely compound M35-4. ESI-MS m / z: 696.9 [M+H] + .

[0534] Step 5: Synthesis of Compound M35

[0535] M35-4 (135.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. The reaction was monitored by LCMS for completion. The reaction solution was directly concentrated and 1 M NaOH solution was added until the pH of the reaction solution reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 109.0 mg of a white solid, compound M35. ESI-MS m / z: 596.9 [M+H] + .

[0536] Synthesis of intermediate M36:

[0537] Step 1: Synthesis of compound M36-1

[0538] Compound piperazine-1-carboxylic acid tert-butyl ester (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 hours. Finally, M34 (6.0 g) was added. Stirred at 145°C for 5 hours. LCMS monitored the completion of the reaction. H2O and EA were added and extracted twice. The organic layer was washed three times with saturated brine and then dried over anhydrous sodium sulfate. Purification by column chromatography gave a light yellow solid (4.2 g). This is compound M36-1. ESI-MS m / z: 368.1 [M+H] + .

[0539] Step 2: Synthesis of compound M36-2

[0540] Compound M36-1 (4.2 g) was added to tetrahydrofuran (5 mL), methanol (5 mL), water (5 mL), and lithium hydroxide monohydrate (1.0 g). Stirred at 20°C for 1 hour. LCMS monitored the completion of the reaction. 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 light yellow solid (3.6 g) was obtained. This is compound M36-2. ESI-MS m / z: 354.3 [M+H] + .

[0541] Step 3: Synthesis of compound M36-4

[0542] Compounds M36-2 (3.5 g) and M29-2 (3.3 g) were added to a 25 mL single-necked bottle, and N,N-dimethylacetamide (30.00 mL) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (7.6 g) and N,N-diisopropylethylamine (4.9 mL) were added. Stir at 20°C for 0.5 hours. LCMS monitored the completion of the reaction. H2O and EA were added and extracted twice. The organic layer was washed three times with saturated brine and then dried over anhydrous sodium sulfate. The crude product M36-3 was separated by SFC to obtain a light yellow solid (3.4 g). This is compound M36-4. ESI-MS m / z: 667.2 [M+H] + .

[0543] Step 4: Synthesis of Compound M36

[0544] Compound M36-4 (80.0 mg) was added to a 10 mL single-necked bottle, and dichloromethane (2.00 mL) and hydrochloric acid (4M in dioxane) (1.00 mL) were added. Stir at 20°C for 0.5 hours. LCMS monitored the completion of the reaction. Concentrated under reduced pressure, then 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 light yellow solid (73.0 mg) was obtained. That is, compound M36. ESI-MS m / z: 567.3 [M+H] + .

[0545] Synthesis of intermediate M37:

[0546] Step 1: Synthesis of compound M37-1

[0547] 5-Ethynyl-2-fluoropyridine (500 mg), 1-Boc-piperazine (922 mg), acetone 5 mL, DIEA (1.6 g) were added to a 50 mL flask and heated to 60 ° C for 5 h. After desolvation, EA was added to dissolve the mixture, washed with water, washed with brine, dried over sodium sulfate, filtered, and the filtrate was decompressed to obtain a crude product. The product M37-1 (1.02 g) was obtained by column chromatography.

[0548] Step 2: Synthesis of compound M37-2

[0549] 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 were added to a 50 mL flask and reacted at room temperature for 1 hour. After the reaction was detected to be complete, EA was added for extraction. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was decompressed to obtain a crude product, which was then passed through a column to obtain the product M37-2 (198 mg).

[0550] Step 3: Synthesis of Compound M37

[0551] M27-2 (198 mg) and 4N HCl in dioxane (5 mL) were added to a 50 mL flask, reacted at room temperature for 1 hour, and desolventized under reduced pressure to obtain about 200 mg of crude M37.

[0552] Synthesis of intermediate M38:

[0553] Step 1: Synthesis of compound M38-1

[0554] 7-tert-Butyloxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (500.0 mg) was dissolved in 5.0 mL of THF, and a borane tetrahydrofuran solution (4.64 mL, 1 mol / L) was added. The mixture was reacted at room temperature for 1 h. 5 mL of HCl / MeOH solution was slowly added to the reaction solution and stirred until no bubbles were generated. 1 mol / L NaOH solution was added to adjust the pH to alkaline. An appropriate amount of ethyl acetate was then added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M38-1 (450.0 mg). ESI-MS m / z: 200 [M+H-56] + .

[0555] Step 2: Synthesis of compound M38-2

[0556] M38-1 (250.0 mg) was dissolved in 5.0 mL of DCM, and Dess-Martin reagent (387.0 mg) was added. The mixture was allowed to react at room temperature for 1 h. An appropriate amount of ethyl acetate was added to the reaction solution, and the precipitated solid was removed by filtration. The filtrate was added with 1 mol / L NaOH solution to adjust the pH to alkaline. Extraction was performed, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M38-2 (180.0 mg). ESI-MS m / z: 198 [M+H-56] + .

[0557] Step 3: Synthesis of compound M38-3

[0558] 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 h. The reaction solution was extracted with appropriate amounts 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] + .

[0559] Step 4: Synthesis of compound M38-4

[0560] Compound M29 (200 mg) and compound M38-3 (131 mg) were dissolved in tert-butanol (2 mL), tetrahydrofuran (2 mL) and water (2 mL), and anhydrous copper sulfate (63 mg) and sodium ascorbate (226 mg) were added. The mixture was reacted at room temperature for 2 h. The reaction solution was spin-dried, DCM and water were added, extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and spin-dried through a column (DCM / MeOH=15:1) to obtain compound M38-4 (295 mg). ESI-MS m / z: 706 [M+H] + .

[0561] Step 5: Synthesis of Compound M38

[0562] Compound M38-4 (295 mg) was dissolved in 6 mL of DCM and 3 mL of dioxane hydrochloride (4 mol / L) solution and reacted at room temperature for 0.5 h. The reaction solution was spin-dried, and DCM / isopropanol (3:1) and saturated sodium bicarbonate solution were added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and spin-dried to obtain compound M38 (240 mg). ESI-MS m / z: 606 [M+H] + .

[0563] The preparation of intermediate M39 was prepared by referring to 176-4 in Example 176 of WO2023138524A1.

[0564] Synthesis of intermediate M40:

[0565] Step 1: Synthesis of compound M40-1

[0566] To a 50 mL single-necked flask, add (S)-3-(4-bromophenyl)-3-((tert-butoxycarbonyl)amino)propanoic acid (1.5 g), dissolve in DMF (15 mL), add iodomethane (0.74 g) and potassium carbonate (1.2 g), and react at room temperature for 2 h. Add saturated brine (5 mL) to the reaction solution, extract with EA, and dry the organic phase over anhydrous sodium sulfate to yield 1.4 g of a yellow solid, compound M40-1.

[0567] Step 2: Synthesis of compound M40-2

[0568] Compound M40-1 (1.4 g) was added to a 50 mL single-necked 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. Under nitrogen, the mixture was heated to 80°C for 5 h. Saturated brine (5 mL) was added to the reaction solution, and the mixture was 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.

[0569] Step 3: Synthesis of Compound M40

[0570] Compound M40-2 (0.82 g) was added to a 25 mL single-necked flask, dissolved in HCl in dioxane (20 mL), and methanol (1 mL) was added. The mixture was allowed to react at room temperature for 1 h. The reaction solution was evaporated to dryness to obtain 0.55 g of a yellow solid, compound M40.

[0571] Synthesis of intermediate M41:

[0572] Step 1: Synthesis of compound M41-1

[0573] 7-tert-Butyloxycarbonyl-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-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (300.0 mg) were dissolved in 5.00 mL of DMF, followed by the addition of N,N-diisopropylethylamine (0.35 mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (310.0 mg). The mixture was reacted at room temperature for 30 minutes. 100.0 mL of water was added to the reaction solution, and the precipitated solid was filtered to obtain 400.0 mg of compound M41-1. ESI-MS m / z: 696 [M+H] + .

[0574] Step 2: Synthesis of Compound M41

[0575] Compound M41-1 (400.0 mg) was dissolved in 5.00 mL of DCM, followed by the addition of 2.00 mL of TFA. The mixture was allowed to react at room temperature for 0.5 h. The reaction solution was then added dropwise to a saturated sodium bicarbonate solution and extracted with an appropriate amount of a 10 / 1 DCM / MeOH solution. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 258.0 mg of compound M41. ESI-MS m / z: 596 [M+H] + .

[0576] Synthesis of intermediate M42:

[0577] Step 1: Synthesis of compound M42-1

[0578] Compound tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5.00 g, 23.22 mmol), TEA (6.46 mL, 46.45 mmol), and TosCl (6.64 g, 34.84 mmol) were added sequentially to DCM (50.00 mL) and reacted at room temperature for 16 h. 80 mL of ice water was added to the reaction solution, which was 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 afford compound M 42-1 (8.00 g, 93.23%).

[0579] ESI-MS m / z:270.16[M+H] + .

[0580] Step 2: Synthesis of compound M42-2

[0581] Compound M 42-1 (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 h. Water was added to the reaction solution to precipitate the product, which was filtered. The filter cake was washed with water and dried to obtain compound M 42-2 (6100.00 mg, 88.21%).

[0582] ESI-MS m / z:220.15[M+H] + .

[0583] Step 3: Synthesis of Compound M42-3

[0584] 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). Dimethyl (1-diazo-2-oxopropyl)phosphonate (1.83 mL, 12.21 mmol) was added with stirring and allowed to react at room temperature for 6 h. The reaction solution was concentrated to dryness, 50 mL of water was added, and the mixture was extracted twice with EA (100.00 mL). The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (PE:EA = 90%:10%) to obtain compound M42-3 (2.30 g, 77.64%).

[0585] ESI-MS m / z:216.19[M+H] + .

[0586] Step 4: Synthesis of Compound M42-4

[0587] Compound M42-3 (276.36 mg, 0.88 mmol), intermediate compound 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 h. The reaction solution 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 obtain compound M42-4 (300.00 mg, 88.71%).

[0588] ESI-MS m / z:772.52[M+H] + .

[0589] Step 5: Synthesis of Compound M42

[0590] Compound M42-4 (300.00 mg, 0.39 mmol) and trifluoroacetic acid (1.00 mL) were added sequentially to dichloromethane (2.00 mL) and reacted at room temperature for 1 h. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the base, and the solution was extracted twice with DCM (80.00 mL), dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 93%:7%) to obtain compound M 42 (130.00 mg, 49.79%).

[0591] ESI-MS m / z:672.72[M+H] + .

[0592] Synthesis of intermediate M43:

[0593] Step 1: Synthesis of compound M43-1

[0594] Compound M28-3 (16.5 g) was dissolved in DCM (200 mL), and DMP (18.4 g) was slowly added in batches at 0°C. The temperature was naturally raised to room temperature and the reaction was allowed to proceed for 2 hours. After the reaction was completed, water was added to dilute the mixture, and the mixture was extracted with DCM. The organic phase was washed with saturated brine and purified by column chromatography to obtain compound M43-1 (9.5 g). ESI-MS m / z: 395.2 [M+H] + .

[0595] Step 2: Synthesis of Compound M43

[0596] Compound M43-1 (9.5 g), M6 (15.21 g), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (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 under nitrogen for 1.5 hours. After completion of the reaction, 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] + .

[0597] Synthesis of intermediate M44:

[0598] Step 1: Synthesis of compound M44-1

[0599] 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) were added to a reaction flask. After nitrogen replacement, the mixture was reacted at 100°C under nitrogen protection for 10 h. The mixture was diluted with H2O (100 mL) and extracted twice with EA (80 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was concentrated and purified by column chromatography to obtain compound M44-1 (2.01 g) as a yellow solid. ESI-MS m / z: 335.29 [M+H] + .

[0600] Step 2: Synthesis of compound M44-2

[0601] Compound M44-1 (2.01 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to the reaction flask. 4 M hydrogen chloride dioxane solution (10.00 mL) was added with stirring at 0°C. The mixture was reacted at room temperature for 1 h. The solvent was concentrated to give a yellow solid crude product M44-2 (1.85 g). ESI-MS m / z: 218.21 [M-OH] + .

[0602] Step 3: Synthesis of compound M44-3

[0603] 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 the reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.16 g) was added with stirring. The reaction was carried out at room temperature for 0.5 h, and 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 separated by column chromatography to obtain a yellow solid M44-3 (2.02 g). ESI-MS m / z: 448.20 [M+H] + .

[0604] Step 4: Synthesis of compound M44-4

[0605] Compound M44-3 (2.02 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to a reaction flask. A 4M solution of hydrogen chloride in dioxane (10.00 mL) was added with stirring at 0°C. The mixture was reacted at room temperature for 1 h. The solvent was concentrated to obtain a crude yellow solid product, M44-4 (1.86 g). ESI-MS m / z: 348.18 [M+H] + .

[0606] Step 5: Synthesis of Compound M44-5

[0607] 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 the reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (2.21 g) was added under stirring. The reaction was carried out at room temperature for 0.5 h, and 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 separated by column chromatography to obtain a yellow solid M44-5 (2.01 g).

[0608] ESI-MS m / z:547.30[M+H] + .

[0609] Step 6: Synthesis of Compound M44-6

[0610] Compound M44-5 (2.01 g), dichloromethane (20.00 mL), and methanol (10.00 mL) were added to the reaction flask. 4 M hydrogen chloride dioxane solution (10.00 mL) was added with stirring at 0°C. The mixture was reacted at room temperature for 1 h. The solvent was concentrated and sodium bicarbonate aqueous solution was added under ice bath to adjust the pH to 8. The mixture was purified by reverse phase column (MeOH / H2O=95%:5%) to obtain a light yellow solid M44-6 (1.5 g).

[0611] ESI-MS m / z:447.30[M+H] + .

[0612] Step 7: Synthesis of Compound M44

[0613] 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 then slowly added to the reaction solution. After the addition, the mixture was reacted at this temperature for 1 h. An appropriate amount of saturated brine was added to the reaction solution, 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, concentrated, and the product was separated by column chromatography to obtain a light yellow solid M44 (0.92 g). ESI-MS m / z: 473.20 [M+H] + .

[0614] Synthesis of intermediate M45:

[0615] Step 1: Synthesis of compound M45-1

[0616] 4-Bromo-2-methylacetophenone (3.0 g) and tert-butylsulfenamide (6.9 g) were dissolved in 30.00 mL of anhydrous tetrahydrofuran, and ethyl titanate (31.0 mL) was added. The reaction was allowed to react at 80°C for 3.0 h. The reaction solution was cooled to room temperature and quenched by dropwise addition of ice water. The mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography (PE / EA = 5 / 1) to obtain 3.0 g of the product, compound M45-1. ESI-MS m / z: 316 [M+H] + ;

[0617] Step 2: Synthesis of compound M45-2

[0618] Compound M45-1 (3.0 g) was dissolved in 30.00 mL of anhydrous tetrahydrofuran, and lithium tri-sec-butylborohydride (28.46 mL) was added. The reaction was allowed to react at room temperature for 2.0 h. The reaction solution was quenched by adding it dropwise to ice water. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3.0 g of crude product, which was used directly in the next step, namely compound M45-2. ESI-MS m / z: 318 [M+H] + ;

[0619] Step 3: Synthesis of compound M45-3

[0620] Compound M45-2 (3.0 g) was dissolved in 4 M hydrogen chloride in dioxane (35.00 mL) and allowed to react at room temperature for 2.0 h. The solvent was evaporated under reduced pressure, and the mixture was slurried with EA and filtered to obtain 2.0 g of a white product, compound M45-3. ESI-MS m / z: 214 [M+H] + ;

[0621] Step 4: Synthesis of compound M45-4

[0622] Compound M45-3 (2.0 g) was dissolved in 20.0 mL of anhydrous dichloromethane, and triethylamine (5.57 mL) and di-tert-butyl dicarbonate (2.76 mL) were added sequentially. The mixture was allowed to react at room temperature for 1.0 h. The solvent was evaporated under reduced pressure, and the reaction solution was purified by column chromatography to obtain 2.0 g of an off-white product, compound M45-4. ESI-MS m / z: 314 [M+H] + ;

[0623] Step 5: Synthesis of Compound M45-5

[0624] Compound M45-4 (2.0 g), 4-methylthiazole (0.95 g), palladium acetate (0.29 g), and potassium carbonate (2.64 g) were dissolved in 20.0 mL of DMAc and reacted at 120°C for 2.0 h. The reaction solution was cooled to room temperature and quenched with water dropwise. The solution was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 2.0 g of the product, compound M45-5.

