HPK1 inhibitors and their medical applications

Abstract

The present invention relates to a compound represented by general formula (I), its stereoisomers, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, which have cancer therapeutic activity. The present invention also relates to methods for preparing these compounds and pharmaceutical compositions containing them. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a compound of formula (I), its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a drug for treating cancer. Background Art

[0002] Hematopoietic progenitor cell kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase 1 (MAP4K1), is a member of the serine / threonine kinase subfamily Ste20, which also includes MAP4K2 (GCK), MAP4K3 (GLK), MAP4K4 (HGK), MAP4K5 (KHS), and MAP4K6 (MINK). HPK1 is a negative regulator of B cell, T cell, and dendritic cell activation responses. Inhibiting its expression can specifically enhance anti-tumor immunity. HPK1 is primarily expressed in hematopoietic cells, such as T cells, B cells, dendritic cells, macrophages, mast cells, and neutrophils.

[0003] In T cells, HPK1 regulates T cell activation through the TCR signaling pathway. Following TCR activation, HPK1 interacts with the T cell receptor protein and is phosphorylated by the tyrosine kinases Zap70 and Lck. It also phosphorylates the SLP-76 receptor protein, negatively regulating TCR signaling and thereby inhibiting T cell activation and proliferation. Studies have shown that HPK1 participates in numerous signaling cascades, including the MAKP signaling pathway, the Fas-induced apoptosis pathway, and the NF-κB signaling pathway. Furthermore, HPK1 inhibits AP-1, which plays a role in promoting cell proliferation, inhibiting differentiation, and promoting tumor cell invasion and metastasis during tumor formation and progression.

[0004] Therefore, drugs targeting HPK1 have become a hot area in current drug development, with some already entering clinical trials. However, there are currently no marketed drugs targeting hematopoietic progenitor cell kinase (HPK1). This invention provides a novel small molecule HPK1 inhibitor with excellent anti-tumor activity. Summary of the Invention

[0005] The present invention provides a compound represented by general formula (I), its stereoisomers, tautomers, deuterated compounds or pharmaceutically acceptable salts:

[0006]

[0007]

[0008] in,

[0009] Ring A is selected from C 5-14 Bis(carbonyl), 5-14-membered bi(heterocyclic), C 10-18 Bicyclic aryl or 10-18 membered bicyclic heteroaryl;

[0010] L is selected from a bond, NH, O or S;

[0011] R1 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl is optionally further substituted with one or more R a Replacement; R a are independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-S(=O)R b 、-C 0-3 Alkylene-S(=O)2R b 、-C 0-3 Alkylene-SR b 、-C 0-3 Alkylene-S(R b )5. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl), the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C 3-14 Cycloalkyl, -C 0-3 Alkylene-(3-14 membered heterocyclic group), -C 0-3 Alkylene-C 6-18 Aryl or -C 0-3 Alkylene-(5-18 membered heteroaryl) is optionally further substituted with one or more R b Replace, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0012] R2 is selected from H, C 1-6 Alkyl or haloalkyl;

[0013] R3 is selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 N(R b )2、-(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3-5-18 membered heteroaryl optionally further substituted with one or more R c replaced by;

[0014] R c independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、-O(CH2) 0-3 C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 substituted by one or more substituents of aryl and 5-18 membered heteroaryl;

[0015] R4 or R5 are each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, -(CH2) 1-3 N(R b )2、C 2-6 Alkenyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, -(CH2) 1-3 N(R b )2、C 2-6 Alkenyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl is optionally further substituted with one or more R d replaced by;

[0016] R4 or R5 independently form a C atom directly connected to the A ring 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl is optionally further substituted with one or more R d replaced; or

[0017] R4 and R5 are connected to the atoms on the A ring to form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl is optionally further substituted with one or more R d replaced by;

[0018] R d Selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, cyano, amino, nitro, hydroxy or hydroxyalkyl;

[0019] X is selected from CR6 or N;

[0020] R6 is selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0021] m is selected from 0, 1, 2, 3 or 4.

[0022] n is selected from 0, 1 or 2.

[0023] In some embodiments, R3 in formula (I) is selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, -(CH2) 0-3 N(R b )2、-(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl optionally further substituted with one or more R c replaced by;

[0024] The R cindependently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、-O(CH2) 0- 3C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 The aryl group and the 5-18 membered heteroaryl group are substituted by one or more substituents.

[0025] In some embodiments, each R in formula (I) b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0026] Said R3 is selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, -(CH2) 0-3 N(R b )2、-(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl optionally further substituted with one or more R c replaced by;

[0027] The R c independently selected from halogen, C 1-6 Alkyl, C 1-6Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、-O(CH2) 0- 3C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 substituted by one or more substituents of aryl and 5-18 membered heteroaryl;

[0028] n is selected from 1 or 2.

[0029] In some embodiments, each R in formula (I) b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0030] Said R3 is selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, -(CH2) 0-3 N(R b )2、-(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxyalkyl, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, -(CH2) 0-3 -C 6-18 Aryl or -(CH2) 0-3 -5-18 membered heteroaryl optionally further substituted with one or more R c replaced by;

[0031] The R c independently selected from halogen, C 1-6 Alkyl, C 1-6Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、-O(CH2) 0- 3C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 substituted by one or more substituents of aryl and 5-18 membered heteroaryl;

[0032] The n is selected from 1 or 2.

[0033] In some embodiments, R4 or R5 in formula (I) independently form a C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl, the C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 6-18 membered heteroaryl is optionally further substituted with one or more R d substituted; said R d Selected from H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 haloalkyl, cyano, amino, nitro, hydroxy or hydroxyalkyl.

[0034] In some embodiments, L in formula (I) is selected from a bond or NH, preferably NH.

[0035] In some embodiments, R1 in formula (I) is selected from C 6-18 Aryl or 6-18 membered heteroaryl, the C 6-18 Aryl or 6-18 membered heteroaryl is optionally further substituted with one or more R a Replacement; R a are independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-C(=O)R b 、-C0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl; each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0036] In some embodiments, R1 in formula (I) is selected from described further by one or more R a Replacement; R a are independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b )2、C 2-6 Alkenyl, C 2-6 Alkynyl; each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0037] In some embodiments, R1 in formula (I) is selected from

[0038] In some embodiments, R1 in formula (I) is selected from

[0039] In some embodiments, R2 in formula (I) is preferably H.

[0040] In some embodiments, ring A in formula (I) is selected from C 8-10 Bicarbonyl, 8-10 membered biheterocyclic alkyl, C 10-12 Bicyclic aryl or 10-12 membered bicyclic heteroaryl, preferably selected from

[0041] In some embodiments, ring A in formula (I) is selected from C 8-10 Bicarbonyl, 8-10 membered biheterocyclic alkyl, C 10-12 Bicyclic aryl or 10-12 membered bicyclic heteroaryl, preferably selected from

[0042] In some embodiments, R3 in formula (I) is selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group or -(CH2) 0-3 N(R b )2, the C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, haloalkyl group, hydroxyalkyl group, C 2-6 Alkenyl or C 2-6 Alkynyl, optionally further substituted with one or more R c substituted; said R c independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、-O(CH2) 0-3 C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C6-18 substituted by one or more substituents of aryl and 5-18 membered heteroaryl; each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0043] In some embodiments, R3 in formula (I) is H, -(CH2) 0-3 N(R b )2, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -3-14 membered heterocyclic group or C 1-6 Alkyl, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) 0-3 C 1-6 Alkoxy or C 1-6 Halogenated alkyl.

[0044] In some embodiments, the atoms directly connected to R4 and A ring in formula (I) form C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 aryl or 6-18 membered heteroaryl.

[0045] In some embodiments, Formula (I) is selected from Formula (IA):

[0046]

[0047] in,

[0048] The ring B is selected from C 3-14 Cycloalkyl, 3-14 membered heterocycloalkyl, C 6-18 Aryl or 6-18 membered heteroaryl;

[0049] The R1, R2, R3, R5, X, L, A ring, R d The definitions of m and n are the same as those in formula (I).

[0050] In some embodiments, Ring A in Formula (IA) is selected from C 8-10 Bicarbonyl, 8-10 membered biheterocyclic alkyl, C 10-12 Bicyclic aryl or 10-12 membered bicyclic heteroaryl.

