Prodrug compound of cbl-b inhibitor

Abstract

Disclosed in the present invention is a prodrug compound of a Cbl-b inhibitor. The compound has excellent Cbl-b inhibitory activity and pharmacokinetic characteristics (particularly for oral administration), and is expected to have significant research and application value in the prevention and treatment of Cbl-b activity-related diseases.

Description

A prodrug compound of a Cbl-b inhibitor Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, specifically to a prodrug compound of a Cbl-b inhibitor, its preparation method, and its application. Background Technology

[0002] The Casitas B-cell lymphoma (Cbl) protein family is a group of E3 ubiquitin ligases with a RING (Really Interesting New Gene) finger domain, including three members: Cbl, Cbl-b, and Cbl-C. Cbl-b has been identified as a key regulator of adaptive immune responses. Cbl-b is crucial for establishing T cell activation thresholds and regulating peripheral T cell tolerance through various mechanisms. Recent studies have shown that Cbl-b also regulates innate immune responses and plays a key role in host defense against pathogens and anti-tumor immunity. (See, for example, Tang R, Langdon WY, Zhang J. Regulation of immune responses by E3 ubiquitin ligase Cbl-b[J]. Cellular Immunology, 2018.) These studies suggest that targeting Cbl-b may represent a potential therapeutic strategy, such as using Cbl-b inhibitors to treat human immune-related diseases, such as autoimmune diseases, infections, and tumors. However, there are currently few reports on Cbl-b inhibitors. Summary of the Invention

[0003] To overcome the shortcomings of the prior art, the inventors prepared a heterocyclic compound (especially a pyridone pentane heterocyclic compound) that can be used as a Cbl-b inhibitor (as described in patent application PCT / CN2024 / 073346). Based on this, the inventors further studied and obtained the prodrug compound of the inhibitor, which has better pharmacokinetic properties.

[0004] Specifically, the technical solution of the present invention is as follows:

[0005] In a first aspect of the present invention, a compound or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof is provided, said compound having the following structure:

[0006] in,

[0007] Ring A is an aromatic ring or a heteroaromatic ring;

[0008] R A It is one or more independent substituents on the ring, each independently selected from the following groups: H, D, L1 is selected from: single bond, C(O), Cl-C 10 Alkylene, C(R3R4), L2 are selected from: single bond, C1-C 10 Alkylene, O, S, C(R3R4), N(R5) R 001 Selected from: single bond, C1-C 10 Alkylene; R 002 Selected from: single bond, C1-C 10 Alkylene, O, S, N(R2), S(O)2, S(O)2N(R2), S(O), S(O)N(R2), C(O), C(O)O, C(O)N(R2), OC(O), OC(O)N(R2), N(R2)C(O)O, N(R2)C(O), N(R2)S(O)2, R 003 Selected from: hydroxyl, H, D, halogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic group); wherein the H on the alkylene, alkyl, haloalkyl, alkenyl, ynyl, cycloalkyl, aryl, and 4-10 heterocyclic groups is optionally replaced by one or more independent R groups;

[0009] R2 is selected from: H, D, Cl-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl);

[0010] R3 and R4 are independently selected from the following groups: H, D, halogen, cyano, nitro, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); wherein the H on the alkylene, haloalkyl, alkyl, alkenyl, ynyl, cycloalkyl, aryl, and 4-10 heterocyclic groups is optionally replaced by one or more independent R groups;

[0011] Alternatively, R3 and R4 together with the carbon atom they are connected to form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more separate R groups;

[0012] The J ring is a 3-10 membered nitrogen-containing heterocycle (the J ring is connected to the L2 ring via a carbon atom), and the J ring is optionally substituted by one or more groups selected from the following: hydroxyl, oxo (=O), halogen, cyano, nitro, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10Alkamidoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylamidoalkyl groups is optionally substituted by one or more independent R groups;

[0013] The carbon atom connecting the J ring and L2 is optionally replaced by D, halogen, cyano, nitro, or C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); wherein the H on the alkylene, haloalkyl, alkyl, alkenyl, ynyl, cycloalkyl, aryl, and 4-10 heterocyclic groups is optionally replaced by one or more independent R groups;

[0014] R5 and R6 are independently selected from the following groups: hydroxyl, halogen, H, D, C. 1-10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); wherein the alkylene, alkyl, cycloalkyl, aryl, and 4-10 heterocyclic groups are each optionally substituted by one or more independent substituents selected from the following: halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic), -(C0-C6 alkylene)-O(C0-C 10 Alkyl), -(C0-C6 alkylene)-O(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-O(3-10 membered heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, aryl, 4-10 membered heterocyclic, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylaminoalkyl groups is optionally substituted by one or more independent R groups;

[0015] Alternatively, R5 and R6 together with the nitrogen atom they are connected to form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independent substituents selected from: oxo (=O), halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C)10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl is optionally substituted by one or more independent R groups; or the H on the heterocyclic group formed by R5 and R6 together with the nitrogen atom they are connected to is substituted by one or more R groups. p Group substitution;

[0016] R7 is one or more independent substituents on ring A, each independently selected from the following groups: H, D, halogen, cyano, nitro, ... Among them, R 701 Selected from: single bond, C 1-10 Alkylene; R 702 Selected from: single bond, C 1-10 Alkylene, O, S, N(R) 704 S(O)2, S(O)2N(R) 704 ), S(O), S(O)N(R) 704 ), C(O), C(O)O, C(O)N(R) 704 ), OC(O), OC(O)N(R) 704 ), N(R 704 C(O)O、N(R) 704 C(O), N(R) 704 S(O)2, R 703 Selected from: H, D, halogen, cyano, nitro, C 1-10 Alkyl, C1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R 704 Selected from: H, D, C 1-10 Alkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, haloalkyl, and 4-10 membered heterocyclic groups is optionally substituted by one or more independent R groups;

[0017] R8 and R9 are independently selected from the following groups: H, D, halogen, cyano, nitro, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkamidoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylamidoalkyl groups is optionally substituted by one or more independent R groups;

[0018] Alternatively, R8 and R9 together with their commonly attached carbon atom form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more independent substituents selected from: oxo (=O), (=alkylene), hydroxyl, halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl is optionally substituted by one or more independent R groups; or the H on the cycloalkyl or heterocyclic group formed by R8 and R9 together with the carbon atom they are connected to is substituted by one or more R groups. p Group substitution;

[0019] W represents a single bond. Or S; where R 15 and R 16 Independently selected from: H, D, halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkamidoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylamidoalkyl groups is optionally substituted by one or more independent R groups;

[0020] Or, R 15 and R 16 Together with the carbon atom it is attached to, it forms a cycloalkyl or heterocyclic group, wherein the H on the cycloalkyl or heterocyclic group is optionally substituted by one or more independent substituents selected from the following: oxo (=O), (=alkylene), halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl group is optionally substituted by one or more separate R groups; or the R 15 and R 16 The H atom on the cycloalkyl or heterocyclic group formed together with the carbon atom it is attached to is affected by one or more R atoms. p Group substitution;

[0021] Or, R 15 R9, together with the carbon atom in between, forms a cycloalkyl, aryl, or heterocyclic group, wherein the H atom on the cycloalkyl, aryl, or heterocyclic group is optionally substituted by one or more independent substituents selected from: oxo (=O), (=alkylene), halogen, cyano, nitro, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl group is optionally substituted by one or more separate R groups; or the R 15 R9, together with the carbon atom in the middle, forms a cycloalkyl, aryl, or heterocyclic group. The H atom on the group is formed by one or more R atoms. p Group substitution;

[0022] Y1, Y2, Y3, and Y4 are independently selected from: C, N, O, and S (provided that there are two O atoms, two S atoms, or the O and S atoms are not directly connected).

[0023] R 10 For one or more independent substituents on the ring, each R 10 Independently selected from the following groups: H, D, oxo (=O), halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl group is optionally substituted by one or more separate R groups; or at least one R group. 10 With R p Definition of identical groups;

[0024] R 11 Selected from: H, D, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic group); wherein the alkylene, alkyl, alkenyl, ynyl, cycloalkyl, aryl, and 4-10 membered heterocyclic group are each optionally substituted by one or more independent R groups; or R 11 With R p Definition of identical groups;

[0025] The R pThe group comprises at least one of the following: ester bond C(O)O, thioester bond SC(O), phospholipid bond OPO, OP(O)(OR”')(NR”'), HOP(O)OH, OP(O)O, P(O)O3 phosphodiester bond, phosphite bond P(OR”'), thiophospholipid bond P(S)O3, peptide bond C(O)NH, ether bond R”'OR”', thioether bond R”'SR”', silane ether bond SiOSi, thiosilane ether bond SiSSi, carbonate bond OC(O)O, thiourea bond HNC(S)NH, amide bond C(O)NH, thioamide bond C(S)NH, carbamate bond OC(O)NH, and urea bond HNC(O)NH, wherein the H on each of the groups is optionally replaced by one or more independent R groups; or phospholipid bonds OPO, OP(O)(OR”')(NR”'), HOP(O)OH, OP(O)O, etc. 、 The P and O atoms on the phosphodiester bond P(O)O3, the phosphite bond P(OR”'), and the thiophospholipid bond P(S)O3 together form a cycloalkyl group, which is optionally substituted by one or more independent R groups;

[0026] Each R group is independently selected from: hydroxyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, D, halogen, cyano, nitro. L4 and L5 are independently selected from: single bond, O, S, N(R”'), S(O)2, S(O)2N(R”'), S(O), S(O)N(R”'), C(O), C(O)O, C(O)N(R”'), OC(O), OC(O)N(R”'), N(R”')C(O)O, N(R”')C(O), N(R”')S(O)2, SC(O) (thioester bond), OPO, OP(O) (OR”') (NR”'), HOP(O)OH, P(O) )O3 (phosphodiester bond), P(OR”') (phospholipid bond), P(S)O3 (thiophospholipid bond), C(O)NH (peptide bond), R”'OR”' (ether bond), R”'SR”' (thioether bond), SiOSi (silane ether bond), SiSSi (thiosilane ether bond), OC(O)O (carbonate bond), HNC(S)NH (thiourea bond), C(O)NH (amide bond), C(S)NH (thioamide bond), OC(O)NH (carbamate bond), HNC(O)NH (urea bond),

[0027] Each R' is independently selected from: single bond, C1-C 10 Alkylene, C2-C 10 alkenyl, phenylene, C3-C 10 Cycloalkylene, 4-10 membered heterocyclic alkylene;

[0028] Each R is independently selected from: H, D, -CD3, halogen, cyano, nitro, C1-C10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 cycloalkyl groups, 4-10 membered heterocyclic groups;

[0029] Each R' is independently selected from: H, D, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups.

[0030] In some embodiments of the present invention, R p The group is -(C0-C6 alkylene)-XYR p1 Where X is selected from: single bond, -O-, -S-, -SS-, -Si(R) p3 )2-、-N(R p3 -, Y is selected from: single bond, -C(O)-, -C(S)-, -C(O)O-, -C(O)S-, -C(O)N(R) p3 )-、-P(OR p2 )O-、-P(O)(OR p2 )-、-P(O)(OR p2 )O-、-P(O)(OR p2 )N(R p3 )-、-P(O)(NHR p2 )N(R p3 )-、-P(S)(OR p2 )-、-P(S)(OR p2 )O-、-P(S)(OR p2 )N(R p3 )-、 -N=C(R p3 )-, R p1 Selected from: H, C1-C 30 Alkyl, C2-C 30 alkenyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic groups), amino acid residues, polypeptide residues, monosaccharide residues, polysaccharide residues, ethylene glycol structural moieties; R p2 and R p3 Selected independently from: H, D, C 1-10Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); or R p1 With R p2 Together with the atoms they are attached, they form a carbocyclic or heterocyclic ring, wherein the hydrogen atoms on the carbocyclic or heterocyclic ring are optionally substituted by one or more independent substituents selected from the following: oxo (=O), (=alkylene), halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10Alkamidoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylamidoalkyl groups is optionally replaced by one or more independent R groups or amino acid residues, polypeptide residues, monosaccharide residues, polysaccharide residues, or ethylene glycol structural portions.

[0031] In some embodiments of the present invention, R p The group is selected from: -(C0-C2 alkylene)-OC(O)-R p1 -(C0-C2 alkylene)-OC(O)N(R) p3 )-R p1 -(C0-C2 alkylene)-C(O)N(R) p3 )-R p1 -(C0-C2 alkylene)-OP(O)(OR p2 OR p1 -(C0-C2 alkylene)-OP(O)(OR p2 )N(R p3 )-R p1 -(C0-C2 alkylene)-P(O)(OR p2 OR p1 -(C0-C2 alkylene)-P(O)(OR p2 )-R p1 -(C0-C2 alkylene)-P(O)(OR p2 )N(R p3 )-R p1 ; wherein the H on each of the alkylene groups is optionally substituted by a group selected from the following: D, -CD3, halogen, C1-C6 alkyl, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, amino, C1-C6 aminoalkyl, C1-C6 alkylaminoalkyl.

[0032] In some embodiments of the present invention, R p The functional group is -(C0-C2 alkylene)-OC(O)-R p1 -(C0-C2 alkylene)-C(O)OR p1 or -(C0-C2 alkylene)-OC(O)N(R) p3 )-R p1 R p1 Selected from: H, C1-C 20 Alkyl, C2-C 20 alkenyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10Aryl), -(C0-C6 alkylene)-(4-15 membered heterocyclic groups), oligomeric glycol structural moieties (such as...) m is an integer from 1 to 10; R p3 Selected from: H, C1-C 20 Alkyl; wherein the H on the alkylene, alkyl, cycloalkyl, aryl, or 4-15 membered heterocyclic group is optionally substituted by a group selected from: D, -CD3, halogen (e.g., -Cl), C1-C 20 Alkyl, -OH, -O (C1-C) 20 Alkyl groups (e.g.) -S(C1-C) 20 Alkyl groups (e.g.) ), -COO(C0-C 20 Alkyl group), -COO (C6-C) 10 aryl), -COO(C7-C 20 arylalkyl), -OC(O)(C0-C 20 Alkyl), -OC(O)(C6-C 10 Aryl), -OC(O)(C7-C 20 (arylalkyl).

[0033] In some embodiments of the present invention, R p1 Selected from: H, C1-C 20 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 Cycloalkyl), phenyl, naphthyl, benzyl, 4-15 member nitrogen-containing heterocyclic groups (such as 5-10 member nitrogen-containing saturated heterocyclic groups, 5-10 member nitrogen-containing heteroaryl groups), Wherein, the H on the alkyl, alkylene, cycloalkyl, phenyl, naphthyl, benzyl, and nitrogen-containing heterocyclic groups is optionally substituted by groups selected from the following: C1-C 12 Alkyl, -OH, -O (C1-C) 10 alkyl), -S(C1-C 10 alkyl), -COOH, -COO(C1-C 10 Alkyl), -COO (phenyl), -COO (benzyl), -OC(O) (C1-C) 10 Alkyl), -OC(O) (phenyl), -OC(O) (benzyl).

[0034] In some embodiments of the present invention, R p3 Selected from: H, C1-C 20 alkyl.

[0035] In some embodiments of the present invention, R p1 Selected from:

[0036] In some embodiments of the present invention, R p The radical group is selected from:

[0037] In some embodiments of the present invention, R p for Among them, R p1a Selected from: C4-C 20 Alkyl, R p1b Selected from: H, C1-C 20 Alkyl, C2-C 20 alkenyl, -(C0-C3 alkylene)-(C3-C 10 cycloalkyl), -(C0-C3 alkylene)-(C6-C 10 (aryl); or, R p1a and R p1b Together with the carbon atoms they are connected to, they form a carbocyclic ring; wherein the H atoms on the alkyl, alkenyl, alkylene, cycloalkyl, aryl, and carbocyclic rings are each optionally substituted with groups selected from the following: C1-C 12 Alkyl, halogen, C1-C6 haloalkyl, -OH, C1-C3 alkoxy, amino, C1-C6 alkylamine -COOH, -COO (C1-C3 alkyl groups).

[0038] In some embodiments of the present invention, R p1a Selected from: C4-C 14 Straight-chain alkyl groups, for example

[0039] In some embodiments of the present invention, R p1a for

[0040] In other embodiments of the invention, R p1a for

[0041] In some embodiments of the present invention, R p1b Selected from:

[0042] In some embodiments of the present invention, R p for More specifically, R p Selected from:

[0043] In some embodiments of the present invention, R p -(C0-C2 alkylene)-OP(O)(OR p2 OR p1 R p1 and R p2 Independently selected from: H, C1-C 20 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkylene, alkyl, cycloalkyl, aryl, phenyl, and 4-10 membered heterocyclic groups is optionally substituted by groups selected from the following: D, -CD3, halogen (e.g., -Cl), C1-C6 alkyl, -OH, C1-C6 alkoxy (e.g., -C1-C6 alkoxy group). ), -COO (C0-C6 alkyl). Specifically, R p1 and R p2 Independently selected from: H, C1-C 10 Alkyl, phenyl, naphthyl, benzyl; wherein the H on the alkyl, alkoxy, phenyl, naphthyl, and benzyl groups is optionally substituted by a group selected from the following: halogen (e.g., -Cl), C1-C3 alkyl, -OH, C1-C3 alkoxy, -COO (C0-C6 alkyl).

[0044] In some embodiments of the present invention, R p The radical group is selected from:

[0045] In some embodiments of the present invention, R p Group is Where n is an integer between 0 and 2 (e.g., 0, 1, 2), z is an integer between 0 and 2 (e.g., 0 or 1), and R p4 To R p9 Independently selected from: H, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C6-C 10Aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkylene, alkyl, aryl, and 4-10 membered heterocyclic groups is optionally substituted by groups selected from: D, -CD3, halogen (e.g., -Cl), C1-C6 alkyl, -OH, C1-C6 alkoxy (e.g., -Cl), -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -OH, -C1-C6 alkoxy, -C1-C6 alkyl ... ), -COO (C0-C6 alkyl). Specifically, R p4 To R p9 Independently selected from: H, C1-C6 alkyl, phenyl, naphthyl, pyridyl; wherein the H on the alkyl, phenyl, naphthyl, and pyridyl groups is optionally substituted by groups selected from: halogens (e.g., -Cl, Br), C1-C3 alkyl, -OH, C1-C3 alkoxy (e.g., ... ).

[0046] In some embodiments of the present invention, R p4 It is phenyl or pyridyl, which is optionally substituted with a group selected from: halogen (e.g., -Cl, Br), C1-C3 alkoxy group, etc. z is 1, R p5 To R p9 All are H.

[0047] In some embodiments of the present invention, R p The radical group is selected from:

[0048] In some embodiments of the present invention, R p Group is Where n is an integer from 0 to 2 (e.g., 0, 1, 2), R p2 To R p11 Independently selected from: H, C1-C 20 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkylene, alkyl, cycloalkyl, aryl, phenyl, and 4-10 membered heterocyclic groups is optionally substituted by groups selected from the following: D, -CD3, halogen (e.g., -Cl), C1-C6 alkyl, -OH, C1-C6 alkoxy (e.g., -C1-C6 alkoxy group). ), -COO (C0-C6 alkyl). Specifically, R p2 Selected from: H, C1-C 10 Alkyl, phenyl, naphthyl, benzyl; R p10 Selected from: H, C1-C10 Alkyl, phenyl, benzyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic alkyl; R p11 Selected from: H, C1-C6 alkyl, benzyl; wherein the H on the alkyl, phenyl, naphthyl, benzyl, cycloalkyl, heterocycloalkyl is optionally substituted by a group selected from: halogen (e.g. -Cl), C1-C3 alkyl, -OH, C1-C3 alkoxy, -COO (C0-C6 alkyl).

[0049] In some embodiments of the present invention, R p The radical group is selected from:

[0050] In some embodiments of the present invention, R p The group is -(C1-C2 alkylene)-OR p1 R p1 Selected from: H, C1-C6 alkyl groups. Specifically, R p It is -CH2-OH.

[0051] In some embodiments of the present invention, R p Group is

[0052] In some embodiments of the present invention, ring A is a benzene ring or a 5-6 membered heteroaromatic ring, for example... Especially the benzene ring.

[0053] In some embodiments of the present invention Selected from: in particular

[0054] In some embodiments of the present invention, R7 may be selected from: H, D, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C6 cycloalkyl), -(C0-C6 alkylene)-(4-6 membered heterocyclic), -C(O)(C1-C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)(C0-C6 alkyl), -N(C0-C6 alkyl)((C0-C6 alkylene)-(C 3-6 cycloalkyl)), -N(C) 0-6 Alkyl)((C 0-6 alkylene)-(4-6 membered heterocyclic)), -O-(C 0-6The terms -O-(C0-C6 alkylene)-(4-6 membered heterocyclic group), -S(O)2(C0-C6 alkylene), -S(O)2-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-6 membered heterocyclic group), -S(O)2N(C0-C6 alkyl)(C0-C6 alkyl), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(C3-C6 cycloalkyl)), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(4-6 membered heterocyclic group)). More specifically, the 4-6 membered heterocyclic group is a 4-6 membered saturated heterocyclic group, for example...

[0055] In some embodiments of the present invention, R7 is selected from: -H, D, -Cl, -CN, -COOH, -CONH2,

[0056] In one embodiment of the present invention, R7 is H.

[0057] In some embodiments of the present invention, R8 and R9 may be independently selected from: H, D, halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, etc. V' is selected from: single bond, O, n is 1, 2, or 3, R v01 'and R v02 'Independently selected from the following groups: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, C3-C6 cycloalkyl, 3 to 8-membered heterocyclic alkyl (e.g., 3, 4, 5, 6, 7, 8-membered heterocyclic alkyl containing O and / or N), or, R v01 'and R v02 Together with the carbon atom it is attached to, it forms a cycloalkyl or heterocyclic group; wherein the alkyl group is optionally substituted by one or more independent substituents selected from: halogen, cyano, nitro, hydroxy, C1-C6 alkoxy (e.g., ), amino, C1-C6 alkylamine (e.g. ), -S(O)2(C0-C6 alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-6 membered heterocyclic), -S(O)2N(C0-C6 alkyl)(C0-C6 alkyl), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(C3-C6 cycloalkyl)), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(4-6 membered heterocyclic)) (e.g. -C(O)(C0-C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl) (e.g.) More specifically, R8 and R9 can be independently selected from: H, D, F, -CH3, -CHF2, -CH2F, -CF3,

[0058] In some embodiments of the present invention, R8 is H, and R9 is selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl.

[0059] In other embodiments of the invention, R8 and R9 are independently selected from: halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups.

[0060] In some embodiments of the present invention, R8 and R9 are both methyl groups.

[0061] In other embodiments of the present invention, both R8 and R9 are H.

[0062] In other embodiments of the invention, R8 and R9 are both halogens (such as F).

[0063] In other embodiments of the invention, R8 is methyl and R9 is halogen (such as F).

[0064] In other embodiments of the present invention, R8 is H, and R9 is...

[0065] In some embodiments of the invention, R8 and R9 are formed together with the carbon atom they are commonly bonded to. W represents a single bond. Or S, where V is selected from: single bond, O, m is 1, 2, or 3, R v01 and R v02 Independently selected from the following groups: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 deuterated alkoxy, or, R v01 and Rv02 Together with the carbon atom it is attached to, it forms a cycloalkyl or heterocyclic group; wherein the alkyl group is optionally substituted by one or more independent substituents selected from: halogen, cyano, nitro, hydroxy, C1-C6 alkoxy (e.g., ), amino, C1-C6 alkylamine (e.g. ), -S(O)2(C0-C6 alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-6 membered heterocyclic), -S(O)2N(C0-C6 alkyl)(C0-C6 alkyl), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(C3-C6 cycloalkyl)), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(4-6 membered heterocyclic)) (e.g. -C(O)(C0-C6 alkyl), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl) (e.g.) ); or, R v01 and R v02 Together they form C1-C6 alkylene groups (e.g. ).

[0066] In some embodiments of the present invention, R v01 and R v02 It can be independently selected from the following groups: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl (e.g., -CH3, ...). ), C1-C6 deuterated alkyl groups (e.g. C1-C6 haloalkyl groups (e.g., -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2Cl), C1-C6 cyanoalkyl groups (e.g.) ), C1-C6 hydroxyalkyl (e.g. ), C1-C6 alkoxyalkyl (e.g. ), C1-C6 deuterated alkoxy groups (e.g. ), C1-C6 aminoalkyl (e.g. ), C1-C6 alkylaminoalkyl (e.g. ).

[0067] In some embodiments of the present invention, R v01 For H, R v02 Not H, It can be

[0068] In one embodiment of the present invention, R v01 and R v02 All are H.

[0069] In one embodiment of the present invention, R v01 For H, R v02 It is -CD3.