[0625] ESI-MS m / z:333[M+H] + ;

[0626] Step 6: Synthesis of Compound M45-6

[0627] Compound M45-5 (2.0 g) was dissolved in 4 M hydrogen chloride in dioxane (10.00 mL) and allowed to react at room temperature for 1.0 h. The reaction solution was evaporated under reduced pressure to remove the solvent. After re-dissolving in methanol, the solvent was again evaporated under reduced pressure to obtain 1.1 g of a yellow product, which was used directly in the next step, namely compound M45-6. ESI-MS m / z: 233 [M+H] + ;

[0628] Step 7: Synthesis of Compound M45-7

[0629] Compound M45-6 (1.1 g), (2S,4R)-1-tert-butyloxycarbonyl-2-carbamoyl-4-hydroxypyrrolidine (1.31 g), and DIPEA (2.47 mL) were dissolved in 10.00 mL of DMF. HATU (1.98 g) was added and the mixture was allowed to react at room temperature for 1.0 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 2.0 g of compound M45-7. ESI-MS m / z: 446 [M+H] + ;

[0630] Step 8: Synthesis of Compound M45-8

[0631] Compound M45-7 (2.0 g) was dissolved in 4 M hydrogen chloride in dioxane (15.00 mL) and 3.0 mL of methanol and allowed to react at room temperature for 1.0 h. 50 mL of EA was added to the reaction solution, and a yellow solid precipitated. Filtering afforded 1.1 g of the yellow product, which was used directly in the next step, yielding compound M45-8. ESI-MS m / z: 346 [M+H] + ;

[0632] Step 9: Synthesis of Compound M45-9

[0633] Compound M45-8 (1.1 g), N-tert-butyloxycarbonyl-L-valine (0.76 g), and DIPEA (2.77 mL) were dissolved in 15.00 mL of DMF. HATU (1.98 g) was added and the mixture was allowed to react at room temperature for 1.0 h. The reaction mixture was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 1.4 g of compound M45-9. ESI-MS m / z: 545 [M+H] + ;

[0634] Step 10: Synthesis of Compound M45-10

[0635] Compound M45-9 (1.4 g) was dissolved in 4 M hydrogen chloride in dioxane (15.00 mL) and allowed to react at room temperature for 1.0 h. The reaction mixture was adjusted to pH 12 by dropwise addition of 4 M NaOH solution under an ice bath. The mixture was then extracted three times with a 10 / 1 DCM / MeOH mixture. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 1.1 g of the product, compound M45-10.

[0636] ESI-MS m / z:445[M+H] + ;

[0637] Step 11: Synthesis of Compound M45

[0638] Compound M45-10 (1.1 g) was dissolved in a mixture of anhydrous acetonitrile (15.00 mL) and tetrahydrofuran (8.0 mL). Triethylamine (2.06 mL) was added, and 2-azido-1,3-dimethylimidazolium hexafluorophosphate (1.41 g) was added under ice-cooling. The mixture was allowed to react at room temperature for 1.5 h. The reaction solution was quenched with water and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography to obtain 1.1 g of compound M45. ESI-MS m / z: 471 [M+H] + .

[0639] Synthesis of intermediate M46:

[0640] Step 1: Synthesis of compound M46-1

[0641] 5-Chloropyrazine-2-carboxaldehyde (1.0 g) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.59 g) were dissolved in methanol (10 mL). After reacting at room temperature for 1 hour, sodium cyanoborohydride was added in batches. After completion of the reaction, ethyl acetate and water were added, and the mixture was extracted three times. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain compound M46-1 (480 mg). ESI-MS m / z: 353.2 [M+H] + .

[0642] Step 2: Synthesis of Compound M46

[0643] Compound M46-1 (480 mg), bistriphenylphosphine palladium dichloride (85 mg), and cuprous iodide (46 mg) were dissolved in TEA (0.84 mL) under nitrogen protection. Trimethylsilyl acetylene (0.33 mL) was added and the mixture was allowed to react overnight at 60°C. LCMS monitored the reaction for completion. The reaction solution was directly concentrated, and EA (10 mL) was added to the reaction solution. The mixture was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound M46 (210 mg). ESI-MS m / z: 415.1 [M+H] + .

[0644] Synthesis of intermediate M47:

[0645] Step 1: Synthesis of compound M47-1

[0646] N-tert-Butyloxycarbonyl-4-hydroxypiperidine (1.0 g) was added to a 25 mL single-necked flask and dissolved in THF (10 mL). NaH (300.0 mg) and 2,5-dibromopyrazine (1.18 g) were then added. The mixture was heated to 50°C for 5 h. The reaction solution was evaporated to dryness. Purification by column chromatography (PE:EA = 6:1) afforded 1.38 g of a pale yellow solid, compound M47-1.

[0647] Step 2: Synthesis of compound M47-2

[0648] Compound M47-1 (690.0 mg) was added to a 25 mL single-necked flask and dissolved in DMF (10 mL). Trimethylethynylsilane (283.7 mg), CuI (73.3 mg), PdCl2(PPh3)2 (135.2 mg), and DIPEA (0.95 mL) were added. Under nitrogen, the mixture was heated to 50°C for 3 h. Saturated brine (5 mL) was added to the reaction solution, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate and the product was isolated by column chromatography (PE:EA = 6:1) to obtain 522.2 mg of a light yellow solid, compound M47-2.

[0649] Step 3: Synthesis of Compound M47

[0650] Compound M47-2 (522.2 mg) was added to a 25 mL single-necked flask and dissolved in THF (10 mL). A 1 M solution of TBAF in tetrahydrofuran (2.2 mL) was added and allowed to react at room temperature for 2 h. The reaction solution was evaporated to dryness. Purification by column chromatography (PE:EA = 4:1) afforded 378.2 mg of a pale yellow solid, Compound M47.

[0651] Synthesis of intermediate M48:

[0652] Step 1: Synthesis of compound M48-1

[0653] To a reaction flask, add 5-chloropyrazine-2-carboxaldehyde (336.23 mg), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (500.00 mg), methanol (8.00 mL), and acetic acid (0.02 mL). Stir at room temperature for 1 hour, cool to 0°C, add sodium borohydride (148.72 mg), react at room temperature for 0.5 hour, dilute with water, extract with DCM, dry the organic phase, and concentrate. Purify by column chromatography (PE:EA = 2:1) to obtain 250 mg of a yellow oil, compound M48-1.

[0654] Step 2: Synthesis of compound M48-2

[0655] Compound M48-1 (240.00 mg), trimethylsilyl acetylene (0.18 mL), bistriphenylphosphine palladium dichloride (44.22 mg), cuprous iodide (12.0 mg), triethylamine (0.53 mL), and tetrahydrofuran (5.00 mL) were added to the reaction flask. After nitrogen replacement, the mixture was reacted at 50° C. under nitrogen protection for 2 h. The reaction liquid was filtered and rinsed three times with EA. The mother liquor was concentrated and purified by column chromatography (PE:EA=1:1) to give 220 mg of a brown liquid, namely compound M48-2.

[0656] Step 3: Synthesis of compound M48-3

[0657] Compound M48-2 (220.00 mg), methanol (4.00 mL), and potassium carbonate (137.38 mg) were added to the reaction flask and reacted at room temperature for 0.2 h. The mixture was filtered and the filter cake was washed several times with EA. The mother liquor was concentrated and purified by column chromatography (DCM:MeOH=10:1) to obtain 50 mg of a brown liquid, namely compound M48-3.

[0658] Step 4: Synthesis of compound M48-4

[0659] Compound M48-3 (50.00 mg), M29 (61.6 mg), copper sulfate (19.39 mg), sodium ascorbate (69.54 mg), tetrahydrofuran (1.00 mL), tert-butanol (1.00 mL), and water (1.00 mL) were added to the reaction flask and reacted at room temperature for 0.5 h. The mixture was diluted with water and then extracted with DCM. The organic phase was dried, concentrated, and purified by column chromatography (DCM: ammonia methanol = 14:1) to give 65 mg of a yellow solid, namely compound M48-4.

[0660] Step 5: Synthesis of Compound M48

[0661] Compound M48-4 (65.00 mg) and dichloromethane (2.00 mL) were added to the reaction flask, and 4 M hydrogen chloride dioxane solution (0.40 mL) was added with stirring. The reaction was carried out at room temperature for 0.2 h, and then the pH was adjusted to 8 with aqueous sodium bicarbonate solution. The mixture was extracted with DCM, dried, and concentrated to obtain 45 mg of a yellow solid, namely compound M48.

[0662] Example 1: (2S,4R)-1-((2S)-2-(4-)(1-((1-)((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-(3-hydroxy-3-methyl)piperazinyl)-4-methyl-4-benzamido-3,3-dimethylbutenyl-4-hydrogen(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0663] Step 1: Synthesis of compound 1-1

[0664] Compound M1 (0.25 g) was added to a 50 mL single-necked 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. The mixture was reacted at 40°C under nitrogen for 5 h. After cooling to room temperature, an appropriate amount of water was added to the reaction solution. The layers were separated, and the aqueous phase was extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The product was isolated by column chromatography (DCM:MeOH = 10:1) to obtain 0.278 g of a light yellow solid, compound 1-1.

[0665] Step 2: Synthesis of compound 1-2

[0666] Compound 1-1 (200.0 mg) was added to a 25 mL single-necked flask and dissolved in THF (10 mL) and water (2 mL). M5 (379.3 mg), K3PO4 (321.0 mg), and CataCXium A Pd G3 (36.7 mg) were added. The mixture was reacted at 75°C under N2 protection for 2 h. The reaction solution was evaporated to dryness. Purification by column chromatography (DCM:MeOH = 10:1) afforded 210.5 mg of a yellow solid, compound 1-2.

[0667] Step 5: Synthesis of Compound 1-3

[0668] Compound 1-2 (210.0 mg) was added to a 25 mL single-necked flask and dissolved in DCM (10 mL). DMP (299.5 mg) was added and allowed to react at room temperature for 4 h. The reaction mixture was quenched with sodium thiosulfate solution and extracted three times with DCM. The organic phase was washed with water and saturated brine, and the product was isolated by column chromatography (DCM:MeOH = 10:1) to afford 192 g of a pale yellow solid, compound 1-3.

[0669] Step 6: Synthesis of Compound 1-4

[0670] Compound 1-3 (100 mg) was added to a 25 mL single-necked flask and dissolved in MeOH (3 mL). M26 (167.5 mg) and 1 M ZnCl2 / THF solution (0.1 mL) were added. The mixture was heated to 40°C and allowed to react for 2 h. NaBH3CN (53.1 mg) was then added and allowed to react overnight. The reaction solution was evaporated to dryness. Purification by column chromatography (DCM:MeOH = 8:1) afforded 84.0 mg of a light yellow solid, compound 1-4.

[0671] Step 11: Synthesis of Compound 1

[0672] Compound 1-4 (84.0 mg) was added to a 25 mL single-necked vial and dissolved in DCM (2 mL). TFA (1 mL) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was evaporated to dryness and the product was isolated by reverse-phase chromatography (CH3CN / H2O = 30%-55%) to obtain 30.6 mg of a white solid, Compound 1 (purity 99.14%).

[0673] LCMS: 1 / 2 [M+2H] + =598.31

[0674] 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,5 H),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).

[0675] Example 2: ((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-pyrrolazin-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

[0676] Step 1: Synthesis of compound 2-1

[0677] To a 25 mL single-necked flask, ((3R,7aR)-3-((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (100.0 mg) was added and dissolved in THF (5 mL). NaH (38.7 mg) was added and allowed to react at room temperature for 0.5 h. Compound M12 (82.0 mg) was then added and allowed to react at room temperature for 2 h. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with EA. The organic phase was washed with water and saturated brine, and the product was isolated by column chromatography (DCM:MeOH = 10:1) to afford 104.0 mg of a light yellow solid, compound 2-1.

[0678] Step 2: Synthesis of compound 2-2

[0679] Compound 2-1 (104.0 mg) was added to a 25 mL single-necked flask and dissolved in THF (10 mL) and water (2 mL). M5 (124.0 mg), K3PO4 (109.8 mg), and CataCXium A Pd G3 (12.5 mg) were added. The mixture was reacted at 75°C under N2 protection for 2 h. The reaction solution was evaporated to dryness. Purification by column chromatography (DCM:MeOH = 10:1) afforded 106.0 mg of a yellow solid, compound 2-2.

[0680] Step 3: Synthesis of compound 2-3

[0681] Compound 2-2 (106.0 mg) was added to a 25 mL single-necked flask and dissolved in THF (3 mL). 1 M TBAF in THF (2 mL) was added and the mixture was allowed to react at room temperature for 4 h. The reaction solution was evaporated to dryness. Purification by column chromatography (DCM:MeOH = 10:1) afforded 67.0 mg of a yellow solid, compound 2-3.

[0682] Step 4: Synthesis of compound 2-4

[0683] Compound 2-3 (67.0 mg) was added to a 25 mL single-necked flask and dissolved in THF (4 mL). CDI (24.6 mg) was added and the mixture was heated to 40°C for 2 h. Compound M15 (300.6 mg) was then added and heated to 80°C for overnight. The reaction solution was evaporated to dryness. Purification by column chromatography (DCM:MeOH = 10:1) afforded 62.0 mg of a pale yellow solid, compound 2-4.

[0684] Step 5: Synthesis of compound 2

[0685] Compound 2-4 (62.0 mg) was added to a 25 mL single-necked vial and dissolved in DCM (2 mL). TFA (1 mL) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was evaporated to dryness and the product was isolated by reverse-phase chromatography (CH3CN / H2O = 30%-55%) to obtain 18.5 mg of a white solid, compound 2 (purity 96.48%).

[0686] LCMS: 1 / 2 [M+2H] + =621.93

[0687] 1 H NMR(500MHz,MeOD)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=9.3H z,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).

[0688] 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

[0689] Step 1: Synthesis of compound 67

[0690] 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) in sequence. After reacting at room temperature for 0.5 h, 2-methylpyridine borane (38.22 mg) was added and the mixture was allowed to react at room temperature for another 2 h. 30 mL of saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted three times with DCM. The concentrated organic phases were combined and purified by Pre-HPLC to obtain compound 67 (42.4 mg, 29.43%).

[0691] ESI-MS m / z:583.27 1 / 2[M+2H] + .

[0692] 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).