[0051] In some embodiments, Ring A in Formula (IA) is selected from The D, E, and G are each independently selected from C, N, or O.

[0052] In some embodiments, Ring A in Formula (IA) is selected from

[0053] In some embodiments, in formula (IA) Selected from The D, E, G, and Z are each independently selected from C, N, or O.

[0054] In some embodiments, in formula (IA) Selected from

[0055] In some embodiments, R3 in formula (IA) is selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group or -(CH2) 0-3 N(R b )2, the C 1-6 Alkyl, C 1-6 Alkoxy, -(CH2) 0-3 -C 3-14 Cycloalkyl, -(CH2) 0-3 -3-14 membered heterocyclic group, haloalkyl group or hydroxyalkyl group optionally further substituted with one or more R c replaced by;

[0056] R c independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、O(CH2) 0-3 C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18substituted by one or more substituents in aryl and 5-18 membered heteroaryl, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0057] m is selected from 0, 1, 2 or 3.

[0058] In some embodiments, R3 in formula (IA) is H, -(CH2) 0-3 N(R b )2, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -3-14 membered heterocyclic group or C 1-6 Alkyl, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) 0-3 C 1-6 Alkoxy or C 1-6 Halogenated alkyl.

[0059] In some embodiments, R5 in formula (IA) is selected from C 1-6 Alkyl, wherein n is selected from 0 or 1.

[0060] In some embodiments, L in Formula (IA) is NH.

[0061] In some embodiments, R1 in formula (IA) is selected from described further by one or more R a Replacement; R a are independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-OR b 、-OC(=O)C 1-6 Alkyl, -C 0-3 Alkylene-N(R b )2. -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)OR b 、-C 0-3 Alkylene-C(=O)N(R b)2、C 2-6 Alkenyl, C 2-6 Alkynyl, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

[0062] In some embodiments, R1 in formula (IA) is selected from

[0063] In some embodiments, R2 in Formula (IA) is H.

[0064] In some embodiments, in formula (I) Selected from

[0065]

[0066]

[0067] In some embodiments, formula (I) is selected from:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] In another aspect, the present invention provides an intermediate compound for synthesizing the compound of formula (I) or its stereoisomers, tautomers, deuterated compounds, or pharmaceutically acceptable salts, selected from:

[0074]

[0075]

[0076] The compounds of this invention can effectively inhibit the function of the HPK1 protein, inducing the secretion of cytokines such as IL2 and IFNγ in T cells, thereby activating the immune system. Furthermore, these compounds have excellent oral absorption in various animal models and significantly inhibit tumor cell growth in mouse tumor models, with efficacy far exceeding that of HPK1 inhibitors currently in clinical stages. Furthermore, the compounds of this invention possess the advantages of strong selectivity, low toxicity, and a wide safety window, and are expected to achieve even better clinical efficacy in the future.

[0077] The present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts.

[0078] The present invention provides the use of a compound represented by structural formula (I), its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in preparing medicines.

[0079] The present invention further provides a preferred technical solution for the application:

[0080] Preferably, the application is application in the preparation of drugs for treating and / or preventing cancer.

[0081] Preferably, the application is for preparing a drug for treating a disease mediated by HPK1. Preferably, the disease is cancer.

[0082] Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

[0083] The present invention also provides a method for treating and / or preventing a disease, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition containing the same.

[0084] The present invention also provides a method for treating and / or preventing diseases mediated by HPK1, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition containing the same.

[0085] The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition containing the same.

[0086] Preferably, in the above method, the HPK1-mediated disease is cancer.

[0087] Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

[0088] Unless otherwise indicated, general chemical terms used in the structural formulae have their usual meanings.

[0089] For example, the term "halogen," as used herein, refers to fluorine, chlorine, bromine, or iodine, unless otherwise indicated.

[0090] In the present invention, unless otherwise specified, "alkyl" includes a linear or branched monovalent saturated hydrocarbon group. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, "C 1-6 "alkyl" in 1-6 ” refers to a group containing 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain.

[0091] "Alkoxy" refers to the oxygen ether form of the aforementioned straight-chain or branched alkyl groups, ie, -O-alkyl.

[0092] The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane with two C—H bonds replaced as the point of attachment of the alkylene to the rest of the compound. Similarly, C 1-3 The "C" in the alkylene 1-3 ” refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.

[0093] The term "haloalkyl" refers to an alkyl group in which one or more H groups have been replaced by a halogen atom.

[0094] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when attached to C, and forms a sulfoxide group or a sulfone group or an N-oxide group when attached to a heteroatom.

[0095] In the present invention, unless otherwise specified, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" refers to a polyunsaturated carbon ring or heterocycle with aromatic characteristics (having (4n+2) delocalized π electrons, where n is an integer).

[0096] The term "aryl", in the present invention, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or condensed ring aromatic group containing carbon ring atoms. 6-18 Aryl, more preferably C 6-10 A monocyclic or bicyclic aromatic ring group. Preferably, it is phenyl or naphthyl. Most preferably, it is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl group, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include but are not limited to benzocyclopentyl.

[0097] The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic ring, wherein the heteroatom is selected from N, O and / or S. The heterocyclyl group may include a monocyclic or polycyclic ring (e.g., having 2, 3 or 4 fused rings, spirocyclic rings, bridged rings, etc.). The heterocyclyl group may be connected to the other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, the heterocyclyl group is a 3-14 membered group, wherein the "3-14 members" in the 3-14 membered heterocyclyl group refers to a heterocyclyl group consisting of 3-14 C, N, O or S ring atoms; more preferably a 3-8 membered heterocyclyl group, and even more preferably a 3-6 membered heterocyclyl group. The nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of these heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group.

[0098] The term "heteroaryl" as used herein, unless otherwise specified, refers to a monocyclic or polycyclic (e.g., 2, 3, or 4 fused, spiro, or bridged) aromatic heterocycle having at least one heteroatom, wherein the heteroatom is selected from N, O, and / or S, and wherein the nitrogen or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. A 5- to 18-membered heteroaryl is preferred, wherein the "5- to 18-membered" in the 5- to 18-membered heteroaryl refers to a heteroaryl group consisting of 5 to 18 ring atoms of C, N, O, or S. A 5- to 10-membered heteroaryl is more preferred; a 5- to 6-membered heteroaryl is even more preferred. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolyl, or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring.

[0099] The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. 3-14 Cycloalkyl, where "C 3-14 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms. The cycloalkyl group may include a monocyclic ring and a polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group may also be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring connected to the parent structure is a cycloalkyl group.

[0100] The term "bicarbocyclyl" refers to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring containing no heteroatoms, including bicyclic rings of 5-14 carbon atoms, one of which may be aromatic, but the bicarbocyclyl as a whole is not aromatic. Bicyclic rings of 7-12 carbon atoms are preferred. Bicyclic rings of 7-12 carbon atoms may be bicyclic [4,5], [5,5], [5,6], or [6,6] systems, while bicyclic rings of 9 or 10 carbon atoms may be bicyclic [5,6] or [6,6] systems. Suitable bicyclic carbocyclyl groups include, but are not limited to, fused bicyclic rings, spirobicyclic rings, and bridged bicyclic rings. Examples further include, but are not limited to, fused bicyclo[3.3.0]octanyl, fused bicyclo[3.1.0]hexanyl, 1,2,3,4,4a,5,8,8a-octahydronaphthyl, bicyclo[2.2.1]heptanyl, and the like. One or more ring hydrogen atoms are independently optionally replaced with one or more substituents described herein.

[0101] The term "biheterocyclyl" refers to a bicyclic ring system in which one or more ring atoms are independently optionally substituted with heteroatoms. The rings may be fully saturated or contain one or more degrees of unsaturation. One of the rings may be aromatic, but the biheterocyclyl as a whole is not aromatic. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom to form a stable compound. One or more ring hydrogen atoms may be independently optionally substituted with one or more substituents described herein. Biheterocyclyl groups include, but are not limited to, fused heterobicyclyls, spiro heterobicyclyls, and bridged heterobicyclyls. In some embodiments, each ring system of the bicyclic heterocyclyl comprises 3-7 ring atoms, i.e., 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, and S, wherein S or P is optionally replaced by one or more oxygen atoms to form groups such as SO, SO2, PO, and PO2. In some embodiments, the biheterocyclyl includes a heterocyclyl-fused heterocyclyl, a heterocyclyl-fused carbocyclyl, a heterocyclyl-fused heteroaryl, or a heterocyclyl-fused aryl, connected to the main structure through the carbocyclyl, heteroaryl, or heterocyclyl group.