[0070] In one embodiment of the present invention, R v01 and R v02 All are halogens (such as F).

[0071] In one embodiment of the present invention, R v01 For H, R v02 It is a halogen (such as F).

[0072] In one embodiment of the present invention, R v01 For H, R v02 It is a methyl group.

[0073] In other embodiments of the present invention, R v01 It is cyano or C 1-6 Cyanoalkyl, R v02 Selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl.

[0074] In one embodiment of the present invention, R v01 For -CN or -CH2-CN, R v02 For H.

[0075] In one embodiment of the present invention, R v01 For H, R v02 It is a hydroxyl group.

[0076] In one embodiment of the present invention, R v01 For H, R v02 It is a C1-C3 alkoxy group (such as a methoxy group).

[0077] In one embodiment of the present invention, R v01 For H, R v02 C 1- C3 deuterated alkoxy groups (such as deuterated methoxy groups).

[0078] In some embodiments of the present invention, R v01 and R v02 Together with the carbon atoms they are connected to, they form C3-C6 cycloalkyl groups.

[0079] In one embodiment of the present invention, R v01 and R v02 Together

[0080] In some embodiments of the present invention for in particular

[0081] In some embodiments of the present invention, W is a single bond, -CH2-, Or S.

[0082] In some embodiments of the present invention Selected from:

[0083] Among them, R 10c R is one or more independent substituents on the ring. 10a To R 10c Each has R as described above 10 Definition.

[0084] In some embodiments of the present invention, R 10a To R 10c Representing R respectively 10a R 10b and R 10c .

[0085] In some embodiments of the present invention, R 10a R 10b and R 10c It can be independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; more specifically, R 10a R 10b and R 10c It can be independently selected from: H, D, -CH3, -CHF2, -CH2F, -CF3,

[0086] In some embodiments of the present invention for

[0087] In some embodiments of the present invention, R 10a Selected from: -CH3, -CHF2, -CH2F, -CF3 Especially -CH3.

[0088] In some embodiments of the present invention, R 10b For H.

[0089] In some embodiments of the present invention, R 10b With R P Definition of a functional group.

[0090] In some embodiments of the present invention for

[0091] In some embodiments of the present invention for

[0092] In some embodiments of the present invention, the compound has the following structure:

[0093] in,

[0094] R0 is For example

[0095] R1 is Among them, R 001 Selected from: single bonds, C1-C6 alkylene groups; R 002 Selected from: single bond, C1-C6 alkylene, O, S, N(R2), S(O)2, S(O)2N(R2), S(O), S(O)N(R2), C(O), C(O)O, C(O)N(R2), OC(O), OC(O)N(R2), N(R2)C(O)O, N(R2)C(O), N(R2)S(O)2, R 003 Selected from: H, D, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C 10 Cycloalkylalkyl, 4- to 10-membered saturated heterocyclic group, heterocyclic alkyl; R1 is optionally substituted by one or more independent substituents selected from the following: halogen, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, cyano, carboxyl.

[0096] Specifically, In the structure, R3 and R4 can be independently selected from: H, D, halogens, C1-C6 alkyl groups (e.g., -CH3, ...). C1-C6 haloalkyl groups (e.g., -CHF2, -CH2F, -CF3, -CH2-CF3, -CH2Cl), C1-C6 cyanoalkyl groups (e.g.) ), C1-C6 hydroxyalkyl (e.g. ), C1-C6 alkoxyalkyl (e.g. C 1-6 aminoalkyl (e.g.) ), C1-C6 alkylaminoalkyl (e.g. ), C3-C6 cycloalkyl (e.g. C4-C 10 cycloalkyl (e.g.) ).

[0097] In some embodiments of the present invention, R3 is H; R4 may be selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0098] In one embodiment of the present invention, R3 is H and R4 is H.

[0099] In one embodiment of the present invention, R3 is D and R4 is D.

[0100] In one embodiment of the present invention, R3 is H and R4 is -CH3.

[0101] In one embodiment of the present invention, R3 is H and R4 is cyclopropyl.

[0102] In one embodiment of the present invention, R3 is H and R4 is cyclobutyl.

[0103] In one embodiment of the present invention, R3 is H, and R4 is

[0104] In one embodiment of the present invention, R3 is H, and R4 is

[0105] In one embodiment of the present invention, R3 is H, and R4 is

[0106] In one embodiment of the present invention, R3 is H, and R4 is

[0107] In one embodiment of the present invention, R5 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl; more specifically, R5 may be selected from: H, D, -CH3, -CHF2, -CH2F, -CH2Cl, -CF3, -CH2OH, -CH2NH2, -CH2CN.

[0108] In some embodiments of the present invention, R5 is H.

[0109] In some embodiments of the present invention, R5 is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, or isopropyl.

[0110] In one embodiment of the present invention, R6 is selected from: H, D, C1-C6 alkyl (e.g., -CH3, ...). ), C3-C6 cycloalkyl (e.g. C4-C 10 cycloalkyl (e.g.) ), 4 to 10 saturated heterocyclic groups (e.g. ( ), heterocyclic alkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, saturated heterocyclic, heterocyclic alkyl is optionally substituted by one or more independent substituents selected from the following: C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic, halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, cyano, C1-C6 cyanoalkyl, carboxyl, C1-C6 carboxylalkyl, C1-C6 haloalkyl, C2-C6 sulfonyl.

[0111] In some embodiments of the present invention, R6 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl, 4 to 10-membered saturated heterocyclic group, wherein the alkyl, cycloalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, saturated heterocyclic group is optionally substituted by one or more independent substituents selected from the following: halogen, C1-C3 alkyl.

[0112] In some embodiments of the present invention, R6 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl,

[0113] In some embodiments of the present invention Partially selected from:

[0114] In some embodiments of the present invention Partially selected from:

[0115] In one embodiment of the invention, R5 and R6 together with the nitrogen atom they are connected to form a heterocyclic group. Right now It can be The E ring is a 4-14 membered heterocycle (which can be a monocyclic or polycyclic system (including fused, helical, or bridged systems), each ring can be a saturated or unsaturated heterocycle, and optionally contains one or more additional heteroatoms, such as a 3- to 10-membered monocyclic, fused bicyclic, or bridged heterocyclic alkyl, or a 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein optionally, each heterocyclic alkyl or heteroaryl contains one or two additional heteroatoms selected from nitrogen and oxygen);

[0116] R 17 For one or more independent substituents on the E ring, each R 17 Independently selected from: H, D, (=O), halogen, cyano, nitro, C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C10 Alkoxyalkyl, C1-C 10 Alkamidoalkyl; wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylaminoalkyl are each optionally substituted by one or more independent substituents selected from: D, halogen, cyano, nitro, C 1-10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)); wherein the 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl is optionally substituted by one or more independent substituents selected from the following: halogen, cyano, nitro, hydroxy, amino, C1-C 10 Alkyl, substituted or unsubstituted phenyl or 4-6 membered heterocyclic groups.

[0117] In some embodiments of the present invention, at least one R 17 With R P Definition of a functional group.

[0118] In some embodiments of the present invention, the E ring is a saturated heterocyclic ring, for example:

[0119] in particular

[0120] In some embodiments of the present invention, the E ring is a partially unsaturated heterocycle, for example:

[0121] In some embodiments of the present invention, each R 17 It can be independently selected from: H, D, (=O), halogen (e.g., -F), C1-C6 alkyl (e.g., -CH3, ...). ), C1-C6 deuterated alkyl groups (e.g. ), C2-C6 alkenyl (e.g. C1-C6 haloalkyl groups (e.g., -CHF2, -CH2F, -CH2Cl, -CF3, -CH2CF3, -CH2CH2F), cyano, C1-C6 cyanoalkyl groups (e.g. ), -OH, C1-C6 alkoxy groups (e.g.) ), C1-C6 deuterated alkoxy groups (e.g. ), C1-C6 hydroxyalkyl (e.g. ), C1-C6 alkoxyalkyl (e.g. ), -NH2, C1-C6 alkylamine groups (e.g.) ), C1-C6 alkylaminoalkyl (e.g. -(C0-C3 alkylene)-(C3-C6 cycloalkyl) (e.g.) -(C0-C6 alkylene)-(4-10 saturated heterocyclic groups) (e.g.) ), -S(O)2(C0-C6 alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-6 membered heterocyclic), -S(O)2N(C0-C6 alkyl)(C0-C6 alkyl), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(C3-C6 cycloalkyl)), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(4-6 membered heterocyclic)) (e.g. ), -C(O)(C0-C6 alkyl)(e.g. ), -C(O)O (C0-C6 alkyl) (e.g. ), -C(O)N(C0-C6 alkyl)(C0-C6 alkyl)(e.g. ), C1-C6 haloalkoxy groups (e.g., -OCF3), -C(O)O (C0-C6 alkyl groups) (e.g., -COOH, -COOCH3).

[0122] In some embodiments of the present invention for Specifically Where R 17a To R 17g Each has R as described above 17 The definition, or R 17a To R 17g The two atoms in the middle together form cycloalkyl or heterocyclic groups with the carbon atom in between.

[0123] In this invention, R 17a To R 17g R represents 17a R 17b R 17c R 17d R 17e R 17f R 17g .

[0124] Specifically, R 17a and R 17g Independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, C1-C6 cyanoalkyl, C1-C6 alkoxyalkyl.

[0125] In some embodiments of the present invention, R 17a It can be H, D, -CH3, -CF3 or -CH2OH, especially H.

[0126] In some embodiments of the present invention, R 17a With R P Definition of a functional group.

[0127] In some embodiments of the present invention, R 17g It can be H, D, -CH3, -CF3 or -CH2OH, especially H.

[0128] In some embodiments of the present invention, R 17b Selected from: H, D, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, C1-C6 cyanoalkyl, C1-C6 alkoxyalkyl, R 17c Selected from: H, D, halogens, C1-C6 alkyl, C1-C6 deuterated alkyl; or, R 15b and R 15cTogether with the carbon atoms they are connected to, they form 3 to 6-membered cycloalkyl or heterocycloalkyl groups.

[0129] In some embodiments of the present invention, R 17b Selected from: H, D, -CD3, -CN, -CH3, -CF3, -CH2-CN, -CH2-OH, -CH2OCH3.

[0130] In some embodiments of the present invention, R 17b With R P Definition of a functional group.

[0131] In some embodiments of the present invention, R 17c Selected from: H, D, halogens, C1-C6 alkyl, C1-C6 deuterated alkyl.

[0132] In some embodiments of the present invention, R 17c Selected from: H, D, -CD3, F, -CH3.

[0133] In some embodiments of the present invention, R 17b and R 17c It can form 4- to 5-membered heterocyclic alkyl or 3- to 4-membered cycloalkyl together with the carbon atoms it is connected to.

[0134] In some embodiments of the present invention, R 17b and R 17c It can form together with the carbon atoms it is bonded to:

[0135] In some embodiments of the present invention, R 17d and R 17e Independently selected from: H, D, halogen, C1-C6 alkyl; or, R 15d and R 15e Together with the carbon atoms they are connected to, they form 3- to 4-membered cycloalkyl groups.

[0136] In some embodiments of the present invention, R 17d and R 17e Independently selected from: H, D, halogens, C1-C3 alkyl groups.

[0137] In some embodiments of the present invention, R 17d Selected from: H, D, F, -CH3.

[0138] In some embodiments of the present invention, R 17e Selected from: H, D, F, -CH3.

[0139] In some embodiments of the present invention, R 17d and R17e It forms together with the carbon atoms it is connected to.

[0140] In some embodiments of the present invention, R 17d With R P Definition of a functional group.

[0141] In some embodiments of the present invention, R 17f Selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, C1-C6 cyanoalkyl.

[0142] In some embodiments of the present invention, R 17f Selected from: -CN, -CH3, -CF3, -CH2-CN, -CH2-OH, -CH2OCH3.

[0143] In some embodiments of the present invention for Specifically Where R 17a 'To R 17e 'each has R as described above 17 The definition, or R 17a 'To R 17e The two atoms in ', together with the ring atom in the middle, form a cycloalkyl or heterocyclic group.

[0144] In this invention, R 17a To R 17g R represents 17a '、R 17b '、R 17c '、R 17d '、R 17e '.

[0145] In some embodiments of the present invention, R 17a Selected from: H, D, C1-C6 alkyl groups (e.g., -CH3, ... ), C3-C4 cycloalkyl (e.g. ).

[0146] In some embodiments of the present invention, R 17b Selected from: H, D, C1-C6 alkyl (e.g., methyl, ethyl, isopropyl).

[0147] In some embodiments of the present invention, R 17c Selected from: H, D, halogens, C1-C6 alkyl groups (e.g., -CH3, ... C1-C6 haloalkyl groups (e.g., -CHF2, -CH2F, -CH2Cl, -CF3, -CH2CF3, -CH2CH2F), -C(O)O (C0-C6 alkyl groups) (e.g.) ).

[0148] In some embodiments of the present invention, R 17d Selected from: H, D, C1-C6 alkyl groups (e.g., -CH3, ... ), C3-C4 cycloalkyl (e.g. ).

[0149] In some embodiments of the present invention, R 17e Selected from: H, D, C1-C6 alkyl, especially H.

[0150] In some embodiments of the present invention Selected from the following structure:

[0151] In some embodiments of the present invention Selected from the following structure:

[0152] In some embodiments of the present invention Selected from the following structure:

[0153] In some embodiments of the present invention for

[0154] In some embodiments of the present invention, R1 is selected from: H, D, halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxyalkyl, C1-C6 haloalkoxyalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C 10Cycloalkylalkyl, 4- to 6-membered saturated heterocyclic groups, -S(O)2(C0-C6 alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C6 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-6-membered heterocyclic group), -S(O)2N(C0-C6 alkyl)(C0-C6 alkyl), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(C3-C6 cycloalkyl)), -S(O)2N(C0-C6 alkyl)((C0-C6 alkylene)-(4-6-membered heterocyclic group)).

[0155] In some embodiments of the present invention, R1 is selected from: H, D, F, Br, -CH3, -CHF2, -CH2F, -CF3, -CH2-CF3, -OH、 -OCHF2, -OCH2F, -OCF3

[0156] In some embodiments of the present invention, R1 is selected from: H, halogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkoxyalkyl, C1-C6 haloalkoxyalkyl, C3-C6 cycloalkyl.

[0157] In some embodiments of the present invention, R 11 Selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0158] In some embodiments of the present invention, R 11 For H.

[0159] In some embodiments of the present invention, the compound has the following structure:

[0160] In some embodiments of the present invention, the compound has the following structure:

[0161] In some embodiments of the present invention, the compound has the following structure:

[0162] In some embodiments of the present invention, R 11 R 17b R 10b R v01 One, two, three or four with Rp Definition of a functional group (R) 11 R 17b R 10b R v01 Two or more of them have R p When defining groups, they may be the same or different.

[0163] In some embodiments of the present invention, R 11 With R p Definition of a functional group.

[0164] In some embodiments of the present invention, R 17b With R p Definition of a functional group.

[0165] In some embodiments of the present invention, R 10b With R p Definition of a functional group.

[0166] In some embodiments of the present invention, R v01 With R p Definition of a functional group.

[0167] In some embodiments of the present invention, R 11 R 17b Independently possessing R p Definition of a functional group.

[0168] In some embodiments of the present invention, R 11 R 10b Independently possessing R p Definition of a functional group.

[0169] In some embodiments of the present invention, R 11 R v01 Independently possessing R p Definition of a functional group.

[0170] In some embodiments of the present invention, R 17b R 10b Independently possessing R p Definition of a functional group.

[0171] In some embodiments of the present invention, R 17b R v01 Independently possessing R p Definition of a functional group.

[0172] In some embodiments of the present invention, the compound has the following structure:

[0173] In other embodiments of the present invention, the compound has the following structure:

[0174] In other embodiments of the present invention, the compound has the following structure:

[0175] In other embodiments of the present invention, the compound has the following structure:

[0176] In some embodiments of the present invention, the stereoisomers of the compound have the following structures:

[0177] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 For C1-C 10 Halogenated alkyl groups.

[0178] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 It is hydrogen.

[0179] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 For C1-C 10 alkyl.

[0180] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 For C2-C 10 Alkenyl group.

[0181] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 For C2-C 10 Alkenyl group.

[0182] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For O, R 003 For C1-C 10 alkyl.

[0183] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For O, R 003 For C1-C 10 Alkyl, C1-C 10 The alkyl group is replaced by one or more halogens.

[0184] In some embodiments of the present invention, R A for R 001 For C1-C 10 Alkylene, R 002 For O, R 003 For C1-C 10 Alkyl, C1-C 10 The alkyl group is replaced by one or more halogens.

[0185] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), C3-C 10 The cycloalkyl group is replaced by one or more halogens.

[0186] In some embodiments of the present invention, R A for R 001 For a single bond, R 002For a single bond, R 003 -(C0-C6 alkylene)-(C3-C 10 (cycloalkyl).

[0187] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 It is -(C0-C6 alkylene)-(4-10 membered heterocyclic group).

[0188] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 It is S(O)2N(R2) or N(R2)S(O)2, R 003 For C1-C 10 Alkyl group, R2 is hydrogen.

[0189] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For S(O)2, R 003 For C1-C 10 alkyl.

[0190] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 It is a halomethyl group.

[0191] In some embodiments of the present invention, R A for R 001 For a single bond, R 002 For a single bond, R 003 It is a trifluoro-substituted methyl group.

[0192] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is H.

[0193] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is a methyl group.

[0194] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is H, and the J ring is bonded by one or more C1-C bonds. 10 Halogenated alkyl substitution.

[0195] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is H, and the J ring is bonded by one or more C1-C bonds. 10 Alkyl, C1-C 10 The alkyl group may optionally be replaced by one or more halogens or hydroxyl groups.

[0196] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is H, and the J ring is bonded by one or more -C(O)O(C0-C) bonds. 10 Alkyl) substitution.

[0197] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is hydrogen, and the J ring is bonded by one or more C1-C1 bonds. 10 Alkyl substitution.

[0198] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 membered nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is hydrogen, and the J ring is substituted by one or more of the following groups: C1-C 10 Alkyl, hydroxyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), halogen, R group, R p Groups, cyano groups, alkoxyalkyl groups, -C(O)O(C0-C) 10 Alkyl) substitution; C3-C 10 cycloalkyl groups are optionally R p Groups may be substituted or not substituted.

[0199] In this invention, R pThe group comprises at least one of the following: ester bond C(O)O, thioester bond SC(O), phospholipid bond OPO, HOP(O)OH, OP(O)O, P(O)O3 phosphodiester bond, phosphite bond P(OR”'), thiophospholipid bond P(S)O3, peptide bond C(O)NH, ether bond R”'OR”', thioether bond R”'SR”', silane ether bond SiOSi, thiosilane ether bond SiSSi, carbonate bond OC(O)O, thiourea bond HNC(S)NH, amide bond C(O)NH, thioamide bond C(S)NH, carbamate bond OC(O)NH, and urea bond HNC(O)NH, wherein the H on each of the groups is optionally replaced by one or more independent R groups, the R groups being defined as above.

[0200] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is hydrogen, and the J ring is bonded by one or more C1-C1 bonds. 10 Alkyl and hydroxyl substitutions.

[0201] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 membered nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is hydrogen, and the J ring is bonded by one or more -(C0-C6 alkylene)-(C3-C6) bonds. 10 Cycloalkyl) substitution.

[0202] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, R6 is hydrogen, and the J ring is substituted by one or more -(C0-C6 alkylene)-(4-10 member heterocyclic groups).

[0203] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 membered nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is hydrogen, and the J ring is bonded by one or more -(C0-C6 alkylene)-(C3-C6) bonds. 10 Cycloalkyl) substitution, C3-C 10 The cycloalkyl group is replaced by an R group, which is either a halogen or a hydroxyl group.

[0204] In some embodiments of the present invention, R A for L2 is a single bond, and the J ring is a 3-10 member nitrogen-containing heterocycle, which is bonded by a -(C0-C6 alkylene)-(C3-C6) ring. 10The ring is substituted with cycloalkyl groups, and the C0-C6 alkylene groups are C0 alkylene groups. The J ring is connected to the L2 ring through a carbon atom, and the R6 ring is H.

[0205] In some embodiments of the present invention, R A for L2 is a single bond, and the J ring is a 3-10 member nitrogen-containing heterocycle. The nitrogen-containing heterocycle is bonded by a C3-C4 bond. 10 Cycloalkyl substitution, J ring is connected to L2 via a carbon atom, and R6 is H.

[0206] In some embodiments of the present invention, R A for L2 is a single bond, and the J ring is a 3-10 member nitrogen-containing heterocycle. The nitrogen-containing heterocycle is bonded by a C3-C4 bond. 10 Cycloalkyl substitution, J ring is connected to L2 via a carbon atom, R6 is H, C3-C 10 The cycloalkyl group is replaced by a halogen.

[0207] In some embodiments of the present invention, R A for L2 is a single bond, and the J ring is a 3-10 member nitrogen-containing heterocycle. The nitrogen-containing heterocycle is bonded by a C3-C4 bond. 10 Cycloalkyl substitution, J ring is connected to L2 via a carbon atom, R6 is H, C3-C 10 The cycloalkyl group is substituted with halogens or -(C0-C6 alkylene)-(4-10 heterocyclic group).

[0208] In some embodiments of the present invention, R A for L2 is a single bond, and the J ring is a 3-10 membered nitrogen-containing heterocycle, which is substituted by a -(C0-C6 alkylene)-(4-10 membered heterocyclic group). The J ring is connected to L2 via a carbon atom, R6 is H, and the 4-10 membered heterocyclic group is... In the substitution, L4 and L5 are both single bonds, R' is a single bond, and R” is C1-C. 10 alkyl.

[0209] In some embodiments of the present invention, R A for L2 is a single bond, and the J ring is a 3-10 membered nitrogen-containing heterocycle, which is substituted by a -(C0-C6 alkylene)-(4-10 membered heterocyclic group), C3-C6 10 The cycloalkyl group is replaced by one or more independent R groups, the J ring is connected to L2 via a carbon atom, and R6 is H.

[0210] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 6-membered nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is H.

[0211] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, and R6 is a carbon atom. 1-10 alkyl.

[0212] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is H, and the J ring is bonded by C1-C2 atoms. 10 Alkyl substitution, C1-C 10 One or more hydrogen atoms in an alkyl group are replaced by halogens.

[0213] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, R6 is H, and the J ring is bonded by -C(O)O(C0-C) 10 Alkyl) substitution.

[0214] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is a halogen.

[0215] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is a hydroxyl group.

[0216] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is a halogen.

[0217] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 through a carbon atom, and R6 is a hydroxyl group and a halogen.

[0218] In some embodiments of the present invention, R A for L2 is a single bond, the J ring is a 3-10 member nitrogen-containing heterocycle, the J ring is connected to L2 via a carbon atom, and R6 is a carbon atom. 1-10 Alkyl, C 1-10 The alkyl group is replaced by a cyano group.

[0219] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylenes, R5 and R6 are both C 1-10 alkyl.

[0220] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is C 1-10 Alkyl, C 1-10 One or more hydrogen atoms in an alkyl group are replaced by one or more of a hydroxyl group, a hydroxyalkyl group, or a halogen.

[0221] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is C1-C 10 Halogenated alkyl groups.

[0222] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is hydroxyalkyl, and one or more hydrogen atoms on the hydroxyalkyl group are replaced by halogens.

[0223] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is C1-C 10 Alkoxyalkyl, C1-C 10 The alkoxyalkyl group is replaced by one or more halogens.

[0224] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is -(C0-C6 alkylene)-O(C0-C6) 10 alkyl).

[0225] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is -(C0-C6 alkylene)-O(C3-C6) 10 (cycloalkyl).

[0226] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is -(C0-C6 alkylene)-(C3-C6 alkylene) 10 (cycloalkyl).

[0227] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), C3-C 10 The cycloalkyl group is replaced by an etheralkyl group or an alkyl group.

[0228] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is hydrogen, R6 is C 1-10 alkyl.

[0229] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylenes, R5 and R6 are both C 1-10 Alkyl, C 1-10 One or more hydrogen atoms in an alkyl group are replaced by halogens.

[0230] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is C 1-10 Alkyl group, R6 is -(C0-C6 alkylene)-(C3-C6 alkylene)-(C3-C6 alkylene)-(C6 ... 10 (cycloalkyl).

[0231] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is H, R6 is -(C0-C6 alkylene)-(C3-C6 alkylene) 10 (cycloalkyl).

[0232] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is H, R6 is -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), C3-C 10 cycloalkyl In the substitution, L4 and L5 are both single bonds, R' is a single bond, and R” is C1-C. 10alkyl.

[0233] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is H, R6 is -C(O)(C0-C) 10 Alkyl), C0-C 10 The alkyl group is replaced by an R group, where the R group is a halogen.