[0693] 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-1-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0694] Step 6: Synthesis of compound 69-1

[0695] Compound M42 (62.35 mg, 0.09 mmol), intermediate compound M28 (50.00 mg, 0.08 mmol), and a tetrahydrofuran solution of zinc chloride (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 the mixture was reacted at 40°C for 1 h. Sodium cyanoborohydride (53.04 mg, 0.84 mmol) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution 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 obtain compound 69-1 (80.00 mg, 75.92%).

[0696] ESI-MS m / z:625.35,1 / 2[M+2H] + .

[0697] Step 7: Synthesis of compound 69

[0698] 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 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 69 (19.00 mg, 23.75%).

[0699] ESI-MS m / z:603.18,1 / 2[M+2H] + .

[0700] 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).

[0701] 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)pyridin[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

[0702] Step 1: Synthesis of compound 71-1

[0703] Compound M29 (200.00 mg) and M16-3 (142.00 mg) were added to tetrahydrofuran (4.00 mL), tert-butyl alcohol (2.00 mL), and water (2.00 mL). Copper sulfate (62.93 mg) and sodium ascorbate (225.67 mg) were then added. Stir at 20°C for 6 hours. LCMS monitored the reaction completion. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain a light yellow solid (291.00 mg, 94.10% yield). This is compound 71-1.

[0704] Step 2: Synthesis of compound 71-2

[0705] Compound 71-2 (291.00 mg) was added to a 25 mL single-necked flask, followed by dichloromethane (5.00 mL) and hydrochloric acid (4 M in dioxane) (2.00 mL). Stir at 20°C for 0.5 hours. LCMS monitored the reaction completion. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO₃ solution, 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 light yellow solid (290.00 mg) was obtained. This is compound 71-2.

[0706] Step 3: Synthesis of compound 71-3

[0707] Compound M28 (80.00 mg) and 71-2 (98.14 mg) were added to a 25 mL single-necked flask. Methanol (2.00 mL) was added, followed by zinc chloride (0.20 mL, 1.00 mol / L). The reaction was heated to 40°C and stirred for 2 hours. Finally, sodium cyanoborohydride (29.69 mg) was added, and the mixture was stirred at 40°C for 12 hours. LCMS monitored the reaction for completion. The mixture was concentrated under reduced pressure and purified by column chromatography to afford a pale yellow solid (130.00 mg, 81.44% yield). This was compound 71-3.

[0708] Step 4: Synthesis of compound 71

[0709] Compound 71-3 (130.00 mg) was added to a 25 mL single-necked flask, followed by dichloromethane (4.00 mL) and trifluoroacetic acid (2.00 mL). Stir at 20°C for 0.5 hours. LCMS monitored the reaction for completion. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to yield a pale yellow solid (50.00 mg, 37.47% yield). This is compound 71.

[0710] ESI-MS m / z:570.23 1 / 2[M+2H] +

[0711] 1H 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).

[0712] Example 73: Synthesis of Compound (2S,4R)-1-((S)-2-(4-(7-((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)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

[0713] Step 1: Synthesis of compound 73-1

[0714] 7-tert-Butoxycarbonyl-7-azaspiro[3.5]-2-nonanol (500 mg) was dissolved in 6 mL of DCM, and triethylamine (0.58 mL) was added. Methanesulfonyl chloride (0.19 mL) was added under ice-bath. After returning to room temperature and stirring for 2 h, the reaction was quenched by adding water under ice-bath. Extraction was performed once with EA and once with DCM. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product 73-1 (660 mg). ESI-MS m / z: 320.1 [M+H] + .

[0715] Step 2: Synthesis of compound 73-2

[0716] 73-1 (660 mg) was added to a 50 mL single-necked flask, along with 10 mL of DMF, (4-hydroxyphenylalkynyl)trimethylsilane (511 mg), and cesium carbonate (2.01 g). The mixture was reacted at 60°C for 3 h. 50 mL of water was added dropwise to the reaction mixture, filtered, and 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 yield the desired product 73-2 (330 mg). ESI-MS m / z: 413.3 [M+H] + .

[0717] Step 3: Synthesis of compound 73-3

[0718] 73-2 (330 mg) was added to a 10 mL single-necked flask, followed by 3 mL of DMF and 500 mg of cesium fluoride. The mixture was stirred at room temperature for 3 h. 20 mL of water was added dropwise to the reaction mixture, filtered, and the filter cake was washed with water and dried to obtain the desired product 73-3 (300 mg). ESI-MS m / z: 342.2 [M+H] + .

[0719] Step 4: Synthesis of compound 73-4

[0720] 73-3 (300 mg) was added to a 50 mL single-necked flask, along with 3 mL of tetrahydrofuran, 3 mL of tert-butyl alcohol, and 3 mL of water. M29 (269 mg), copper sulfate (95 mg), and sodium ascorbate (338 mg) were then added and allowed to react at room temperature for 30 min. The reaction solution was diluted with water and extracted twice with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and the concentrate was purified by column chromatography to yield the desired product 73-4 (280 mg). ESI-MS m / z: 798.4 [M+H] + .

[0721] Step 5: Synthesis of compound 73-5

[0722] 73-4 (280 mg) was added to a 10 mL single-necked vial, followed by 3 mL of a 4 M hydrochloric acid solution in dioxane. The mixture was allowed to react at room temperature for 30 min. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted twice with EA. The organic phases were collected and combined, dried over anhydrous sodium sulfate, and concentrated to afford crude product 73-5 (220 mg). ESI-MS m / z: 698.4 [M+H] + .

[0723] Step 6: Synthesis of compound 73-6

[0724] M28 (80 mg) was added to a 10 mL single-necked flask, followed by 1 mL of methanol, X-5 (94 mg), and 0.2 mL of zinc chloride (1 mol / L in THF). The mixture was stirred at room temperature for 3 h. Sodium cyanoborohydride (25 mg) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted twice with EA. The organic phases were collected and 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] + .

[0725] Step 7: Synthesis of compound 73

[0726] 73-6 (100 mg) was added to a 10 mL single-necked vial, followed by 2 mL of DCM and 2 mL of trifluoroacetic acid. The mixture was reacted at room temperature for 1 h. After spin drying, the product was purified by pre-HPLC to obtain the target product 73 (51.4 mg).

[0727] ESI-MS m / z:616.4 1 / 2[M+2H] + .

[0728] 1H NMR(500MHz,DMSO)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=2.8Hz, 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).

[0729] 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

[0730] Step 1: Synthesis of compound 75-1

[0731] 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), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (3.30 g), and cesium carbonate (12.96 g) were added to toluene (30.00 mL). The atmosphere was replaced with nitrogen and the mixture was reacted at 90°C for 7 h. 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 afford compound 75-1 (1.40 g, 26.50%).

[0732] ESI-MS m / z:398.28[M+H] + .

[0733] Step 2: Synthesis of compound 75-2

[0734] Compound 75-1 (1400.00 mg) and potassium carbonate (1456.26 mg) were added to methanol (20.00 mL) and reacted at room temperature for 16 h. The reaction solution was concentrated to dryness, diluted with DCM, filtered, and the filter cake was washed with DCM. The filtrate was concentrated and separated by column chromatography (PE:EA = 90%:10%) to give compound 75-2 (650.00 mg, 56.69%).

[0735] ESI-MS m / z:327.25[M+H] + .

[0736] Step 3: Synthesis of compound 75-3

[0737] 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 THF / tetrahydrofuran (2.00 mL), H2O / water (2.00 mL), and t-BuOH / tert-butanol (2.00 mL) and reacted at room temperature for 3 h. 50 mL of water was added to the reaction solution, extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 95%:5%) to obtain compound 75-3 (230 mg, 67.05%).

[0738] ESI-MS m / z:783.59[M+H] + .

[0739] Step 4: Synthesis of compound 75-4

[0740] Compound 75-3 (230.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) in sequence and reacted at room temperature for 1 h. 40 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the base, and the mixture was extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH=90%:10%) to obtain compound 75-4 (129.00 mg, 64.32%).

[0741] ESI-MS m / z:683.49[M+H] + .

[0742] Step 5: Synthesis of compound 75-5

[0743] Compound 75-4 (120.00 mg), compound M28 (104.13 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.35 mL, 1.00 mol / L) were added to methanol (3.00 mL) and 1,2-dichloroethane (3.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (55.20 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 75-5 (110.00 mg, 49.71%).

[0744] ESI-MS m / z:630.71 1 / 2[M+2H] + .

[0745] Step 6: Synthesis of compound 75-6

[0746] Compound 75-5 (110.00 mg) and TFA / trifluoroacetic acid (1.50 mL) were added to dichloromethane (3.00 mL) and reacted at room temperature for 1 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 75 (26.10 mg, 23.43%).

[0747] ESI-MS m / z:608.68 1 / 2[M+2H] + .

[0748] 1H NMR(500MHz,Methanol-d4)δ9.21(d,J=5.5Hz,1H),8.87(d,J=6.9Hz,1H),8.2 5(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).

[0749] 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

[0750] Step 1: Synthesis of compound 79-1

[0751] Methyl 2-(3-hydroxyisoxazol-5-yl)-3-methylbutanoate (500 mg), tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (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 completion of the reaction, ethyl acetate and water were added for extraction. The organic phase was washed three times with saturated brine and purified by column chromatography (petroleum ether / ethyl acetate) to obtain compound 79-1 (920 mg). ESI-MS m / z: 433.22 [M+Na] + .

[0752] Step 2: Synthesis of compound 79-2

[0753] 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 completion of the reaction, the pH was adjusted to 4 with citric acid, and the mixture was extracted three times with dichloromethane / isopropanol (10:1). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 79-2 (883 mg). ESI-MS m / z: 297.31 [M+H-100] + .

[0754] Step 3: Synthesis of compound 79-3

[0755] 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 completion of the reaction, ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine and purified by column chromatography (dichloromethane / methanol). Compound 79-3 (263 mg) was obtained by chiral column separation. ESI-MS m / z: 710.53 [M+H] + .

[0756] Step 4: Synthesis of compound 79-4

[0757] Compound 79-3 (263 mg) was dissolved in dichloromethane (5 mL), and a 4M hydrochloric acid solution in dioxane (1 mL) was added. The mixture was reacted at 25°C for 20 minutes. After the reaction was complete, the mixture was dissolved in water, neutralized with sodium bicarbonate solution, and extracted with dichloromethane / isopropanol (10:1). The mixture was dried and concentrated to obtain compound 79-4 (203 mg). ESI-MS m / z: 610.41 [M+H] + .

[0758] Step 5: Synthesis of compound 79-

[0759] 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 then added and the reaction continued at 25°C for 1 hour. After completion of the reaction, sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane / isopropanol (10:1). The mixture was concentrated and purified by column chromatography (dichloromethane / methanol) and Pre-TLC to afford compound 79 (32.5 mg).

[0760] ESI-MS m / z:552.18 1 / 2[M+2H] + .

[0761] 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),6.6 8(s,1H),6.07(s,1H),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),4.21–4.17(m,2H),4.10(dd,J=25.0,13.4Hz,1H),3.70(dd,J=10.6,4.4 Hz,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),2.28–2.08(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).

[0762] 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)pyridin[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

[0763] To a reaction flask, intermediate M33 (30 mg), intermediate M35 (35.15 mg), dichloromethane (1.00 mL), isopropanol (0.10 mL), and acetic acid (0.02 mL) were added. The mixture was allowed to react at room temperature for 10 minutes, followed by the addition of lutidine borane (31.27 mg) and the reaction was continued at room temperature for 1 hour. The pH was adjusted to 8 with aqueous sodium bicarbonate solution, and the mixture was extracted with DCM, dried, and concentrated. Pre-HPLC separation afforded the title compound 80 (12 mg). ESI-MS m / z: 545.19 1 / 2 [M+2H] + .

[0764] 1 H 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).

[0765] Example 88 ((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-pyrrolazin-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

[0766] Step 1: Synthesis of compound 88-1

[0767] (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, NaH (72 mg) was added, followed by a solution of ((3R,7aR)-3-((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (259 mg) in THF (1 mL). The mixture was stirred at 25°C for 2 h. LC-MS monitored the reaction completion. The reaction solution was slowly quenched by the addition of 10 mL of saturated ammonium chloride solution. The mixture was extracted three times with EA. 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 to afford 315 mg of a pale yellow solid, compound 88-1.

[0768] ESI-MS m / z:580[M+H] + ;

[0769] Step 2: Synthesis of compound 88-2

[0770] 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. The mixture was purged with nitrogen and reacted at 90°C for 3 h. LCMS monitored the reaction completion. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with EA three times, 30 mL each time. The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by column chromatography to obtain 146 mg of a light yellow solid, namely, compound 88-2. ESI-MS m / z: 778 [M+H] + .

[0771] Step 3: Synthesis of compound 88-3

[0772] Compound 88-2 (146 mg) was dissolved in 3 mL of DCM, followed by the addition of 1.5 mL of triethylamine trihydrofluoride. The mixture was allowed to react at room temperature for 2 h. LCMS monitored the reaction for completion. 10.0 mL of water was added to the reaction solution, and the mixture was extracted with a 10:1 ratio of DCM:MeOH. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The organic phase was purified by column chromatography to afford 80 mg of a pale yellow solid, compound 88-3.

[0773] Step 4: Synthesis of compound 88-4

[0774] Compound 88-3 (43 mg) was dissolved in 3 mL of THF, followed by the addition of 14 mg of CDI. The reaction was allowed to proceed at 40°C for 1 h. The intermediate was monitored by LC-MS. M15 (58 mg) was then added and stirred at 80°C for 12 h. The reaction was complete as monitored by LC-MS. The mixture was quenched by the addition of 5.00 mL of methanol. The organic phase was concentrated and purified by column chromatography to afford 29 mg of a light yellow solid, compound 88-4.

[0775] ESI-MS m / z:643 1 / 2[M+2H] + .

[0776] Step 5: Synthesis of Compound 88

[0777] 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 react at room temperature for 30 min. LCMS monitored the reaction for completion. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 13.6 mg of a light yellow powder, namely compound 88.

[0778] ESI-MS m / z:621 1 / 2[M+2H] + . 1H NMR(500MHz, Methanol-d4)δ9.29(s,1H),8.92(s,1H),7.70-7.67(m,1H),7.43(q,J=8.2Hz,4H),7.32–7.24(m,2H),7.06-7.05(m,1 H),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=10.9 Hz,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),1.82-1.80(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).

[0779] Example 89 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-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide

[0780] Step 1: Synthesis of compound 89-1

[0781] To a solution of intermediate compound M27 (270 mg) in DCM (5 mL) was added DIEA (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 this 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 afford compound 89-1 (416 mg).

[0782] ESI-MS m / z:424.3[M+H] + .

[0783] Step 2: Synthesis of compound 89-2

[0784] To a solution of compound 89-1 (416 mg) in DMF (5 mL) was added 1,1-cyclopropane dimethanol (150 mg), Cs2CO3 (639 mg), and DABCO (22 mg) at room temperature. The reaction was stirred at this temperature for 12 h. After completion of the reaction, EA and water were added to the reaction system. The aqueous phase was extracted twice with EA. The combined organic phases were 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 afford compound 89-2 (220 mg).

[0785] ESI-MS m / z:490.3[M+H] + .

[0786] Step 3: Synthesis of compound 89-3

[0787] Compound 89-2 (220 mg), M10 ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-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 single-necked bottle at room temperature. THF (5 mL) and H2O (1 mL) were then added. The system was purged with nitrogen 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 extracted once more with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by preparative thin-layer chromatography (8% MeOH / DCM) to give compound 89-3 (196 mg).

[0788] ESI-MS m / z:840.7[M+H] + .