[0102] The term "bicyclic aryl" refers to a bicyclic carbocyclic ring system, wherein the bicyclic aromatic ring system is fused to form a ring, the bicyclic aromatic ring system as a whole is aromatic, wherein each ring system contains 5-9 atoms. It may include naphthyl. One or more ring hydrogen atoms are independently optionally replaced with one or more substituents described herein.

[0103] The term "bicyclic heteroaryl" refers to a bicyclic ring system in which the bicyclic heteroaryl ring system is fused to form a ring. The bicyclic heteroaryl ring system is aromatic as a whole, and one or more ring atoms are independently optionally substituted with heteroatoms (heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to form groups such as SO, SO2, PO, and PO2). The bicyclic heteroaryl system may be attached to the main structure at any heteroatom or carbon atom to form a stable compound. The bicyclic heteroaryl system group may be a bicyclic ring of 7-15 atoms or a bicyclic ring of 7-10 atoms. The bicyclic ring of 7-10 atoms may be a bicyclic [4,5], [5,5], [5,6], or [6,6] system. One or more ring hydrogen atoms are independently optionally substituted with one or more substituents described herein.

[0104] The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -OR 1 、-SR 1 , =O, =S, -C(O)R 1 、-C(S)R1 、=NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 , cyano, nitro, -S(O)2R 1 、-OS(O2)OR 1 、-OS(O)2R 1 、-OP(O)(OR 1 )(OR 2 ); where R 1 and R 2 Independently selected from -H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , formaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethylamino, methylthio, sulfonyl, and acetyl.

[0105] Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, phenylmethyl, dioxolylmethyl, and piperazinylmethyl.

[0106] Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, and 3-hydroxypropoxy.

[0107] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond, (R3)0 means that there is no R3 substitution at that position, and (R5)0 means that there is no R5 substitution at that position.

[0108] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.

[0109] When the compound provided by the present invention is an acid, its corresponding salt can be easily prepared from pharmaceutically acceptable nontoxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low valence), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low valence), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0110] When compound provided by the invention is a base, it is possible to conveniently prepare its corresponding salt from pharmaceutically acceptable nontoxic acid, including inorganic and organic acids. Such acid includes, as, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, tamoxifen, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.

[0111] Prodrugs of the compounds of the present invention are included within the scope of protection of the present invention. Generally, such prodrugs are functional derivatives that are readily converted into the desired compound in vivo. For example, any pharmaceutically acceptable salt, ester, ester salt, or other derivative of the compounds of the present invention, which, upon administration to a recipient, can directly or indirectly provide the compounds of the present invention or their pharmaceutically active metabolites or residues.

[0112] The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers and pharmaceutically acceptable salts thereof.

[0113] When the compound represented by formula (I) exists in tautomers, unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0114] Substitution of compounds of formula (I) with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0115] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0116] In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable excipient composition can be interpreted as indicating that the pharmaceutical composition includes "one or more" pharmaceutically acceptable excipients.

[0117] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0118] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0119] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0120] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0121] The term "effective amount" means an amount of a compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0122] Synthesis Scheme 1:

[0123]

[0124] Step I: Compounds I-1 and I-2 undergo a Buchwald coupling reaction in the presence of a Pd catalyst such as Pd2(dba)3 to obtain compound I-3;

[0125] Step II: Compound I-3 and Boron esterification is carried out in the presence of a Pd catalyst such as Pd2(dba)3 to give I-4;

[0126] Step III: Compound I-4 and In the presence of a metal catalyst such as PdCl2(dppf).CH2Cl2 or PdCl2(dppf), R1 is introduced through a Suzuki coupling reaction to obtain compound I, wherein P is Cl, Br or I.

[0127] To make the above content clearer and more specific, the present invention will further illustrate the technical solutions of the present invention with the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described are conventional technical means or methods in the art.

[0128] Unless otherwise indicated, all temperatures herein are in degrees Celsius.

[0129] The following abbreviations are used in the examples:

[0130] DMF: N,N-dimethylformamide;

[0131] NBS: N-bromosuccinimide;

[0132] THF: tetrahydrofuran;

[0133] [PdCl2(dppf)]: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0134] [PdCl2(dppf)]CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex;

[0135] EA: ethyl acetate;

[0136] PE: petroleum ether;

[0137] DCM: dichloromethane;

[0138] MeOH: methanol;

[0139] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium;

[0140] Sphos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl;

[0141] BPO: benzoyl peroxide;

[0142] DMAP: 4-dimethylaminopyridine;

[0143] MsCl: methanesulfonyl chloride;

[0144] AIBN: azobisisobutyronitrile;

[0145] TMSCN: trimethylsilyl cyanide;

[0146] TBAF: tetrabutylammonium fluoride;

[0147] LDA: lithium diisopropylamide;

[0148] TBAF: tetrabutylammonium fluoride;

[0149] LiHMDS: lithium bis(trimethylsilyl)amide;

[0150] TMSCl: trimethylchlorosilane;

[0151] XantPhos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;

[0152] Dioxane: dioxane;

[0153] RT: room temperature;

[0154] (Boc)2O: di-tert-butyl dicarbonate;

[0155] DIBAL-H: diisobutylaluminum hydride;

[0156] RuPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium(II);

[0157] i-PrOH: isopropyl alcohol;

[0158] PPA: polyphosphoric acid;

[0159] B2Pin2: pinacol borate;

[0160] Noyoricatalyst (ss): (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium(II) chloride;

[0161] BocNH2: tert-butyl carbamate;

[0162] TFA: trifluoroacetic acid;

[0163] TFAA: trifluoroacetic anhydride;

[0164] MTBE: methyl tert-butyl ether;

[0165] Ti(OEt)4: ethyl titanate;

[0166] DMSO: dimethyl sulfoxide;

[0167] Solutol / HS15 / SolutolHS15: Macrogol-15 hydroxystearate.

[0168] Synthesis of intermediate M1:

[0169]

[0170] Step 1: Synthesis of compound M1-1

[0171] 3-Chloro-2-methylbenzoic acid (200.00 g) and potassium carbonate (405.09 g) were added to DMF (1300.00 mL) at room temperature. Methyl iodide (80.28 mL) was added dropwise in an ice-water bath and allowed to react at room temperature for 16 h. 2000 mL of water was added to the reaction solution, and extraction with 1000 mL of EA was repeated three times. The organic phases were combined, washed six times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the target compound M1-1 (213.00 g, 98.41% yield).

[0172] Step 2: Synthesis of Compound M1-2

[0173] Compound M1-1 (103.00 g), NBS (109.22 g), and BPO (2.70 g) were added to chloroform (700.00 mL) at room temperature and reacted at 90°C for 16 h. 1000 mL of water was added to the reaction solution, and extraction with 1000 mL of DCM was repeated three times. The organic phases were combined, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound M1-2 (145.00 g, 98.63% yield).

[0174] Step 3: Synthesis of Compound M1-3

[0175] Compound M1-2 (350.00 g) was added to a 7 M ammonia in methanol solution (1000.00 mL) in an ice-water bath and allowed to react for 1 h. The reaction solution was concentrated to obtain a solid, which was washed three times with water and dried to obtain the target compound M1-3 (213.80 g, 96.05% yield).

[0176] ESI-MS m / z:167.9[M+H] + .

[0177] Step 4: Synthesis of Compound M1-4

[0178] Compound M1-3 (100.00 g) was added to concentrated sulfuric acid (600.00 mL) at room temperature. Concentrated nitric acid (50.00 mL) was added dropwise in an ice-water bath. The mixture was stirred for 1 hour in an ice-water bath and then for another hour at room temperature. The reaction mixture was slowly poured into ice water, filtered, and the filter cake was washed three times with water. The filter cake was then dried to obtain the target compound M1-4 (116.08 g, 91.51% yield). ESI-MS m / z: 213.0 [M+H] + .