[0234] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is H, R6 is -C(O)(C0-C) 10 Alkyl), C0-C 10 The alkyl group is replaced by an R group, where the R group is... L4 and L5 are single bonds, R' is a single bond, and R” is a C3-C bond. 10 Cycloalkyl.

[0235] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is H, R6 is -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), C3-C 10 The cycloalkyl group is replaced by an ether.

[0236] In some embodiments of the present invention, R A for L1 is C1-C 10 Alkylene, R5 is H, and R6 are all -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), C3-C 10 The cycloalkyl group is replaced by an R group, where the R group is... L4 and L5 are single bonds, R' is a single bond, and R” is a C1-C bond. 10 alkyl.

[0237] In some embodiments of the present invention, R A for L1 is C(R3R4), R4 is H, R3 is -(C0-C6 alkylene)-(4-10 membered heterocyclic group), wherein the 4-10 membered heterocyclic group is optionally substituted by one or more independent R groups, wherein the R groups are phenyl groups substituted by phosphodiester bonds, and the phenyl groups are either substituted by alkyl groups or unsubstituted, R5 is H, and R6 is C. 1-10 Alkyl, alkyl group with -C(O)O(C0-C 10 Alkyl) substitution.

[0238] In some embodiments of the present invention, R A for L1 is C(R3R4), R4 is H, R3 is -(C0-C6 alkylene)-(4-10 membered heterocyclic group), wherein the 4-10 membered heterocyclic group is optionally substituted by one or more independent R groups, wherein the R group is a hydrogen atom, a halogen, or an alkyl group, R5 is H, and R6 is C. 1-10 Alkyl, alkyl group with -C(O)O(C0-C 10 Alkyl) substitution.

[0239] In some embodiments of the present invention, R 11 For R p Group.

[0240] In some embodiments of the present invention, R 11 For H.

[0241] In some embodiments of the present invention, R 11 For C1-C 10 Alkyl, and C1-C 10 The alkyl group is substituted by one or more independent R groups, and the R groups are OC(O) and... L4 and L5 are both single bonds, and R' is C1-C. 10 Alkylene and R” are C1-C 10 alkyl.

[0242] In some embodiments of the present invention, R 11 For C1-C 10 Alkyl, and C1-C 10 The alkyl group is replaced by one or more independent R groups, and the R groups are alkyl, cycloalkyl, or aryl groups containing P(O)O3 (phosphodiester bond).

[0243] In some embodiments of the present invention, R 11 For C1-C 10 Alkyl, and C1-C 10 The alkyl group is substituted by one or more independent R groups, and the R groups are alkyl, cycloalkyl, or aryl groups containing P(O)O3 (phosphodiester bond), and the H on the alkyl, cycloalkyl, or aryl group is substituted by one or more halogens.

[0244] In some embodiments of the present invention, R 11 -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), C0-C6 alkylene groups are replaced by cycloalkyl groups containing OP(O)O, C3-C 10 The cycloalkyl group is replaced by a halogen.

[0245] In some embodiments of the present invention, R11 C1-C containing ester bond C(O)O 10 alkyl.

[0246] In some embodiments of the present invention, R 11 It is -(C0-C6 alkylene)-(4-10 heterocyclic group), where the hydrogen atoms on the 4-10 heterocyclic group are replaced by alkyl groups.

[0247] In some embodiments of the present invention, R 11 C1-C containing HOP(O)OH 10 alkyl.

[0248] In some embodiments of the present invention, R 11 C1-C containing ester bond C(O) 10 Alkyl, and C1-C 10 One or more hydrogen atoms on the alkyl group are and Both L4 and L5 are single bonds, R' is H and R” is C1-C. 10 alkyl.

[0249] In some embodiments of the present invention, R 11 For C1-C containing C(O)N(R”') 10 Alkyl group, R”' is C1-C 10 alkyl.

[0250] In some embodiments of the present invention, R 11 C1-C containing C(O)O 10 alkyl.

[0251] In some embodiments of the present invention, R 11 C1-C containing C(O)O 10 Alkyl, C1-C 10 One or more hydrogen atoms on the alkyl group are surrounded by a 4-10 membered heterocyclic group or a C3-C group. 10 Cycloalkyl or halogen substitution.

[0252] In some embodiments of the present invention, R 11 C1-C containing C(O)O 10 Alkyl, and C1-C 10 One or more hydrogen atoms on an alkyl group are C1-C 10 Alkyl substitution.

[0253] In some embodiments of the present invention, R 11 C1-C containing 2 C(O)O 10 alkyl.

[0254] In some embodiments of the present invention, R 11C1-C containing C(O)O 10 Alkyl, and C1-C 10 One or more hydrogen atoms on the alkyl group are Replacement, R' is a single bond, L4 and L5 are both single bonds, and R” is C1-C 10 alkyl.

[0255] In some embodiments of the present invention, R 11 C1-C containing C(O)O 10 Alkyl, and C1-C 10 One or more hydrogen atoms on the alkyl group are replaced by 4-10 membered heterocyclic groups.

[0256] In some embodiments of the present invention, R 11 It is -(C0-C6 alkylene)-(4-10 membered heterocyclic group).

[0257] In some embodiments of the present invention, R 11 It is -(C0-C6 alkylene)-(4-10 heterocyclic group), and the 4-10 heterocyclic group is surrounded by one Replacement, R' is a single bond, L4 and L5 are both single bonds, and R” is C1-C 10 alkyl.

[0258] In some embodiments of the present invention, R7 is H.

[0259] In some embodiments of the present invention, R7 is a halogen or a cyano group.

[0260] In some embodiments of the present invention, R7 is... R 701 For a single bond, R 702 For C(O)O, R 703 For H.

[0261] In some embodiments of the present invention, R7 is... R 701 For a single bond, R 702 C(O)N(R) 704 ), R 703 For H, R 704 For H.

[0262] In some embodiments of the present invention, R7 is... R 701 For a single bond, R 702 For a single bond, R 703 For H or C 1-10 alkyl.

[0263] In some embodiments of the present invention, R7 is H, cyano, or halogen.

[0264] In some embodiments of the present invention, W is a single bond.

[0265] In some embodiments of the present invention, R8 and R9 together with the carbon atom to which they are connected form a cycloalkyl or heterocyclic group.

[0266] In some embodiments of the invention, R8 and R9, together with their commonly linked carbon atoms, form a cycloalkyl or heterocyclic group, which is then converted by R... p Group substitution.

[0267] In some embodiments of the present invention, R8 and R9 together with their commonly linked carbon atoms form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group being hydroxyl or -O (CO-C) group. 10 Alkyl groups or halogen-substituted compounds.

[0268] In some embodiments of the invention, R8 and R9, together with their commonly attached carbon atoms, form a cycloalkyl or heterocyclic group, which is C2-C3 bonded together. 10 Alkenyl or cyano substitution.

[0269] In some embodiments of the invention, R8 and R9, together with their commonly attached carbon atom, form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group being C1-C2... 10 Alkyl substitution.

[0270] In some embodiments of the invention, R8 and R9, together with their commonly linked carbon atoms, form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is bonded by a -(C0-C6 alkylene)-(C3-C6) group. 10 Cycloalkyl) substitution.

[0271] In some embodiments of the present invention, R8 and R9 together with their commonly attached carbon atom form a cycloalkyl or heterocyclic group, the cycloalkyl or heterocyclic group being coated with a halogen, hydroxyl group, cyano group, or -O (CO-C). 10 Alkyl) substitution.

[0272] In some embodiments of the invention, R8 and R9, together with their commonly attached carbon atom, form a cycloalkyl group, the cycloalkyl group being -O(C0-C) 10 Alkyl) substitution, C0-C 10 One or more hydrogen atoms in an alkyl group are replaced by halogens.

[0273] In some embodiments of the present invention, Y1, Y2, Y3 and Y4 are independently selected from C, N, O and S, and the two O atoms, the two S atoms, or the O and S atoms are not directly connected.

[0274] In some embodiments of the present invention, R 10 For R p Group.

[0275] In some embodiments of the present invention, R 10 For H or C1-C 10 alkyl.

[0276] In some embodiments of the present invention, R 10 The C1-C of the P(O)O3 phosphate diester bond 10 alkyl.

[0277] In some embodiments of the present invention, R 10 -(C0-C6 alkylene)-(C6-C 10 (aryl), and C6-C 10 The aryl group is replaced by the P(O)O3 phosphate diester bond.

[0278] In a second aspect of the invention, a method for preparing the compound described in the first aspect is provided.

[0279] In a third aspect of the invention, a pharmaceutical composition is provided comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0280] In some embodiments of the present invention, the pharmaceutically acceptable excipient may be selected from one or more of the following: disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, preservatives, etc.

[0281] In some embodiments of the present invention, the pharmaceutical composition may be administered via any suitable route of administration, such as gastrointestinal or non-gastrointestinal routes (e.g., intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, intravenous drip, intracerebral, rectal, etc.).

[0282] In some embodiments of the present invention, the pharmaceutical composition may be any suitable dosage form, such as gastrointestinal dosage forms, including, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; non-gastrointestinal dosage forms, such as injectable dosage forms (e.g., for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), respiratory dosage forms (e.g., sprays, aerosols, powder inhalers, etc.), skin dosage forms (e.g., topical solutions, lotions, ointments, plasters, pastes, patches, etc.), mucosal dosage forms (e.g., eye drops, ophthalmic ointments, nasal drops, mouthwashes, sublingual tablets, etc.), and cavity dosage forms (e.g., suppositories, aerosols, effervescent tablets, drops, pills, etc., for use in the vagina, urethra, nasal cavity, ear canal, etc.).

[0283] In some embodiments of the present invention, the pharmaceutical composition is an oral dosage form.

[0284] In some embodiments of the present invention, the pharmaceutical composition is an injection.

[0285] Specifically, the various dosage forms of the pharmaceutical composition can be prepared according to conventional pharmaceutical manufacturing methods. For example, the active ingredient is mixed with one or more pharmaceutically acceptable excipients and then formulated into the desired dosage form.

[0286] Specifically, in the pharmaceutical composition, the weight percentage of the compound described in the first aspect, or its pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound, may be 0.1-99.5%, for example 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

[0287] In some embodiments of the present invention, in the pharmaceutical composition, the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound (first active ingredient), may be used alone or in combination with other types of active ingredients (second active ingredients).

[0288] In some embodiments of the present invention, the other types of active ingredients are serotonin receptor antagonists, which, when used in combination with the compounds described in the first aspect of the present invention, or their pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, or deuterated compounds, produce a synergistic effect.

[0289] In some embodiments of the present invention, the serotonin receptor antagonist is a serotonin inhibitor, such as one or more of ondansetron, granisetron, palonosetron, and dolasetron.

[0290] In some embodiments of the present invention, the serotonin receptor antagonist is ondansetron.

[0291] In some embodiments of the invention, an 8 mg dose of ondansetron may be administered at least 30 minutes or one hour before the administration of the first active ingredient.

[0292] In some embodiments of the invention, a dose of 16 mg of ondansetron may be administered before the administration of the first active ingredient.

[0293] In some embodiments of the invention, a dose of 24 mg of ondansetron may be administered before the administration of the first active ingredient.

[0294] In some embodiments of the present invention, the serotonin receptor antagonist is granisetron.

[0295] In some embodiments of the invention, a dose of 1 mg of granisetron may be administered one hour before the administration of the first active ingredient.

[0296] In some embodiments of the invention, a 2 mg dose of granisetron may be administered before the first active ingredient.

[0297] In some embodiments of the present invention, the serotonin receptor antagonist is dolasetron.

[0298] In some embodiments of the invention, a dose of 100 mg of dolasetron may be administered at least one hour before the administration of the first active ingredient.

[0299] In some embodiments of the invention, a dose of 200 mg of dolesetron may be administered before the administration of the first active ingredient.

[0300] In some embodiments of the present invention, the serotonin receptor antagonist is palonosetron.

[0301] In some embodiments of the invention, a dose of 0.25 mg of palonosetron may be administered at least 30 minutes before the administration of the first active ingredient.

[0302] In some embodiments of the invention, a dose of 0.5 mg of palonosetron may be administered at least 30 minutes before the administration of the first active ingredient.

[0303] In some embodiments of the invention, a dose of 0.75 mg of palonosetron may be administered at least 30 minutes before the administration of the first active ingredient.

[0304] In some embodiments of the present invention, the other types of active ingredients are oncolytic viruses.

[0305] In some embodiments of the present invention, for combined use, the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and the second active ingredient may be in the same dosage form or in different dosage forms, and the two may be administered simultaneously, separately, or sequentially.

[0306] In some embodiments of the present invention, the amount of the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof, in the pharmaceutical composition is a therapeutically effective amount, and may range from 0.1 mg to 1000 mg, 0.1 mg to 900 mg, 0.1 mg to 800 mg, 0.1 mg to 750 mg, 0.1 mg to 700 mg, 0.1 mg to 600 mg, 0.1 mg to 500 mg, 0.1 mg to 400 mg, 0.1 mg to 300 mg, 0.1 mg to 250 mg, 0.1 mg to 200 mg, 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0. The dosage may be varied or adjusted between 1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 0.25 mg to 20 mg, 0.25 mg to 15 mg, 0.25 mg to 12 mg, 0.25 mg to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 12 mg, 0.5 mg to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg, depending on the specific application and potency of the active ingredient.

[0307] If the pharmaceutical composition further comprises a second active ingredient, wherein the amount of the second active ingredient is a therapeutically effective amount, it may be from 0.1 mg to 1000 mg, 0.1 mg to 900 mg, 0.1 mg to 800 mg, 0.1 mg to 750 mg, 0.1 mg to 700 mg, 0.1 mg to 600 mg, 0.1 mg to 500 mg, 0.1 mg to 400 mg, 0.1 mg to 300 mg, 0.1 mg to 250 mg, 0.1 mg to 200 mg, 0.1 mg to 200 mg, 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 10 mg, or 0.1 mg to 7 mg. The dosage may be changed or adjusted between 5 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 0.25 mg to 20 mg, 0.25 mg to 15 mg, 0.25 mg to 12 mg, 0.25 mg to 10 mg, 0.25 mg to 7.5 mg, 0.25 mg to 5 mg, 0.25 mg to 2.5 mg, 0.5 mg to 20 mg, 0.5 mg to 15 mg, 0.5 mg to 12 mg, 0.5 mg to 10 mg, 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 7.5 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

[0308] In a fourth aspect of the invention, the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof in the preparation of a medicament for the prevention and / or treatment of diseases associated with Cbl-b activity is provided.

[0309] In some embodiments of the present invention, the diseases associated with Cbl-b activity are those for which inhibition of Cbl-b can be beneficial for prevention and / or treatment, such as autoimmune diseases, inflammatory diseases, tumors, diseases caused by pathogen infection or diseases related to pathogen infection.

[0310] In some embodiments of the present invention, the autoimmune diseases include, but are not limited to, organ-specific autoimmune diseases and systemic autoimmune diseases, such as achalasia, Addison's disease, adult-onset Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, antiglomerular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, acute motor-sensory axonal neuropathy, and Barlow's disease (also known as idiopathic ... Cardiac sclerosis, Behcet's disease, benign mucosal pemphigoid (also known as cicatricial pemphigoid), bullous pemphigoid, giant lymphadenopathy, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome (also known as allergic granulomatous vasculitis or eosinophilic granulomatous polyangiitis), Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackievirus myocarditis, CREST syndrome, Crohn's disease, herpetic dermatitis, dermatomyositis, Dervex disease (also known as neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, Erythema nodosum, primary mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatous polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (also known as allergic purpura), herpes pregnancy or pemphigoid of pregnancy, hidradenitis suppurativa, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosis (also known as IgG4-related systemic disease, hyperIgG4 disease, and IgG4-related disease), immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile dementia Type 1 arthritis, juvenile myositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytospora vasculitis (also known as allergic vasculitis), lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease, chronic Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, keratodermal ulcer, Mucha-Habermann disease (also known as acute pityriasis lichenoides), multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, somnolencephaly, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis, panda disease (PANDAS), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria.Parry-Romberg syndrome, pars plana cyclitis (also known as peripheral uveitis), Parsonage-Turner syndrome (also known as brachial neuritis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyadenomas type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy (also known as pain syndrome), relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis Wet arthritis, sarcoidosis, Schmidt syndrome (also known as polyglandular autoimmune syndrome type 2), scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, thyroid ophthalmopathy, Tolosa-Hunt syndrome, type 1 diabetes mellitus (also known as autoimmune diabetes mellitus or insulin-dependent diabetes mellitus), ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Koyanagi-Harada disease; especially one or more of the following: systemic lupus erythematosus, type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, psoriasis, ulcerative colitis, and Crohn's disease.

[0311] In some embodiments of the present invention, the aforementioned inflammatory diseases include, but are not limited to, one or more of the following: gout, chronic obstructive pulmonary disease, interstitial lung disease, inflammatory bowel disease, sepsis, asthma, and allergies.

[0312] In some embodiments of the present invention, the tumor includes, but is not limited to, one or more of the following: blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), adenocarcinoma of lung cancer, squamous cell carcinoma of the lung, peritoneal carcinoma, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer (especially metastatic breast cancer), colon cancer, rectal cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, Merkel cell carcinoma, esophageal cancer, biliary tract tumor, head and neck cancer, and hematologic malignancies.

[0313] In some embodiments of the present invention, the tumor is a hematologic malignancy, such as leukemia, lymphoma, or multiple myeloma (MM).

[0314] In some embodiments of the present invention, the leukemia can be one or more of chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute monocytic leukemia, especially acute myeloid leukemia. Specifically, the leukemia can be relapsed, refractory, or drug-resistant.

[0315] In some embodiments of the present invention, the lymphoma may be one or more of B-cell lymphomas (e.g., diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), small lymphocytic lymphoma / chronic lymphocytic leukemia, mantle cell lymphoma (MCL)), T / NK-cell lymphoma, particularly diffuse large B-cell lymphoma (DLBCL).

[0316] In one embodiment of the present invention, the aforementioned tumor is a solid tumor, including but not limited to neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, squamous cell carcinoma, melanoma, gastric cancer, esophageal cancer, gastroesophageal junction (GEJ) cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, head and neck cancer, urothelial carcinoma, etc.; particularly, one or more of ovarian cancer, gastric cancer, gastroesophageal junction (GEJ) cancer, head and neck squamous cell carcinoma, metastatic or unresectable melanoma, non-small cell lung cancer, metastatic castration-resistant prostate cancer (mCRPC), malignant pleural mesothelioma (MPM), breast cancer, metastatic urothelial carcinoma, cervical cancer, and metastatic colorectal cancer.

[0317] In some embodiments of the present invention, the pathogens may be microorganisms, parasites (protozoa, worms, etc.) or other vectors. Specifically, the microorganisms may be selected from one or more of the following: viruses, chlamydia, rickettsia, mycoplasma, bacteria, spirochetes, fungi, etc.

[0318] In some embodiments of the present invention, the aforementioned pathogens are viruses, such as, but not limited to, adenoviridae (e.g., adenovirus), herpesviruses (e.g., HSV1 (oral herpes), HSV2 (genital herpes), VZV (varicella), EBV (Ebola virus), CMV (cytomegalovirus)), poxviruses (e.g., smallpox virus, vaccinia virus), papillomaviruses (e.g., papillomavirus (HPV)), parvoviruses (e.g., B19 virus), hepatotropic DNA viruses (e.g., hepatitis B virus), polyomaviruses (e.g., polyomavirus), reoviridae (e.g., reovirus, rotavirus), picoronaviridae (e.g., enterovirus, foot-and-mouth disease virus), caliciviruses (e.g., norovirus, hepatitis E virus), scabraviruses (e.g., rubella virus), arenaviruses (e.g., lymphocytic choriomeningitis virus), retroviridae (HIV-1, HIV-2, HTLV-1), and flaviviridae (e.g., dengue fever). The virus is classified as one or more of the following: * **Orthomyxoviridae (e.g., influenza viruses such as influenza A, influenza B, and influenza C)**, * **Parmyxoviridae (e.g., human parainfluenza virus type 1 (HPIV), HPV types 2, 3, and 4, Sendai virus, mumps virus, measles virus, respiratory syncytial virus, Newcastle disease virus, etc.)**, * **Bunyaviridae (e.g., California encephalitis virus, Hantavirus)**, * **Rhabdoviridae (e.g., rabies virus)**, * **Filoviridae (e.g., Ebola virus, Marburg virus)**, * **Coronaviridae (e.g., HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, SARS-CoV-2, etc.)**, * **Astroviridae (e.g., astroviruses)**, and * **Bornaviridae (e.g., Bornaviruses)**.

[0319] In some embodiments of the present invention, the diseases caused by or related to pathogen infection include, but are not limited to, influenza, SARS, COVID-19, viral hepatitis (such as hepatitis A, hepatitis B, hepatitis C, hepatitis D, etc.), AIDS, rabies, dengue fever, Ebola virus disease, etc.

[0320] In a fifth aspect of the invention, a method for preventing and / or treating diseases associated with Cbl-b activity is provided, comprising administering to a subject in need the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, or pharmaceutical composition of the third aspect thereof.

[0321] In some embodiments of the present invention, the subject may be a mammal, particularly a human.

[0322] In some embodiments of the present invention, the disease has the disease definition in the fourth aspect of the present invention.

[0323] In some embodiments of the present invention, the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof, may be used alone or in combination with other types of pharmaceutical preparations and / or treatment methods.

[0324] In some embodiments of the present invention, the other types of pharmaceutical preparations and / or treatment methods include, but are not limited to: immune checkpoint inhibitors, antitumor agents, glucocorticoids, nonsteroidal anti-inflammatory drugs, antitumor vaccines, TLR (Toll-like receptor) agonists and inhibitors, adoptive cellular immunotherapy, or radiotherapy.

[0325] In some embodiments of the present invention, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule, including but not limited to: PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT, TIM3 (CD366), and VISTA; more specifically, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152).

[0326] In some embodiments of the present invention, the at least one inhibitory checkpoint molecule comprises PD-1, optionally wherein the immune checkpoint inhibitor is selected from pembrolizumab, nivolumab, cimipril, and their bioanalytes.

[0327] In some embodiments of the invention, the at least one inhibitory checkpoint molecule comprises PD-L1, optionally wherein the immune checkpoint inhibitor is selected from atezolizumab, avelumab, durvalumab, and bioanalytes thereof.

[0328] In some embodiments of the invention, the at least one inhibitory checkpoint molecule includes CTLA-4, optionally wherein the immune checkpoint inhibitor is selected from ipilimumab, tremelimumab, and their bioanalytes.

[0329] In some embodiments of the present invention, the antitumor agent includes, but is not limited to, one or more of the following: cytotoxic antibiotics, plant alkaloids, antimetabolites, alkylating agents, platinum compounds, and protein kinase inhibitors.

[0330] In some embodiments of the present invention, the cytotoxic antibiotics include, but are not limited to, one or more of the following: ixaspirin, mitomycin, procainamide, bleomycin, pinantrone, amarabin, varabin, pirarubicin, mitoxantrone, idarubicin, zorarabin, ararubicin, epirubicin, daunorubicin, doxorubicin, and dermatomycin.

[0331] In some embodiments of the present invention, the plant alkaloids include, but are not limited to, one or more of the following: trabectedin, carbamate, paclitaxel polyaniline, docetaxel, paclitaxel, dimethoprim, teniposide, etoposide, vinblastine, vinflunine, vinorelbine, vindesin, vincristine, and vinblastine.

[0332] In some embodiments of the present invention, the antimetabolites include, but are not limited to, one or more of the following: fluorouridine, trifluuridine, tegafur, fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmoflu, cytarabine, nelabine, clofarabine, fludarabine, cladribine, thioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate.

[0333] In some embodiments of the present invention, the alkylating agent includes, but is not limited to, one or more of the following: dacarbazine, temozolomide, piperobroman, mitoxobromide, etoluidine, uracil mustard, ramustine, nimustine, flutimustine, streptozotocin, semustine, lomustine, carmustine, carpoquinone, triazinon, thiotepa, mannitol, trothion, busulfan, bendamustine, prednimustine, trophosphoramide, ifosfamide, methyl chloroethylamine, melphalan, chlorambucil, and cyclophosphamide.

[0334] In some embodiments of the present invention, the platinum compound includes, but is not limited to, one or more of cisplatin, carboplatin, oxaliplatin, saxaplatin, and polyplatin.

[0335] In some embodiments of the present invention, the protein kinase inhibitor includes, but is not limited to, one or more of the following: BTK inhibitor, PI3K inhibitor, SYK inhibitor, and JAK inhibitor.

[0336] In some embodiments of the present invention, the glucocorticoids include, but are not limited to, one or more of hydrocortisone, dexamethasone, betamethasone, and prednisone.