[0789] Step 4: Synthesis of compound 89-4

[0790] 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 this temperature for 3 h. After completion of the reaction, saturated sodium sulfite solution was added to the reaction system to quench the reaction. An appropriate amount of DCM was then added for extraction. The aqueous phase was extracted twice with DCM. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (0-5% MeOH / DCM) to afford compound 89-4 (180 mg).

[0791] ESI-MS m / z:838.7[M+H] + .

[0792] Step 5: Synthesis of compound 89-5

[0793] To a solution of compound 89-4 (180 mg) and M26 (156 mg) in MeOH (5 mL) was added ZnCl2 (0.2 mL) at room temperature, and the system was stirred at room temperature for 1 h. NaBH3CN (67 mg) was then added, and the reaction was stirred at 40°C overnight. After completion of the reaction, saturated sodium bicarbonate solution was added to the reaction system to quench the reaction, followed by extraction with a mixed solvent (DCM / MeOH = 9:1). The aqueous phase was extracted twice with the mixed solvent, and 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 afford compound 89-5 (23 mg).

[0794] ESI-MS m / z:742.5 1 / 2[M+2H] + .

[0795] Step 6: Synthesis of compound 89-6

[0796] CsF (47 mg) was added to a solution of compound 89-5 (23 mg) in DCM (1 mL) at room temperature, and the mixture was stirred at this temperature for 3 h. After the reaction, EA and saturated brine were added to the reaction system for extraction and separation. The organic phase was then 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 obtain compound 89-6 (17 mg).

[0797] ESI-MS m / z:664.3 1 / 2[M+2H] + .

[0798] Step 7: Synthesis of Compound 89

[0799] Boron trifluoride etherate (0.4 mL) was added to a solution of compound 89-6 (17 mg) in DCM (2 mL) at room temperature, and the mixture was stirred at this temperature for 1 h. After completion of the reaction, the reaction system was poured into a cooled saturated sodium carbonate solution and extracted three times with a mixed solvent (DCM / MeOH = 9:1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by preparative thin-layer chromatography (12% MeOH / DCM) to afford compound 89 (7 mg).

[0800] ESI-MS m / z:642.8 1 / 2[M+2H] + .

[0801] 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).

[0802] Example 90 (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-pyrrolazin-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

[0803] Step 1: Synthesis of Compound 90-1

[0804] 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (1 g) was dissolved in 10 mL of DCM, DIEA (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. A nitrogen balloon was placed under the mixture, and the mixture was stirred at 0°C for 0.5 h. LC-MS monitored the reaction for completion. 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, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography to yield 1.26 g of a pale yellow solid, compound 90-1.

[0805] ESI-MS m / z:317[M+H] + ;

[0806] Step 2: Synthesis of compound 90-2

[0807] ((3R,7aR)-3-((tert-butyldimethylsilyl)oxy)methyl)tetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (1.08 g) was dissolved in 4 mL of THF under nitrogen protection. NaH (230 mg) was added and stirred at room temperature for 0.5 h. Then, a solution of compound 90-1 (600 mg) in THF (2 mL) was added and stirred at room temperature for 0.5 h. LC-MS monitored the reaction completion. 10 mL of saturated ammonium chloride solution was slowly added to the reaction solution to quench the reaction. The mixture was extracted with EA three times, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. After purification by column chromatography, 790 mg of a light yellow solid, i.e., compound 90-2, was obtained.

[0808] ESI-MS m / z:566[M+H] + ;

[0809] Step 3: Synthesis of Compound 90-3

[0810] Compound 90-2 (790 mg), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxyborane-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. The mixture was purged with nitrogen and reacted at 90°C for 3 h. The reaction was monitored for completion by LCMS. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with EA three times (30 mL each). The organic phases were combined, washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by column chromatography to obtain 620 mg of a light yellow solid, namely, compound 90-3.

[0811] ESI-MS m / z:916[M+H] + .

[0812] Step 4: Synthesis of Compound 90-4

[0813] 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 h. LCMS monitored the reaction for completion. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with a 10:1 ratio of DCM:MeOH. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated. The organic phase was purified by column chromatography to afford 500 mg of a pale yellow solid, compound 90-4.

[0814] Step 5: Synthesis of Compound 90-5

[0815] Compound 90-4 (89 mg) was dissolved in 3 mL of THF, followed by the addition of 23 mg of CDI. The reaction was allowed to proceed at 40°C for 1 h. The intermediate was monitored by LC-MS. Intermediate compound M15 (99 mg) was then added and stirred at 80°C for 12 h. The reaction was complete as monitored by LC-MS. The reaction was quenched by the addition of 5.00 mL of methanol. The organic phase was concentrated and purified by column chromatography to afford 101 mg of a pale yellow solid, compound 90-5.

[0816] ESI-MS m / z:712 1 / 2[M+2H] + .

[0817] Step 6: Synthesis of Compound 90-6

[0818] Compound 90-5 (101 mg) was dissolved in 3 mL of DMF, followed by the addition of CsF (108 mg). The mixture was allowed to react at room temperature for 1 h. LCMS monitored the reaction for completion. The organic phases were extracted with water and ethyl acetate, combined, dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure and purified by column chromatography to yield 70 mg of a pale yellow solid, compound 90-6.

[0819] ESI-MS m / z:634 1 / 2[M+2H] + ;

[0820] Step 7: Synthesis of compound 90

[0821] Compound 90-6 (70 mg) was dissolved in 3 mL of DCM, followed by the addition of 1.5 mL of boron trifluoride etherate. The reaction was allowed to react at room temperature for 30 min, and the reaction was monitored for completion by LCMS. The reaction solution was dropwise added to an aqueous sodium carbonate solution, and extracted with DCM:isopropanol (10:1). The organic phases were combined, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Preparative liquid chromatography (HPLC) was used to obtain 33.2 mg of a yellow powder, Compound 90.

[0822] ESI-MS m / z:612 1 / 2[M+2H] + .

[0823] 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).

[0824] 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

[0825] Step 1: Synthesis of compound 93-1

[0826] N-Boc-4-hydroxypiperidine (300.00 mg) and 1-(bromomethyl)-4-ethynylbenzene (377.98 mg) were added to tetrahydrofuran (5.00 mL). Sodium hydride (149.06 mg, 60%) was added portionwise at 0°C. The reaction was heated to 50°C and stirred for 3 hours. LCMS monitored the reaction completion. H2O and EA were added for extraction twice. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded a light yellow solid (249.00 mg, 52.96% yield). This was compound 93-1.

[0827] Step 2: Synthesis of compound 93-2

[0828] Compound M29 (280.00 mg) and 93-1 (251.47 mg) were added to tetrahydrofuran (6.00 mL), tert-butyl alcohol (3.00 mL), and water (3.00 mL). Copper sulfate (88.10 mg) and sodium ascorbate (315.91 mg) were then added. Stir at 20°C for 4 hours. LCMS monitored the reaction completion. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain a light yellow solid (306.00 mg, 64.63% yield). This was compound 93-2.

[0829] Step 3: Synthesis of compound 93-3

[0830] Compound 93-2 (306.00 mg) was added to a 25 mL single-necked flask, followed by dichloromethane (5.00 mL) and hydrochloric acid (4 M in dioxane) (2.00 mL). Stir at 20°C for 0.5 hours. LCMS monitored the reaction for completion. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO₃ solution, 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 light yellow solid (278.00 mg) was obtained, which is compound 93-3.

[0831] Step 4: Synthesis of compound 93-4

[0832] Compound M28 (80.00 mg) and 93-3 (108.84 mg) were added to a 25 mL single-necked flask. Methanol (2.00 mL) was added, followed by zinc chloride (0.20 mL, 1.00 mol / L). The reaction temperature was raised to 40°C and stirred for 2 hours. Finally, sodium cyanoborohydride (29.69 mg) was added, and the mixture was stirred at 40°C for 12 hours. LCMS monitored the reaction completion. The mixture was concentrated under reduced pressure and purified by column chromatography to yield a light yellow solid (77.00 mg, 45.68% yield). This was compound 93-4.

[0833] Step 5: Synthesis of compound 93

[0834] Compound 93-4 (77.00 mg) was added to a 25 mL single-necked vial, followed by dichloromethane (3.00 mL) and trifluoroacetic acid (1.50 mL). Stir at 20°C for 0.5 hours. LCMS monitored the reaction for completion. The mixture was concentrated under reduced pressure, and the crude product was purified by Pre-HPLC to yield a white solid (33.00 mg, 42.19% yield). This is Compound 93.

[0835] ESI-MS m / z:603.18 1 / 2[M+2H] +

[0836] 1H 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,2H),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=1 2.6Hz,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,1 H),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).

[0837] 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

[0838] Step 1: Synthesis of compound 100-1

[0839] 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 completion of the reaction, 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] + .

[0840] Step 2: Synthesis of compound 100-2

[0841] 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 reacted at 25°C for 1 hour. After completion of the reaction, citric acid was added to adjust the pH to 4, and the mixture was extracted three times with dichloromethane / isopropanol (10:1). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 100-2 (683 mg). ESI-MS m / z: 301.22 [M+H-100] + .

[0842] Step 3: Synthesis of compound 100-3

[0843] 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 completion of the reaction, ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine and purified by column chromatography (dichloromethane / methanol). Compound 100-3 (170 mg) was obtained by chiral column separation. ESI-MS m / z: 714.54 [M+H] + .

[0844] Step 4: Synthesis of compound 100-4

[0845] Compound 100-3 (170 mg) was dissolved in dichloromethane (5 mL), and a 4M hydrochloric acid solution in dioxane (1 mL) was added. The mixture was reacted at 25°C for 20 minutes. After completion of the reaction, the solvent was decanted, the mixture was washed twice with dichloromethane, the mixture was decanted, dissolved in water, neutralized with sodium bicarbonate solution, extracted with dichloromethane / isopropanol (10:1), dried, and concentrated to obtain compound 100-4 (118 mg).

[0846] ESI-MS m / z:614.50[M+H] + .

[0847] Step 5: Synthesis of compound 100-5

[0848] 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 then added and the reaction continued at 40°C for 8 hours. After completion of the reaction, ammonium chloride solution was added to quench the reaction, the mixture was concentrated, and the mixture was purified by column chromatography (dichloromethane / methanol) to afford compound 100-5 (177 mg).

[0849] ESI-MS m / z:596.27 1 / 2[M+2H] + .

[0850] Step 6: Synthesis of Compound 100

[0851] Compound 100-5 (177 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated and purified by Pre-HPLC (C18 column, A: 0.05% trifluoroacetic acid aqueous solution, B: acetonitrile, concentration gradient: 20% B to 75% B, 11 min, flow rate: 15 mL / min, 254 nm). The mixture was concentrated and neutralized with sodium bicarbonate solution. The product precipitated and was filtered to obtain compound 100 (29.9 mg).

[0852] ESI-MS m / z:574.10 1 / 2[M+2H] + . 1H 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).

[0853] Example 104: Synthesis of Compound (2R,4S)-1-(R)-2-(3-(4-(1-((1-((7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyridin[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-((R)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0854] Step 1: Synthesis of compound 104-1

[0855] M36 (80.0 mg) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (30.0 mg) were dissolved in dichloromethane (5 mL). One drop of acetic acid was added dropwise and the mixture was allowed to react at room temperature for 1 hour. Then, sodium cyanoborohydride (17.8 mg) was added and the mixture was allowed to react at room temperature for 10 minutes. The reaction was monitored by LCMS for completion. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction. DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 73.0 mg of a white solid, i.e., compound 104-1. ESI-MS m / z: 764.3 [M+H] + .

[0856] Step 2: Synthesis of compound 104-2

[0857] Compound 104-1 (73.0 mg) was added to DCM (1 mL) and TFA (1 mL) and allowed to react at room temperature for 10 minutes. LCMS monitored the reaction for completion. The reaction solution was concentrated directly and 1 M NaOH solution was added until the pH reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 55.0 mg of a white solid, compound 104-2. ESI-MS m / z: 664.1 [M+H] + .

[0858] Step 3: Synthesis of compound 104-3

[0859] 104-2 (55.0 mg) and M28 (61.6 mg) were dissolved in methanol (8 mL), and zinc chloride solution (0.25 mL / 1 Min Et2O) was added. The mixture was reacted at 40°C for 1 hour, followed by sodium cyanoborohydride (29.2 mg) and reacted at 60°C for 8 hours. The reaction was monitored for completion by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution (5.0 mL). DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 78.0 mg of a white solid, compound 104-3. ESI-MS m / z: 621.4 1 / 2 [M+2H] + .

[0860] Step 4: Synthesis of compound 104

[0861] 104-3 (78.0 mg) was added to DCM (2 mL) and TFA (1 mL), and the mixture was reacted at room temperature for 10 minutes. The reaction was monitored by LCMS to be complete. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 15.3 mg of a white powder, namely compound 104.

[0862] ESI-MS m / z:599.2 1 / 2[M+2H] + .

[0863] 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

[0864] Step 1: Synthesis of compound 105-1

[0865] 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) were added to the reaction flask and reacted at 150°C for 1 h. The mixture was extracted with EA and water, dried, and concentrated. The product was separated by column chromatography to obtain compound 105-1 (300 mg) as a yellow solid.

[0866] ESI-MS m / z:408.24[M+H] + .

[0867] Step 2: Synthesis of compound 105-2

[0868] 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 h. The solvent was concentrated, then the pH was adjusted to 3 with dilute hydrochloric acid, extracted with DCM and methanol, dried, and concentrated to obtain a yellow oil 105-2 (270 mg). ESI-MS m / z: 394.23 [M+H] + .

[0869] Step 3: Synthesis of compound 105-3

[0870] Compound 105-2 (260 mg), M29-2 (4-hydroxy-N-1-4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide (241 mg), N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (0.33 mL) were added to the reaction flask. N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (301 mg) was added with stirring. The mixture was reacted at room temperature for 0.5 h, extracted with EA and water, dried, and concentrated. The product was separated by column chromatography (DCM:MeOH=20:1) to obtain 310 mg of a yellow solid, which was then separated by SFC to obtain a single compound 105-3 (105 mg). ESI-MS m / z: 707.35 [M+H] + .

[0871] Step 4: Synthesis of compound 105-4

[0872] Compound 105-3 (105 mg) and dichloromethane (3 mL) were added to the reaction flask, and 4M HCl in dioxane (0.5 mL) was added with stirring. The mixture was reacted at room temperature for 0.2 h. A large amount of solid precipitated. The supernatant was discarded and concentrated to give a yellow solid compound 105-4 (70 mg). ESI-MS m / z: 707.35 [M+H] + .

[0873] Step 5: Synthesis of compound 105-5

[0874] To the reaction flask were added intermediate M28 (50 mg), compound 105-4 (56 mg), methanol (1.50 mL), 1,2-dichloroethane (1.50 mL), and zinc chloride (0.08 mL, 1.0 mol / L). The mixture was reacted at 40°C for 1 h. Then, sodium cyanoborohydride (53.04 mg) was added and the mixture was reacted at 40°C for 8 h. The mixture was extracted with aqueous sodium bicarbonate and DCM, dried, concentrated, and separated by Pre-TLC using DCM:ammonia methanol as the developing solvent in a ratio of 15:1 to obtain 105-5 (50 mg) as a white solid. ESI-MS m / z: 592.68 1 / 2 [M+2H] + .

[0875] Step 6: Synthesis of compound 105

[0876] Compound 105-5 (50.00 mg), dichloromethane (1.50 mL), and trifluoroacetic acid (1.50 mL) were added to a reaction flask and reacted at room temperature for 0.5 h. The mixture was concentrated and then separated by Pre-HPLC to obtain the target compound 105 (21 mg).