[0179] Step 5: Synthesis of Compound M1-5

[0180] Compound M1-4 (244.00 g) and ammonium chloride (368.68 g) were added to ethanol (2500.00 mL) and water (500.00 mL). Iron powder (320.51 g) was added portionwise at 65°C and the mixture was allowed to react at 65°C for 2 h. The reaction mixture was filtered while hot, and the filter cake was washed six times with EA. The filtrate was concentrated and water was added. Solids precipitated and filtered. The filter cake was washed three times with water, dried, and then slurried with PE / EA = 3 / 1, filtered, and dried to obtain the target compound M1-5 (162.00 g, 77.29% yield). ESI-MS m / z: 183.0 [M+H] + .

[0181] Step 6: Synthesis of Compound M1-6

[0182] Compound M1-5 (129.00 g) was added to hydrogen bromide (48% aqueous solution, 900.00 mL). A solution of sodium nitrite (73.11 g) in water (600.00 mL) was added dropwise at -10°C. The mixture was reacted at -10°C for 1 hour. CuBr (111.47 g) was added, the temperature was raised to 80°C, and the mixture was stirred for 1 hour. The reaction solution was poured into ice water to precipitate the product, which was filtered and washed three times with water. The filter cake was dried to obtain the target compound M1-6 (143.00 g, 82.12% yield).

[0183] ESI-MS m / z: 247.9 [M+H] + .

[0184] Step 7: Synthesis of Compound M1

[0185] Compound M1-6 (143.00 g) and DMAP (7.09 g) were added to THF (1300.00 mL). (Boc)2O (159.94 mL) was added dropwise in an ice-water bath and allowed to react at room temperature for 1 h. The reaction solution was quenched by adding water (1000.00 mL) and extracted with 8000 mL of EA three times. The organic phases were combined, washed three times with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and then slurried with PE, filtered, and the filter cake was dried to obtain the target compound M1 (185.00 g, 92.00% yield).

[0186] ESI-MS m / z: 289.9 [M+H] + .

[0187] Synthesis of intermediate M2:

[0188]

[0189] Step 1: Synthesis of compound M2-1

[0190] 2-Chloro-3-methyl-5-bromopyridine (5.00 g) was dissolved in THF (50 mL) at room temperature. LDA (14.53 mL, 2 M) was slowly added dropwise at -78°C under N2 protection. The reaction was incubated for 40 min, and then CO2 was slowly introduced. The temperature was then slowly raised to room temperature for 40 min to stop the reaction. The reaction was quenched with saturated sodium bicarbonate solution, and EA was added. The layers were separated, and the aqueous phase was retained. The organic phase was back-extracted with water twice. The aqueous phases were combined, the pH was adjusted to 4 with HCl, and then extracted five times with DCM / i-PrOH = 3:1. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound M2-1 (2.83 g, 46.66% yield). ESI-MS m / z: 250.5 [M+H] + .

[0191] Step 2: Synthesis of compound M2-2

[0192] At room temperature, compound M2-1 (2.83 g) was dissolved in DMF (30 mL), potassium carbonate (3.12 g) was added, and CH3I (2.41 g) was slowly added dropwise under nitrogen. The mixture was allowed to react at room temperature for 16 h before being stopped. The reaction was quenched with water and extracted three times with EA. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target compound M2-2 (1.80 g, 60.23% yield). ESI-MS m / z: 265.5 [M+H] + .

[0193] Step 3: Synthesis of Compound M2-3

[0194] Compound M2-2 (1.50 g) was dissolved in CCl4 (20 mL) at room temperature, and NBS (2.02 g) and AIBN (90.00 mg) were added. Under nitrogen protection, the reaction was allowed to proceed at 80°C for 16 h, after which the reaction was stopped. The reaction was quenched with water and extracted three times with DCM. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target compound M2-3 (1.80 g, 92.30% yield). ESI-MS m / z: 344.4 [M+H] + Step 4: Synthesis of Compound M2-4

[0195] Compound M2-3 (1.80 g) was dissolved in ammonia in methanol (20 mL) at room temperature and allowed to react for 2 h. The reaction was then stopped. The reaction mixture was filtered, the filter cake washed with methanol, and dried to obtain the target compound M2-4 (1.28 g, yield 98.52%). ESI-MS m / z: 397.2 [M+H] + .

[0196] Step 5: Synthesis of Compound M2

[0197] Compound M2-4 (1.28 g) was dissolved in 1,4-dioxane (60 mL) at room temperature, DMAP (70 mg) was added, and di-tert-butyl dicarbonate (1.40 g) was slowly added dropwise. The mixture was allowed to react at room temperature for 2 h, after which the reaction was stopped. The reaction was quenched with water and extracted three times with EA. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target compound M2 (1.57 g, 87.75% yield). ESI-MS m / z: 347.3 [M+H] + .

[0198] Synthesis of intermediate M3

[0199]

[0200] Step 1: Synthesis of compound M3-2

[0201] Under nitrogen protection and -78 ° C, LiHMDS (4.95 mL, 1M / THF) was added dropwise to a solution of M3-1 (1 g) in THF (10 mL) over 30 minutes. After stirring for 30 minutes, TMSCl (0.66 mL) was added, stirred for 5 minutes, and LiHMDS (9.67 mL, 1M / THF) was added dropwise over 30 minutes. The temperature was raised to -30 ° C to -20 ° C, stirred for 30 minutes, and bis (2-bromoethyl) ether (1.09 g) was added. The temperature was gradually raised to room temperature and stirred overnight. The reaction solution was quenched with saturated ammonium chloride solution, concentrated under reduced pressure to remove part of the solvent, extracted with EA, and the organic layers were combined, washed with 1M HCl, water and saturated brine in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 70:30-65:35) to obtain compound M3-2 (246 mg, 18% yield). ESI-MS m / z: 281.99 [M+H] + .

[0202] Step 2: Synthesis of Compound M3-3

[0203] Under ice bath, sodium borohydride (99 mg) was added portionwise to a solution of M3-2 in MeOH (6 mL) and THF (2 mL). The ice bath was removed and the reaction was allowed to react at room temperature for 1 hour. The mixture was quenched with water and concentrated under reduced pressure to remove some of the solvent. The mixture was extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M3-3 (217 mg, 88% yield). ESI-MS m / z: 283.98 [M+H] + .

[0204] Step 3: Synthesis of Compound M3-4

[0205] Under ice-bath, thionyl chloride (0.28 mL) was added dropwise to a DCM (5 mL) solution of M3-3. The ice-bath was removed, the temperature was raised to 40°C, and the reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=85:15) to obtain compound M3-4 (148 mg, 64% yield). ESI-MS m / z: 301.96 [M+H] + .

[0206] Step 4: Synthesis of Compound M3-5

[0207] M3-4 (148 mg), potassium carbonate (203 mg), and potassium iodide (16 mg) were dissolved in acetonitrile (5 mL) at room temperature. Dimethylamine (2.45 mL, 2M / THF) was added and the temperature was raised to 80°C for 3 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain compound M3-5 (85 mg, 56% yield). ESI-MS m / z: 311.02 [M+H] + .

[0208] Step 5: Synthesis of Compound M3-6

[0209] M3-5 (85 mg), benzophenone imine (59 mg), Pd2(dba)3 (25 mg), XantPhos (32 mg), and cesium carbonate (267 mg) were dissolved in 1,4-Dioxane (5 mL) at room temperature. The atmosphere was replaced with nitrogen and the temperature was raised to 100°C for 6 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 92:8) to obtain compound M3-6 (86 mg, 77% yield). ESI-MS m / z: 412.25 [M+H] + .

[0210] Step 6: Synthesis of Compound M3

[0211] M3-6 (86 mg) was dissolved in MeOH (2 mL) at room temperature, and hydrochloric acid (0.52 mL, 4M / 1,4-Dioxane) was added. The temperature was raised to 50°C and the reaction was allowed to react for 1 hour. The mixture was cooled, concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=92:8, 1‰ ammonia water) to obtain compound M3 (45 mg, 87% yield). ESI-MS m / z: 248.15 [M+H] + . Synthesis of intermediate M4:

[0212]

[0213] Step 1: Synthesis of compound M4-1

[0214] NaH (4.62 g, 60% content) was added to DMSO (200 ml) in batches. Under N2 protection, the temperature was controlled at 15-20 degrees. The raw materials p-bromophenylacetonitrile (10.3 g) and 2,2'-dibromodiethyl ether (12.79 g) in ether (50 ml) were added dropwise. The addition time lasted for 2 hours. After the dropwise addition was completed, the temperature was raised to room temperature and the reaction was carried out for 12 hours. The reaction was detected to be complete. The reaction solution was slowly added dropwise to ice water to precipitate a solid, which was filtered, washed with water, filtered, and dried to obtain the target product M4-1 (14.0 g, yield 100%). ESI-MS m / z: 266.1 [M+H] + .