[0337] In some embodiments of the present invention, the nonsteroidal anti-inflammatory drugs include, but are not limited to, one or more of aspirin, ibuprofen, diclofenac, and rofecoxib.

[0338] In some embodiments of the present invention, the TLR agonists include, but are not limited to, one or more of the following: TLR3 agonist Poly-ICLC, TLR4 agonist MPLA, TLR7 agonist GS-9620, TLR8 agonist ssRNA40, TLR7 agonist TLR7-agonist-1, TLR8 agonist Motolimod, TLR9 agonist CPG7079, or 1018ISS.

[0339] In some embodiments of the present invention, the TLR inhibitors include, but are not limited to, one or more of the following: TLR1 / 2 inhibitor CU CPT 22, TLR4 inhibitor atractylodes lactone, TLR2 inhibitor C29, TLR8 inhibitor CU-CPT-9a, and TLR7 / 8 / 9 inhibitor CPG-52364.

[0340] In a sixth aspect of the invention, a method for preventing and / or treating immune-related diseases (e.g., autoimmune diseases, inflammatory diseases, tumors) is provided, comprising the step of administering to a subject in need the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, or pharmaceutical composition of the third aspect thereof.

[0341] In some embodiments of the present invention, the method is a method for preventing and / or treating autoimmune diseases.

[0342] In other embodiments of the present invention, the method is a method for preventing and / or treating inflammatory diseases.

[0343] In other embodiments of the present invention, the method is a method for preventing and / or treating tumors.

[0344] In some embodiments of the present invention, the subject may be a mammal, particularly a human.

[0345] In some embodiments of the present invention, the disease has the disease definition in the fifth aspect of the present invention.

[0346] In a seventh aspect of the invention, a method for regulating the activity of immune cells is provided, comprising the step of contacting immune cells with an effective amount of the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, or pharmaceutical composition described in the third aspect, to regulate the activity of immune cells.

[0347] In some embodiments of the present invention, the immune cells include T cells, B cells, or NK cells.

[0348] In some embodiments of the present invention, the immune cells are isolated from blood samples of mammalian subjects.

[0349] In some embodiments of the present invention, the immune cells are tumor-infiltrating lymphocytes (TILs) isolated from tumors in mammalian subjects with tumors.

[0350] In some embodiments of the present invention, the immune cells are human immune cells.

[0351] In an eighth aspect of the invention, a method for modulating an immune response is provided, comprising the step of administering to a subject in need the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, or pharmaceutical composition described in the third aspect thereof.

[0352] In a ninth aspect of the invention, a method for preparing modified immune cells is provided, comprising the step of culturing a population of cells containing immune cells in the presence of an effective amount of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound, or pharmaceutical composition of the third aspect, to modulate the activity of the immune cells, thereby producing modified immune cells.

[0353] In a tenth aspect of the invention, a modified immune cell is provided, which is prepared by the method described in the ninth aspect.

[0354] In an eleventh aspect of the invention, a method is provided for treating or preventing nausea or vomiting, or both, in a patient receiving Cbl treatment, comprising administering an effective amount of a serotonin receptor antagonist to the subject.

[0355] Specifically, the Cbl treatment comprises administering an effective amount of the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof.

[0356] In some embodiments of the present invention, the serotonin receptor antagonist is as described in the third aspect of the present invention.

[0357] In a twelfth aspect of the invention, the use of the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof, in the preparation of a protein degradation-targeting chimeric compound (PROTAC) is provided.

[0358] In a thirteenth aspect of the invention, a PROTAC compound is provided, comprising an E3 ubiquitin ligase ligand structural portion (E3L), a target protein ligand structural portion (PL), and, optionally, a linker or linker group for connecting E3L and PL, wherein E3L is derived from one or more of the compound described in the first aspect or its pharmaceutically acceptable salts, stereoisomers, solvates, and deuterated compounds.

[0359] This invention prepares a series of compounds with good Cbl-b inhibitory activity and pharmacokinetic properties, which are expected to have great research and application value in the prevention and treatment of Cbl-b activity-related diseases. Detailed Implementation

[0360] Unless otherwise defined, all scientific and technical terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0361] In this invention, the term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain (e.g., "alkyl", "alkenyl", "alkynyl") that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group (also referred to herein as "alicyclic" or "cycloalkyl") that is fully saturated or contains one or more unsaturated units, connected to other parts of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc.

[0362] In this invention, alkoxyalkyl means an alkyl group substituted with one or more alkoxy groups, wherein the alkyl group is as defined herein and the alkoxy group is as defined herein; for example, -CH2OCH3. In this invention, C0 means absent, for example, C0-C6 alkylene indicates that the alkylene group is absent.

[0363] The term "carbon ring" is composed entirely of carbon atoms and can be divided into aliphatic rings and aromatic rings.

[0364] The term "alkyl" refers to a straight-chain or branched hydrocarbon radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, particularly 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. In this invention, CO alkyl refers to -H. If the alkyl group is replaced by a cycloalkyl group, it is referred to as "cycloalkylalkyl", such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. In this invention, cycloalkylalkyl can be -(alkylene)-(cycloalkyl), for example, C 4-10 Cycloalkyl alkyl groups can be -(C 1-4 alkylene)-(C 3-6 (Cycloalkyl). If the alkyl group is replaced by an aryl group, then it is correspondingly "aralkyl", such as benzyl, diphenylmethyl, or phenethyl. In this invention, the aralkyl group can be -(alkylene)-(aryl), for example, C 6-10 Aryl groups can be, for example, -(C 1-4(alkylene)-(phenyl). If the alkyl group is substituted with a heterocyclic group, then it is correspondingly "heterocyclic alkyl". In this invention, the heterocyclic alkyl group can be -(alkylene)-(heterocyclic), for example -(C 1-4 Alkylene group (4-10 membered heterocyclic group).

[0365] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by the loss of two hydrogen atoms from an alkane molecule. Typical alkylenes described herein have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms. Examples of alkylenes include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-, -CH(CH3)CH2-, or -CH2-CH(CH3)-), etc. In this invention, CO alkylene refers to a single bond, CO-C6 alkylene refers to CO alkylene (single bond) and C1-C6 alkylene, and CO-C2 alkylene refers to a single bond, methylene, or ethylene.

[0366] The term "cycloalkyl" refers to an alicyclic hydrocarbon, which can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can be a fused, spirocyclic, or bridged ring system. Cycloalkyl groups can contain 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, particularly monocyclic groups containing 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl.

[0367] The term "cycloalkylene" refers to a divalent group formed by the loss of two hydrogen atoms from an alicyclic hydrocarbon. Typical cycloalkylene groups described herein have 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 3 to 6 carbon atoms. Examples of cycloalkylene groups include...

[0368] The term "alkoxy" refers to a substituent formed when the hydrogen in a hydroxyl group is replaced by an alkyl group, such as alkoxy groups containing 1-10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0369] The term "alkylamine" refers to a substituent formed when one or two hydrogen atoms of an amino group (-NH2) are replaced by an alkyl group, such as an alkylamine group containing 1-10 carbon atoms, for example...

[0370] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0371] The term "halogenated alkyl" refers to a group formed when one or more hydrogen atoms in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), such as -CHF2, -CH2F, -CH2Cl, -CF3, -CH2-CF3, -CH2CH2-CF3, and -CH2CH2CH2-CF3. In particular, methyl and ethyl groups are substituted with one, two, or three halogen atoms (F, Cl, Br, I).

[0372] The term "aryl" refers to monocyclic or polycyclic free radicals, including polycyclic free radicals containing monoaryl groups and / or fused aryl groups, such as those containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, such as phenyl, naphthyl, biphenyl, indene, etc.

[0373] The term "heterocyclic group" refers to a 3- to 18-membered saturated or unsaturated cyclic group containing at least one heteroatom, for example, it may contain 2 to 17 carbon atoms and 1 to 10 heteroatoms. Heterocyclic groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and may contain fused, spirocyclic, or bridged ring systems. Heterocyclic groups can be heteroaryl (aromatic) or heterocyclic alkyl (partially or fully saturated). Suitable heteroaryl groups in the compounds of the present invention are 5- to 10-membered (e.g., 5, 6, 7, 8, 9, 10-membered) heteroaryl groups containing 1, 2, or 3 heteroatoms selected from N, O, or S atoms. The heteroaryl groups include, for example, coumarin (including 8-coumarin), quinolinyl (including 8-quinolinyl), isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrroleyl, thiopheneyl, and thiocarbamate. Azolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazole, indolyl, isoindolyl, indazole, inazinyl, phthalazinyl, pteridinyl, purine, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinolinyl, benzimidazolyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzooxazolyl, quinazolinyl, quinoxolinyl, naphthidyl, and furanylpyridinyl. Suitable heterocyclic alkyl groups in the compounds of the present invention are 4-10 membered (e.g., 4, 5, 6, 7, 8, 9, 10 membered) heterocyclic alkyl groups containing 1, 2, or 3 heteroatoms selected from N, O, or S atoms. The heterocyclic alkyl groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothiophenyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiocyclohexyl, piperazine, azahexyl, oxobutyl, thiobutyl, homopiperidinyl, oxopropyl, and thiopropane. Acetyl, acrylonitrile, oxazolidinyl, diacylonitrile, triacylonitrile, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxazolidinyl, 1,3-dioxopentyl, pyrazolinyl, dithiadinyl, dithiopentanyl, dihydropyranyl, dihydrothiophenyl, pyrazolyl, imidazolinyl, imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinazinyl.

[0374] In this invention, "D" refers to deuterium; "replaced by deuterium" means replacing one or more hydrogen atoms with a corresponding number of deuterium atoms.

[0375] It should be recognized that, depending on the source of the chemical materials used in the synthesis, there are variations in the natural isotopic abundance in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0376] In the compounds of this invention, any atom not specifically designated as deuterium is present at its natural isotopic abundance. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position should be understood as having hydrogen according to its natural abundance isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", that position should be understood as having deuterium at an abundance at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium doping).

[0377] The term “isotope enrichment coefficient” used in this article refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance.

[0378] In other embodiments, the compounds of the present invention have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping at each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0379] The term "isotope" refers to a substance whose chemical structure differs from that of a specific compound of the present invention only in terms of its isotopic composition.

[0380] The term "pharmaceutically acceptable salt" includes acid addition salts and base addition salts.

[0381] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids (such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid), as well as salts derived from organic acids (such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids). Therefore, these salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromates, iodates, acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, octanoates, sebacic acid salts, fumarates, maleates, amygdalinates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, tartrates, and methanesulfonates, as well as salts of amino acids such as arginine salts, gluconates, and galacturonic acids. Acid addition salts can be prepared by contacting a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt with a base, and the free base can be separated in a conventional manner.

[0382] The term "base addition salt" refers to a salt formed with a metal or amine, such as hydroxides of alkali metals and alkaline earth metals, or with an organic amine. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid, and the free acid can be separated in a conventional manner.

[0383] The term "stereoisomer" includes enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that can be substituted on more than one carbon atom; in this case, all their geometric forms, including cis and trans, and mixtures thereof, are within the scope of the present invention.

[0384] The term "solvent" refers to the physical bond between the compound of this invention and one or more solvent molecules. This physical bond includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvents include solution phases and separable solvates. Representative solvates include ethanolides, methanolides, etc.

[0385] The term "prodrug" refers to a Formula I compound that is suitable for administration to patients without excessive toxicity, irritation, or allergic reactions, and is effective for its intended purpose. Prodrugs include acetals, esters, and zwitterionic forms. Prodrugs are converted in the body, such as through hydrolysis in the blood, to yield the parent compound.

[0386] The terms “patient” or “subject”, etc., may be used interchangeably herein to refer to any animal or its cells, whether in vitro or in situ, treated according to the methods described herein. Specifically, the aforementioned animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, or humans, especially humans.

[0387] The term "treatment" refers to the prevention, cure, reversal, relief, reduction, minimization, suppression, cessation, and / or cessation of one or more clinical symptoms of a disease after its onset.

[0388] The term "prevention" refers to the treatment taken before a disease develops to avoid, minimize, or prevent the disease from developing or progressing.

[0389] The term "diseases associated with Cbl-b activity" mainly refers to diseases associated with abnormal Cbl-b activity, especially diseases for which inhibition of Cbl-b can be beneficial for prevention and / or treatment, such as autoimmune diseases, inflammatory diseases, and tumors.

[0390] The term "tumor" refers to an abnormal mass of tissue that grows beyond and out of harmony with the growth of normal tissue. Tumors can be "benign" or "malignant," depending on characteristics such as the degree of cell differentiation (including morphology and function), growth rate, local invasion, and metastasis. "Benign tumors" are typically well-differentiated, characterized by slower growth than malignant tumors, and remain confined to their site of origin. Furthermore, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites. In some cases, certain "benign" tumors may later develop into malignant tumors, possibly due to additional genetic alterations in a subset of the tumor's proliferative cells, and these tumors are called "precancerous tumors." "Malignant tumors" are typically poorly differentiated (anaplastic) and characterized by rapid growth, accompanied by progressive infiltration, invasion, and destruction of surrounding tissues. Furthermore, malignant tumors often have the ability to metastasize to distant sites.

[0391] The term "solid tumor" refers to a tangible tumor, a palpable mass that can be detected through clinical examinations such as X-ray, CT scan, ultrasound, or palpation. In some embodiments of the present invention, the solid tumor is selected from advanced or metastatic malignant solid tumors. The term "advanced or metastatic malignant solid tumor" refers to a histologically or cytologically confirmed advanced, unresectable, and / or metastatic recurrent or refractory malignant solid tumor that is unresponsive to standard therapy or for which no proven effective therapy exists. According to the present invention, malignant solid tumors include, but are not limited to, carcinomas, sarcomas, melanomas, and lymphomas.

[0392] The term “cancer” refers to a malignant tumor (Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).

[0393] The term "autoimmune disease" refers to diseases caused by damage to one's own tissues due to an immune response to self-antigens. The American Autoimmune Related Diseases Association (AAA) has compiled a comprehensive list of autoimmune diseases.

[0394] The term "inflammation" refers to the body's defensive response to stimuli, manifested as redness, swelling, heat, pain, and functional impairment. It can be infectious inflammation caused by infection, or non-infectious inflammation not caused by infection, such as inflammation caused by immune responses (e.g., various types of hypersensitivity reactions, inflammation caused by some autoimmune diseases). The term "inflammatory disease" refers to a disease characterized by inflammation.

[0395] The term "CAR-T immunotherapy" refers to chimeric antigen receptor T-cell immunotherapy, which is one of the more effective treatments for malignant tumors. Its basic principle is to use the patient's own immune cells to eliminate cancer cells, and it belongs to a type of cell therapy.

[0396] The terms "Cbl-b inhibitor" and "Cbl-b antagonist" have the same meaning, referring to molecules that reduce, inhibit, or otherwise diminish one or more biological activities of Cbl-b. Inhibition with a Cbl-b inhibitor does not necessarily indicate complete elimination of Cbl-b activity. Compared to a control, Cbl-b activity may be reduced by a significant amount, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0397] All publications, patents, and published patent specifications cited in this article are incorporated herein in their entirety through citation.

[0398] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0399] Synthesis Example:

[0400] Example 1: Synthesis of compound T058

[0401] 1. General steps for preparing 4-iodo-7-methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)pyrrolo[2,3-c]pyridine

[0402] DMEDA (179 mg, 2.03 mmol) was added to a solution of 4-bromo-7-methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)pyrrolo[2,3-c]pyridine (500 mg, 1.02 mmol), NaI (913 mg, 6.09 mmol), and CuI (387 mg, 2.03 mmol) in dioxane (10.0 mL). The mixture was stirred at 120 °C for 24 hours under N2. TLC (PE / EtOAc = 5 / 1, product 1R) f =0.50) showed the formation of a spot. The reaction mixture was diluted with EtOAc (50.0 mL). The mixture was filtered, and the filter cake was washed with EtOAc (10.0 mL × 3). The filtrate was washed with brine (50 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0-10 / 1). 4-Iodo-7-methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluenesulfonyl)pyrrolo[2,3-c]pyridine (450 mg, 790 μmol, 77.8% yield, 94.7% purity) was given as a yellow solid, confirmed by 1H NMR and LCMS.

[0403] 1 H NMR: (400MHz, CDCl3)

[0404] δ8.39(d,J=8.0Hz,2H),8.05(s,1H),7.29(d,J=8.4Hz,2H),6.46(s,1H),3.95(s,2H),3.81-3.84(m,3H),2.88-2.99(m,2H ),2.43(s,3H),1.98(t,J=10.0Hz,1H),1.70-1.81(m,2H),1.57-1.69(m,3H),0.93(d,J=12.4Hz,1H),0.87(d,J=5.6Hz,3H)

[0405] LCMS: m / z = 539.9(M+H) + Rt = 1.063 min

[0406] 2. General steps for preparing 7-methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-tolylsulfonyl)-4-(trifluoromethyl)pyrrolo[2,3-c]pyridine

[0407] To a DMF (8 mL) solution of 4-iodo-7-methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)pyrrolo[2,3-c]pyridine (200 mg, 370 μmol), methyl 2,2-difluoro-2-fluorosulfonyl-acetate (143 mg, 744 μmol) and CuI (106 mg, 556 μmol) were added. The mixture was stirred at 90 °C for 2 hours under N2. TLC (PE / EtOAc = 3 / 1, product 1R) f =0.60) showed the formation of new spots. The reaction mixture was slowly poured into a saturated aqueous solution of NH4Cl (10.0 mL). The mixture was extracted with EtOAc (10.0 mL × 2). The organic phase was washed with brine (20.0 mL), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0-10 / 1). 7-Methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)pyrrolo[2,3-c]pyridine (60.0 mg, 121 μmol, 32.8% yield, 97.7% purity) was given as a yellow solid, confirmed by LCMS.

[0408] LCMS: m / z = 482.0(M+H) + Rt = 1.073

[0409] 3. General steps for preparing 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-tolylsulfonyl)-4-(trifluoromethyl)-6H-pyrrolo[2,3-c]pyridin-7-one

[0410] A solution of 7-methoxy-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)pyrrolo[2,3-c]pyridine (60.0 mg, 124 μmol) in HCl / dioxane (4 M, 2 mL). The mixture was stirred at 50 °C for 1 hour under N2. TLC (DCM / MeOH = 10 / 1, product 1R) f =0.40) showed the formation of new spots. The reaction mixture was slowly poured into a saturated NaHCO3 aqueous solution (30 mL) and the pH was adjusted to 8 (saturated NaHCO3 aqueous solution). The aqueous phase was extracted with EtOAc (20 mL × 2). The organic phase was washed with brine (30 mL), dried over Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0-19 / 1). 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)-6H-pyrrolo[2,3-c]pyridin-7-one (60.0 mg, 112 μmol, 90.0% yield, 87.4% purity) was given as a yellow solid, confirmed by LCMS.

[0411] LCMS: m / z = 468.0(M+H) + Rt = 0.465 min

[0412] 4. General steps for preparing 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-toluenesulfonyl-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0413] To a NMP (1.00 mL) solution of 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)-6H-pyrrolo[2,3-c]pyridin-7-one (30.0 mg, 64.1 μmol) and 3-((1s,3s)-1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (21.6 mg, 70.5 μmol), K3PO4 (40.9 mg, 192 μmol), DMEDA (11.3 mg, 128 μmol), and CuI (12.2 mg, 64.0 μmol) were added. The suspension was degassed under vacuum and purged several times with N2. The mixture was stirred at 130 °C for 1 hour under N2. TLC (DCM / MeOH = 10 / 1, product 1R) was recorded. f =0.35) showed the formation of new spots. The reaction mixture was slowly poured into a saturated aqueous solution of NH4Cl (10 mL). The mixture was extracted with EtOAc (10.0 mL × 2). The organic phase was washed with brine (20.0 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0-15 / 1). 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-toluenesulfonyl-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30.0 mg, 33.7 μmol, 52.5% yield, 77.9% purity) was obtained as a yellow solid and confirmed by LCMS.

[0414] LCMS: m / z = 693.2(M+H) + Rt = 1.278 min

[0415] 5. General steps for preparing 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (compound T058)

[0416] KOH (72.9 mg, 1.30 mmol) was added to a solution of 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-1-toluenesulfonyl-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30.0 mg, 43.3 μmol) in MeOH (3.00 mL). The mixture was stirred at 40 °C for 1 hour under N2. The desired mass was detected by LCMS. The reaction mixture was diluted with EtOAc (30.0 mL), washed with brine (30.0 mL), and dried over Na2SO4. The organic phase was concentrated under vacuum. The crude product was purified by Prep-HPLC (column: Ultimate C18 150×40mm×10μm; mobile phase: [water (HCl)-ACN]; gradient: 8%-48% B, over 30 minutes). 6-(3-((1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (11.8 mg, 20.0 μmol, 46.3% yield, 97.71% purity, HCl) was obtained as a white solid and confirmed by 1H NMR and LCMS.

[0417] 1 H NMR: (400MHz, CD3CN)

[0418] δ12.49(s,1H),8.76(s,1H),7.61(d,J=6.0Hz,2H),7.51-7.59(m,2H),7.43(d,J=7 .2Hz,1H),6.62(s,1H),4.24-4.40(m,2H),3.44(s,3H),3.31-3.36(m,1H),3.23(br d,J=12.0Hz,1H),2.74-2.90(m,2H),2.55-2.72(m,4H),2.42-2.51(m,1H),2.03-2.14(m ,1H),1.80-1.91(m,3H),1.14-1.20(m,1H),1.13(d,J=5.2Hz,3H),0.92(d,J=6.4Hz,3H)

[0419] LCMS: m / z = 539.2(M+H) + Rt = 1.588 min

[0420] Example 2: Synthesis of compound P01

[0421] The synthesis route is as follows:

[0422] The specific steps are as follows:

[0423] 1. A general method for preparing (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl dodecanoate.

[0424] Under N2 and 25°C, 6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-[[racemic-(3S)-3-methyl-1-piperidinyl]methyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridin-7-one (100 mg, 185 μmol) was added to the mixture, followed by the addition of methyl dodecanoate (139 mg, 558 μmol) at 25°C and N2. The mixture was stirred at 25°C and N2 for 12 hours. LCMS (EB6211-811-P1A) showed the desired mass was detected. Brine (5.00 mL) was slowly added to the reaction mixture at 0°C. The mixture was extracted with ethyl acetate (5.00 mL x 2). The organic phase was washed with brine (5.00 mL * 2), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 40 × 200 mm 7 μm; mobile phase: [water (FA)-ACN]; gradient: 26.0%-66.0% B, 25 min). Methyl (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)dodecanoate (29.0 mg, 34.7 μmol, yield 18.7%, purity 95.5%, FA) was obtained as a white solid, which was confirmed by 1H NMR (EB6211-811-P1A H NMR), 1F NMR (EB6211-811-P1A F NMR), LCMS (EB6211-811-P1A1 LCMS) and HPLC (EB6211-811-P1A2 HPLC).

[0425] LCMS:EB6211-811-P1A,m / z=751.3(M+H) + Rt = 1.742 min

[0426] 1 H NMR:EB6211-811-P1A H NMR, (400MHz, DMSO-d6)

[0427] δ8.29(s,1H),7.83(d,J=1.2Hz,1H),7.47-7.55(m,2H),7.34(dd,J=8.0,1.6Hz,2H),6.50-6.57(m,2H),6.44(d,J=1.2Hz,1H),3.63(br s,2H),3.22(s,3H),2.83-2.89(m,2H),2.67-2.72(m,2H),2.53(br d,J=6.0Hz,2H),2.25(t,J=7.2Hz,2H),1.90(br t,J=10.8Hz,1H),1.56-1.67(m,3H),1.36-1.53(m,4H),1.10-1.32(m,18H),1.06(d,J=5.2Hz,3H),0.82-0.86(m,3H),0.79-0.81(m,3H)

[0428] F NMR: EB6211-811-P1A F NMR

[0429] LCMS:EB6211-811-P1A1 LCMS, m / z=751.4(M+H) + Rt = 1.437 min

[0430] HPLC: EB6211-811-P1A2 HPLC, Rt=6.234min

[0431] Example 3: Synthesis of compound PO2

[0432] The synthesis route is as follows:

[0433] The specific steps are as follows:

[0434] 1. A general method for preparing chloromethyl 2,2-dimethyldodecanoate

[0435] Na₂CO₃ (556 mg, 5.25 mmol) and hydrogen sulfate were added; tetrabutylammonium (44.6 mg, 131 μmol) was added to a solution of 2,2-dimethyldodecanoic acid (300 mg, 1.31 mmol) in dichloromethane (4.00 mL) and H₂O (5.00 mL), and stirred at 0 °C for 5 minutes. Then, a solution of chloro(chlorosulfonyloxy)methane (260 mg, 1.58 mmol) in dichloromethane (1.00 mL) was added dropwise to the mixture at 0–5 °C and N₂. The mixture was stirred at 25.0 °C for 4 hours. TLC (petroleum ether:ethyl acetate = 5 / 1, product 1R) f =0.78) showed the formation of new spots. The reaction mixture was extracted with dichloromethane (10.0 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 55 / 1 to 50 / 1). Compound chloromethyl 2,2-dimethyldodecanoate (305 mg, 1.10 mmol, yield 83.8%) was given as a colorless oil, which was confirmed by 1H NMR (EB12379-59-P1B1 1H NMR).