[0877] 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,1H),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).

[0878] 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-pyrrolizin-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

[0879] Step 5: Synthesis of compound 110-1

[0880] Compound M36 (73.0 mg) was added to the reaction mixture of intermediate M32 and stirred at 20°C for 1 hour. LCMS monitored the reaction completion. H2O and EA were added for extraction twice. The organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography afforded a light yellow solid (55.1 mg). This was compound 110-1. ESI-MS m / z: 635.2 1 / 2 [M+2H] +

[0881] Step 6: Synthesis of compound 110

[0882] 110-6 (55.1 mg) was added to DCM (2 mL) and TFA (1 mL), and the mixture was reacted at room temperature for 10 minutes. The reaction was monitored by LCMS to be complete. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 22.2 mg of a white powder, namely compound 110.

[0883] ESI-MS m / z:613.2 1 / 2[M+2H] + . 1 H 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),4.50-4.49(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),1.8 9-1.72(m,5H),1.55-1.45(m,3H),1.40-1.20(m,2H),1.10-0.79(m,9H).

[0884] 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)pyridin[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

[0885] Step 1: Synthesis of compound 111-1

[0886] Tert-butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (400.00 mg), compound M34 (815.16 mg), and DIEA (0.70 mL, 4.23 mmol) were added to DMA (3.00 mL) and reacted at 150°C for 2 h. 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%).

[0887] ESI-MS m / z:465.33[M+H] + .

[0888] Step 2: Synthesis of compound 111-2

[0889] Compound 111-1 (370.00 mg) and anhydrous lithium hydroxide (47.68 mg) were added to water (2.00 mL), methanol (2.00 mL), and tetrahydrofuran (2.00 mL) and allowed to react at room temperature for 1 h. The mixture was diluted with water, adjusted to pH 3 with 1N aqueous hydrochloric acid, and extracted three times with dichloromethane (DCM). The mixture was dried over anhydrous sodium sulfate and concentrated to dryness to afford compound 111-2 (350 mg, 97.54%).

[0890] ESI-MS m / z:451.35[M+H] + .

[0891] Step 3: Synthesis of compound 111-3

[0892] Compound 111-2 (340.00 mg), DIEA (0.62 mL), HATU (373.01 mg), and compound M29-2 (250.10 mg) were added sequentially to dichloromethane (8.00 mL) and allowed to react at room temperature for 2 h. Water was added, the mixture was extracted with DCM, washed with saturated brine, dried, and separated by column chromatography (DCM:MeOH = 91%:9%). The mixture was then resolved on a chiral column to afford compound 111-3 (100 mg, 17.35%).

[0893] ESI-MS m / z:764.55[M+H] + .

[0894] Step 4: Synthesis of compound 111-4

[0895] 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 h. 40 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the base, and the solution was extracted twice with DCM, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound 111-4 (80.00 mg, 92.06%).

[0896] ESI-MS m / z:664.49[M+H] + .

[0897] Step 5: Synthesis of compound 111-5

[0898] Compound 111-4 (80.00 mg), compound M28 (71.41 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.24 mL, 1.00 mol / L) were added to methanol (3.00 mL) and 1,2-dichloroethane (3.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (75.72 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 111-5 (70.00 mg, 46.83%).

[0899] ESI-MS m / z:621.24 1 / 2[M+2H] + .

[0900] Step 6: Synthesis of compound 111

[0901] Compound 111-5 (70.00 mg) and TFA / trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 111 (25.40 mg, 36.67%).

[0902] ESI-MS m / z:599.17 1 / 2[M+2H] + .

[0903] 1H 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).

[0904] 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

[0905] Step 1: Synthesis of compound 112-1

[0906] Compound M36 (50.00 mg), compound M28 (52.27 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.18 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (27.71 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 112-1 (15.00 mg, 14.87%).

[0907] ESI-MS m / z:572.74 1 / 2[M+2H] + .

[0908] Step 2: Synthesis of compound 112

[0909] Compound 112-1 (15.00 mg) and TFA / trifluoroacetic acid (0.50 mL) were added to dichloromethane (1.00 mL) and reacted at room temperature for 1 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 112 (8.50 mg, 56.67%).

[0910] ESI-MS m / z:550.57 1 / 2[M+2H] + .

[0911] 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

[0912] Step 1: Synthesis of compound 113-1

[0913] Compound (3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (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 hours. Finally, M34 (500.00 mg) was added. The mixture was stirred at 120°C for 5 hours. LCMS monitored the reaction completion. H2O and EA were added for extraction twice, and the organic layer was washed three times with saturated brine and dried over anhydrous sodium sulfate. Purification by column chromatography gave a light yellow solid (212.00 mg, 51.86% yield). This is compound 113-1.

[0914] Step 2: Synthesis of compound 113-2

[0915] Compound 113-1 (212.00 mg) was added to tetrahydrofuran (2.00 mL), methanol (2.00 mL), water (2.00 mL), and lithium hydroxide monohydrate (113.04 mg, 2.69 mmol). Stir at 20°C for 1 hour. LCMS monitored the reaction completion. 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 light yellow solid (209.00 mg) was obtained, which is compound 113-2.

[0916] Step 3: Synthesis of compound 113-3

[0917] Compound 113-2 (201.53 mg) and M29-2 (160.00 mg) were added to a 25 mL single-necked flask. 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 also added. Stir at 20°C for 0.5 hours. LCMS monitored the reaction completion. H2O and EA were added for extraction twice. The organic layer was washed three times with saturated brine and then dried over anhydrous sodium sulfate. The crude product was separated by SFC to obtain a light yellow solid (96.00 mg). This is compound 113-3.

[0918] Step 4: Synthesis of compound 113-4

[0919] Compound 113-3 (96.00 mg) was added to a 25 mL single-necked flask, followed by dichloromethane (2.00 mL) and hydrochloric acid (4 M in dioxane) (1.00 mL). Stir at 20°C for 0.5 hours. The reaction was monitored by LCMS for completion. The mixture was concentrated under reduced pressure, adjusted to pH 8 with saturated NaHCO₃ solution, 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 light yellow solid (84.00 mg) was obtained, which is compound 113-4.

[0920] Step 5: Synthesis of compound 113-5

[0921] Compound M28 (70.00 mg) and 113-4 (83.99 mg) were added to a 25 mL single-necked flask. Methanol (2.00 mL) was added, followed by zinc chloride (0.18 mL, 1.00 mol / L). The reaction mixture was heated to 40°C and stirred for 2 hours. Finally, sodium cyanoborohydride (25.98 mg, 0.41 mmol) was added, and the mixture was stirred at 50°C for 12 hours. LCMS monitored the reaction completion. The residue was concentrated under reduced pressure and purified by column chromatography to afford a pale yellow solid (88.00 mg, 63.72% yield). This was compound 113-5.

[0922] Step 6: Synthesis of compound 113

[0923] Compound 113-5 (88.00 mg) was added to a 25 mL single-necked vial, followed by dichloromethane (4.00 mL) and trifluoroacetic acid (1.50 mL). The mixture was stirred at 20°C for 0.5 hours. LCMS monitored the reaction for completion. The mixture was concentrated under reduced pressure, and the crude product was purified by HPLC to yield a white solid (42.20 mg, 48.01% yield). This is compound 113.

[0924] ESI-MS m / z:563.70 1 / 2[M+2H] +

[0925] 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).

[0926] 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

[0927] Step 1: Synthesis of compound 114-1

[0928] 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, diisopropyl azodicarboxylate (863 mg) was slowly added and the mixture was allowed to react at 60°C for 4 hours. LCMS monitored the reaction completion. EA (20 mL) was added to the reaction solution, and the mixture was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 850.0 mg of a white solid, Compound 114-1. ESI-MS m / z: 383.2 [M+H] + .

[0929] Step 2: Synthesis of compound 114-2

[0930] 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 react at room temperature for 1 hour. LCMS monitored the reaction to completion. The pH of the reaction solution was adjusted to 3, and EA (20 mL) was added. The organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 825.0 mg of a white solid, namely compound 114-2. ESI-MS m / z: 369.2 [M+H] + .

[0931] Step 3: Synthesis of compound 114-3

[0932] 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), and DIPEA (1.18 mL) was added. The mixture was reacted 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 solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1291.0 mg of a white solid, i.e., compound 114-3. ESI-MS m / z: 682.3 [M+H] + .

[0933] Step 4: Synthesis of compound 114-4

[0934] Compound 114-3 (1291 mg) was separated by SFC and concentrated to obtain 502 mg of a white solid, namely compound 114-4. ESI-MS m / z: 682.3 [M+H] + .

[0935] Step 5: Synthesis of compound 114-5

[0936] Compound 114-4 (502.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. LCMS monitored the reaction for completion. The reaction solution was concentrated directly and 1 M NaOH solution was added until the pH reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 426 mg of a white solid, compound 114-5. ESI-MS m / z: 582.3 [M+H] + .

[0937] Step 6: Synthesis of compound 114-6

[0938] Compound 114-5 (200.0 mg) and M28 (207 mg) were dissolved in methanol (10 mL). Zinc chloride solution (0.52 mL / 1.0 M in Et2O) was added and 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. DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 310 mg of a white solid, compound 114-6. ESI-MS m / z: 579.8 1 / 2 [M+2H] + .

[0939] Step 7: Synthesis of compound 114

[0940] Compound 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 to be complete by LCMS. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 48.0 mg of a white powder, namely compound 114.

[0941] ESI-MS m / z:558.1 1 / 2[M+2H] + . 1 H NMR(500MHz,Methanol-d4)δ9.19(d,J=8.4Hz,

[0942] 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,4 H),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).

[0943] 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

[0944] Step 1: Synthesis of compound 115-1

[0945] Compound M36 (90.00 mg), tert-butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (63.28 mg), and a 1.0 M tetrahydrofuran solution of zinc chloride (0.32 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (49.90 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 115-1 (87.00 mg, 73.35%).

[0946] ESI-MS m / z:750.59[M+H] + .

[0947] Step 2: Synthesis of compound 115-2

[0948] Compound 115-1 (87.00 mg) and TFA / trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 h. 40 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the base. The solution was extracted twice with DCM, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 115-2 (60.00 mg, 79.59%).

[0949] ESI-MS m / z:650.48[M+H] + .

[0950] Step 3: Synthesis of compound 115-3

[0951] Compound 115-2 (50.00 mg), compound M28 (42.19 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.15 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (24.16 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 115-3 (35.00 mg, 38.49%).

[0952] ESI-MS m / z:614.18 1 / 2[M+2H] + .

[0953] Step 4: Synthesis of compound 115

[0954] Compound 115-3 (35.00 mg) and TFA / trifluoroacetic acid (0.50 mL) were added to dichloromethane (1.00 mL) and reacted at room temperature for 1 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 115 (11.40 mg, 33.59%).

[0955] ESI-MS m / z:592.27 1 / 2[M+2H] + .

[0956] 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

[0957] Step 1: Synthesis of compound 116-1

[0958] Compound M36 (80.00 mg), tert-butyl 3-oxoazetidine-1-carboxylate (72.52 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.28 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (44.37 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was 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%).

[0959] ESI-MS m / z:722.57[M+H] + .

[0960] Step 2: Synthesis of compound 116-2

[0961] Compound 116-1 (60.00 mg) and TFA / trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) and reacted at room temperature for 1 h. The reaction mixture was adjusted to a base by adding 40 mL of saturated aqueous sodium bicarbonate. The mixture was extracted twice with DCM, dried over anhydrous sodium sulfate, and isolated by column chromatography (DCM:MeOH = 90%:10%) to afford compound 116-2 (40.00 mg, 77.41%).

[0962] ESI-MS m / z:622.46[M+H] + .

[0963] Step 3: Synthesis of compound 116-3

[0964] Compound 116-2 (40.00 mg), compound M28 (45.75 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.13 mL, 1.00 mol / L) were added to methanol (2.00 mL) and 1,2-dichloroethane (2.00 mL). The mixture was reacted at 40°C for 2 h. Sodium cyanoborohydride (22.20 mg) was then added and the mixture was reacted at 40°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 116-3 (30.00 mg, 38.93%).

[0965] ESI-MS m / z:600.30 1 / 2[M+2H] + .

[0966] Step 4: Synthesis of compound 116

[0967] Compound 116-3 (30.00 mg) and TFA / trifluoroacetic acid (0.50 mL) were added to dichloromethane (1.00 mL) and reacted at room temperature for 1 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 116 (15.00 mg, 49.67%).

[0968] ESI-MS m / z:578.14 1 / 2[M+2H] + .

[0969] 1H NMR(500MHz,Methanol-d4)δ9.24(d,J=3.7Hz,1H),8.87(d,J=3.2Hz,1H),7.6 7(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(dd,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).

[0970] 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

[0971] Step 1: Synthesis of compound 117-1

[0972] To the reaction flask, 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) were added. The temperature was lowered to 0°C, and diisopropyl azodicarboxylate (3.02 g) was slowly added. After addition, the mixture was returned to room temperature and allowed to react for 6 h. The mixture was extracted with water and EA, dried, and concentrated. The product was separated by column chromatography (PE:EA = 4:1) to obtain compound 117-1 (3.3 g), a colorless liquid. ESI-MS m / z: 301.1 [M+Ht-Bu] + .

[0973] Step 2: Synthesis of compound 117-2

[0974] Compound 117-1 (1.00 g), bistriphenylphosphine palladium dichloride (0.10 g), triethylamine (4.67 mL), and tetrahydrofuran (5.00 mL) were added to the reaction flask. After nitrogen substitution, the mixture was reacted at room temperature for 10 min. Cuprous iodide (0.03 g) and ethynyltrimethylsilane (0.41 g) were added. After nitrogen substitution, the mixture was reacted at room temperature for 2.5 h. The reaction solution was directly purified by column chromatography (PE:EA=4:1) to obtain a yellow solid 117-2 (930 mg). ESI-MS m / z: 375.2 [M+H] + .

[0975] Step 3: Synthesis of compound 117-3

[0976] Compound 117-2 (930.00 mg), methanol (3.00 mL), and potassium carbonate (686.35 mg) were added to the reaction flask and reacted at room temperature for 1 h. The mixture was filtered and the filter cake was washed three times with EA. The mother liquor was concentrated and purified by column chromatography (PE:EA=2:1) ​​to obtain a yellow solid 117-3 (702 mg). ESI-MS m / z: 303.4 [M+H] + .

[0977] Step 4: Synthesis of compound 117-4

[0978] 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 the reaction flask and reacted at 60°C for 2 h. The mixture was concentrated, then extracted with DCM, dried, and concentrated. The mixture was then flash column-filtered with a developing solvent changed from DCM to DCM:ammonia methanol = 25:1 to obtain a light yellow solid 117-4 (91 mg). ESI-MS m / z: 759.4 [M+H] + .

[0979] Step 5: Synthesis of compound 117-5

[0980] 117-4 (91.00 mg), dichloromethane (3.00 mL), and hydrochloric acid (4M in dioxane) (0.18 mL, 4.00 mol / L) were added to the reaction flask and reacted at room temperature for 0.2 h. A large amount of solid precipitated. The reaction solution was decanted, and the solid was dissolved in methanol, diluted with DCM, and then adjusted to pH = 8 with aqueous sodium bicarbonate solution. The mixture was extracted, dried, and concentrated to obtain compound 117-5 (72 mg).

[0981] ESI-MS m / z:659.4[M+H] + .