[0215] Step 2: Synthesis of compound M4-2

[0216] Raw material M4-1 (6.0 g) was dissolved in DCM (100.00 mL). Under N2 protection, the temperature was lowered to -78°C and DIBAL-H (27.05 mL) was added dropwise. After the addition was complete, the temperature was maintained at -65°C for 2 hours. The temperature was then slowly raised to 0°C and stirred for 5 minutes. A 15% aqueous solution of HCl (9.6 mL) was added dropwise at 0°C and allowed to react at RT for 2 hours. The reaction mixture was diluted with water and DCM and extracted with DCM (100 mL) three times. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The concentrate was separated by column chromatography (PE:EA = 5:1) to obtain the target product M4-2 (3.26 g, 53.7% yield).

[0217] Step 3: Synthesis of Compound M4-3

[0218] Under N2 protection, the starting material, triethyl phosphonoacetate (3.30 g), was dissolved in THF (25 mL). NaH (0.61 g, 60%) was added portionwise and allowed to react at RT for 1 hour. The temperature was lowered to 0°C and a solution of M4-2 (3.30 g) in THF (8 mL) was added dropwise. After complete addition, the reaction was allowed to react at RT for 2 hours. The reaction solution was diluted with water (30 mL) and EA (25 mL), stirred, and the layers separated. The organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrate was isolated by column chromatography (PE:EA = 5:1) to yield the desired product, M4-3 (3.73 g, 89.7% yield). ESI-MS m / z: 340.2 [M+H] + .

[0219] Step 4: Synthesis of Compound M4-4

[0220] Raw material M4-3 (4.0 g) and nickel chloride hexahydrate (2.80 g) were added to THF (40.00 mL) and MeOH (10.00 mL). Sodium borohydride (1.78 g) was added portionwise under ice-cooling. The mixture turned dark after addition. The temperature was maintained at 0°C for 30 minutes and then allowed to rise to room temperature for 30 minutes. After treatment, the reaction mixture was quenched with water and extracted twice with EA (50 ml). The organic phase was dried over anhydrous sodium sulfate, and the concentrate was isolated by column chromatography (PE:EA = 5:1) to obtain the desired product M4-4 (705 mg, 17.5% yield). ESI-MS m / z: 342.2 [M+H] + .

[0221] Step 5: Synthesis of Compound M4-5

[0222] The raw material M4-4 (705 mg) was dissolved in THF (6.00 mL) and MeOH (2.00 mL). Sodium hydroxide (0.25 g) in water (5.00 mL) was added and the mixture was allowed to react at RT for 2 hours. The organic solvent was removed by rotary evaporation, and the pH was adjusted to 4 by adding dilute HCl. A white solid precipitated, which was filtered, washed with water, and dried to obtain the desired product M4-5 (545 mg, 84.2% yield). ESI-MS m / z: 314.2 [M+H] + .

[0223] Step 6: Synthesis of Compound M4-6

[0224] Add raw material M4-5 (520 mg) to polyphosphoric acid (5.00 mL) and heat at 90°C for 0.5 hours. Add ice water and EA, then adjust the pH to 8-9 with saturated sodium bicarbonate. Separate the organic phase, dry over anhydrous sodium sulfate, and separate the concentrate by column chromatography (PE:EA = 3:1) to obtain the desired product M4-6 (485 mg, 98.9% yield). ESI-MS m / z: 296.2 [M+H] + Step 7: Synthesis of Compound M4-7

[0225] The raw material M4-6 (435.00 mg) was dissolved in methanol (10.00 mL) and tetrahydrofuran (3.00 mL). The temperature was lowered to 0°C, and sodium borohydride (223.00 mg) was added portionwise. The mixture was then reacted at RT for 0.5 hours. The solvent was partially removed by rotary evaporation, and the mixture was extracted three times with water and EA (15 mL). The mixture was dried over anhydrous sodium sulfate, dried in a rotary evaporation cycle, and dehydrated three times with DCM to obtain the crude target product M4-7, which was used directly in the next reaction (404 mg, 92.2% yield). ESI-MS m / z: 298.2 [M+H] + .

[0226] Step 8: Synthesis of Compound M4-8

[0227] The raw material M4-7 (405.00 mg) was dissolved in dichloromethane (12.00 mL). Under an ice bath, thionyl chloride (0.49 mL) was added dropwise, and the mixture was heated at 40°C for 30 minutes. The reaction solution was diluted with DCM, water (5 mL) was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate. The mixture was extracted three times with DCM (15 mL), dried over anhydrous sodium sulfate, and the concentrate was isolated by column chromatography (PE:EA = 20:1) to obtain the target product M4-8 (301 mg, 70.0% yield). ESI-MS m / z: 315.1 [M+H] + .

[0228] Step 9: Synthesis of Compound M4-9

[0229] The raw material M4-8 (300.00 mg) was dissolved in acetonitrile (7.00 mL), and potassium iodide (31.56 mg), potassium carbonate (394.11 mg), and dimethylamine (2M) (2571.12 mg) were added. The mixture was then sealed and heated at 80°C for 8 hours. The reaction solution was cooled to room temperature, filtered, and washed with EA. The filtrate was then dried by rotary evaporation. The concentrate was separated by column chromatography (PE:EA = 1:1) to obtain the target product M4-9 (263 mg, 85.3% yield). ESI-MS m / z: 324.2 [M+H] + .

[0230] Step 10: Synthesis of Compound M4-10

[0231] Under N2 protection, the raw material M4-9 (300.00 mg), benzophenone imine (184.44 mg), cesium carbonate (602.90 mg), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26.79 mg) were added to 1,4-dioxane (8.00 mL), and N2 was bubbled through the mixture. The mixture was heated at 100°C for 12 hours. The reaction mixture was filtered directly, the filter cake was washed with EA, and the filtrate was dried. The concentrate was separated by column chromatography (DCM:CH3OH = 20:1) to obtain the target product M4-10 (253 mg, 64.4% yield). ESI-MS m / z: 425.6 [M+H] + .

[0232] Step 11: Synthesis of Compound M4

[0233] The raw material M4-10 (304.00 mg, 95%) was dissolved in methanol (5.00 mL), and hydrochloric acid (4 M in dioxane) (0.51 mL, 4.00 mol / L) was added. The reaction was allowed to react at RT for 1 hour. The reaction solution was spin-dried to dryness, and a small amount of methanol (0.5 mL) was added. EA (10 mL) was added to precipitate a solid, which was filtered and washed with EA. The solid was dissolved in water, the pH was adjusted to 8 with saturated sodium bicarbonate, and extracted four times with DCM:CH3OH (10:1) (15 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain the desired product M4 (118 mg, 66.6% yield). ESI-MS m / z: 261.4 [M+H] + .

[0234] Synthesis of intermediate M5:

[0235]

[0236] Step 1: Synthesis of compound M5-2

[0237] Under nitrogen protection and -78 ° C, LiHMDS (23.25 mL, 1M / THF) was added dropwise to a solution of M5-1 (4 g) in THF (80 mL) over 30 minutes. After stirring for 30 minutes, TMSCl (3.09 mL) was added, stirred for 5 minutes, and LiHMDS (55.36 mL, 1M / THF) was added dropwise over 30 minutes. The temperature was raised to -30 ° C to -20 ° C, stirred for 30 minutes, and bis (2-bromoethyl) ether (5.39 g) was added. The temperature was gradually raised to room temperature and stirred overnight. The reaction solution was quenched with saturated ammonium chloride solution, concentrated under reduced pressure to remove part of the solvent, extracted with EA, and the organic layers were combined and washed with 1M HCl, water and saturated brine in sequence. It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 75:25-65:35) to obtain compound M5-2 (1.63 g, 29% yield).