[0436] 1 H NMR:EB12379-59-P1B1 H NMR, (400MHz, CHLOROFORM-d)

[0437] δ5.71(s,2H),1.52-1.59(m,2H),1.22-1.35(m,16H),1.19(s,6H),0.81-0.96(m,3H)

[0438] 2. A general method for preparing (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl 2,2-dimethyl dodecanoate

[0439] A solution of 6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridin-7-one (280 mg, 519 μmol), methyl 2,2-dimethyldodecanoate (287 mg, 1.04 mmol), KI (25.8 mg, 155 μmol), and K₂CO₃ (143 mg, 1.04 mmol) in DMF (10.0 mL) was degassed and purged three times with N₂. The mixture was then stirred at 50.0 °C under an N₂ atmosphere for 10.0 h. LCMS (EB12379-63-P1A4) showed the desired mass was detected. The reaction mixture was diluted with 50.0 mL of ethyl acetate and quenched by adding 50.0 mL of semi-saturated NaCl at 25.0 °C, followed by washing with 3 x 50.0 mL of semi-saturated NaCl. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: F-Prepulite XP tC 18 40.0*200 mm*7 μm; mobile phase: [water (FA)-ACN]; gradient: 30.0%-70.0% B, 20.5 min), and the pH of the solution was adjusted to 8.00 (NaHCO₃, solid). The mixture was concentrated under vacuum to remove ACN. The mixture was extracted with ethyl acetate (20.0 mL x 2). The organic phase was washed with brine (20.0 mL), dried over Na₂SO₄, and concentrated under vacuum. The compound (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl 2,2-dimethyl dodecanoate (51.2 mg, 64.8 μmol, yield 12.5%, purity 98.7%) was obtained as a white solid. It was determined by ¹H NMR (EB12379-63-P1H1 ¹H NMR) and F NMR (EB12379-63-P1H1 F NMR). The results were confirmed by NMR, LCMS (EB12379-63-P1F1), HPLC (EB12379-63-P1G1), and SFC (EB12379-63-P1G3).

[0440] LCMS:EB12379-63-P1A4,m / z=779.4(M+H) + ,R t =1.677min

[0441] 1H NMR:EB12379-63-P1H1 H NMR, (400MHz, DMSO-d6)

[0442] δ8.29(s,1H),7.83(s,1H),7.44-7.56(m,2H),7.28-7.37(m,2H),6.50(s,2H),6.44(s,1H),3.67(s,2H),3.21(s,3H),2.84(br d,J=3.2Hz,2H),2.67-2.73(m,2H),1.86-1.97(m,1H),1.50-1.68(m,5H),1.31-1.37(m,2H),0.99-1.19(m,26H),0.75-0.91(m,9H)

[0443] F NMR: EB12379-63-P1H1 F NMR

[0444] LCMS:EB12379-63-P1F1,m / z=779.5(M+H) + ,R t =2.363min

[0445] HPLC: EB12379-63-P1G1,R t =4.342min

[0446] SFC:EB12379-63-P1G3,R t =1.383min

[0447] Example 4: Synthesis of compound PO3

[0448] The synthesis route is as follows:

[0449] The specific steps are as follows:

[0450] 1. A general method for preparing chloromethyldecyl (methyl)carbamate

[0451] A solution of N-methyldecane-1-amine (250 mg, 1.20 mmol, HCl), DIEA (233 mg, 1.80 mmol, 314 μL), and DMAP (29.4 mg, 240 μmol) in dichloromethane (6.00 mL) was degassed and purged three times with N2. Chloromethyl carbide (170 mg, 1.32 mmol, 117 μL) was added to the mixture at 0 °C and N2, and the mixture was stirred at 25 °C and N2 atmosphere for 3 hours. LCMS (EB6214-763-P1A3) showed detection of the desired compound. The reaction mixture was diluted with an aqueous solution of NaHCO3O (8.00 mL), extracted with dichloromethane (12.0 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0% to 8%), (plate 1, petroleum ether / ethyl acetate = 5 / 1, R... f (Product) = 0.57). The compound chloromethyl N-decyl-N-methyl-carbamate (209 mg, crude product) was obtained as a colorless oil. This was confirmed by ¹H NMR (EB6214-763-P1C2).

[0452] LCMS:EB6214-763-P1A3,m / z=264.1(M+H) +, Rt = 1.540 min

[0453] 1 H NMR:EB6214-763-P1C2, (400MHz, DMSO-d6)

[0454] δ5.87(d,J=3.2Hz,2H),3.22(q,J=6.8Hz,2H),2.85(s,3H),1.43-1.51(m,2H),1.24(s,14H),0.81-0.89(m,3H)

[0455] 2. A general method for preparing (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyldecyl(methyl)carbamate

[0456] At 25°C, 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (200 mg, 371 μmol) was added dropwise to a KOH (62.5 mg, 1.11 mmol) DMF (2.00 mL). The mixture was stirred at 25°C and N2 for 30 min. Chloromethyl N-decyl-N-methylcarbamate (195 mg, 742 μmol) was added to the mixture and stirred for 2 h. LCMS (EB6214-768-P1A2) showed detection of the desired compound. The reaction mixture was diluted with NH4Cl (12.0 mL) at 0 °C, extracted with ethyl acetate (10.0 mL * 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: F-Prepulite XP tC 18 40 × 200 mm × 7 μm; mobile phase: [water (FA)-ACN]; gradient: 24.0%-64.0% B, 20.5 min). Neutralization with saturated NaHCO3 was then performed. The compound (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyldecyl(methyl)carbamate (113 mg, 147 μmol, yield 39.8%, purity 99.7%) was obtained as a white solid and was confirmed by ¹H NMR (EB6214-768-P1D3), F NMR (EB6214-768-P1D3), LCMS (EB6214-768-P1D1), and HPLC (EB6214-768-P1D2).

[0457] LCMS:EB6214-768-P1A2,m / z=766.5(M+H) +, Rt = 0.603 min

[0458] 1 H NMR:EB6214-768-P1D3,(400MHz,DMSO-d6)

[0459] δ8.29(s,1H),7.81(s,1H),7.44-7.54(m,2H),7.29-7.37(m,2H),6.47(s,2H),6.40(s,1 H),3.67(s,2H),3.22(s,3H),3.16(s,1H),3.06(s,1H),2.85(s,2H),2.77(s,2H),2.69( s,3H),2.53(s,3H),1.90(t,J=9.6Hz,1H),1.54-1.66(m,4H),1.42(s,2H),1.22(s,8H), 1.12(s,2H),1.06(d,J=4.4Hz,3H),0.97(s,4H),0.83-0.90(m,2H),0.80(d,J=6.0Hz,6H)

[0460] F NMR:EB6214-768-P1D3,(400MHz,DMSO-d6)

[0461] LCMS:EB6214-768-P1D1,m / z=766.5(M+H) +, Rt = 2.763 min

[0462] HPLC:EB6214-768-P1D2,Rt=4.781

[0463] Example 5: Synthesis of compound PO4

[0464] The synthesis route is as follows:

[0465] The specific steps are as follows:

[0466] 1. A general method for preparing (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyldecanoate

[0467] KOH (31.5 mg, 556 μmol) was added dropwise to a DMF (1.00 mL) solution of 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (100 mg, 185 μmol). After addition, the mixture was stirred at 25 °C and N2 for 30 min. Chloromethyl decanoate (81.9 mg, 371 μmol) was added to the mixture and stirred for 2 h. LCMS (EB6214-772-P1A1) showed detection of the desired compound. The reaction mixture was diluted with NH4Cl (12.0 mL) at 0 °C, extracted with ethyl acetate (10.0 mL * 3), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: F-Prepulite XP tC 18 40 × 200 mm × 7 μm; mobile phase: [water (FA)-ACN]; gradient: 24.0%-64.0% B, 20.5 min). Neutralization with saturated NaHCO3 was then performed. The compound (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)decanoate (113 mg, 154 μmol, yield 83.4%, purity 98.6%) was obtained as a white solid and was confirmed by ¹H NMR (EB6214-772-P1D3), F NMR (EB6214-772-P1D3), LCMS (EB6214-772-P1D1), and HPLC (EB6214-772-P1D2).

[0468] LCMS:EB6214-772-P1A1,m / z=723.5(M+H) +, Rt = 0.587 min

[0469] 1 H NMR:EB6214-772-P1D3,(400MHz,DMSO-d6)

[0470] δ8.29(s,1H),7.84(s,1H),7.48-7.53(m,2H),7.35(s,2H),6.54(s,2H),6.45( s,1H),3.63(s,2H),3.22(s,3H),2.86(s,2H),2.69(d,J=8.0Hz,2H),2.53(d,J =6.0Hz,2H),2.26(t,J=7.2Hz,2H),1.90(t,J=10.8Hz,1H),1.54-1.67(m,4H), 1.42-1.51(m,3H),1.12-1.24(m,14H),1.07(d,J=4.4Hz,3H),0.78-0.83(m,6H)

[0471] F NMR:EB6214-772-P1D3,(400MHz,DMSO-d6)

[0472] LCMS:EB6214-772-P1D1,m / z=723.4(M+H) +, Rt = 2.607 min

[0473] HPLC:EB6214-772-P1D2,Rt=4.500

[0474] Example 6: Synthesis of compound P05

[0475] The synthesis route is as follows:

[0476] The specific steps are as follows:

[0477] 1. A general method for preparing chloromethyl tetradecanoate

[0478] Na₂CO₃ (1.86 g, 17.5 mmol) and hydrogen sulfate were added; tetrabutylammonium (149 mg, 438 μmol) was added to a solution of tetradecanoic acid (1.00 g, 4.38 mmol) in dichloromethane (6.00 mL) and H₂O (7.00 mL), and the mixture was stirred at 0 °C for 5 min. Then, a solution of chloro(chlorosulfonyloxy)methane (867 mg, 5.25 mmol) in dichloromethane (1.00 mL) was added dropwise to the mixture at 0–5 °C and N₂. The mixture was stirred at 20 °C for 4 h. TLC (petroleum ether:ethyl acetate = 5:1, product 1Rf = 0.65) showed that most of the reactants were consumed and a new main spot was formed. The reaction mixture was extracted with dichloromethane (10.0 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 100:0 to 5:1). Chloromethyl tetradecanoate (859 mg, 3.10 mmol, 70.9% yield) was given as a white solid, confirmed by ¹H NMR (EB11563-274-P1A1).

[0479] 1 H NMR:EB11563-274-P1A1 H NMR, (400MHz, CDCl3)

[0480] δ5.71(s,2H),2.39(t,J=7.6Hz,2H),1.31(br s,4H),1.27(s,18H),0.84-0.93(m,3H)

[0481] 2. A general method for preparing [6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-7-oxo-4-(trifluoromethyl)pyrrolo[2,3-C]pyridin-1-yl]methyltetradecanoate

[0482] KOH (59.4 mg, 1.06 mmol) was added to DMF (6.00 mL). 6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridin-7-one (190 mg, 353 μmol) was added to the mixture, and the mixture was stirred at 20 °C for 5 minutes. Chloromethyl tetradecanoate (195.32 mg, 705.53 μmol, 2.0 equivalent) was added dropwise to the mixture at 25 °C, and the mixture was stirred at 25 °C for 2 hours. LCMS (EB11563-287-P1A1) showed that the reactants were consumed and the desired mass was detected. Slowly add a saturated aqueous solution of NH4Cl to the reaction mixture at 0°C to adjust the pH to 7-8 (saturated NH4Cl aqueous solution). Dilute the mixture with brine (2.00 mL) and extract with ethyl acetate (20.0 mL × 3). Wash the organic phase with brine (15.0 mL × 3), dry with Na2SO4, and concentrate under vacuum. [6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-2-[[(3S)-3-methyl-1-piperidinyl]methyl]-7-oxo-4-(trifluoromethyl)pyrrolo[2,3-C]pyridin-1-yl]tetradecanoate (400 mg, crude) is obtained as a yellow oil, confirmed by LCMS (EB11563-287-P1B1).

[0483] LCMS:EB11563-287-P1A1,m / z=779.3(M+H) + Rt = 1.225 min

[0484] LCMS:EB11563-287-P1B1,m / z=779.5(M+H) + Rt = 6.098 min

[0485] Example 7: Synthesis of compound P06

[0486] The synthesis route is as follows:

[0487] The specific steps are as follows:

[0488] 1. A general method for preparing 6-(3-((1S,3R)-1-(5-(hydroxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one

[0489] To a solution of 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (100 mg, 185 μmol) in dioxane (2.00 mL), K₂CO₃ (77.0 mg, 557 μmol) was added, followed by the addition of (HCHO) in three portions to the mixture. n (150 mg). The mixture was stirred at 90 °C and N2 for 3 hours. LCMS (EB6211-683-P1D) showed the desired mass. The reaction mixture was diluted with brine (10.0 mL) and extracted with ethyl acetate (10.0 mL * 2). The organic phase was dried over Na2SO4 and concentrated under vacuum. Unpurified. 6-(3-((1S,3R)-1-(5-(hydroxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (100 mg, crude) was given as a yellow solid.

[0490] LCMS:EB6211-683-P1D,m / z=569.0(M+H) + Rt = 1.068 min

[0491] 2. A general method for preparing (4-methyl-5-((1S,3R)-3-methyl-1-(3-(2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-1,7-dihydro-6H-pyrrolo[2,3-C]pyridin-6-yl)phenyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)methyldiphenyl phosphate

[0492] TEA (53.3 mg, 527 μmol) was added to a solution of 6-(3-((1S,3R)-1-(5-(hydroxymethyl)-4-methyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (100 mg, 175 μmol) in dichloromethane (4.00 mL). The mixture was stirred at 25 °C and N2 for 1 h. LCMS (EB6211-685-P1B) showed the desired mass. The reaction mixture was concentrated under vacuum at 25 °C. The reaction mixture was diluted with brine (10.0 mL) and extracted with ethyl acetate (10.0 mL * 2). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 40×200 mm 7 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 52.0%-92.0% B, 25 min). (4-Methyl-5-((1S,3R)-3-methyl-1-(3-(2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-1,7-dihydro-6H-pyrrolo[2,3-C]pyridin-6-yl)phenyl)cyclobutyl)-4H-1,2,4-triazol-3-yl)methyldiphenyl phosphate (12.6 mg, 15.0 μmol, yield 8.58%, purity 95.9%) was obtained as a white solid, confirmed by LCMS (EB6211-685-P1A1), HPLC (EB6211-685-P1A2), SFC (EB6311-685-P1 ASFC), and NOE (EB8211-685P1B).

[0493] LCMS:EB6211-685-P1B,m / z=801.3(M+H) + Rt = 1.830 min

[0494] 1 H NMR:EB6211-685-P1A H NMR, (400MHz, DMSO-d6)

[0495] δ12.21-12.60(s,1H),7.69(s,1H),7.61(s,1H),7.43-7.49(m,1H),7.37(t,J=7.6Hz,5H),7.28(d,J= 7.6Hz,1H),7.19-7.26(m,2H),7.16(d,J=8.0Hz,4H),6.28(s,1H),5.42(d,J=9.2Hz,2H),3.56-3.65(m ,2H),3.18(s,3H),2.85-2.92(m,2H),2.76(s,2H),2.51-2.58(m,1H),2.43-2.49(m,2H),1.86-1.96( m,1H),1.55-1.67(m,4H),1.42-1.51(m,1H),1.04(d,J=5.6Hz,3H),0.81(d,J=5.6Hz,3H),0.75(m,1H)

[0496] F NMR: EB6211-685-P1A F NMR

[0497] LCMS:EB6211-685-P1A1,m / z=801.1(M+H) + Rt = 1.482 min

[0498] HPLC:EB6211-685-P1A2, purity:95.9%

[0499] SFC:EB6211-685-P1A SFC,Rt=0.875min

[0500] NOE:EB6211-685-P1B

[0501] Example 8: Synthesis of compound P07

[0502] The synthesis route is as follows:

[0503] The specific steps are as follows:

[0504] 1. General method for preparing 2-ethylbutyl((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ester

[0505] Dichlorophosphoryloxybenzene (13.0 g, 52.8 mmol, 9.22 mL, HCl) was added dropwise to a solution of 2-ethylbutyl (2S)-2-aminopropionic acid (10.0 g, 47.6 mmol, HCl) in dichloromethane (100 mL), followed by the slow addition of TEA (10.6 g, 104 mmol, 14.6 mL) at -78 °C and N2. After addition, the mixture was stirred at -78 °C for 2 h and then at 25 °C for 18 h. TEA (5.31 g, 52.4 mmol, 7.30 mL) was added to the mixture at 0 °C, followed by the slow addition of a solution of 4-nitrophenol (6.63 g, 47.6 mmol) in DCM (50.0 mL). The mixture was stirred at 0 °C for 2 h and then at 25 °C for 6 h. LCMS (EB6214-585-P1B6) showed detection of the desired compound. The reaction mixture was concentrated and diluted with ethyl acetate (20.0 ml). The combined organic layers were washed with 10% K₂CO₃ aqueous solution (15.0 ml * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 7.00% to 15.0%), (plate 1, petroleum ether / ethyl acetate = 3 / 1, R...). f (Product) = 0.42). Compound 2-ethylbutyl((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ester (2.10 g, crude) was obtained as a colorless oil. It was confirmed by LCMS (EB6214-585-P1G1).

[0506] LCMS:EB6214-585-P1B6,m / z=451.0(M+H) + Rt = 1.910 min

[0507] LCMS:EB6214-585-P1G1,m / z=451.1(M+H) + Rt = 1.610 min

[0508] 2. General method for preparing ((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine 2-ethylbutyl ester

[0509] A solution of 2-ethylbutyl((4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine (2.00 g, 4.44 mmol) and I-Pr₂O (14.40 g, 140 mmol, 20.0 mL) was mixed. The mixture was stirred at 0 °C for 1 hour. The mixture was filtered and concentrated under reduced pressure to obtain the residue. Compound 2-ethylbutyl((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ester (390 mg, purity: 100%) was given as a white solid. The compound was confirmed by ¹H NMR (EB6214-616-P1C1), HPLC (EB6214-616-P1C1), and SFC (EB6214-616-P1D1).

[0510] 1 H NMR:EB6214-616-P1C1(DMSO-d6,400MHz)

[0511] δ8.23(s,1H),8.20(s,1H),7.38-7.42(m,2H),7.31-7.36(m,2H),7.23(s,1H),7.21(d,J=0.8Hz,1H),7.16-7.20(m,1H), 4.11-4.18(m,1H),4.02-4.07(m,2H),1.46-1.52(m,1H),1.40(d,J=7.2Hz,3H),1.27-1.37(m,5H),0.86(t,J=7.2Hz,6H)

[0512] HPLC:EB6214-616-P1C1,Purity=100%

[0513] SFC:EB6214-616-P1D1

[0514] 3. A general method for preparing (R)-3-(((R)-(((S)-1-(2-ethylbutoxy)-1-oxopropyl-2-yl)amino)(phenoxy)phosphoryl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0515] 2-Ethylbutyl-2-ethylbutyl((S)-(4-nitrophenoxy)(phenoxy)phosphoryl)-L-alanine ester (174 mg, 387 μmol) and tert-butyl(R)-3-hydroxypiperidine-1-carboxylic acid ester (65.0 mg, 322 μmol) were added to THF (2.00 mL), and MgCl2 (30.7 mg, 322 μmol, 13.2 μL) was added to the mixture. The mixture was heated to 50 °C and stirred for 20 minutes. DIEA (104 mg, 807 μmol, 140 μL) was added to the mixture, and the mixture was stirred at 50 °C under a N2 atmosphere for 1 hour. TLC showed no residue of reactant 1. The reaction mixture was diluted with NH4Cl aqueous solution (8.00 mL), extracted with ethyl acetate (12.0 mL * 3), the combined organic layers were washed with H2O (8.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1), (plate 1, petroleum ether / ethyl acetate = 1 / 1, R) f (Product) = 0.5). The compound (R)-3-(((R)-(((S)-1-(2-ethylbutoxy)-1-oxopropyl-2-yl)amino)(phenoxy)phosphoryl)oxy)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 134 μmol, yield 41.5%) was obtained as a colorless oil. It was confirmed by LCMS (EB6214-638-P1D2).

[0516] LCMS:EB6214-638-P1D2,m / z=513.2(M+H) + Rt = 1.980 min

[0517] 4. A general method for preparing 2-ethylbutyl((R)-phenoxy(((R)-piperidin-3-yl)oxy)phosphoryl)-L-alanine ester

[0518] To a solution of (R)-3-(((R)-((((S)-1-(2-ethylbutoxy)-1-oxopropyl-2-yl)amino)(phenoxy)phosphoryl)oxy)piperidin-1-carboxylic acid tert-butyl ester (60.0 mg, 117 μmol) in dichloromethane (1.00 mL), HCl / dioxane (2 M, 0.50 mL) was added dropwise. After addition, the mixture was stirred at 25 °C for 1 hour. LCMS (EB6214-656-P1A2) showed detection of the desired compound. The residue was concentrated under reduced pressure to give compound 2-ethylbutyl((R)-phenoxy(((R)-piperidin-3-yl)oxy)phosphoryl)-L-alanine ester (36.0 mg, crude) as a colorless oil.

[0519] LCMS:EB6214-656-P1A2,m / z=413.5(M+H) + Rt = 0.662 min

[0520] 5. A general method for preparing 2-ethylbutyl((R)-((R)-1-((6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-2-yl)methyl)piperidin-3-yl)oxy)(phenoxy)phosphoryl)-L-alanine ester

[0521] TEA (8.83 mg, 87.2 μmol, 12.1 μL) was added dropwise to a solution of 6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridine-2-carboxaldehyde (30.8 mg, 69.8 μmol) in dichloromethane (1.00 mL) to adjust the pH to 7. 2-ethylbutyl((R)-phenoxy((R)-piperidin-3-yloxy)phosphono)-L-alanine salt (36.0 mg, 87.2 μmol) was added to the mixture, and the mixture was stirred at 25 °C for 0.5 h. Then, NaBH(OAc)3 (46.2 mg, 218 μmol) was added to the mixture, and the mixture was stirred at 25 °C for 1 h. LCMS (EB6214-659-P1A2) showed detection of the desired compound. The reaction mixture was diluted with aqueous NaHCO3 solution (8.00 mL), extracted with dichloromethane (12.0 mL * 3), and the combined organic layers were washed with H2O (8.00 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. SFC (EB6214-659-P1O1) showed two peaks. The residue was purified by SFC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: [Co2-i-PrOH (0.1% NH3H2O)]; B%: 50.0%, isocratic elution mode) and preparative HPLC (column: Daicel Chiralpak AD (250 mm × 30 mm, 10 μm); mobile phase: [CO2-i-PrOH (0.1% NH3H2O)]; B%: 50.0%, isocratic elution mode). The compound 2-ethylbutyl-2-ethylbutyl((R)-(((R)-1-((6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-2-yl)methyl)piperidin-3-yl)oxy)(phenoxy)phosphoryl)-L-alanine ester (14.9 mg, 17.5 μmol, yield 20.1%, purity 98.7%) was obtained as a white solid. It was analyzed by ¹H NMR (EB6214-659-P1G3), F-NMR (EB6214-659-P1G3), LCMS (EB6414-659P1H1), HPLC (EB 6214-659P1G2), and SFC (EB6414-659P1H1). 6414-659p1G2) confirmed.