[0982] Step 6: Synthesis of compound 117-6

[0983] 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 h. Sodium cyanoborohydride (53.04 mg) was then added and the reaction continued for 4 h. The solvent was concentrated, diluted with water, and then extracted with DCM and MeOH, dried, and concentrated. Pre-TLC separation and purification gave 117-6 (52 mg) as a yellow solid. ESI-MS m / z: 618.8 1 / 2 [M+2H] + .

[0984] Step 7: Synthesis of compound 117

[0985] 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 h. The mixture was then concentrated and dissolved in DCM. The reaction mixture was added to an icy sodium bicarbonate solution, adjusted to pH 8, extracted with DCM and methanol, dried, and concentrated. Pre-TLC was performed using a developing solvent of DCM:MeOH = 11:1 to obtain the target compound 117 (24 mg).

[0986] ESI-MS m / z:596.66 1 / 2[M+2H] + . 1H 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).

[0987] 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)pyridin[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

[0988] Step 1: Synthesis of compound 118-1

[0989] 2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (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 at 50°C for 3 h. 40 mL of water was added to the reaction solution, which was 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%).

[0990] ESI-MS m / z:328.33[M+H] + .

[0991] Step 2: Synthesis of compound 118-2

[0992] 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 h. 50 mL of water was added to the reaction solution, which was extracted twice with EA, dried over anhydrous sodium sulfate, and separated by column chromatography (DCM:MeOH = 93%:7%) to obtain compound 118-2 (230 mg, 78.80%).

[0993] ESI-MS m / z:784.61[M+H] + .

[0994] Step 3: Synthesis of compound 118-3

[0995] Compound 118-2 (230.00 mg) and trifluoroacetic acid (1.00 mL) were added to dichloromethane (2.00 mL) in sequence and reacted at room temperature for 1 h. 40 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the base, and the solution was extracted twice with DCM, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain compound 118-3 (200.00 mg, 99.68%).

[0996] ESI-MS m / z:684.50[M+H] + .

[0997] Step 4: Synthesis of compound 118-4

[0998] Compound 118-3 (190.00 mg), compound M28 (164.63 mg), and zinc chloride in a 1.0 M tetrahydrofuran solution (0.56 mL, 1.00 mol / L) were added to methanol (3.00 mL) and 1,2-dichloroethane (3.00 mL). The mixture was reacted at 60°C for 2 h. Sodium cyanoborohydride (87.28 mg) was then added and the mixture was reacted at 60°C for 3 h. The reaction solution was concentrated, 30 mL of water was added, and the mixture was extracted twice with DCM. The mixture was dried over anhydrous sodium sulfate and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain compound 118-4 (100.00 mg, 28.56%).

[0999] ESI-MS m / z:631.21 1 / 2[M+2H] + .

[1000] Step 5: Synthesis of compound 118

[1001] 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 h. The reaction solution was concentrated and purified by Pre-HPLC to obtain compound 118 (42.40 mg, 43.40%).

[1002] ESI-MS m / z:609.32 1 / 2[M+2H] + .

[1003] 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,1 H),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,1 H),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),1.9 3(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).

[1004] Example 119: Synthesis of (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)pyridin[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

[1005] Step 1: Synthesis of compound 119-1

[1006] M39 (0.155 g) and M28 (0.100 g) were dissolved in 4.00 mL of anhydrous methanol, and zinc chloride (0.337 mL, 1.0 mol / L) was added. The mixture was reacted at 40°C for 1 h, followed by sodium cyanoborohydride (106 mg) and the reaction was continued at 40°C for 4 h. The reaction solution was quenched by the addition of 50 mL of saturated aqueous sodium bicarbonate solution and extracted three times with a 10 / 1 DCM / MeOH mixture. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was then purified by column chromatography (10 / 1 DCM / MeOH) to afford 0.150 g of a yellow solid, compound 119-1. ESI-MS m / z: 617.3 1 / 2 [M+2H] + ;

[1007] Step 2: Synthesis of compound 119

[1008] At room temperature, 119-1 (150 mg) was dissolved in 5.00 mL of dichloromethane, followed by the addition of 2.00 mL of trifluoroacetic acid. The reaction was allowed to react at room temperature for 1 h. The solvent was evaporated under reduced pressure, redissolved in dichloromethane, the solvent was evaporated again, and redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, followed by the addition of solid sodium carbonate, which was stirred for 20 min. The mixture was then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and purified to obtain 66.5 mg of a white solid product, compound 119.

[1009] 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).

[1010] 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 ester)-1H-1-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S,-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxylic acid hydroxyoxime

[1011] Step 1: Synthesis of compound 120-1

[1012] M31 (100 mg) was dissolved in 3 mL of THF, and NaH (12 mg) was added. The mixture was stirred at room temperature for 30 minutes, followed by the addition of 3-bromopropyne (15 μl). A nitrogen balloon was placed under the mixture, and the mixture was stirred at 25°C for 2 hours. LC-MS monitored the reaction for completion. The reaction mixture was slowly quenched by the addition of 10 mL of saturated ammonium chloride solution. The mixture was extracted three times with EA. 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 to afford 65 mg of a pale yellow solid, compound 120-1. ESI-MS m / z: 714 [M+H] + ;

[1013] Step 2: Synthesis of compound 120-2

[1014] Compound 120-1 (65 mg) and M29 (50 mg) were dissolved in 2 mL of THF, 2 mL of H₂O, and 2 mL of tert-butanol. Sodium ascorbate (47 mg) and anhydrous copper sulfate (13 mg) were then added sequentially. The mixture was allowed to react at room temperature for 0.5 h, and the reaction was monitored for completion by LCMS. 20.0 mL of water was added to the reaction solution, and the mixture was extracted with DCM:MeOH = 4:1 (3*20 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The organic phase was separated and purified by column chromatography to obtain 54 mg of a light yellow solid, namely compound 120-2.

[1015] ESI-MS m / z:586 1 / 2[M+2H] + .

[1016] Step 3: Synthesis of compound 120

[1017] 120-2 (54 mg) was dissolved in 2 mL of DCM, and then 1 mL of TFA was added. The reaction was allowed to react at room temperature for 30 min. The reaction was monitored by LCMS for completion. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 18.4 mg of a white powder, i.e., compound 120.

[1018] 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).

[1019] 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)pyrrolo[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methylenehexahydro-1H-pyrrolazin-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

[1020] Step 1: Synthesis of compound 121-1

[1021] 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 solution and reacted at room temperature for 3 hours. LCMS monitored the completion of the reaction, and DCM (10 mL) was added to the reaction solution. The mixture was 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] + .

[1022] Step 2: Synthesis of compound 121-2

[1023] 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 mixed solvent of THF / tert-butanol / water (1 / 1 / 1 mL) and reacted at room temperature for 1 hour. LCMS monitored the completion of the reaction, and DCM (10 mL) was added to the reaction solution. The mixture was washed once with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 15.0 mg of a yellow solid, i.e., compound 121-2. ESI-MS m / z: 618.3 1 / 2 [M+2H] + .

[1024] Step 3: Synthesis of compound 121

[1025] 121-2 (15.0 mg) was added to DCM (2 mL) and TFA (1 mL), and the mixture was reacted at room temperature for 10 minutes. The reaction was monitored by LCMS to be complete. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 5.7 mg of a white powder, namely compound 121.

[1026] ESI-MS m / z:595.8 1 / 2[M+H] + . 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).

[1027] Example 122: Synthesis of Compound (2S,4R)-1-((S)-2-(4-(4-(((3S,7aS)-7a-((((7-(8-ethyl-7-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrrolidin-2-yl)oxy)methyl-4,3-d]pyrimidin-2-ylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1028] Step 1: Synthesis of compound 122-1

[1029] A 50 mL flask was added with (R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-8-fluoro-2-(((5S,7aS)-5-(hydroxymethyl)-2-methyltetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy]pyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperidin-3-ol (M31) 140 mg and THF 10 mL. The temperature was lowered to 0°C, and NaH 41 mg was added. The temperature was raised 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 and quenched with saturated ammonium chloride. The mixture was extracted with EA, and the organic phase was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure to obtain a crude product. The product was purified by column chromatography to obtain 49 mg of compound 122-1.

[1030] Step 2: Synthesis of compound 122-2

[1031] A 50 mL flask was added 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), 1 mL of tert-butanol, 1 mL of THF, and 1 mL of water. The mixture was reacted at room temperature for 1 hour. After the reaction was detected to be complete, EA was added for extraction. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure to obtain a crude product. 32 mg of the product, i.e., compound 122-2, was obtained by column chromatography.

[1032] Step 3: Synthesis of compound 122

[1033] 122-2 (32 mg), DCM 3 mL, and TFA 1 mL were added to a 50 mL flask and reacted at room temperature for 0.5 h. After detection, the mixture was desolvated under reduced pressure, dissolved in DCM, and the pH was adjusted to 7-8 with a saturated aqueous solution of baking soda. The mixture was stirred, separated, washed with brine, dried over sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure to obtain a crude product. Pre-HPLC analysis yielded 13.3 mg of the product, namely compound 122.

[1034] ESI-MS m / z:602.14 1 / 2[M+2H] +

[1035] 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-pyrrolazin-3-yl)methylpiperidin-4-yl)-1H-1-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-(((S,-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1036] Step 1: Synthesis of compound 123-1

[1037] M31 (100 mg), DCM 2 mL, TEA 75 mg, and methanesulfonyl chloride 23 uL were added to a 10 mL flask and reacted at room temperature for 2 hours. The mixture was diluted with DCM, washed with a saturated sodium bicarbonate solution, separated, washed with brine, dried over sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure to obtain a crude product. The product was purified by column chromatography to obtain 45 mg of the product, i.e., compound 123-1.

[1038] Step 2: Synthesis of compound 123-2

[1039] 123-1 (45 mg), 2 mL of DMF, cesium carbonate (145 mg), and 4-ethynylpiperidine (43 mg) were added to a 10 mL flask and heated to 60°C for 3 hours. The mixture was diluted with EA, washed with water, washed with brine, dried over sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure to obtain a crude product. The product was purified by column chromatography to obtain 39 mg of the product, namely compound 123-2.

[1040] Step 3: Synthesis of compound 123-3

[1041] A 10 mL flask was added 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), 1 mL of tert-butanol, 1 mL of THF, and 1 mL of water. The mixture was reacted at room temperature for 1 hour. After the reaction was detected to be complete, EA was added for extraction. The organic phase was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was desolvated under reduced pressure to obtain a crude product. The product was purified by column chromatography to obtain 25 mg of compound 123-3.

[1042] Step 4: Synthesis of compound 123

[1043] 123-3 (25 mg), DCM 3 mL, and TFA 1 mL were added to a 10 mL flask and reacted at room temperature for 0.5 h. After detection, the solvent was removed under reduced pressure, DCM was added for dissolution, and the pH was adjusted to 7-8 with a saturated aqueous solution of baking soda. The mixture was stirred, separated, washed with brine, dried over sodium sulfate, filtered, and the filtrate was removed under reduced pressure to give crude 123. Pre-HPLC analysis yielded 1.7 mg of the product.

[1044] ESI-MS m / z:590.80 1 / 2[M+2H] +

[1045] Example 124: Synthesis of Compound (2S,4R)-1-((S)-2-(4-(6-(((3S,7aS)-7a-((7-(8-ethyl-7-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-4-((R)-3-hydroxy-3-methylpiperidin-1-yl)pyrrolopyridin-2-yl)oxy)methyl)-6-methyl-1H-pyrroloazine-3-ylmethoxymethyl-4-pyridin-3-yl-1,1,2,1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[1046] Step 1: Synthesis of compound 124-1

[1047] M31 (150.00 mg, 0.22 mmol) in tetrahydrofuran (6.00 mL) was cooled in an ice-water bath under nitrogen. Sodium hydride (26.64 mg, 60%, 0.67 mmol) was added and the mixture was allowed to react at 0°C for 0.5 h. 5-Ethynyl-2-fluoropyridine (53.77 mg, 0.44 mmol) was then added and the mixture was allowed to react at 20°C for 4 h. The reaction solution was added to 20 mL of saturated ammonium chloride and 15 mL of EA. The organic phase was separated and the aqueous phase was extracted once more with 5 mL of EA. The organic phases were combined and the aqueous phase, free of product, was discarded. The organic phase was dried, filtered, concentrated under reduced pressure, and purified by column chromatography to yield 85 mg of a yellow foamy solid. This was compound 124-1. ESI-MS m / z: 777.30 [M+H] + .

[1048] Step 2: Synthesis of compound 124-2

[1049] To a solution of 124-1 (60.00 mg) and M29 (35.25 mg) in tert-butanol (1.50 mL) and tetrahydrofuran (1.50 mL) were added copper sulfate (12.32 mg) and water (0.75 mL) containing sodium ascorbate (45.88 mg). The mixture was allowed to react at 20°C for 1 h. LCMS showed complete conversion. The reaction mixture was added to 20 mL of water and extracted with EA. The aqueous phase, free of product, was discarded. The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (MEOH:DCM = 1% to 7%) to yield 75.00 mg of a yellow foamy solid. This was compound 124-2. ESI-MS m / z: 617.7 1 / 2 [M+2H] + .

[1050] Step 3: Synthesis of compound 124

[1051] To 124-2 (80.00 mg) in dichloromethane (4.00 mL) was added trifluoroacetic acid (0.96 mL) and the mixture was allowed to react at 20°C for 0.5 h. LCMS showed complete conversion. The reaction mixture was concentrated without heating and purified by Pre-HPLC to yield 31.80 mg of a white powder, compound 124.

[1052] 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).

[1053] 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)pyrrolo[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-carboxylate

[1054] Step 1: Synthesis of compound 125-1

[1055] M35 (30.0 mg) was dissolved in THF (2 mL), and CDI (10.8 mg) was added. The mixture was reacted at 40°C for 1 hour, followed by the addition of M31 (39.7 mg) and the reaction was continued at 60°C for 12 hours. The reaction was monitored for completion by LCMS. Methanol (5.0 mL) was added to quench the reaction, and the reaction solution was directly concentrated and purified by column chromatography to obtain 35.0 mg of a light yellow solid, compound 125-1. ESI-MS m / z: 650.3 1 / 2 [M+2H] + .

[1056] Step 2: Synthesis of compound 125

[1057] Compound 125-1 (35.0 mg) was added to DCM (5 mL) and TFA (2 mL) and reacted at room temperature for 10 minutes. The reaction was monitored by LCMS for completion. The reaction solution was directly concentrated and purified by Pre-HPLC to obtain 15.3 mg of a white powder, namely compound 125.

[1058] ESI-MS m / z:627.81 / 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).

[1059] Example 126: 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)-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

[1060] Step 1: Synthesis of compound 126-1

[1061] 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 react at room temperature for 3 h. 50 mL of saturated sodium bicarbonate solution was slowly added to the reaction solution to quench the reaction. The mixture was extracted three times with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 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).

[1062] Step 2: Synthesis of compound 126-2

[1063] Compound 126-1 (1.40 g) was dissolved in 20.0 mL of THF, cooled to -40°C, and lithium aluminum tetrahydride (0.330 g) was added. The temperature was naturally raised to room temperature and reacted for 2 h. The reaction solution was cooled to 0°C, and then 0.33 mL of water, 0.33 mL of 15% NaOH solution, and 0.33 mL of water were gradually added dropwise to the reaction solution. After stirring for 30 min, the insoluble impurities were removed by filtration through celite. The filter cake was eluted three times with 20.0 mL of EA. The filtrate was collected and dried over anhydrous sodium sulfate. After filtration and reduced pressure evaporation of the solvent, 0.910 g of a light yellow oily product, namely compound 126-2, was obtained. 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).