[0238] Step 2: Synthesis of Compound M5-3

[0239] To a solution of M5-2 (1.63 g) in MeOH (10 mL) and THF (6 mL) was added sodium borohydride (0.74 g) in portions under an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 1 hour. The mixture was quenched with water and concentrated under reduced pressure to remove some of the solvent. The mixture was extracted with EA, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound M5-3 (1.60 g, 97% yield). 1HNMR(500MHz, CDCl3)δ7.22(s,1H),7.07(s,1H),5.15(t,J=6.3Hz,1H),4.03–3.92(m,2H),3.67-3.61(m,2H),2 .6-2.61(m,1H),2.57-2.51(m,1H),2.38-2.31(m,1H),2.05-2.01(m,1H),1.54-1.51(m,1H),1.26-1.22(m,1H).

[0240] Step 3: Synthesis of Compound M5-4

[0241] To a solution of M5-3 (1.76 g) in DCM (20 mL) was added dropwise thionyl chloride (2.53 mL) under ice-cooling. The ice-cooling was removed, the temperature was raised to 40°C, and the reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 85:15) to afford compound M5-4 (1.72 g, 91% yield).

[0242] Step 4: Synthesis of Compound M5-5

[0243] At room temperature, M5-4 (1.72 g), potassium carbonate (1.75 g), and potassium iodide (0.11 g) were dissolved in acetonitrile (20 mL). Dimethylamine (4.77 mL, 2M / THF) was added and the temperature was raised to 80°C for 3 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 96:4) to obtain compound M5-5 (1.18 g, 66% yield). ESI-MS m / z: 280.2 [M+H] + .

[0244] Step 5: Synthesis of Compound M5-6

[0245] M5-5 (300 mg), benzophenone imine (251 mg), RuPhos Pd G3 (77 mg), and cesium carbonate (904 mg) were dissolved in xylene (10 mL) at room temperature, replaced with nitrogen, and heated to 120°C for 6 hours. The mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 93:7) to obtain compound M5-6 (303 mg, 77% yield). ESI-MS m / z: 425.3 [M+H] + .

[0246] Step 6: Synthesis of Compound M5

[0247] M5-6 (363 mg) was dissolved in MeOH (5 mL) at room temperature, and hydrochloric acid (5 mL, 4M / 1,4-Dioxane) was added. The temperature was raised to 50°C and the reaction was allowed to react for 2 hours. The mixture was cooled, concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=92:8, 1‰ ammonia water) to obtain compound M5 (186 mg, 83% yield). ESI-MS m / z: 261.3 [M+H] + .

[0248] Synthesis of intermediate M6:

[0249]

[0250] Step 1: Synthesis of compound M6-1

[0251] NaH (2.86 g) was added to DMF (100.00 mL) at room temperature. The atmosphere was then replaced with N2. A solution of 2-(4-bromo-2-methylphenyl)acetonitrile (5.00 g) in 10 mL of DMF was added dropwise under an ice-water bath. The reaction was continued for 15 minutes. A solution of 1,2-dibromoethane (6.71 g) in 10 mL of DMF was added dropwise. The ice-water bath was removed and the reaction was continued at room temperature for 2 hours. The reaction solution was added to 300 mL of ice water and extracted three times with 150 mL of water. The organic phases were combined, washed with saturated sodium chloride, and concentrated. The concentrate was isolated and purified by column chromatography (PE:EA = 95:5 to 90:10) to obtain the target product M6-1 (4.25 g, 75.63%). ESI-MS m / z: 236.0 [M+H]. + .

[0252] Step 2: Synthesis of compound M6-2

[0253] Compound M6-1 (26.84 g) was dissolved in THF / tetrahydrofuran (270.00 mL) at room temperature. The atmosphere was replaced with nitrogen. Under nitrogen protection and in an ice-water bath, BH3.THF (568.38 mL) was slowly added dropwise. The reaction was continued at this temperature for 15 minutes. The ice-water bath was removed and the reaction was refluxed for 5 hours. The reaction solution was cooled, the pH was adjusted to 2-3 with 1M HCl, and the reaction solution was refluxed for 1 hour. The pH was then adjusted to 8-9 with saturated sodium bicarbonate, and the solution was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield the desired product M6-2 (28.80 g). ESI-MS m / z: 240.0 [M+H] + .

[0254] Step 3: Synthesis of compound M6-3

[0255] Compound M6-2 (25.50 g) was dissolved in dichloromethane (300.00 mL) at room temperature. Triethylamine (44.28 mL) was added under nitrogen protection in an ice-water bath, followed by the slow dropwise addition of TFAA (22.14 mL). The reaction mixture was allowed to react at room temperature for 3 h. The reaction solution was added to a certain amount of ice water and extracted three times with DCM. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phases were concentrated to obtain a crude product, mixed, and purified by column chromatography (PE:EA = 95:5 to 91:9) to obtain the desired product (20.60 g, 57.71% yield). ESI-MS m / z: 336.1 [M+H] + .

[0256] Step 4: Synthesis of compound M6-4

[0257] At room temperature, compound M6-3 (15.60 g) was dissolved in HOAc (206.00 mL). Under nitrogen protection, concentrated sulfuric acid (138.00 mL) was slowly added dropwise in an ice-water bath. The reaction was kept warm for 0.5 h, and then paraformaldehyde (2.09 g) was added in batches. The temperature was returned to room temperature and the reaction was allowed to react for 16 h. The reaction solution was slowly poured into a certain amount of ice water and extracted three times with EA. The organic phases were combined and washed with saturated sodium bicarbonate solution and saturated brine. The organic phase was concentrated to obtain the crude product, mixed, and column chromatography (PE:EA = 100:0 to 91:9) was performed to obtain the target product M6-4 (6.00 g, 37.13% yield). ESI-MS m / z: 348.0 [M+H] + .

[0258] Step 5: Synthesis of Compound M6-5

[0259] Compound M6-4 (8.20 g) was dissolved in EtOH (147.00 mL) and H₂O (49.00 mL) at room temperature, and potassium carbonate (16.28 g) was added. The mixture was reacted at 80°C for 1 h. The reaction solution was cooled to room temperature, and ethanol was removed by rotary evaporation. The mixture was then extracted three times with EA, washed three times with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the desired product M6-5 (5.70 g, 95.98% yield). ESI-MS m / z: 252.0 [M+H] + .

[0260] Step 6: Synthesis of Compound M6-6

[0261] At room temperature, compound M6-5 (5.70 g) was dissolved in methanol (57.00 mL) and HOAc (38.00 mL). Under nitrogen protection, 37% formaldehyde aqueous solution (2.75 g) was slowly added dropwise in an ice-water bath. The reaction was kept warm for 1 hour, and then sodium triacetoxyborohydride (14.37 g) was added in batches. The mixture was then returned to room temperature and reacted for 2 hours. The pH of the reaction solution was adjusted to 8-9 with saturated sodium bicarbonate solution, and then extracted with EA 2-3 times. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 100:0 to 95:5) to obtain the target product M6-6 (4.80 g, 79.77%). ESI-MS m / z: 266.1 [M+H] + .

[0262] Step 7: Synthesis of Compound M6-7

[0263] Compound M6-6 (1.00 g), p-methoxybenzylamine (1.03 g), Ruphos-Pd-G3 (0.31 g), and cesium carbonate (2.45 g) were added to DMF (15.00 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 24 hours before being stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 96:4 to 90:10) to obtain the desired product, M6-7 (0.72 g, 59.43% yield). ESI-MS m / z: 323.26 [M+H] + .

[0264] Step 8: Synthesis of Compound M6

[0265] Compound M6-7 (720.00 mg) was added to dichloromethane (20.00 mL) at room temperature. Trifluoroacetic acid (5.0 mL) was then added under N2 protection in an ice-water bath. The reaction was refluxed for 1 h to terminate the reaction. The solvent was removed by rotary evaporation, and the reaction solution was added with 10 mL of H2O and 10 mL of DCM. NaOH was then added to adjust the pH to >12. The solution was then extracted three times with 25 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and concentrated to yield the crude product. The crude product was then separated by column chromatography (DCM:MeOH = 96:4 to 90:10) to afford the desired product, M6 (350.00 mg, 77.49% yield). ESI-MS m / z: 203.22 [M+H] + .