[0522] LCMS:EB6214-659-P1A2,m / z=838.5(M+H) + Rt = 0.775 min

[0523] H NMR:EB6214-659-P1G3(DMSO-d6,400MHz)

[0524] δ12.47(s,1H),8.35(s,1H),7.73(d,J=1.2Hz,1H),7.48-7.54(m,1H),7.43(s,1H),7.35(d,J=8.0Hz,1H),7.28-7.33(m,2H),7.2 6(d,J=8.0Hz,1H),7.10-7.16(m,3H),6.29(s,1H),4.20-4.36(m,1H),3.91-3.97(m,2H),3.75-3.83(m,1H),3.67(d,J=2.8Hz,2H) ,3.27(s,3H),2.91-2.97(m,3H),2.68-2.74(m,2H),2.61(s,1H),2.04-2.11(m,2H),1.99(dd,J=8.0,5.2Hz,2H),1.83-1.91(m,1H ),1.64-1.72(m,1H),1.41-1.47(m,2H),1.29-1.32(m,2H),1.28(s,2H),1.26(s,2H),1.20(d,J=7.2Hz,3H),0.82(t,J=7.2Hz,6H)

[0525] F NMR: EB6214-659-P1G3

[0526] HPLC: EB6214-659-P1G2, Purity=98.7%

[0527] SFC:EB6214-659-P1G2

[0528] Example 9: Synthesis of compound P08

[0529] The synthesis route is as follows:

[0530] The specific steps are as follows:

[0531] 1. A general method for preparing (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl neopentyl ester

[0532] At 25°C and N2, 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (60.0 mg, 111 μmol) was added to a solution of KOH (18.8 mg, 335 μmol) in DMF (4.00 mL), and the mixture was stirred at 25°C and N2 for 0.5 h. Then, methyl 2,2-dimethylpropionate (50.3 mg, 334 μmol) was added to the mixture at 25°C and N2. The mixture was stirred at 25°C and N2 for 2 h. LCMS (EB6211-770-P1A) showed the desired mass was detected. The reaction mixture was slowly poured into brine (5.00 mL). The mixture was extracted with ethyl acetate (5.00 mL × 2). The organic phase was washed with brine (5.00 mL × 2), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 40 × 200 mm 7 μm; mobile phase: [water (NH₃H₂O + NH₄HCO₃) - ACN]; gradient: 60.0% - 100% B, 25 min). Methyl neopentanoate (6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)neopentaate (23.2 mg, 35.5 μmol, yield 31.9%, purity 100%) was obtained as a white solid and confirmed by ¹H NMR (EB6211-770-P1A ¹H NMR), F NMR (EB6211-770-P1A F NMR), LCMS (EB6211-770-P1A1 LCMS), and HPLC (EB6211-770-P1A2 HPLC).

[0533] LCMS:EB6211-770-P1A,m / z=653.2(M+H) + Rt = 1.285 min

[0534] 1 H NMR:EB6211-770-P1A H NMR, (400MHz, DMSO-d6)

[0535] δ8.28(s,1H),7.83(d,J=1.2Hz,1H),7.48-7.55(m,2H),7.33(t,J=8.4Hz,2H),6.50( s,2H),6.45(s,1H),3.60-3.69(m,2H),3.21(s,3H),2.82-2.91(m,2H),2.69(d,J=8. 4Hz,2H),2.53(d,J=2.4Hz,3H),1.92(t,J=10.4Hz,1H),1.54-1.70(m,4H),1.37-1.4 7(m,1H),1.09(s,9H),1.06(d,J=5.2Hz,3H),0.84-0.92(m,1H),0.81(d,J=6.4Hz,3H)

[0536] F NMR: EB6211-770-P1A F NMR

[0537] LCMS:EB6211-770-P1A1 LCMS, m / z=653.2(M+H) + Rt = 2.032 min

[0538] HPLC:EB6211-770-P1A2 HPLC, purity:100%

[0539] Example 10: Synthesis of compound P09

[0540] The synthesis route is as follows:

[0541] The specific steps are as follows:

[0542] 1. A general method for preparing 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((5-methyl-2-oxo-1,3-dioxacyclopentan-4-yl)methyl)-2-((S)-3-methylpiperidin-1-yl)methyl-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[0543] At 25°C and N2, 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (60.0 mg, 111 μmol) was added to a solution of KOH (18.8 mg, 335 μmol) in DMF (3.00 mL), and the mixture was stirred at 25°C and N2 for 0.5 hours. Then, 4-(chloromethyl)-5-methyl-1,3-dioxacyclopenten-2-one (49.6 mg, 333 μmol) was added to the mixture at 25°C and N2. The mixture was stirred at 25°C and N2 for 2 hours. LCMS (EB6211-784-P1D) showed the desired mass was detected. Brine (5.00 mL) was slowly added to the reaction mixture at 0 °C. The mixture was extracted with ethyl acetate (5.00 mL * 2). The organic phase was washed with brine (5.00 mL * 2), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 40 × 200 mm 7 μm; mobile phase: [water (NH₃H₂O + NH₄HCO₃) - ACN]; gradient: 50.0% - 90.0% B, 25 min). 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-1-((5-methyl-2-oxo-1,3-dioxacyclopentan-4-yl)methyl)-2-((S)-3-methylpiperidin-1-ylmethyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (10.0 mg, 14.6 μmol, yield 13.1%, purity 95.1%) was obtained as a grayish-white solid. It was analyzed by ¹H NMR (EB6211-784-P1A ¹H NMR), F NMR (EB6211-784-P1A F NMR), and LCMS (EB6211-784-P1C2 LCMS). HPLC (EB6211-784-P1C1 HPLC) confirmed this.

[0544] LCMS:EB6211-784-P1D,m / z=651.2(M+H) + Rt = 1.198 min

[0545] 1 H NMR:EB6211-784-P1A H NMR, (400MHz, DMSO-d6)

[0546] δ8.29(s,1H),7.79(s,1H),7.54(s,1H),7.49-7.53(m,1H),7.34(t,J=9.2Hz,2H), 6.41(s,1H),5.85(s,2H),3.66(s,2H),3.22(s,3H),2.86(d,J=3.2Hz,2H),2.68(d, J=8.0Hz,2H),2.53(s,3H),2.09(s,3H),1.91(t,J=10.8Hz,1H),1.55-1.69(m,4H) ,1.39-1.49(m,1H),1.06(d,J=5.2Hz,3H),0.84-0.92(m,1H),0.81(d,J=6.4Hz,3H)

[0547] F NMR: EB6211-784-P1A F NMR

[0548] LCMS:EB6211-784-P1C2 LCMS, m / z=651.3(M+H) + Rt = 1.925 min

[0549] HPLC:EB6211-784-P1C1 HPLC, purity:95.1%

[0550] Example 11: Synthesis of compound P10

[0551] Example 12: Synthesis of compound T033

[0552] 1. General steps for preparing methyl 1-(3-bromophenyl)cyclobutane carboxylate

[0553] Under N2, at 0 °C, NaH (3.49 g, 87.3 mmol, 60.0% purity) was added to a DMF (100 mL) solution of methyl 2-(3-bromophenyl)acetate (10.0 g, 43.6 mmol) and 1,3-dibromopropane (9.25 g, 45.8 mmol, 4.67 mL). The mixture was stirred at 25 °C for 2 hours under N2. TLC showed the reaction was complete. TLC (plate 1, PE / EtOAc = 5 / 1, iodine (I2), R) f(Product) = 0.5%. The reaction mixture was slowly poured into a saturated aqueous solution of NH4Cl (200 mL). The reaction mixture was diluted with EtOAc (200 mL), washed with brine (200 mL × 3), and dried over Na2SO4. The organic phase was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EtOAc = 1 / 0-94 / 6). The compound methyl 1-(3-bromophenyl)cyclobutanecarboxylate (9.20 g, 34.1 mmol, 78.3% yield) was given as a colorless oil. The result was confirmed by ¹H NMR.

[0554] 1 ¹H NMR: (400MHz, CD₃Cl)

[0555] δ7.47-7.52(m,1H),7.39-7.47(m,1H),7.27-7.34(m,1H),7.22-7.27(m,1H),3.72 (s,3H),2.85-2.92(m,2H),2.50-2.58(m,2H),2.08-2.15(m,1H),1.88-1.99(m,1H)

[0556] 2. General steps for preparing 1-(3-bromophenyl)cyclobutane carbazide

[0557] Under N2, N2H4·H2O (68.1 g, 1.33 mol, 66.0 mL, 98.0% purity) was added to a solution of methyl 1-(3-bromophenyl)cyclobutanecarbamate (9.00 g, 33.4 mmol) in EtOH (20.0 mL). The mixture was stirred at 80 °C for 12 hours under N2. LCMS showed that the reaction was complete. The reaction mixture was concentrated under vacuum. The mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL × 2). The organic phase was dried over Na2SO4 and concentrated under vacuum. The compound 1-(3-bromophenyl)cyclobutanecarbazide (9.00 g, 33.4 mmol, 100% yield) was given as a white solid.

[0558] 3. General steps for preparing 1-[[1-(3-bromophenyl)cyclobutanecarbonyl]amino]-3-methyl-thiourea

[0559] Under N2 at 25 °C, methylimino(thio)methane (3.67 g, 50.1 mmol, 3.43 mL) was added to a solution of 1-(3-bromophenyl)cyclobutanecarbonylhydrazine (9.00 g, 33.4 mmol) in THF (80.0 mL). The mixture was stirred under N2 at 80 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under vacuum to give compound 1-[[1-(3-bromophenyl)cyclobutanecarbonyl]amino]-3-methyl-thiourea (9.00 g, 26.3 mmol, 78.6% yield) as a yellow solid.

[0560] 4. General steps for preparing 5-[1-(3-bromophenyl)cyclobutyl]-4-methyl-1,2,4-triazol-3-thiol

[0561] Under N2 at 25 °C, KOH (5.70 M, 22.5 mL) was added to a THF (10.0 mL) solution of 1-[[1-(3-bromophenyl)cyclobutanecarbonyl]amino]-3-methyl-thiourea (8.80 g, 25.7 mmol). The mixture was stirred under N2 at 80 °C for 3 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under vacuum to give compound 5-[1-(3-bromophenyl)cyclobutyl]-4-methyl-1,2,4-triazol-3-thiol (10.4 g, crude) as a yellow solid.

[0562] 5. General steps for preparing 3-[1-(3-bromophenyl)cyclobutyl]-4-methyl-1,2,4-triazole

[0563] Under N2 at 0 °C, HNO3 (32.2 g, 332 mmol, 23.0 mL, 65.0% purity) and NaNO2 (22.1 g, 321 mmol) were added to a solution of 5-[1-(3-bromophenyl)cyclobutyl]-4-methyl-1,2,4-triazol-3-thiol (10.4 g, 32.1 mmol) in H2O (100 mL) and THF (100 mL). The mixture was stirred under N2 at 0 °C for 3 hours. LCMS showed that the reaction was complete. The mixture was quenched with a saturated aqueous solution of NaHCO3 and then extracted with EtOAc (100 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0-98 / 2). TLC (plate 1, DCM / MeOH = 10 / 1, iodine (I2), R f(Product) = 0.4). The compound 3-[1-(3-bromophenyl)cyclobutyl]-4-methyl-1,2,4-triazole (3.90 g, 13.3 mmol, 41.5% yield) was given as a white solid. The result was confirmed by ¹H NMR.

[0564] 1 H NMR: (400MHz, DMSO-d6)

[0565] δ8.36(s,1H),7.42-7.51(m,1H),7.36(t,J=1.6Hz,1H),7.33(t,J=7.6Hz,1H),7.22 -7.27(m,1H),3.16(s,3H),2.86-2.93(m,2H),2.60-2.67(m,2H),1.92-2.00(m,2H)

[0566] 6. General steps for the preparation of 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-(p-tolylsulfonyl)-4-(trifluoromethyl)pyrrolo[2,3-c]pyridin-7-one

[0567] To a solution of 3-[1-(3-bromophenyl)cyclobutyl]-4-methyl-1,2,4-triazole (75.0 mg, 256 μmol), 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)-6H-pyrrolo[2,3-c]pyridin-7-one (100 mg, 213 μmol) in NMP (1.00 mL), CuI (122 mg, 641 μmol), K3PO4 (45.4 mg, 213 μmol), and DMEDA (18.8 mg, 213 μmol, 23.0 μL) were added. The mixture was stirred at 130 °C under N2 for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was diluted with EtOAc (10.0 mL). The mixture was filtered, and the filter cake was washed with EtOAc (10.0 mL × 3). The filtrate was washed with brine (10.0 mL) and dried over Na₂SO₄. The organic phase was concentrated under vacuum to give compound 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)pyrrolo[2,3-c]pyridin-7-one (50.0 mg, 73.6 μmol, 34.4% yield), as a green solid.

[0568] 7. General steps for preparing 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-one (compound T033)

[0569] To a solution of 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-(p-toluylsulfonyl)-4-(trifluoromethyl)pyrrolo[2,3-c]pyridin-7-one (100 mg, 147 μmol) in MeOH (2.00 mL), KOH (165 mg, 2.95 mmol) was added. The mixture was stirred at 40 °C for 1 hour under N2. LCMS showed that the reaction was complete. The reaction mixture was diluted with EtOAc (10.0 mL). The mixture was filtered, and the filter cake was washed with EtOAc (10.0 mL × 3). The filtrate was washed with brine (10.0 mL) and dried over Na2SO4. The organic phase was concentrated under vacuum. The product was purified by Prep-HPLC (column: Ultimate C18 150×40mm×10μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; gradient: 30%-70% B, over 32 minutes). The compound 2-[[(3S)-3-methyl-1-piperidinyl]methyl]-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-one (26.8 mg, 50.9 μmol, 34.6% yield, 99.8% purity) was obtained as a green solid. The compound was confirmed by LCMS and ¹H NMR.

[0570] 1 H NMR: (400MHz, CD3CN)

[0571] δ8.06(s,1H),7.54(d,J=1.2Hz,1H),7.46-7.52(m,1H),7.39(t,J=2.0Hz,1H),7.28-7.33(m,2H),6.35(s,1H), 3.59(s,2H),3.21(s,3H),2.96-3.03(m,2H),2.73-2.78(m,2H),2.67-2.72(m,2H),2.05-2.09(m,2H),2.03(br d,J=1.2Hz,1H),1.82-1.91(m,1H),1.63-1.72(m,2H),1.60(br dd,J=8.8,3.6Hz,2H),1.47-1.55(m,1H),0.82(d,J=6.0Hz,3H)

[0572] LCMS: m / z = 525.0(M+H) + Rt = 1.012 min

[0573] Example 13: Synthesis of compound P11

[0574] The synthesis route is as follows:

[0575] The specific steps are as follows:

[0576] 1. A general method for preparing (S)-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one

[0577] A solution of 6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridine-2-carboxaldehyde (50.0 mg, 113 μmol) in dichloromethane (1.00 mL) was prepared by adding TEA (11.4 mg, 113 μmol, 15.7 μL) dropwise to adjust the pH to 9. Then, (S)-3-methylamphetamine hydrochloride (23.0 mg, 169 μmol, HCl) was added to the mixture, and the mixture was stirred at 25 °C for 1 hour. Finally, NaBH(OAc)3 (60.0 mg, 283 μmol) was added to the mixture, and the mixture was stirred at 25 °C for 1 hour. LCMS (EB6214-749-P1A2) showed detection of the desired compound. The reaction mixture was diluted with 8.00 mL of NaHCO3 aqueous solution, extracted with dichloromethane (12.0 mL * 3), and the combined organic layers were washed with 8.00 mL of H2O, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 0% to 10%), (plate 1, dichloromethane / methanol = 10 / 1, R... f (Product) = 0.41). The compound (S)-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (52.0 mg, 87.4 μmol, yield 77.1%, purity 88.2%) was obtained as a colorless oil.

[0578] LCMS:EB6214-749-P1A2,m / z=525.1(M+H) + Rt = 0.717 min

[0579] 2. A general method for preparing (S)-(6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl dodecanoate.

[0580] At 25°C, (S)-6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (52.0 mg, 99.1 μmol) was slowly added to a solution of KOH (16.6 mg, 297 μmol) in DMF (1.50 mL). After addition, the mixture was stirred at 25°C for 0.5 h. Then, chloromethyl dodecanoate (73.9 mg, 297 μmol) was added at 25°C. The resulting mixture was stirred at 25°C for 2 h. LCMS (EB6214-753-P1A1) showed detection of the desired compound. The reaction mixture was diluted with H2O (8.00 mL) at 0 °C, extracted with ethyl acetate (8.00 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: F-Prepulite XP tC 18 40 × 200 mm × 7 μm; mobile phase: [water (FA)-ACN]; gradient: 26.0%-66.0% B, 20.5 min) and neutralized with saturated NaHCO3. The compound (S)-(6-(3-(1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-2-((3-methylpiperidin-1-yl)methyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl dodecanoate (26.1 mg, 34.6 μmol, yield 34.9%, purity 97.7%) was obtained as a colorless oil and was confirmed by 1H NMR (EB6214-753-P1D1), LCMS (EB6214-753-P1F1), HPLC (EB6214-753-P1F2), and SFC (EB6214-753-P1O1).

[0581] LCMS:EB6214-753-P1A1,m / z=737.5(M+H) + Rt = 0.668 min

[0582] 1 H NMR:EB6214-753-P1D1,(400MHz,DMSO-d6)

[0583] δ8.35(s,1H),7.83(d,J=1.2Hz,1H),7.47-7.54(m,1H),7.42(s,1H),7.34(d,J=8.0Hz,1H),7.24(d,J=8. 0Hz,1H),6.54(s,2H),6.45(s,1H),3.63(s,2H),3.24(s,3H),2.89-2.98(m,2H),2.65-2.73(m,4H),2.26 (t,J=7.2Hz,2H),1.95-2.05(m,2H),1.85-1.93(m,1H),1.62(d,J=10.0Hz,2H),1.57(s,2H),1.42-1.49( m,2H),1.32-1.42(m,1H),1.23(s,3H),1.19(d,J=10.4Hz,14H),0.82-0.86(m,3H),0.81(d,J=6.8Hz,3H)

[0584] LCMS:EB6214-753-P1F1,m / z=737.5(M+H) + Rt = 2.823 min

[0585] HPLC:EB6214-753-P1F2, Rt=4.056min

[0586] SFC:EB6214-753-P1O1,Rt=1.254min

[0587] Example 14: Synthesis of compound T005

[0588] 1. General steps for preparing 2-(diethylaminomethyl)-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-one (compound T005)

[0589] A solution of 6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-7-oxo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (50.0 mg, 113 μmol) in dichloromethane (2.50 mL) was prepared by adding TEA (11.4 mg, 113 μmol, 15.7 μL) dropwise to adjust the pH to 7. N-ethylethylamine (18.6 mg, 169 μmol, 26.2 μL, HCl) was then added to the mixture, and the mixture was stirred at 25 °C for 0.5 h. NaBH(OAc)3 (60.0 mg, 283 μmol) was then added to the mixture, and the mixture was stirred at 25 °C for 1 h. LC-MS showed detection of the desired compound. The reaction mixture was diluted with an aqueous solution of NaHCO3 (8.00 mL) and extracted with dichloromethane (12.0 mL × 3). The combined organic layers were washed with H₂O (8.00 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 40×200 mm×7 μm; mobile phase: [water (HCl)-ACN]; gradient: 0%-38% B, over 20.5 min). The compound 2-(diethylaminomethyl)-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridin-7-one (10.1 mg, 18.7 μmol, 16.5% yield, 99.3% purity, HCl) was given as a white solid. The compound was confirmed by ¹H NMR and LCMS.

[0590] 1 H NMR: (DMSO-d6, 400MHz)

[0591] δ12.84(s,1H),9.26(s,1H),7.83(d,J=1.2Hz,1H),7.54-7.60(m,1H),7. 52(s,1H),7.42-7.46(m,1H),7.39(d,J=8.0Hz,1H),6.79(s,1H),4.45(d ,J=4.8Hz,2H),3.40(s,3H),3.05-3.15(m,4H),2.94-3.02(m,2H),2.72- 2.81(m,2H),2.04-2.10(m,1H),1.98-2.03(m,1H),1.27(t,J=7.2Hz,6H)

[0592] LCMS: m / z = 499.2(M+H) + Rt = 1.333 min

[0593] Example 15: Synthesis of compound P12

[0594] The synthesis route is as follows:

[0595] The specific steps are as follows:

[0596] 1. A general method for preparing [2-(diethylaminomethyl)-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-7-oxo-4-(trifluoromethyl)pyrrolo[2,3-C]pyridin-1-yl]methyl dodecanoate.

[0597] 2-(diethylaminomethyl)-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridin-7-one (100 mg, 200 μmol) was added to a solution of KOH (33.8 mg, 602 μmol) in DMF (3.00 mL) under N2 and 20 °C. The mixture was stirred for 0.5 h under N2 and 20 °C. Then, methyl dodecanoate (99.8 mg, 401 μmol) was added to the mixture under N2 and 20 °C. The mixture was stirred for 2 h under N2 and 20 °C. LCMS (EB6211-940-P1B) showed the desired mass was detected. A saturated aqueous solution of NH4Cl (0.20 mL) was slowly added to the reaction mixture at 0 °C to adjust the pH to 8 (saturated aqueous solution of NH4Cl). The mixture was diluted with brine (5.00 mL) and extracted with ethyl acetate (5.00 mL × 2). The organic phase was washed with brine (10.0 mL × 2), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 40 × 200 mm 7 μm; mobile phase: [water (FA)-ACN]; gradient: 24.0%-64.0% B, 20 min). The solution was slowly diluted with saturated NaHCO₃ aqueous solution (20.0 mL) to adjust the pH to 8 (saturated NaHCO₃ aqueous solution). The mixture was extracted with ethyl acetate (10.0 mL × 2). The organic phase was washed with saturated NaHCO₃ aqueous solution (20.0 mL), dried over Na₂SO₄, and concentrated under vacuum. Methyl [2-(diethylaminomethyl)-6-[3-[1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-7-oxo-4-(trifluoromethyl)pyrrolo[2,3-C]pyridin-1-yl]dodecanoate (47.9 mg, 67.1 μmol, yield 33.4%, purity 99.7%) was obtained as a white solid, confirmed by 1H NMR (EB6211-940-P1A 1H NMR), 1F NMR (EB6211-940-P1A 1F NMR), LCMS (EB6211-940-P1A1 LCMS) and HPLC (EB6211-940-P1A2 HPLC).

[0598] LCMS:EB6211-940-P1B,m / z=711.4(M+H) + Rt = 1.143 min

[0599] 1 H NMR:EB6211-940-P1A H NMR, (400MHz, DMSO-d6)

[0600] δ8.35(s,1H),7.83(d,J=1.2Hz,1H),7.46-7.54(m,1H),7.43(t,J=1.6H z,1H),7.35(dd,J=8.0,1.2Hz,1H),7.24(d,J=8.0Hz,1H),6.56(s,2H),6 .49(s,1H),3.74(s,2H),3.24(s,3H),2.90-2.98(m,2H),2.65-2.72(m,2 H),2.44-2.47(m,2H),2.26(t,J=7.2Hz,2H),1.93-2.03(m,2H),1.47(br t,J=6.8Hz,2H),1.13-1.28(m,18H),0.96(t,J=7.2Hz,6H),0.84(t,J=6.8Hz,3H)

[0601] F NMR: EB6211-940-P1A F NMR

[0602] LCMS:EB6211-940-P1A1 LCMS, m / z=711.4(M+H) + Rt = 1.157 min

[0603] HPLC: EB6211-940-P1A2 HPLC, Rt=3.803min

[0604] Example 16: Synthesis of compound T159

[0605] 1. General steps for preparing 2-((ethyl(isopropyl)amino)methyl)-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (compound T159)

[0606] N-ethylpropyl-2-amine (14.3 mg, 164 μmol) was added to a mixture of 6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-7-oxo-4-(trifluoromethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (50.0 mg, 109 μmol) and dichloromethane (2.00 mL). The mixture was stirred at 25.0 °C under N2 for 0.50 h. Sodium triacetoxyborohydride (58.1 mg, 274 μmol) was added to the mixture. The mixture was stirred at 25.0 °C under N2 for 3.50 h. Then methanol (1.00 mL) and sodium cyanoborohydride (6.90 mg, 109 μmol) were added to the mixture. The mixture was stirred at 25.0 °C under N2 for 8.00 h. LCMS showed the desired mass was detected. The reaction mixture was diluted with NaHCO3 (1.00 mL) and extracted with dichloromethane (2.00 mL × 2). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Prep-HPLC (column: Welch Xtimate C18 40.0 × 200 mm × 7.00 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3) - ACN]; gradient: 38.0% - 78.0% B, over 25 minutes). The compound 2-((ethyl(isopropyl)amino)methyl)-6-(3-((1s,3s)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (10.8 mg, 20.4 μmol, 18.6% yield, 99.5% purity) was obtained as a white solid and was confirmed by 1H NMR and LCMS.