[1064] Step 3: Synthesis of compound 126-3

[1065] 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). The mixture was allowed to react at room temperature for 2 h. The reaction solution was then dried and purified by column chromatography (PE / EA = 5 / 1) to yield 0.480 g of a white solid, compound 126-3. 1H NMR (500MHz, Chloroform-d) δ4.47(s,1H),3.16(s,2H),2.09(s,1H),1.97(s,6H),1.44(s,9H).

[1066] Step 4: Synthesis of compound 126-4

[1067] 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 mixture of 4.00 mL of tert-butanol, 4.00 mL of tetrahydrofuran, and 4.00 mL of water at room temperature and allowed to react for 1 h. The reaction mixture was quenched by the addition of 50 mL of aqueous solution and extracted three times with a 10 / 1 mixture of DCM / MeOH. 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 afford 1.050 g of a yellow solid, compound 126-4. ESI-MS m / z:678[M+H] + ;

[1068] Step 5: Synthesis of compound 126-5

[1069] Compound 126-4 (0.800 g) was dissolved in 10.0 mL of dichloromethane at room temperature, followed by the addition of 3.00 mL of trifluoroacetic acid and the reaction was allowed to proceed at room temperature for 1 h. 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, followed by the addition of 1.00 mL of water. Solid sodium carbonate was added and stirred for 20 min. The mixture was then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated 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.

[1070] ESI-MS m / z:578[M+H] + ;

[1071] Step 6: Synthesis of compound 126-6

[1072] M31 (100 mg) was dissolved in tetrahydrofuran (2.00 mL) at room temperature, and triethylamine (0.165 mL), p-nitrophenyl chloroformate (60.0 mg), and 4-dimethylaminopyridine (5.50 mg) were added sequentially. After reacting at room temperature overnight, compound 8-5 (103 mg) was added and reacted at room temperature for 0.5 h. The reaction solution was extracted three times with appropriate amounts of water and DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 150 mg of a yellow solid, compound 126-6. ESI-MS m / z: 640.7 1 / 2 [M+2H] + ;

[1073] Step 7: Synthesis of compound 126

[1074] Compound 126-6 (150 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 reaction was allowed to proceed at room temperature for 1 h. The solvent was evaporated under reduced pressure, redissolved in dichloromethane, the solvent was evaporated again, redissolved in 5.00 mL of tetrahydrofuran, and 1.00 mL of water was added. Solid sodium carbonate was added and stirred for 20 min, followed by drying over anhydrous sodium sulfate, filtering, and distilling off the solvent under reduced pressure. The product was purified to obtain 25.1 mg of a white solid, compound 126.

[1075] ESI-MS m / z:618.8 1 / 2[M+2H] + ; 1H 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=9.3H z,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,3 H), 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).

[1076] Example 127: 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)-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

[1077] Step 1: Synthesis of compound 127-1

[1078] 7-tert-Butyloxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid (500.0 mg) was dissolved in 5.0 mL of THF, and a borane tetrahydrofuran solution (4.64 mL, 1 mol / L) was added. The mixture was allowed to react at room temperature for 1 h. 5 mL of HCl / MeOH solution was slowly added to the reaction solution and stirred until no bubbles were generated. 1 mol / L NaOH solution was added to adjust the pH to alkaline. An appropriate amount of ethyl acetate was then added for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 450.0 mg of a colorless oily product, compound 127-1. ESI-MS m / z: 200 [M+H-56]. +

[1079] Step 2: Synthesis of compound 127-2

[1080] Compound 127-1 (250.0 mg) was dissolved in 5.0 mL of DCM, and Dess-Martin reagent (387.0 mg) was added. The mixture was allowed to react at room temperature for 1 h. An appropriate amount of ethyl acetate was added to the reaction solution, and the precipitated solid was removed by filtration. The filtrate was then added with 1 mol / L NaOH solution to adjust the pH to alkaline. The organic phase was collected by extraction and separation, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 180.0 mg of a colorless oily product, compound 127-2. ESI-MS m / z: 198 [M+H-56] +

[1081] Step 3: Synthesis of compound 127-3

[1082] 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 h. The reaction solution was extracted with appropriate amounts of water and ethyl acetate. 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 obtain 110 mg of a colorless oily product, namely compound 127-3. ESI-MS m / z: 194 [M+H-56]. +

[1083] Step 4: Synthesis of compound 127-4

[1084] 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 mixture of 2.00 mL of tert-butanol, 2.00 mL of tetrahydrofuran, and 2.00 mL of water at room temperature and allowed to react for 1 h. The reaction mixture was quenched by the addition of 50 mL of aqueous solution and extracted three times with a 10 / 1 mixture of DCM / MeOH. 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 afford 300 mg of a yellow solid, compound 127-4. ESI-MS m / z:706[M+H] + ;

[1085] Step 5: Synthesis of Compound 127-5

[1086] At room temperature, 127-4 (300 mg) was dissolved in 5.00 mL of dichloromethane, followed by the addition of 2.00 mL of trifluoroacetic acid and the reaction was allowed to proceed at room temperature for 1 h. 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, followed by the addition of 1.00 mL of water. Solid sodium carbonate was added and stirred for 20 min, followed by drying over anhydrous sodium sulfate, followed by filtration. The solvent was evaporated under reduced pressure, and the mixture was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 225 mg of a yellow solid product, compound 127-5. ESI-MS m / z: 606 [M+H] + ;

[1087] Step 6: Synthesis of compound 127-6

[1088] M31 (100 mg) was dissolved in tetrahydrofuran (2.00 mL) at room temperature. Triethylamine (0.165 mL), p-nitrophenyl chloroformate (60.0 mg), and 4-dimethylaminopyridine (5.50 mg) were added sequentially. After reacting at room temperature overnight, 127-5 (99.2 mg) was added and reacted at room temperature for 0.5 h. The reaction solution was extracted three times with appropriate amounts of water and DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (DCM / MeOH = 10 / 1) to obtain 155 mg of a yellow solid, compound 127-6. ESI-MS m / z: 654.8 1 / 2 [M+2H] + ;

[1089] Step 7: Synthesis of compound 127

[1090] At room temperature, 127-6 (155 mg) was dissolved in 5.00 mL of dichloromethane, followed by the addition of 2.00 mL of trifluoroacetic acid. The reaction was allowed to react at room temperature for 1 h. The solvent was evaporated under reduced pressure, redissolved in dichloromethane, the solvent was evaporated again, and redissolved in 5.00 mL of tetrahydrofuran. 1.00 mL of water was added, followed by the addition of solid sodium carbonate, which was stirred for 20 min. The mixture was then dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure and purified to obtain 26.8 mg of a white solid product, compound 127.

[1091] ESI-MS m / z:632.91 / 2[M+2H] + ; 1 H 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).

[1092] 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)pyrrolo[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

[1093] Step 1: Synthesis of compound 128-1

[1094] 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 mixture of THF / tert-butanol / water (10 / 10 / 10 mL) and reacted at room temperature for 3 hours. LCMS monitored the reaction completion. DCM (30 mL) was added to the reaction solution, and the mixture was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 628.0 mg of a yellow solid, i.e., compound 128-1. ESI-MS m / z: 638.3 [M+H] + .

[1095] Step 2: Synthesis of compound 128-2

[1096] Compound 128-1 (295.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. LCMS monitored the reaction for completion. The reaction solution was concentrated directly and 1 M NaOH solution was added until the pH reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 165.0 mg of a white solid, compound 128-2. ESI-MS m / z: 538.3 [M+H] + .

[1097] Step 3: Synthesis of compound 128-3

[1098] Compound 128-2 (165.0 mg) and N-tert-butyloxycarbonyl-4-piperidone (61.2 mg) were dissolved in methanol (5 mL). Zinc chloride solution (0.46 mL / 1 M in Et2O) was added and the mixture was allowed to react at 40°C for 1 hour. Sodium cyanoborohydride (57.9 mg) was then added and the mixture was allowed to react at 40°C for 10 minutes. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction. DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 120.0 mg of a white solid, compound 128-3. ESI-MS m / z: 721.3 [M+H] + .

[1099] Step 4: Synthesis of compound 128-4

[1100] Compound 128-3 (120.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. LCMS monitored the reaction for completion. The reaction solution was concentrated directly and 1 M NaOH solution was added until the pH reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 80.0 mg of a white solid, compound 128-4. ESI-MS m / z: 621.3 [M+H] + .

[1101] Step 5: Synthesis of compound 128-5

[1102] Compound 128-4 (80.0 mg) and M28 (76.4 mg) were dissolved in methanol (5 mL), and zinc chloride solution (0.19 mL / 1 M in Et2O) was added. The mixture was reacted at 40°C for 1 hour, followed by sodium cyanoborohydride (24.3 mg) and 60°C for 12 hours. The reaction was monitored for completion by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution (5.0 mL). DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 84.0 mg of a white solid, compound 128-5. ESI-MS m / z: 600.3 1 / 2 [M+2H] + .

[1103] Step 6: Synthesis of compound 128

[1104] 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 by LCMS to be complete. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 28.9 mg of white powder, namely compound 128.

[1105] 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).

[1106] 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)pyrrolo[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

[1107] Step 1: Synthesis of compound 129-1

[1108] Compound 128-2 (300.0 mg) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (119.0 mg) were dissolved in methanol (8 mL). Zinc chloride solution (0.61 mL / 1 M in Et2O) was added and the mixture was allowed to react at 40°C for 1 hour. Sodium cyanoborohydride (105.2 mg) was then added and the mixture was allowed to react at 40°C for 10 minutes. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction. DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 267.0 mg of a white solid, compound 129-1. ESI-MS m / z: 735.4 [M+H] + .

[1109] Step 2: Synthesis of compound 129-2

[1110] Compound 129-1 (267.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. LCMS monitored the reaction for completion. The reaction solution was concentrated directly and 1 M NaOH solution was added until the pH reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 230.0 mg of a white solid, compound 129-2. ESI-MS m / z: 635.4 [M+H] + .

[1111] Step 3: Synthesis of compound 129-3

[1112] M28 (128.5 mg) was dissolved in methanol (8 mL), and zinc chloride solution (0.25 mL / 1 M in Et2O) was added. The reaction was allowed to react at 40°C for 1 hour, followed by the addition of sodium cyanoborohydride (31.8 mg). The reaction was allowed to react at 60°C for 12 hours. The reaction was monitored for completion by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution (5.0 mL). DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 82.0 mg of a white solid, compound 129-3.

[1113] ESI-MS m / z:607.3 1 / 2[M+2H] + .

[1114] Step 4: Synthesis of compound 129

[1115] Compound 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 to be complete by LCMS. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 37.6 mg of a white powder, namely compound 129.

[1116] ESI-MS m / z:585.2 1 / 2[M+2H] + . 1 H 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).

[1117] 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)pyrrolo[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

[1118] Step 1: Synthesis of compound 130-1

[1119] M29 (800.0 mg), 1-Boc-4-ethynylpiperidine (476.7 mg), anhydrous copper sulfate (251.7 mg), and sodium ascorbate (902.5 mg) were dissolved in a mixture of THF / tert-butyl alcohol / water (10 / 10 / 10 mL) and allowed to react at room temperature for 3 hours. LCMS monitored the reaction completion. DCM (30 mL) was added to the reaction solution, which was washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 800.0 mg of a yellow solid, Compound 130-1. ESI-MS m / z: 666.3 [M+H] + .

[1120] Step 2: Synthesis of compound 130-2

[1121] 130-1 (800.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. The reaction was monitored by LCMS for completion. The reaction solution was directly concentrated and 1 M NaOH solution was added until the pH of the reaction solution reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 577.0 mg of a white solid, i.e., compound 130-2. ESI-MS m / z: 566.3 [M+H] + .

[1122] Step 3: Synthesis of compound 130-3

[1123] 130-2 (577.0 mg) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (217.5 mg) were dissolved in methanol (10 mL). Zinc chloride solution (1.53 mL / 1 M in Et2O) was added and the mixture was allowed to react at 40°C for 1 hour. Sodium cyanoborohydride (192.3 mg) was then added and the mixture was allowed to react at 40°C for 10 minutes. The reaction was monitored for completion by LCMS. Saturated sodium bicarbonate solution (5.0 mL) was added to quench the reaction. DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 356.0 mg of a white solid, compound 130-3. ESI-MS m / z: 764.1 [M+H] + .

[1124] Step 4: Synthesis of compound 130-4

[1125] 130-3 (356.0 mg) was added to DCM (5 mL) and TFA (2 mL) and allowed to react at room temperature for 10 minutes. The reaction was monitored by LCMS for completion. The reaction solution was directly concentrated and 1 M NaOH solution was added until the pH of the reaction solution reached 8. DCM (20 mL) was added to the reaction solution, and the organic phase was collected and washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 198.0 mg of a white solid, namely compound 130-4. ESI-MS m / z: 664.1 [M+H] + .

[1126] Step 5: Synthesis of compound 130-5

[1127] Compound 130-4 (100.0 mg) and M28 (134.2 mg) were dissolved in methanol (10 mL), and zinc chloride solution (0.25 mL / 1 M in Et2O) was added. The mixture was reacted at 40°C for 1 hour, followed by sodium cyanoborohydride (31.8 mg) and 60°C for 12 hours. The reaction was monitored for completion by LCMS. The reaction was quenched by the addition of saturated sodium bicarbonate solution (5.0 mL). DCM (20 mL) was added to the reaction solution, and the organic phase was collected, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 90.0 mg of a white solid, compound 130-5. ESI-MS m / z: 621.3 1 / 2 [M+2H] + .

[1128] Step 6: Synthesis of compound 130

[1129] 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 by LCMS to completion. The reaction solution was directly concentrated and subjected to preparative liquid separation to obtain 41.2 mg of white powder, namely compound 130.

[1130] 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).

[1131] Example 131: Synthesis of (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

[1132] Step 1: Synthesis of compound 131-1

[1133] Compound M29 (100.0 mg) was added to a 25 mL single-necked flask and dissolved in THF (2 mL). 1-Boc-4-ethynylpiperidine (55.0 mg), copper sulfate (35.2 mg), water (2 mL), tert-butyl alcohol (2 mL), and sodium ascorbate (160.0 mg) were added and reacted at room temperature for 0.5 h. The reaction solution was evaporated to dryness. Column chromatography (DCM:MeOH = 12:1) was used to separate and purify the product to obtain 104.2 mg of a light yellow solid, compound 131-1. ESI-MS m / z: 666 [M+H] +

[1134] Step 2: Synthesis of compound 131-2

[1135] Compound 131-1 (104.2 mg) was added to a 25 mL single-necked flask and dissolved in HCl in dioxane (5 mL). Methanol (1 mL) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was evaporated to dryness, and 5 mL of saturated sodium bicarbonate solution was added to the reaction solution. The pH of the solution was adjusted to 7-8, and the solution was extracted with dichloroisopropanol. 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] +

[1136] Step 3: Synthesis of compound 131-3

[1137] Compound 13-2 (79.0 mg) was added to a 25 mL single-necked flask and dissolved in MeOH (3 mL). M28 (100.0 mg) and 1 M ZnCI2 / THF solution (0.1 mL) were added. The mixture was heated to 40°C and allowed to react for 2 h. NaBH3CN (35.2 mg) was then added and allowed to react overnight. The reaction solution was evaporated to dryness. Column chromatography (DCM:MeOH = 10:1) was used to separate and purify the mixture to obtain 108.2 mg of a light yellow solid, compound 131-3. ESI-MS m / z: 572 1 / 2 [M+2H] +

[1138] Step 4: Synthesis of compound 131

[1139] Compound 131-3 (108.2 mg) was added to a 25 mL single-necked vial and dissolved in DCM (2 mL). TFA (2 mL) was added and the mixture was allowed to react at room temperature for 1 h. The reaction solution was evaporated to dryness, and 5 mL of saturated sodium bicarbonate solution was added to adjust the pH to 7-8. The solution was then extracted with dichloroisopropanol. The organic phase was dried over anhydrous sodium sulfate and the product was isolated by reverse-phase chromatography (CH3CN / H2O = 30%-55%) to obtain 67.6 mg of a white solid, compound 131.