[0266] Synthesis of intermediate M7:

[0267]

[0268] Step 1: Synthesis of intermediate M7-1

[0269] At room temperature, 2-bromo-3-pyridinecarboxaldehyde (15.00 g) was added to MeOH (200.00 mL). Sodium borohydride (3.66 g) was then slowly added in portions under N2 protection, maintaining the temperature at 0-5°C. After the addition was complete, the ice-water bath was removed and the mixture was allowed to react at room temperature at 25°C for 1 h. The reaction mixture was quenched with 150 mL of water to remove the methanol. The mixture was then extracted five times with 100 mL of EA, washed twice with 100 mL of saturated sodium chloride, and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated to dryness to yield the desired product, M7-1 (14.20 g, 93.67% yield). ESI-MS m / z: 188.0 [M+H]. + .

[0270] Step 2: Synthesis of intermediate M7-2

[0271] Compound M7-1 (14.20 g) was added to DCM (350.00 mL) at room temperature. PBr (6.40 mL) was then slowly added in batches under N2 protection, maintaining the temperature at 0-5°C. After the addition was complete, the ice-water bath was removed and the reaction was allowed to proceed at room temperature (25°C) for 18 h. The reaction solution was quenched with 500 mL of ice water and the pH was adjusted to 12-13 by adding 30% NaOH. The solution was then extracted three times with 250 mL of DCM, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was directly concentrated to dryness to yield the desired product, M7-2 (18.00 g, 94.99% yield). ESI-MS m / z: 250.9 [M+H] + .

[0272] Step 3: Synthesis of intermediate M7-3

[0273] Compound M7-2 (18.00 g), TMSCN (12.81 g), and potassium carbonate (19.83 g) were added to THF (200.00 mL) at room temperature. TBAF (7.17 mL, 1M THF) was then slowly added in portions under N2 protection, maintaining the temperature at 0-5°C. After the addition was complete, the ice-water bath was removed and the mixture was allowed to react at room temperature (25°C) for 14 h. The reaction mixture was quenched with 500 mL of ice water and then extracted four times with 150 mL of EA, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was directly concentrated. The concentrate was then isolated by column chromatography (PE:EA = 10:1 to 60:40) to afford the desired product M7-3 (12.10 g, 85.61% yield). ESI-MS m / z: 197.0 [M+H] + .

[0274] Step 4: Synthesis of intermediate M7-4

[0275] Compound NaH (60%) was added to DMSO (240.00 mL) at room temperature. M7-3 (12.10 g) and 2,2'-dibromodiethyl ether dissolved in ether (60.00 mL) and DMSO (15.00 mL) were then slowly added dropwise to the reaction system under N2 protection at 18-25°C. The reaction was allowed to proceed at 25°C for 3 h. The reaction solution was quenched with 500 mL of ice water and then extracted four times with 150 mL of EA, washed five times with 150 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The concentrate was isolated by column chromatography (PE:EA = 10:1 to 60:40) to afford the desired product, M7-4 (13.20 g, 77.89% yield). ESI-MS m / z: 267.2 [M+H] + .

[0276] Step 5: Synthesis of Intermediate M7-5

[0277] Compound M7-4 (6.00 g) was added to anhydrous DCM (100.00 mL) at room temperature. Under nitrogen protection, DIBAL-H (24.33 mL, 1M / Hexane) was slowly added dropwise in portions at -78°C. The reaction was allowed to proceed at -70 to -60°C for 3 h, after which the reaction was stopped. The mixture was warmed to room temperature and quenched with 10 mL of 15% HCl. Saturated sodium bicarbonate was added to adjust the pH to 8-9. The mixture was then extracted four times with 60 mL of DCM, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to yield the crude product, which was then isolated by column chromatography (PE:EA = 10:1 to 40:60) to afford the desired product, M7-5 (4.00 g, 65.93% yield). ESI-MS m / z: 270.2 [M+H]. + .

[0278] Step 6: Synthesis of Intermediate M7-6

[0279] Compound M7-5 (4.00 g), p-toluenesulfonic acid (0.26 g), and ethylene glycol (1.84 g) were added to toluene (50.00 mL) at room temperature. The mixture was then refluxed with water toluene for 3 h, after which the reaction was stopped. The reaction mixture was cooled to room temperature and concentrated to dryness to obtain a crude product. The crude product was then separated by column chromatography (PE:EA = 10:1 to 40:60) to obtain the desired product, M7-6 (4.50 g, 52.58% yield). ESI-MS m / z: 314.2 [M+H] + .

[0280] Step 7: Synthesis of Intermediate M7-7

[0281] Compound M7-6 (4.50 g), tributyl(1-ethoxyethylene)tin (6.72 g), LiCl (1.82 g), triethylamine (4.35 g), and Pd(PPh3)4 (1.66 g) were added to 1,4-dioxane (80.00 mL) at room temperature. The mixture was then incubated at 110°C under nitrogen for 14 h before being stopped. The mixture was cooled to room temperature and quenched with 200 mL of 5% KF aqueous solution for 0.5 h. The mixture was then extracted five times with 60 mL of DCM, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to yield the crude product, which was then separated by column chromatography (PE:EA = 10:1 to 40:60) to afford the desired product, M7-7 (2.30 g, 52.58% yield). ESI-MS m / z: 306.4 [M+H] + .

[0282] Step 8: Synthesis of Intermediate M7-8

[0283] Compound M7-7 (2.30 g) was added to 6 M HCl (10.00 mL) and DCM (10.00 mL) at room temperature. The mixture was then incubated at 50°C for 1 h under N2 protection to terminate the reaction. The reaction solution was quenched with 100 mL of ice water and the pH was adjusted to 12-13 by adding 30% NaOH. The mixture was then extracted three times with 50 mL of DCM, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to obtain the crude product, which was then isolated by column chromatography (DCM:MeOH = 96:4 to 90:10) to afford the desired product, M7-8 (0.9 g, 55.51% yield). ESI-MS m / z: 216.3 [M+H] + .

[0284] Step 9: Synthesis of Intermediate M7-9

[0285] Compound M7-8 (1.80 g) and 10% palladium on carbon (0.18 g) were added to methanol (40.00 mL) at room temperature. The mixture was then heated to 25°C for 34 h under H₂ conditions, after which the reaction was stopped. The palladium on carbon was filtered through celite and then washed five times with 20 mL of methanol. The combined reaction mixture was concentrated to dryness to obtain a crude product. The crude product was then separated by column chromatography (DCM:EA = 10:1 to 50:50) to obtain the desired product M7-9 (1.70 g, 52.58% yield). ESI-MS m / z: 220.3 [M+H] + .

[0286] Step 10: Synthesis of Intermediate M7-10

[0287] Compound M7-9 (1.70 g) was added to DCM (40.00 mL) at room temperature. SOCl (2.48 mL) was then slowly added in portions under N protection, maintaining the temperature at 0-5°C. The ice-water bath was removed upon completion of the addition and the mixture was allowed to react at 25°C for 2 h before stopping the reaction. The reaction mixture was quenched with 50 mL of ice water and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate. The mixture was then extracted three times with 50 mL of DCM, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to yield the crude product, which was then isolated by column chromatography (DCM:MeOH = 95:5-93:7) to afford the desired product, M7-10 (1.40 g, 86.09% yield). ESI-MS m / z: 238.7 [M+H] + .

[0288] Step 11: Synthesis of Intermediate M7-11

[0289] Compound M7-10 (1.43 g) was added to DCM (50.00 mL) at room temperature. Under N2 protection, m-chloroperbenzoic acid (2.44 g, 85%) was slowly added in portions. The reaction was allowed to react at 25°C for 1 h, after which the reaction was stopped. The reaction solution was quenched by adding 100 mL of saturated sodium bicarbonate, then extracted four times with 30 mL of DCM, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was directly concentrated to dryness to obtain the crude product, which was then isolated by column chromatography (DCM:MeOH = 95:5 to 93:7) to afford the desired product, M7-11 (1.50 g, 98.28% yield). ESI-MS m / z: 254.7 [M+H] + .

[0290] Step 12: Synthesis of Intermediate M7-12

[0291] Compound M7-11 (1.30 g) and pyridine (2.06 mL) were added to DCM (40.00 mL) at room temperature. Trifluoromethanesulfonic anhydride (1.72 mL) was then slowly added in portions under N2 protection. The reaction was allowed to proceed at 25°C for 1 h, after which the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then slurried with 10 mL of ether, filtered, and the solid was directly drained to obtain the desired product, M7-12 (2.0 g, 123.59% yield). ESI-MS m / z: 254.7 [M+H] + .