[0607] 1 H NMR: (400MHz, DMSO-d6)

[0608] δ8.28(s,1H),7.70(d,J=1.2Hz,1H),7.47-7.55(m,2H),7.35(br t,J=8.8Hz,2H),6.28(s,1H),3.65(s,2H),3.25(s,3H),2.90-2.98(m,1H),2.88(br d,J=3.6Hz,2H),2.52-2.57(m,3H),2.43-2.48(m,2H),1.07(br d,J=5.6Hz,3H),0.94-1.00(m,9H)

[0609] LCMS: m / z = 527.3(M+H) + ,R t=1.536min

[0610] Example 17: Synthesis of compound P13

[0611] The synthesis route is as follows:

[0612] The specific steps are as follows:

[0613] 1. A general method for preparing 2-(1,3-dioxolane-2-yl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one

[0614] A solution of 2-(1,3-dioxolane-2-yl)-1-(p-toluenesulfonyl)-4-(trifluoromethyl)-6H-pyrrolo[2,3-C]pyridin-7-one (1.30 g, 3.03 mmol) and 3-[1-(3-iodophenyl)-3-methyl-cyclobutyl]-4-methyl-1,2,4-triazole (1.18 g, 3.34 mmol) in NMP (15.0 mL) was degassed and purged three times with N2. K3PO4 (1.93 g, 9.10 mmol) and CuI (1.16 g, 6.07 mmol) were added to the mixture, followed by DMEDA (267 mg, 3.03 mmol, 326 μL). The mixture was stirred at 130 °C under a N2 atmosphere for 1.5 h. LCMS (EB12379-38-P1A1) showed that the desired mass was detected, and TLC (dichloromethane:methanol = 10 / 1, product 1R) was performed. f =0.20, product 2R f=0.34) showed the formation of new spots. The reaction mixture was diluted with 150 mL of ethyl acetate and washed with NH3·H2O / sat NH2Cl solution (15:85, 100 mL × 2). The aqueous phase was extracted with 200 mL of ethyl acetate (100 mL × 2). The combined organic layers were washed with 400 mL of brine (100 mL × 4), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 25 / 1 to 15 / 1). The compound 2-(1,3-dioxolane-2-yl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (702 mg, 1.27 mmol, yield 41.7%, purity 90.1%) was obtained as a white solid, which was confirmed by 1H NMR (EB12379-38-P1C1 1H NMR) and 1F NMR (EB12379-38-P1C1 1F NMR).

[0615] LCMS:EB12379-38-P1A1,m / z=500.3(M+H) + ,R t =1.297min

[0616] 1 H NMR:EB12379-38-P1C1 H NMR, (400MHz, DMSO-d6)

[0617] δ12.83(br s,1H),8.28(s,1H),7.77(d,J=1.2Hz,1H),7.47-7.62(m,2H),7.28-7.43(m,2H),6.49(s,1H),5.97(s,1H),4 .04-4.23(m,2H),3.88-4.01(m,2H),3.24(s,3H),2.82-2.94(m,2H),2.52-2.56(m,3H),1.07(d,J=5.6Hz,3H)

[0618] F NMR: EB12379-38-P1C1 F NMR

[0619] 2. A general method for preparing 6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridine-2-carboxaldehyde

[0620] A mixture of 2-(1,3-dioxolane-2-yl)-6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridin-7-one (1.00 g, 2.00 mmol) and HCl (1 M, 9.09 mL) was degassed and purged three times with N2. The mixture was then stirred at 50.0 °C and N2 for 1 h. LCMS (EB12379-43-P1A2) showed the desired mass. The reaction mixture was adjusted to pH 8.00 (saturated NaHCO3), extracted with ethyl acetate (20.0 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. This residue was not purified. The compound 6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridine-2-carboxaldehyde (895 mg, 1.77 mmol, yield 88.3%, purity 90.0%) was obtained as a white solid and was confirmed by 1H NMR (EB12379-43-P1B1 1H NMR) and 1F NMR (EB12379-43-P1B1 1F NMR).

[0621] LCMS:EB12379-43-P1A2,m / z=456.0(M+H) + ,R t =0.890min

[0622] 1 H NMR:EB12379-43-P1B1 H NMR, (400MHz, DMSO-d6)

[0623] δ13.64(br s,1H),9.91(s,1H),8.29(s,1H),7.87(d,J=1.2Hz,1H),7.49-7.62(m,2H),7.38(dd,J=18.0,8.0Hz, 2H),7.21(d,J=1.2Hz,1H),3.24(s,3H),2.80-2.95(m,2H),2.52-2.61(m,3H),1.07(d,J=5.2Hz,3H)

[0624] F NMR: EB12379-43-P1B1 F NMR

[0625] 3. A general method for preparing 2-((ethyl(isopropyl)amino)methyl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one

[0626] TEA (222 mg, 2.20 mmol, 305 μL) was added to a solution of N-ethylpropane-2-amine (191 mg, 2.20 mmol, 265 μL) in dichloromethane (5.00 mL) to adjust the pH to 8.00. Then, 6-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-7-oxo-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridine-2-carboxaldehyde (200 mg, 439 μmol) was added to the mixture. The mixture was stirred at 25.0 °C and N2 for 0.50 h. Sodium triacetoxyborate (186 mg, 878 μmol) was added to the mixture. The mixture was stirred at 25.0 °C and N2 for 7.50 h. LCMS (EB12379-47-P1A1) showed the desired mass was detected. The reaction mixture was diluted with NaHCO3 (3.00 mL) and extracted with dichloromethane (5.00 mL * 2). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by preparative HPLC (column: F-Prepulite XP tC 18.04 0.0 * 200 mm * 7.00 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3) - ACN]; gradient: 36.0% - 76.0%, 20.0 min). The compound 2-((ethyl(isopropyl)amino)methyl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-1,6-dihydro-7H-pyrrolo[2,3-C]pyridin-7-one (102 mg, 192 μmol, yield 43.8%, purity 99.4%) was obtained as a white solid, which was confirmed by 1H NMR (EB12379-47-P1D2 H NMR), 1F NMR (EB12379-47-P1D2 F NMR), and LCMS (EB12379-47-P1D1).

[0627] LCMS:EB12379-47-P1A1,m / z=527.4(M+H) + ,R t =1.117min

[0628] 1H NMR:EB12379-47-P1D2 H NMR, (400MHz, DMSO-d6)

[0629] δ8.28(s,1H),7.71(s,1H),7.45-7.62(m,2H),7.27-7.40(m,2H),6.29(br s,1H),3.65(s,2H),3.25(s,3H),2.84-2.98(m,3H),2.54(br s,3H),2.42-2.47(m,2H),1.07(br d,J=4.8Hz,3H),0.92-1.01(m,9H)

[0630] F NMR: EB12379-47-P1D2 F NMR

[0631] LCMS:EB12379-47-P1D1,m / z=527.4(M+H) + ,R t =0.433min

[0632] 4. A general method for preparing methyl (2-((ethyl(isopropyl)amino)methyl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)dodecanoate

[0633] Under N2 and 25.0 °C, 2-[[ethyl(isopropyl)amino]methyl]-6-[3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-4-(trifluoromethyl)-1H-pyrrolo[2,3-C]pyridin-7-one (80.0 mg, 151 μmol) was added to a solution of KOH (25.5 mg, 455 μmol) in DMF (3.00 mL). The mixture was stirred under N2 and 25.0 °C for 0.5 h, and then methyl dodecanoate (75.5 mg, 303 μmol) was added to the mixture under N2 and 25.0 °C. The mixture was stirred under N2 and 25.0 °C for 2 h. LCMS (EB12379-54-P1A1) showed the desired mass was detected. Slowly add 2.00 mL of saturated NH4Cl aqueous solution to the reaction mixture at 0 °C to adjust the pH to 8.00 (saturated NH4Cl aqueous solution). Dilute the mixture with brine (10.0 mL) and extract with ethyl acetate (10.0 mL * 2). Wash the organic phase with brine (10.0 mL * 2), dry with Na2SO4, and concentrate under vacuum. The crude product is purified by preparative HPLC (column: F-Prepulite XP tC). 18 40.0*200mm*7.00um; Mobile phase: [water (FA)-ACN]; Gradient: 24.0%-64.0%B, 20.5 minutes). The compound (2-((ethyl(isopropyl)amino)methyl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-oxo-4-(trifluoromethyl)-6,7-dihydro-1H-pyrrolo[2,3-C]pyridin-1-yl)methyl dodecanoate (90.1 mg, 120 μmol, yield 79.3%, purity 98.9%) was obtained as a white solid and was confirmed by ¹H NMR (EB12379-54-P1C5 ¹H NMR), F NMR (EB12379-54-P1C5 F NMR), LCMS (EB12379-54-P1C3), and HPLC (EB12379-54-P1C1).

[0634] LCMS:EB12379-54-P1A1,m / z=739.3(M+H) + ,R t =1.133min

[0635] 1 H NMR:EB12379-54-P1C5 H NMR, (400MHz, DMSO-d6)

[0636] δ8.29(s,1H),7.82(s,1H),7.44-7.60(m,2H),7.34(br t,J=6.4Hz,2H),6.57(s,2H),6.49(s,1H),3.77(s,2H),3.22(s,3H),2.81-2.93(m,3H),2.37-2.47(m,3H),2.27(br t,J=7.2Hz,2H),1.46(br d,J=6.4Hz,2H),1.12-1.26(m,18H),1.06(br d,J=4.4Hz,3H),0.98(br d,J=6.4Hz,6H),0.92(br t,J=6.8Hz,3H),0.84(br t, J = 6.4 Hz, 3H)

[0637] F NMR: EB12379-54-P1C5 F NMR

[0638] LCMS:EB12379-54-P1C3,m / z=739.4(M+H) + ,R t =2.510min

[0639] HPLC: EB12379-54-P1C1,R t =3.936min

[0640] The present invention also includes, but is not limited to, the following compounds, the preparation of which will not be described in detail here.

[0641] Activity testing examples:

[0642] Example 1: Pharmacokinetic Experiment

[0643] 1. Experimental Methods

[0644] Three male Sprague Dawley rats were administered a single oral dose. The compound was prepared into a 1.0 mg / mL solution using 0.5% Methylcellulose, 2.5% NMP:10% Solutol:87.5% PEG-400, or 10% DMSO / 30% PEG400 / 60% Water and administered at a volume of 10 mL / kg.

[0645] After administration, oral blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours. The concentrations of the compounds and their corresponding active metabolites in the samples were detected by LC-MS / MS, with a limit of quantitation of 1 ng / mL. The pharmacokinetic parameters of the compounds were calculated using the WinNolin non-compartmental model.

[0646] 2. Experimental Results

[0647] The pharmacokinetic test results are shown below.

[0648] Table 1 PK Test Results

[0649] Note: The data in parentheses are the corresponding results for the active metabolite (T058).

[0650] As shown in Table 1, compounds P01 and P05 both increased the Cmax and plasma exposure of T058 in rats, and their plasma exposure was also superior to that of compound T058. Furthermore, compound P08 significantly increased the drug's half-life.

[0651] Table 2 PK Test Results

[0652] Note: The data in parentheses are the corresponding results for the active metabolite (T033);

[0653] NA indicates that it was not detected.

[0654] Table 3 PK Test Results

[0655] Note: The data in parentheses are the corresponding results for the active metabolite (T159);

[0656] NA indicates that it was not detected.

[0657] As shown in Table 2-3, compounds T033 and T159 were poorly absorbed orally (below the limit of detection). Similar to P01 vs T058, P11 and P13 significantly improved the oral absorption problem (both plasma exposure AUC increased).

[0658] In summary, the compounds described in this invention can be used as prodrugs. Compared with the original drug compounds (Cbl-b inhibitors, as described in patent application PCT / CN2024 / 073346), they have advantages in pharmacokinetics, bioavailability, and side effects. In particular, they can effectively improve the oral absorption of the original drug compounds and increase blood drug concentrations, thus having very good research value and application prospects in the pharmaceutical field.

[0659] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

[0660] The foregoing embodiments and methods described in this invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0661] Listing the steps of the method in a certain order in this invention does not constitute any restriction on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, solvate, or deuterated compound thereof, said compound having the following structure: wherein, A ring is an aromatic or heteroaromatic ring; R A R is one or more independent substituents on the ring, each independently selected from the group consisting of H, D, wherein L1is selected from the group consisting of: a single bond, C(O), C1-C 10 alkylene, C(R3R4), L2is selected from the group consisting of: a single bond, O, C1-C 10 alkylene, S, C(R3R4), N(R5), R 001 is selected from: a single bond, C1-C 10 alkylene; R 002 is selected from: a single bond, C1-C 10 alkylene, O, S, N(R2), S(O)2, S(O)2N(R2), S(O), S(O)N(R2), C(O), C(O)O, C(O)N(R2), OC(O), OC(O)N(R2), N(R2)C(O)O, N(R2)C(O), N(R2)S(O)2, R 003 is selected from: hydroxyl, H, D, halogen, cyano, nitro, C1-C 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); wherein each H on said alkylene, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl is optionally substituted with one or more independent R groups; R2is selected from: H, D, C1-C6alkyl, -(Co-C6alkylene)-(C3-C6cycloalkyl); 10 alkyl, -(Co-C6alkylene)-(C3-C6cycloalkyl); 10 cycloalkyl); R3 and R4 are independently selected from the following groups: H, D, halogen, cyano, nitro, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(4-10 heterocyclic); wherein the H on the alkylene, haloalkyl, alkyl, alkenyl, ynyl, cycloalkyl, aryl, and 4-10 heterocyclic groups is optionally replaced by one or more independent R groups; or, R3and R4together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with one or more independent R groups; J is a 3-10 membered nitrogen-containing heterocycle (J is connected to L2via a carbon atom), J is optionally substituted with one or more groups selected from hydroxyl, oxo (=0), halogen, cyano, nitro, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkoxyalkyl, C1-C6alkylaminoalkyl; wherein each H on said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent R groups; 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -0(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C1-C 10 haloalkyl, C1-C 10 cyanoalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 carboxyalkyl, C1-C 10 alkoxyalkyl, C1-C 10 alkylaminoalkyl; wherein each H on said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent R groups; the carbon atom connecting J to L2is optionally substituted with D, halo, cyano, nitro, C1-C 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); wherein each H on said alkylene, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl is optionally substituted with one or more independent R groups; R5and R6are independently selected from the group consisting of: hydroxyl, halogen, H, D, C 1-10 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); wherein each of said alkylene, alkyl, cycloalkyl, aryl, 4-10 membered heterocyclyl is optionally substituted with one or more independent substituents selected from the group consisting of: halogen, cyano, nitro, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -(C0-C6alkylene)-O(C0-C 10 alkyl), -(C0-C6alkylene)-O(C3-C 10 cycloalkyl), -(C0-C6alkylene)-O(3-10 membered heterocyclyl), -O(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C1-C 10 haloalkyl, C1-C 10 cyanoalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 carboxyalkyl, C1-C 10 alkoxyalkyl, C1-C 10 alkylaminoalkyl; wherein each H on the alkylene, aryl, 4-10 membered heterocyclyl, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent R groups; Alternatively, R5 and R6 together with the nitrogen atom they are connected to form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more independent substituents selected from: oxo (=O), halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl is optionally substituted by one or more independent R groups; or the H on the heterocyclic group formed by R5 and R6 together with the nitrogen atom they are connected to is substituted by one or more R groups. p Group substitution; R7is one or more independent substituents on the A ring, each independently selected from the group consisting of H, D, halogen, cyano, nitro, Among them, R 701 Selected from: single bond, C 1-10 Alkylene; R 702 Selected from: single bond, C 1-10 Alkylene, O, S, N(R) 704 S(O)2, S(O)2N(R) 704 ), S(O), S(O)N(R) 704 ), C(O), C(O)O, C(O)N(R) 704 ), OC(O), OC(O)N(R) 704 ), N(R 704 C(O)O、N(R) 704 C(O), N(R) 704 S(O)2, R 703 Selected from: H, D, halogen, cyano, nitro, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); R 704 Selected from: H, D, C 1-10 Alkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, haloalkyl, and 4-10 membered heterocyclic groups is optionally substituted by one or more independent R groups; R8 and R9 are independently selected from the following groups: H, D, halogen, cyano, nitro, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkamidoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, and alkylamidoalkyl groups is optionally substituted by one or more independent R groups; Alternatively, R8 and R9 together with their commonly attached carbon atom form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more independent substituents selected from: oxo (=O), (=alkylene), hydroxyl, halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl is optionally substituted by one or more independent R groups; or the H on the cycloalkyl or heterocyclic group formed by R8 and R9 together with the carbon atom they are connected to is substituted by one or more R groups. p groups substituted; W is a single bond, or S; wherein R 15 and R 16 are independently selected from the group consisting of: H, D, halogen, cyano, nitro, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -O(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C1-C 10 haloalkyl, C1-C 10 cyanoalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 carboxyalkyl, C1-C 10 alkoxyalkyl, C1-C 10 alkylaminoalkyl; wherein each H on said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent R groups; Or, R 15 and R 16 Together with the carbon atom it is attached to, it forms a cycloalkyl or heterocyclic group, wherein the H on the cycloalkyl or heterocyclic group is optionally substituted by one or more independent substituents selected from the following: oxo (=O), (=alkylene), halogen, cyano, nitro, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl group is optionally substituted by one or more separate R groups; or the R 15 and R 16 H, together with the carbon atom to which it is attached, form a cycloalkyl or heterocyclyl group which is substituted with one or more R p groups; Or, R 15 R9, together with the carbon atom in between, forms a cycloalkyl, aryl, or heterocyclic group, wherein the H atom on the cycloalkyl, aryl, or heterocyclic group is optionally substituted by one or more independent substituents selected from: oxo (=O), (=alkylene), halogen, cyano, nitro, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)), C1-C 10 Haloalkyl, C1-C 10 Cyanoalkyl, C1-C 10 Hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 Carboxyalkyl, C1-C 10 Alkoxyalkyl, C1-C 10 Alkylaminoalkyl; wherein the H on the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclic, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxylalkyl, alkoxyalkyl, or alkylaminoalkyl group is optionally substituted by one or more separate R groups; or the R 15 and the H in the R9group together with the intermediate carbon atom forms a cycloalkyl, aryl or heterocyclyl group which is substituted by one or more R p groups; Y1, Y2, Y3, and Y4are independently selected from: C, N, O, S (with the proviso that two O atoms, two S atoms, or an O and S atom are not directly connected); R 10 is one or more independent substituents on the ring, said R 10 is independently selected from the group consisting of H, D, oxo (=0), halogen, cyano, nitro, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -0(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C1-C 10 haloalkyl, C1-C 10 cyanoalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 carboxyalkyl, C1-C 10 alkoxyalkyl, C1-C 10 alkylaminoalkyl; wherein each H on said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent R groups; or at least one R 10 has the same definition as R p group; R 11 selected from: H, D, C1-C 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); wherein each of said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl is optionally substituted with one or more independent R groups; or R 11 has the same definition as R p group; said R p group is a group comprising at least one of an ester bond C(O)O, a thioester bond SC(O), a phospholipid bond OPO, OP(O)(OR”’)(NR”’), HOP(O)O, 、 OP(O)O, 、 a phosphodiester bond P(O)O3, a phosphorinidate bond P(OR”’), a thiophospholipid bond P(S)O3, a peptide bond C(O)NH, an ether bond R”’OR”’, a sulfide bond R”’SR”’, a silane ether bond SiOSi, a thio silane ether bond SiSSi, a carbonate bond OC(O)O, a thiourea bond HNC(S)NH, an amide bond C(O)NH, a thioamide bond C(S)NH, a carbamate bond OC(O)NH, and a urea bond HNC(O)NH, each H on said group is optionally substituted with one or more independent R groups; or the P and O atoms on the phospholipid bond OPO, OP(O)(OR”’)(NR”’), HOP(O)OH, OP(O)O, 、 a phosphodiester bond P(O)O3, a phosphorinidate bond P(OR”’), a thiophospholipid bond P(S)O3 together form a cycloalkyl, the cycloalkyl is optionally substituted with one or more independent R groups; said R groups are independently selected from the group consisting of: hydroxyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, D, halogen, cyano, nitro, wherein L4and L5are independently selected from: a single bond, O, S, N(R''), S(O)2, S(O)2N(R''), S(O), S(O)N(R''), C(O), C(O)O, C(O)N(R''), OC(O), OC(O)N(R''), N(R'')C(O)O, N(R'')C(O), N(R'')S(O)2, SC(O) (thioester bond), OPO, HOP(O)OH, P(O)O3 (phosphodiester bond), P(OR'') (phospholipid bond), P(S)O3 (thiophospholipid bond), C(O)NH (peptide bond), R''OR'' (ether bond), R''SR'' (thioether bond), SiOSi (silylether bond), SiSSi (thiolsilylether bond), OC(O)O (carbonate bond), HNC(S)NH (thiourea bond), C(O)NH (amide bond), C(S)NH (thioamide bond), OC(O)NH (carbamate bond), HNC(O)NH (urea bond), said R' is independently selected from: a single bond, C1-C 10 alkylene, C2-C 10 alkenylene, phenylene, C3-C 10 cycloalkylene, 4-10 membered heterocyclyl ene; said R" is independently selected from: H, D, -CD3, halogen, cyano, nitro, C1-C 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl; said R'" is independently selected from: H, D, C1-C 10 alkyl, C1-C 10 haloalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl.

2. The compound of claim 1, wherein R p group is -(C0-C6alkylene)-X-Y-R p1 wherein X is selected from the group consisting of a single bond, -O-, -S-, -S-S-, -Si(R p3 )2-, -N(R p3 )-, and Y is selected from the group consisting of a single bond, -C(O)-, -C(S)-, -C(O)O-, -C(O)S-, -C(O)N(R p3 )-, -P(OR p2 )O-, -P(O)(OR p2 )-, -P(O)(OR p2 )O-, -P(O)(OR p2 )N(R p3 )-, -P(O)(NHR p2 )N(R p3 )-, -P(S)(OR p2 )-, -P(S)(OR p2 )O-, -P(S)(OR p2 )N(R p3 )-, -N=C(R p3 )-, R p1 is selected from the group consisting of H, C1-C 30 alkyl, C2-C 30 alkenyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), an amino acid residue, a polypeptide residue, a monosaccharide residue, a polysaccharide residue, a glycol moiety; R p2 and R p3 are independently selected from the group consisting of H, D, C 1-10 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); or R p1 and R p2 together with the atom to which they are attached form a carbocyclic or heterocyclic ring, which carbocyclic or heterocyclic ring is optionally substituted with one or more independent substituents selected from the group consisting of oxo (=O), (=alkylene), halogen, cyano, nitro, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -0(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C1-C 10 haloalkyl, C1-C 10 cyanoalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 carboxyalkyl, C1-C 10 alkoxyalkyl, C1-C 10 alkylaminoalkyl; wherein each H on said alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent R groups or an amino acid residue, a polypeptide residue, a monosaccharide residue, a polysaccharide residue, an ethylene glycol moiety; R is preferably selected from the group consisting of: -C(O)N(R p )-R p1 , -(C0-C2alkylene)-OC(O)N(R p3 )-R p1 , -(C0-C2alkylene)-C(O)N(R p3 )-R p1 , -(C0-C2alkylene)-OP(O)(OR p2 )O-R p1 , -(C0-C2alkylene)-OP(O)(OR p2 )N(R p3 )-R p1 , -(C0-C2alkylene)-P(O)(OR p2 )O-R p1 , -(C0-C2alkylene)-P(O)(OR p2 )-R p1 , -(C0-C2alkylene)-P(O)(OR p2 )N(R p3 )-R p1 ; wherein each H on said alkylene is optionally substituted with a group selected from the group consisting of: D, -CD3, halogen, C1-C6alkyl, C1-C6haloalkyl, hydroxyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, amino, C1-C6aminoalkyl, C1-C6alkylaminoalkyl.