[1140] ESI-MS m / z:550.1 1 / 2[M+2H] +

[1141] 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).

[1142] Example 132: Synthesis of (2S,4R)-1-((S)-2-(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)methyl-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl)-4-hydroxy-N-((S)-1-(4-(4-m...

Claims

1. A compound having the structure of FLM, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The F is a KRAS protein binding fragment represented by general formula (A); The X is selected from -O- or Said Indicates whether the bonds in the ring are single or double bonds; X4 is CR8, C(R8)2, O, N or NR8; R8 is independently selected from H, hydroxyl, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-14 The cycloalkyl group is optionally further substituted with one or more R a replace; Said X5 is selected from C, CH or N; The X6 is selected from CR 14 , C(R 14 )2, O, N or NR 14 ; R 14 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the hydroxyl group, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-14 The cycloalkyl group is optionally further substituted with one or more R a replace; The R6 is absent or selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; R9 is selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; wherein the amino group, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a replace; The R 10 Absent or selected from -O- or -NR 11 -; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; The R7 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more R a replace; The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, fused, spirocyclic or bridged ring, optionally further substituted by one or more R a substituted, and the 3-14 membered heterocyclic group is not m, n are each independently selected from 0, 1, 2, 3, 4 or 5; The L is a connecting unit connecting F and M; The L is selected from in, The G ring or D ring is independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; The E's are each independently absent or selected from -O-, -NH-, or -NCH3-; The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; wherein the 3-7 membered N-containing heterocyclic groups are optionally further substituted by one or more R a replace; The R 15 , R 16 Each is independently selected from H, halogen, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; Or, R 15 , R 16 Together with the atoms to which it is attached, it forms C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; The n1, n2, n3, and n4 are each independently selected from integers of 0 to 10; preferably 0, 1, 2, 3 or 4; The M is selected from the VHL binding fragment represented by general formula (III), (IV) or (V); Said X1 is selected from C, CH or N; Said X2 is selected from C, CH or N; Said X3 is selected from N, NH, O or S; The R1 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen or cyano; preferably methyl, ethyl, F or cyano; R2 is selected from H or C 1-6 Alkyl; preferably H or methyl; The R3 is selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) n5 N(R 17 )2, -(CH2) n5 -CO-OR 17 or -(CH2) n5 -CO-N(R 17 ) 2, said R 17 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; said n5 is selected from 0, 1, 2 or 3; said R3 is preferably H, methyl or hydroxymethyl; The R4 is selected from or -NH-; R5 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Haloalkoxy; The R 12 Selected from The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -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)2R b , -C 0-3 Alkylene-SR b , -C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b , -C 0-3 Alkylene-C(=O)OR b , -C 0-3 Alkylene-C(=O)N(R b 2. C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 0-3 Alkylene, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxy, amino, oxo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 or two R b Together with its co-attached atoms, it forms C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl C 1-6 Haloalkoxy or C 1-6 Haloalkyl substitution.

2. The compound according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The F is a KRAS protein binding fragment represented by general formula (A); The X is selected from -O- or Said Indicates whether the bonds in the ring are single or double bonds; X4 is CR8, C(R8)2, O, N or NR8; R8 is independently selected from H, hydroxyl, oxo, halogen, cyano Base, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace; Said X5 is selected from C, CH or N; The X6 is selected from CR 14 , C(R 14 )2, O, N or NR 14 ; R 14 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace; The R6 is absent or selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; R9 is selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a replace; The R 10 Absent or selected from -O- or -NR 11 -; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; The R7 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more R a replace; The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, fused, spirocyclic or bridged ring, optionally further substituted by one or more R a substituted, and the 3-14 membered heterocyclic group is not m, n are each independently selected from 0, 1, 2, 3, 4 or 5; The L is a connecting unit connecting F and M; The L is selected from in, The G ring or D ring is independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; Each of the E's is independently selected from -O-, -NH- or -NCH3-; The n1, n2, and n3 are each independently selected from an integer of 0-10, preferably 0, 1, 2, 3 or 4; The M is selected from the VHL binding fragment represented by general formula (III) or (IV); Said X1 is selected from C, CH or N; Said X2 is selected from C, CH or N; Said X3 is selected from N, NH, O or S; The R1 is selected from H, C 1-6 Alkyl, halogen or cyano; preferably methyl, ethyl, F or cyano; R2 is selected from H or C 1-6 Alkyl; preferably H or methyl; The R3 is selected from H, C 1-6 Alkyl or C 1-6 Hydroxyalkyl; preferably H, methyl or hydroxymethyl; The R4 is selected from or -NH-; The R 12 Selected from The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -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)2R b , -C 0-3 Alkylene-SR b , -C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b , -C 0-3 Alkylene-C(=O)OR b , -C 0-3 Alkylene-C(=O)N(R b 2. C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 or two R b The atoms connected to it form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

3. The compound according to claim 1 or 2, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The F is a KRAS protein binding fragment represented by general formula (I) or (II); Said Indicates whether the bonds in the ring are single or double bonds; X4 is CR8, C(R8)2, O, N or NR8; R8 is independently selected from H, hydroxyl, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Halogenation Alkoxy or C 3-14 Cycloalkyl; wherein the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace; Said X5 is selected from C, CH or N; The X6 is selected from CR 14 , C(R 14 )2, O, N or NR 14 ; R 14 Each independently selected from H, hydroxy, oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -SC 1-6 Alkyl, -C 0-3 Alkylene-C 2-4 Alkenyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-14 Cycloalkyl; wherein the C 3-14 Cycloalkyl, C 1-6 The alkyl group is optionally further substituted with one or more R a replace; The R6 is absent or selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; R9 is selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 2-6 Alkenyl, C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 The cycloalkyl group is optionally further substituted with one or more R a replace; The R 10 Absent or selected from -O- or -NR 11 -; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 1-6 aminoalkyl; The R7 is selected from C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more R a replace; The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic, fused, spirocyclic or bridged ring, optionally further substituted by one or more R a substituted, and the 3-14 membered heterocyclic group is not m, n are each independently selected from 0, 1, 2, 3, 4 or 5; The L is a connecting unit connecting F and M; The L is selected from in, The G ring or D ring is independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; Each of the E's is independently selected from -O-, -NH- or -NCH3-; The n1, n2, and n3 are each independently selected from an integer of 0-10, preferably 0, 1, 2, 3 or 4; The M is selected from the VHL binding fragment represented by general formula (III) or (IV); Said X1 is selected from C, CH or N; Said X2 is selected from C, CH or N; Said X3 is selected from N, NH, O or S; The R1 is selected from H, C 1-6 Alkyl, halogen or cyano; preferably methyl, ethyl, F or cyano; R2 is selected from H or C 1-6 Alkyl; preferably H or methyl; The R3 is selected from H, C 1-6 Alkyl or C 1-6 Hydroxyalkyl; preferably H, methyl or hydroxymethyl; The R4 is selected from or -NH-; The R 12 Selected from The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -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)2R b , -C 0-3 Alkylene-SR b , -C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b , -C 0-3 Alkylene-C(=O)OR b , -C 0-3 Alkylene-C(=O)N(R b 2. C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 or two R b Together with its co-attached atoms, it forms C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

4. A compound according to any one of claims 1 to 3, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from or -NH-.

5. The compound according to any one of claims 1 to 3, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is selected from 6. The compound according to any one of claims 1 to 5, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a monocyclic ring and is optionally further substituted by one or more R a replace.

7. The compound according to claim 6, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from 8. The compound according to any one of claims 1 to 5, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a spiro ring and is optionally further substituted by one or more R a replace.

9. The compound according to claim 8, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from 10. The compound according to any one of claims 1 to 5, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a condensed ring, and is optionally further substituted by one or more R a replace.

11. The compound according to claim 10, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from 12. The compound according to any one of claims 1 to 5, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is C 3-14 Cycloalkyl or 3-14 membered heterocyclic group, the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is a bridged ring and is optionally further substituted by one or more R a replace.

13. The compound according to claim 12, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from 14. A compound according to any one of claims 1 to 5, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from 15. The compound according to any one of claims 1 to 14, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The R7 is selected from C 6-18 Aryl or 5-18 membered heteroaryl; wherein the C 6-18 The aryl or 5-18 membered heteroaryl group is optionally further substituted with one or more R a Substitution; said R a Each is independently selected from H, halogen, hydroxyl, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Olefins.

16. A compound according to any one of claims 1 to 15, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The R7 is selected from It is stated Optionally further represented by one or more a Substitution; said R a Each is independently selected from H, halogen, hydroxyl, amino, cyano, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Haloalkyl or C 2-6 Olefins.

17. A compound according to any one of claims 1 to 16, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The R7 is selected from 18. A compound according to any one of claims 1 to 17, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The F is selected from Among them, R7, R8, R9, R 11 , R 14 The definition is as defined in any one of claims 1 to 17; The K is selected from 19. The compound according to claim 18, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The K is selected from 20. The compound according to any one of claims 1 to 19, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The F is selected from 21. The compound according to claim 20, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The F is selected from 22. A compound according to any one of claims 1 to 21, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The G ring or D ring in L is independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with halogen or C 1-3 Alkyl substitution; The C 6-14 The aryl group is preferably The 5-14 membered heteroaryl group is preferably selected from The 3-14 membered heterocyclic group is preferably selected from The C 3-14 The cycloalkyl group is preferably selected from 23. A compound according to any one of claims 1 to 21, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The L is selected from the following structures: Wherein, n1 and n2 are each independently selected from integers of 0-10, preferably 0, 1, 2 or 3.

24. A compound according to any one of claims 1 to 23, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The M is selected from 25. The compound according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The F is a KRAS protein binding fragment represented by the general formula (VI); The R 14 is selected from halogen; The L is a connecting unit connecting F and M; the L is selected from in, The G ring and the D ring are each independently selected from C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 6-14 Aryl, 5-14 membered heteroaryl, C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; the 3-7 membered N-containing heterocyclic groups are optionally further substituted by one or more R a replace; The E's are each independently absent or selected from -O-, -NH-, or -NCH3-; The R 15 , R 16 Each is independently selected from H, halogen, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; Or, R 15 , R 16 Together with the atoms to which it is attached, it forms C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; The n1, n2, n3, and n4 are each independently selected from an integer of 0 to 10, preferably 0, 1, 2, 3 or 4; The M is selected from the VHL binding fragment represented by the general formula (V); Wherein, X1 is selected from C, CH or N; Said X2 is selected from C, CH or N; Said X3 is selected from N, NH, O or S; The R1 is selected from H, C 1-6 Alkyl, halogen or cyano; preferably methyl, ethyl, F or cyano; The R2 is selected from H or C 1-6 Alkyl; preferably H or methyl; The R3 is selected from H, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -(CH2) n5 N(R 17 )2, -(CH2) n5 -CO-OR 17 or -(CH2) n5 -CO-N(R 17 ) 2, said R 17 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; The n5 is selected from 0, 1, 2 or 3; The R4 is selected from or -NH-; R5 is selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl; The R a are independently selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -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)2R b , -C 0-3 Alkylene-SR b , -C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b , -C 0-3 Alkylene-C(=O)OR b , -C 0-3 Alkylene-C(=O)N(R b 2. C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl); wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b replace; Each R b are independently H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, C 1-6 Alkyl or C 1-6 or two R b The atoms connected to it form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl or 5-18 membered heteroaryl is optionally further substituted with one or more halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Haloalkyl substitution.

26. The compound according to claim 25, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is 27. The compound according to claim 25, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is 28. The compound according to claim 25, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The R4 is -NH-.

29. A compound according to any one of claims 25 to 28, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The D rings are each independently selected from 5-6 membered nitrogen-containing heteroaryl groups; wherein the 5-6 membered nitrogen-containing heteroaryl groups are optionally further substituted with one or more R a replace; The G rings are each independently selected from a 3-14 membered heterocyclic group; wherein the 3-14 membered heterocyclic group is optionally further substituted by one or more R a replace; The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; wherein the 3-7 membered N-containing heterocyclic groups are optionally further substituted by one or more R a replace; The E's are each independently absent or selected from -O-, -NH-, or -NCH3-; The R 15 , R 16 Each independently selected from H, halogen, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy; Alternatively, the R 15 , R 16 Together with the atoms to which it is attached, it forms C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; wherein the C 3-14 The cycloalkyl or 3-14 membered heterocyclic group is optionally further substituted with one or more R a replace; The n1, n2, n3, and n4 are each independently selected from an integer of 0-10, preferably 0, 1, 2, 3 or 4.

30. A compound according to any one of claims 25 to 29, in the form of a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The D rings are each independently selected from 5-6 membered nitrogen-containing heteroaryl groups, and the 5-6 membered nitrogen-containing heteroaryl groups are selected from The 5-6 membered nitrogen-containing heteroaryl group is optionally further substituted with one or more R a Substitution; said R a is selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

31. A compound according to any one of claims 25 to 30, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The G rings are each independently selected from 3-14 membered heterocyclic groups, the 3-14 membered heterocyclic groups are optionally further substituted by one or more R a replace; The 3-14 membered heterocyclic group is preferably selected from The R a is selected from H, hydroxy, amino, oxo, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy.

32. A compound according to any one of claims 25 to 31, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The A rings are each independently selected from 3-7 membered N-containing heterocyclic groups; wherein the 3-7 membered N-containing heterocyclic groups are optionally further substituted with one or more halogens or C 1-3 Alkyl substitution.

33. The compound according to claim 32, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The 3-7 membered N-containing heterocyclic group is selected from 34. A compound according to any one of claims 25 to 33, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The E is -O-.

35. A compound according to any one of claims 25 to 33, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The E is -NH-.

36. A compound according to any one of claims 25 to 33, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The E is -NCH3-.

37. A compound according to any one of claims 25 to 33, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The E is 38. A compound according to any one of claims 25 to 33, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The E is 39. A compound according to any one of claims 25 to 38, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The R3 is selected from H, methyl, hydroxymethyl, -CH2-CO-O-CH3, -CH2-N(CH3)2 or -CH2-CO-NH-CH3.

40. A compound according to any one of claims 25 to 39, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The L is selected from 41. A compound according to any one of claims 25 to 39, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The L is selected from 42. A compound according to any one of claims 25 to 41, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The M is selected from 43. The compound according to claim 1, or its tautomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, characterized in that: The compound of the FLM structure is selected from the following compounds:

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43, or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

45. Use of a compound according to any one of claims 1 to 43, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44 in the preparation of a medicament for regulating KRAS protein ubiquitination and degradation in a subject.

46. ​​Use of a compound according to any one of claims 1 to 43, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 44, in the preparation of a medicament for treating and / or preventing a disease mediated by or dependent on the KRAS protein, wherein the disease mediated by the KRAS protein is preferably a tumor.

47. The use according to claim 46, 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 lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

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