3. The compound of claim 1, wherein R p is -(C0-C2alkylene)-OC(O)-R p1 , -(C0-C2alkylene)-C(O)O-R p1 , or -(C0-C2alkylene)-OC(O)N(R p3 )-R p1 , R p1 is selected from: H, C1-C 20 alkyl, C2-C 20 alkenyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-15 membered heterocyclyl), an oligoethylene glycol moiety (such as m is an integer from 1-10 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); R p3 is selected from: H, C1-C 20 alkyl; wherein each of the H on the alkylene, alkyl, cycloalkyl, aryl, 4-15 membered heterocyclyl groups is optionally substituted with a group selected from: D, -CD3, halogen (e.g., -Cl), C1-C 20 alkyl, -OH, -O(C1-C 20 alkyl), -S(C1-C 20 alkyl), -COO(C0-C 20 alkyl), -COO(C6-C 10 aryl), -COO(C7-C 20 arylalkyl), -OC(O)(C0-C 20 alkyl), -OC(O)(C6-C 10 aryl), -OC(O)(C7-C 20 arylalkyl); or, R p The functional group is -(C0-C2 alkylene)-OP(O)(OR p2 OR p1 R p1 and R p2 Independently selected from: H, C1-C 20 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 Cycloalkyl), -(C0-C6 alkylene)-(phenyl), -(C0-C6 alkylene)-(4-10 membered heterocyclic); wherein the H on the alkylene, alkyl, cycloalkyl, aryl, arylalkyl, and 4-10 membered heterocyclic groups is optionally substituted by groups selected from: D, -CD3, halogen (e.g., -Cl), C1-C6 alkyl, -OH, C1-C6 alkoxy (e.g., -Cl), -(C0-C6 alkylene), -OH, -(C1-C6 alkoxy) )、 -COO(C0-C6alkyl); or, R p group is wherein n is an integer from 0-2 (e.g., 0, 1, 2), z is an integer from 0-2 (e.g., 0 or 1), R p4 to R p9 is independently selected from the group consisting of: H, C1-C 10 alkyl, -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); wherein each H on the alkylene, alkyl, aryl, 4-10 membered heterocyclyl, alkoxy groups is optionally substituted with a group selected from D, -CD3, halogen (e.g., -Cl), C1-C6alkyl, -OH, C1-C6alkoxy (e.g., )、 -COO(C0-C6alkyl); or, R p group is wherein n is an integer from 0-2 (e.g., 0, 1, 2), R p2 to R p11 is independently selected from the group consisting of: H, C1-C 20 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(phenyl), -(C0-C6alkylene)-(4-10 membered heterocyclyl); wherein each H on the alkylene, alkyl, cycloalkyl, aryl, phenyl, 4-10 membered heterocyclyl is optionally substituted with a group selected from D, -CD3, halogen (e.g., -Cl), C1-C6alkyl, -OH, C1-C6alkoxy (e.g., 12 alkyl, -OH, C1-C6alkoxy (e.g., -S (C1-C6 alkyl) (e.g.) )、 -COO(C0-C6alkyl); or, R p group is -(C1-C2alkylene)-O-R p1 , R p1 is selected from: H, C1-C6alkyl; or, R p group is 4. The compound of claim 1, wherein R p the group is -(C0-C2alkylene)-OC(O)-R p1 , -(C0-C2alkylene)-C(O)O-R p1 or -(C0-C2alkylene)-OC(O)N(R p3 )-R p1 wherein, R p1 selected from: H, C1-C 20 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), phenyl, naphthyl, benzyl, 4-15 membered nitrogen-containing heterocyclyl (such as 5-10 membered nitrogen-containing saturated heterocyclyl, 5-10 membered nitrogen-containing heteroaryl), wherein the H's on the alkyl, alkylene, cycloalkyl, phenyl, naphthyl, benzyl, 4-15 membered nitrogen-containing heterocyclyl groups are each optionally substituted with a group selected from the group consisting of C1-C6alkyl, -OH, -0(C1-C6alkyl), -S(C1-C6alkyl), -NH2, -N(C1-C6alkyl)2, -CN, -F, -Cl, -Br, and -I; 12 alkyl, -OH, -0(C1-C 10 alkyl), -S(C1-C 10 alkyl), -COOH, -COO(C1-C 10 Alkyl), -COO (phenyl), -COO (benzyl), -OC(O) (C1-C) 10 Alkyl), -OC(O) (phenyl), -OC(O) (benzyl); R p3 selected from: H, C1-C 20 alkyl; Preferably, R p1 selected from the group consisting of:

5. The compound of claim 1, wherein R p R is selected from:

6. The compound of claim 1, wherein R p group is selected from:

7. The compound of claim 1, wherein R p group is selected from:

8. The compound of claim 1, wherein R p group is selected from:

9. The compound of claim 1, wherein R p the group is -CH2-OH; or R p group is 10. The compound of any one of claims 1-9, wherein, The compound has the structure: wherein, R0 is For example R1is Among them, R 001 Selected from: single bonds, C1-C6 alkylene groups; R 002 Selected from: single bond, C1-C6 alkylene, O, S, N(R2), S(O)2, S(O)2N(R2), S(O), S(O)N(R2), C(O), C(O)O, C(O)N(R2), OC(O), OC(O)N(R2), N(R2)C(O)O, N(R2)C(O), N(R2)S(O)2, R 003 Selected from: H, D, halogen, cyano, nitro, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C4-C 10 Cycloalkylalkyl, 4- to 10-membered saturated heterocyclic group, heterocyclic alkyl; R1 is optionally substituted by one or more independent substituents selected from the following: halogen, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, cyano, carboxyl; Preferably, the compound has the structure: R 10a , R 10b is independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; V is selected from: a single bond, O, m is 1, 2, or 3, R v01 and R v02 are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6alkoxy, C1-C6deuteroalkoxy, or R v01 and R v02 together with the carbon atom to which they are both attached form a cycloalkyl or heterocyclyl; wherein said alkyl is optionally substituted with one or more independent substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C1-C6alkoxy, amino, C1-C6alkylamino, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)), -C(O)(C0-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl); or R v01 and R v02 together form C1-C6alkylene; More preferably, the compound has the structure: R 17a to R 17g each has independently the meaning of R 17 or two of R 17a to R 17g form together with the carbon atom in between a cycloalkyl or heterocyclyl; R 17 is independently selected from the group consisting of: H, D, (=0), halogen, cyano, nitro, C1-C 10 alkyl, C1-C 10 deuteroalkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -O(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C1-C 10 haloalkyl, C1-C 10 cyanoalkyl, C1-C 10 hydroxyalkyl, C1-C 10 aminoalkyl, C1-C 10 carboxyalkyl, C1-C 10 alkoxyalkyl, C1-C 10 alkylaminoalkyl; wherein each of the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent substituents selected from the group consisting of: D, halogen, cyano, nitro, C 1-10 alkyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic)); More preferably, one, two, three or four of R 11 , R 17b , R 10b , R V01 have the definition of R p group.

11. The compound of claim 10, wherein said compound has the structure:

12. The compound of claim 11, wherein R3and R4are independently selected from: H, D, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C 1-6 aminoalkyl, C1-C6alkylaminoalkyl, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, R3 is H; R4 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

13. The compound of claim 11, wherein R5is selected from: H, D, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl; R6 is selected from: H, D, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C6 alkyl. 10 Cycloalkylalkyl, 4- to 10-membered saturated heterocyclic group, heterocyclic alkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, 4- to 10-membered saturated heterocyclic group, heterocyclic alkyl is optionally substituted by one or more independent substituents selected from: C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclic group, halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, cyano, C1-C6 cyanoalkyl, carboxyl, C1-C6 carboxylalkyl, C1-C6 haloalkyl, C2-C6 sulfonyl; or, R5and R6together with the nitrogen atom to which they are both attached form a heterocyclyl wherein E ring is a 4-14 membered heterocyclic ring, R 17 is one or more independent substituents on E ring, R 17 is as defined in claim 19 for R 17 ; wherein said R5and R6together with the nitrogen atom to which they are both attached form a heterocyclyl Optionally substituted with one or more independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, amino, C1-C 10 Alkyl, substituted or unsubstituted phenyl or 4-6 membered heterocyclic groups.

14. The compound of claim 11, wherein R5is selected from: H, C1-C6alkyl; R6is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Preferably, selected from the group consisting of:

15. The compound of claim 13, wherein E ring is a saturated heterocyclic ring or a partially unsaturated heterocyclic ring, preferably selected from: Preferably said R 17 is independently selected from the group consisting of H, D, (=0), halogen, C1-C6alkyl, C1-C6deuteroalkyl, C2-C6alkenyl, C1-C6haloalkyl, cyano, C1-C6cyanoalkyl, -OH, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, -NH2, C1-C6alkylamino, C1-C6alkylaminoalkyl, -(C0-C3alkylene)-(C3-C6cycloalkyl), -(C0-C6alkylene)-(4-10 membered saturated heterocyclyl), -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)), -C(O)(C0-C6alkyl), -C(O)O(C0-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), C1-C6haloalkoxy, -C(O)O(C0-C6alkyl); Preferably, selected from the group consisting of:

16. The compound of claim 11, wherein R v01 and R v02 are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6deuteroalkoxy, C1-C6aminoalkyl, C1-C6alkylaminoalkyl; or, R v01 and R v02 together with the carbon atom to which they are both attached form a C3-C6cycloalkyl; or, R v01 and R v02 together form Preferably, selected from the group consisting of:

17. The compound of claim 11, wherein R 10a , R 10b is independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; Preferably, R 10a selected from: -CH3, -CHF2, -CH2F, -CF3, preferably -CH3; or, R 10b is H.

18. The compound of claim 11, wherein R7is selected from: -H, D, -CI, -CN, -COOH, -CONH2, preferably R7is -H.

19. The compound of claim 11, wherein R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); 10 R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); Preferably, R1is selected from: H, D, F, Br, -CH3, -CHF2, -CH2F, -CF3, -CH2-CF3, -OH, -OCHF2, -OCH2F, -OCF3, 20. The compound of claim 11, wherein The compound is selected from the following structures:

21. The compound of claim 10, wherein The compound has the structure:

22. The compound of claim 21, wherein R 11 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl; 10 cycloalkylalkyl; Preferably, R 11 is H.

23. The compound of claim 21, wherein R3and R4are independently selected from: H, D, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C 1-6 aminoalkyl, C1-C6alkylaminoalkyl, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, R3 is H; R4 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

24. The compound of claim 21, wherein R5is selected from: H, D, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl; R6is selected from: H, D, C1-C6alkyl, C3-C6cycloalkyl, C4-C10cycloalkylalkyl, 4- to 10-membered saturated heterocyclyl, heterocyclylalkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl are optionally substituted with one or more independent substituents selected from: C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, halogen, hydroxyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6alkoxyalkyl, cyano, C1-C6cyanoalkyl, carboxyl, C1-C6carboxyalkyl, C1-C6haloalkyl, C2-C6sulfonyl; or, 10 R6is selected from: H, D, C1-C6alkyl, C3-C6cycloalkyl, C4-C10cycloalkylalkyl, 4- to 10-membered saturated heterocyclyl, heterocyclylalkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl are optionally substituted with one or more independent substituents selected from: C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, halogen, hydroxyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6alkoxyalkyl, cyano, C1-C6cyanoalkyl, carboxyl, C1-C6carboxyalkyl, C1-C6haloalkyl, C2-C6sulfonyl; or, R5and R6together with the nitrogen atom to which they are both attached form a heterocyclyl wherein E ring is a 4-14 membered heterocyclic ring, R 17 is one or more independent substituents on the E ring, said R 17 is independently selected from the group consisting of: H, D, (=0), halogen, cyano, nitro, C 10 alkyl, C 10 deuteroalkyl, C 10 alkenyl, C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -0(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C 10 haloalkyl, C 10 cyanoalkyl, C 10 hydroxyalkyl, C 10 aminoalkyl, C 10 carboxyalkyl, C 10 alkoxyalkyl, C 10 alkylaminoalkyl; wherein each of the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent substituents selected from the group consisting of: D, halogen, cyano, nitro, C 1-10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic group)); wherein the heterocyclic group Optionally substituted with one or more independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, amino, C1-C 10 Alkyl, substituted or unsubstituted phenyl or 4-6 membered heterocyclic groups.

25. The compound of claim 21, wherein R5is selected from: H, C1-C6alkyl; R6is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Preferably, are selected from the group consisting of:

26. The compound of claim 24, wherein E ring is a saturated heterocyclic ring or a partially unsaturated heterocyclic ring, preferably selected from: Preferably said R 17 is independently selected from the group consisting of H, D, (=0), halogen, C1-C6alkyl, C1-C6deuteroalkyl, C2-C6alkenyl, C1-C6haloalkyl, cyano, C1-C6cyanoalkyl, -OH, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, -NH2, C1-C6alkylamino, C1-C6alkylaminoalkyl, -(C0-C3alkylene)-(C3-C6cycloalkyl), -(C0-C6alkylene)-(4-10 membered saturated heterocyclyl), -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)), -C(O)(C0-C6alkyl), -C(O)O(C0-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), C1-C6haloalkoxy, -C(O)O(C0-C6alkyl); Preferably, selected from the group consisting of:

27. The compound of claim 21, wherein R v01 and R v02 are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6deuteroalkoxy, C1-C6aminoalkyl, C1-C6alkylaminoalkyl; or, R v01 and R v02 together with the carbon atom to which they are both attached form a C3-C6cycloalkyl; or, R v01 and R v02 together form Preferably, selected from the group consisting of:

28. The compound of claim 21, wherein R 10a selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; Preferably, R 10a selected from: -CH3, -CHF2, -CH2F, -CF3, preferably -CH3.

29. The compound of claim 21, wherein R7is selected from: -H, D, -CI, -CN, -COOH, -CONH2, preferably R7is -H.

30. The compound of claim 21, wherein R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); 10 R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); Preferably, R1is selected from: H, D, F, Br, -CH3, -CHF2, -CH2F, -CF3, -CH2-CF3, -OH, -OCHF2, -OCH2F, -OCF3, 31. The compound of claim 21, wherein The compound is selected from the following structures:

32. The compound of claim 10, wherein The compound has the structure:

33. The compound of claim 32, wherein R 17a , R 17c , R 17d , R 17e , R 17f , R 17g are independently selected from the group consisting of: H, D, (=0), halogen, C1-C6alkyl, C1-C6deuteroalkyl, C2-C6alkenyl, C1-C6haloalkyl, cyano, C1-C6cyanoalkyl, -OH, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, -NH2, C1-C6alkylamino, C1-C6alkylaminoalkyl, -(C0-C3alkylene)-(C3-C6cycloalkyl), -(C0-C6alkylene)-(4-10 membered saturated heterocyclyl), -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)), -C(O)(C0-C6alkyl)), -C(O)O(C0-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), C1-C6haloalkoxy, -C(O)O(C0-C6alkyl); Preferably, R 17a and R 17g Independently selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, C1-C6 cyanoalkyl, C1-C6 alkoxyalkyl; Preferably, R 17c is selected from the group consisting of H, D, halogen, Ci-C6alkyl, Ci-C6deuteroalkyl; R 17d and R 17e are independently selected from the group consisting of: H, D, halogen, Ci-C6alkyl; or, R 15d and R 15e together with the carbon atom to which they are both attached form a 3- to 4- membered cycloalkyl; Preferably, R 17f is selected from the group consisting of H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, C1-C6 cyanoalkyl.

34. The compound of claim 32, wherein R v01 and R v02 are independently selected from the group consisting of H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6deuteroalkoxy, C1-C6aminoalkyl, C1-C6alkylaminoalkyl; or, R v01 and R v02 together with the carbon atom to which they are both attached form a C3-C6cycloalkyl; or, R v01 and R v02 together form Preferably, selected from the group consisting of:

35. The compound of claim 32, wherein R 10a , R 10b is independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; Preferably, R 10a selected from: -CH3, -CHF2, -CH2F, -CF3, preferably -CH3; or, R 10b is H.

36. The compound of claim 32, wherein R7is selected from: -H, D, -CI, -CN, -COOH, -CONH2, preferably R7is -H.

37. The compound of claim 32, wherein R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); 10 R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); Preferably, R1is selected from: H, D, F, Br, -CH3, -CHF2, -CH2F, -CF3, -CH2-CF3, -OH, -OCHF2, -OCH2F, -OCF3, 38. The compound of claim 32, wherein R 11 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl; 10 cycloalkylalkyl; Preferably, R 11 is H.

39. The compound of claim 32, wherein The compound is selected from the following structures:

40. The compound of claim 10, wherein The compound has the structure:

41. The compound of claim 40, wherein R v02 selected from: H, D, halogen, cyano, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C1-C6deuteroalkoxy, C1-C6aminoalkyl, C1-C6alkylaminoalkyl; Preferably, R v02 is H.

42. The compound of claim 40, wherein, R3and R4are independently selected from: H, D, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, C 1-6 aminoalkyl, C1-C6alkylaminoalkyl, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, R3 is H; R4 is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

43. The compound of claim 40, wherein R5is selected from: H, D, C1-C6alkyl, C1-C6haloalkyl, C1-C6cyanoalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl; R6is selected from: H, D, C1-C6alkyl, C3-C6cycloalkyl, C4-C10cycloalkylalkyl, 4- to 10- membered saturated heterocyclyl, heterocyclylalkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, saturated heterocyclyl, heterocyclylalkyl is optionally substituted with one or more independent substituents selected from: C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, 4- to 6- membered heterocyclyl, halogen, hydroxyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6alkoxyalkyl, cyano, C1-C6cyanoalkyl, carboxyl, C1-C6carboxyalkyl, C1-C6haloalkyl, C2-C6sulfonyl; or, 10 R6is selected from: H, D, C1-C6alkyl, C3-C6cycloalkyl, C4-C10cycloalkylalkyl, 4- to 10- membered saturated heterocyclyl, heterocyclylalkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, saturated heterocyclyl, heterocyclylalkyl is optionally substituted with one or more independent substituents selected from: C1-C6alkyl, C2-C6alkenyl, C3-C6cycloalkyl, 4- to 6- membered heterocyclyl, halogen, hydroxyl, C1-C6hydroxyalkyl, C1-C6alkoxy, C1-C6alkoxyalkyl, cyano, C1-C6cyanoalkyl, carboxyl, C1-C6carboxyalkyl, C1-C6haloalkyl, C2-C6sulfonyl; or, R5and R6together with the nitrogen atom to which they are both attached form a heterocyclyl wherein E ring is a 4-14 membered heterocyclic ring, R 17 is one or more independent substituents on the E ring, said R 17 is independently selected from the group consisting of: H, D, (=0), halogen, cyano, nitro, C 10 alkyl, C 10 deuteroalkyl, C 10 alkenyl, C 10 alkynyl, -(C0-C6alkylene)-(C3-C 10 cycloalkyl), -(C0-C6alkylene)-(C6-C 10 aryl), -(C0-C6alkylene)-(4-10 membered heterocyclyl), -0(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -S(O)2(C0-C 10 alkyl), -S(O)2-(C0-C6alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-10 membered heterocyclyl), -S(O)2N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(C3-C 10 cycloalkyl)), -S(O)2N(C0-C 10 alkyl)((C0-C6alkylene)-(4-10 membered heterocyclyl)), C 10 haloalkyl, C 10 cyanoalkyl, C 10 hydroxyalkyl, C 10 aminoalkyl, C 10 carboxyalkyl, C 10 alkoxyalkyl, C 10 alkylaminoalkyl; wherein each of the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, 4-10 membered heterocyclyl, haloalkyl, cyanoalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, alkoxyalkyl, alkylaminoalkyl is optionally substituted with one or more independent substituents selected from the group consisting of: D, halogen, cyano, nitro, C 1-10 Alkyl, -(C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(4-10 heterocyclic), -O(C0-C6) 10 Alkyl), -S(C0-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -S(O)2(C0-C 10 Alkyl), -S(O)2-(C0-C6 alkylene)-(C3-C 10 cycloalkyl), -S(O)2-(C0-C6 alkylene)-(4-10 membered heterocyclic), -S(O)2N(C0-C 10 Alkyl) (C0-C 10 Alkyl), -S(O)2N(C0-C 10 Alkyl)((C0-C6 alkylene)-(C3-C6 alkylene) 10 cycloalkyl), -S(O)2N(C0-C) 10 Alkyl)((C0-C6 alkylene)-(4-10 membered heterocyclic group)); wherein the heterocyclic group Optionally substituted with one or more independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, amino, C1-C 10 Alkyl, substituted or unsubstituted phenyl or 4-6 membered heterocyclic groups.

44. The compound of claim 40, wherein R5is selected from: H, C1-C6alkyl; R6is selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxyalkyl, Preferably, selected from the group consisting of:

45. The compound of claim 43, wherein E ring is a saturated heterocyclic ring or a partially unsaturated heterocyclic ring, preferably selected from: Preferably said R 17 is independently selected from the group consisting of H, D, (=0), halogen, C1-C6alkyl, C1-C6deuteroalkyl, C2-C6alkenyl, C1-C6haloalkyl, cyano, C1-C6cyanoalkyl, -OH, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6hydroxyalkyl, C1-C6alkoxyalkyl, -NH2, C1-C6alkylamino, C1-C6alkylaminoalkyl, -(C0-C3alkylene)-(C3-C6cycloalkyl), -(C0-C6alkylene)-(4-10 membered saturated heterocyclyl), -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)), -C(O)(C0-C6alkyl), -C(O)O(C0-C6alkyl), -C(O)N(C0-C6alkyl)(C0-C6alkyl), C1-C6haloalkoxy, -C(O)O(C0-C6alkyl); Preferably, selected from the group consisting of:

46. The compound of claim 40, wherein R 10a , R 10b is independently selected from the group consisting of H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl; Preferably, R 10a selected from: -CH3, -CHF2, -CH2F, -CF3, preferably -CH3. R 10b is H.

47. The compound of claim 40, wherein R7is selected from: -H, D, -CI, -CN, -COOH, -CONH2, preferably R7is -H.

48. The compound of claim 40, wherein R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); 10 R1is selected from: H, D, halogen, hydroxyl, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6alkoxyalkyl, C1-C6haloalkoxyalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, C4-C6cycloalkylalkyl, 4- to 6-membered saturated heterocyclyl, -S(O)2(C0-C6alkyl), -S(O)2-(C0-C6alkylene)-(C3-C6cycloalkyl), -S(O)2-(C0-C6alkylene)-(4-6 membered heterocyclyl), -S(O)2N(C0-C6alkyl)(C0-C6alkyl), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(C3-C6cycloalkyl)), -S(O)2N(C0-C6alkyl)((C0-C6alkylene)-(4-6 membered heterocyclyl)); Preferably, R1is selected from: H, D, F, Br, -CH3, -CHF2, -CH2F, -CF3, -CH2-CF3, -OH, -OCHF2, -OCH2F, -OCF3, 49. The compound of claim 40, wherein The compound is selected from the following structures:

50. The compound of claim 1, wherein The compound has the structure:

51. A pharmaceutical composition comprising a compound of any one of claims 1-50, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

52. The pharmaceutical composition of claim 51, wherein, said compound or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof is used alone, or said compound or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof is used in combination with a second active ingredient; said compound or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof is used alone, or said compound or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof is used in combination with a second active ingredient; Preferably, the second active ingredient is a serotonin receptor antagonist, preferably a serotonin inhibitor, more preferably selected from one or more of ondansetron, granisetron, palonosetron, dolasetron.

53. Use of a compound of any one of claims 1-50, or a pharmaceutically acceptable salt, stereoisomer, solvate, deuterated compound thereof, in the manufacture of a medicament for the prevention and / or treatment of a disease associated with Cbl-b activity.

54. The use of claim 53, wherein the compound is ###0009### the disease is selected from one or more of an autoimmune disease, an inflammatory disease, a tumor, a disease caused by a pathogen infection or a disease associated with a pathogen infection; Preferably, said autoimmune disease is selected from the group consisting of achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-glomerular basement membrane antibody nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticarial, acute motor-sensory axonal neuropathy, Balo disease, Behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease, discoid lupus, Dressier syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis or pemphigoid gestationis, hidradenitis suppurativa, hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile dermatomyositis, Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease, Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, panda syndrome, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry-Romberg syndrome, pars planitis, Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, type II, type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestin dermatitis, psoriasis, psoriatic arthritis, pure red cell anemia,Gangrenous pyoderma, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis, Susac's syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, temporal arteritis, thyroid eye disease, Tolosa-Hunt syndrome, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, one or more of Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Bechterew, Morbus Be preferably, the inflammatory disease is selected from one or more of gout, chronic obstructive pulmonary disease, interstitial lung disease, inflammatory bowel disease, sepsis, asthma, allergy; preferably, the tumor is selected from one or more of blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, squamous cell carcinoma, epithelial squamous cell carcinoma, lung cancer, peritoneal cancer, hepatocellular carcinoma, gastric cancer, intestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, head and neck cancer, urothelial cancer, head and neck squamous cell carcinoma, metastatic or unresectable melanoma, non-small cell lung cancer, metastatic castration-resistant prostate cancer, malignant pleural mesothelioma, metastatic urothelial cancer, metastatic colorectal cancer; more preferably, the tumor is a hematological malignancy, preferably one or more of leukemia, lymphoma, multiple myeloma, more preferably selected from one or more of chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute monocytic leukemia, B-cell lymphoma, T / NK-cell lymphoma; more preferably, the tumor is a solid tumor, preferably one or more of neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, esophageal cancer, gastroesophageal junction cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, head and neck cancer, urothelial cancer, head and neck squamous cell carcinoma, metastatic or unresectable melanoma, non-small cell lung cancer, metastatic castration-resistant prostate cancer, malignant pleural mesothelioma, metastatic urothelial cancer, metastatic colorectal cancer; preferably one or more of ovarian cancer, gastric cancer, gastroesophageal junction cancer, head and neck squamous cell carcinoma, metastatic or unresectable melanoma, non-small cell lung cancer, metastatic castration-resistant prostate cancer, malignant pleural mesothelioma, breast cancer, metastatic urothelial cancer, cervical cancer, metastatic colorectal cancer.

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