[0292] Step 13: Synthesis of Intermediate M7-13

[0293] Compound M7-12 (2.00 g) and ethanolamine (11.91 mL) were added to ethanol (15.00 mL) at room temperature. The mixture was then reacted at 25°C under N2 protection for 3 h, after which the reaction was stopped. The reaction solution was quenched by adding 20 mL of saturated sodium bicarbonate. A large amount of light yellow solid precipitated, which was filtered and directly dried to obtain the desired product M7-13 (1.10 g, 68.72% yield). ESI-MS m / z: 253.8 [M+H] + .

[0294] Step 14: Synthesis of Intermediate M7

[0295] Compound M7-13 (1.05 g), KI (137.97 mg), cesium carbonate (4.06 g), and dimethylamine (16.62 mL, 2 M in THF) were added to DMA (15.00 mL) at room temperature. The mixture was then heated to 100°C under nitrogen for 4 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the desired product, M7 (1.05 g, 96.70% yield). ESI-MS m / z: 262.1 [M+H] + .

[0296] Synthesis of intermediate M8:

[0297]

[0298] Step 1: Synthesis of compound M8-1

[0299] To a DCM solution (1500 mL) of compound 6,7-dihydro-5H-cyclopenta[b]pyridine (240.0 g) was added portionwise with mCPBA (490.7 g, 85%) in an ice-water bath at 15-30°C. After addition, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was directly purified by column chromatography to obtain compound M8-1 (143.60 g, 52% yield). ESI-MS m / z: 136.05 [M+H] + .

[0300] Step 2: Synthesis of compound M8-2

[0301] Under nitrogen protection, a solution of M8-1 (41.0 g) in acetic anhydride (200 mL) was heated at 110-120°C for 1.5 hours. The solvent was partially removed by concentration under reduced pressure, water was added, and the mixture was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE / EA = 100-3 / 1) to obtain compound M8-2 (37.7 g, 71% yield). ESI-MS m / z: 178.12 [M+H] + .

[0302] Step 3: Synthesis of compound M8-3

[0303] Under ice bath, a solution of NaOH (40.3 g) in water (400 mL) was added dropwise to a solution of M8-2 (89.2 g) in EtOH (400 mL). The ice bath was removed, the temperature was raised to room temperature, and the reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with DCM. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M8-3 (59.8 g, 88% yield). ESI-MS m / z: 136.08 [M+H] + .

[0304] Step 4: Synthesis of Compound M8-4

[0305] The temperature was controlled at 15-30°C in an ice-water bath. Dess-Martin periodinane (206.4g) was added in batches to M8-3 (59.8g) in DCM (400mL). After the addition was complete, the reaction was stirred at room temperature for 2 hours. The reaction solution was quenched by adding 10% aqueous sodium carbonate solution, filtered, the filtrate was extracted with DCM, the organic layer was washed with 5% aqueous sodium sulfite solution, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=1:1-1:4) to obtain compound M8-4 (47.8g, 81% yield). ESI-MSm / z:134.11[M+H] + .

[0306] Step 5: Synthesis of Compound M8-5

[0307] To M8-4 (59.0 g) in THF (700 mL) was added DBU (132.4 mL) at room temperature. The temperature was maintained below 25°C in an ice-water bath. Tert-butyldimethylsilyl chloride (80.1 g) was added dropwise. The reaction was stirred at room temperature for 2 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride, extracted with EA, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 95:5) to obtain compound M8-5 (103.5 g, 94% yield).

[0308] Step 6: Synthesis of Compound M8-6

[0309] Under nitrogen protection, M8-5 (56.0g) was dissolved in THF (700mL), cooled to -70 with a dry ice ethanol bath, and LiHMDS (679mL, 1.0mol / L) was added dropwise. After the addition was completed, the temperature was slowly raised to -30 to -20°C and the reaction was kept for 2 hours. Then 2,2'-dibromodiethyl ether (57.7) was added dropwise. After the addition was completed, the temperature was naturally raised to room temperature and stirred for 3 hours. The reaction solution was added to a saturated aqueous ammonium chloride solution to quench, extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude compound M8-6 (88.2g), which was directly used in the next reaction. ESI-MSm / z: 318.33[M+H] + Step 7: Synthesis of Compound M8-7

[0310] M8-6 (88.0 g, crude product) was dissolved in THF (400 mL) and cooled in an ice-water bath. A solution of hydrochloric acid (92 mL) in water (90 mL) was then added dropwise. After completion of the addition, the mixture was stirred at room temperature for 4 hours. The THF was removed by concentration, and the mixture was dissolved in water. Impurities were removed by extraction with EA. The acidic aqueous layer was then neutralized with sodium carbonate to a pH of approximately 9 and extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M8-7 (40.5 g, 72% yield). ESI-MS m / z: 204.16 [M+H] + Step 8: Synthesis of Compound M8-8

[0311] Compound M8-7 (24.3 g) was dissolved in THF (100 mL) and MeOH (300 mL), cooled in an ice-water bath, and sodium borohydride (6.8 g) was added portionwise. After addition, the reaction mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and the concentrate was added to saturated ammonium chloride. The mixture was extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM / MeOH = 100 to 100 / 5) to obtain compound M8-8 (17.0 g, 69% yield). ESI-MS m / z: 206.25 [M+H] + .

[0312] Step 9: Synthesis of Compound M8-9

[0313] Compound M8-8 (17.0 g) was dissolved in DCM (350 mL) and cooled in an ice-water bath. Thionyl chloride (29.6 g) was added dropwise. After addition, the reaction was stirred at room temperature for 3 hours. The reaction solution was quenched by adding cold aqueous sodium bicarbonate solution, and sodium carbonate was added to a pH of approximately 7-8. The mixture was extracted with DCM, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M8-9 (18.5 g, 99% yield). ESI-MS m / z: 224.20 [M+H] + .

[0314] Step 10: Synthesis of Compound M8-10

[0315] Compound M8-9 (18.1 g) was dissolved in DCM (250 mL), cooled in an ice-water bath, and mCPBA (36 g) was added portionwise after addition, with the temperature controlled at 15-30°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was cooled to below 5°C and the temperature controlled below 10°C. Aqueous sodium carbonate solution was added dropwise to a pH of approximately 8-9 to quench the reaction. The mixture was extracted with DCM, and the organic phases were combined, washed with 5% aqueous sodium sulfite solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound M8-10 (12.6 g, 65% yield). ESI-MS m / z: 240.08 [M+H] + .

[0316] Step 11: Synthesis of Compound M8

[0317] Compound M8-10 (6.8 g) was dissolved in DMF (100 mL), cooled in an ice-water bath, and the temperature was controlled at 0-10°C. Phosphorus oxychloride (21.8 g) was added dropwise. After completion of the addition, the mixture was stirred at room temperature for 9 hours. The reaction solution was added to the ice-water mixture, filtered, and the filter cake was collected, dissolved in DCM, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M8 (5.4 g, 71% yield). ESI-MS m / z: 258.14 [M+H] + .

[0318] Synthesis of intermediate M9:

[0319]

[0320] Step 1: Synthesis of compound M9-1

[0321] 2-Amino-4-fluoropyridine (3.00 g) was dissolved in acetonitrile (30.00 mL) at room temperature, and NCS (3.93 g) was then added portionwise. The reaction was allowed to react at room temperature for 3 h, after which the reaction was stopped. The reaction was quenched with saturated sodium thiosulfate solution and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to obtain the desired product M9-1 (1.00 g, 25.50% yield). ESI-MS m / z: 113.0 [M+H] + .

[0322] Step 2: Synthesis of compound M9-2

[0323] Compound M9-1 (986.00 mg), chloroacetaldehyde (4.00 g, 40% in water), and NaHCO₃ (1.13 g) were dissolved in ethanol (20.00 mL) at room temperature and allowed to react at 80°C for 13 h before stopping the reaction. The reaction solution was directly concentrated, mixed, and separated by column chromatography (PE:EA = 3:1) to obtain the desired product M9-2 (259 mg, 22.57% yield). ESI-MS m / z: 171.0 [M+H] + .

[0324] Step 3: Synthesis of Compound M9

[0325] Compound M9-2 (259.00 mg) was dissolved in chloroform (5.00 mL) at room temperature, and NCS (3.93 g) was added portionwise. The reaction was allowed to react at room temperature for 7 h, after which the reaction was stopped. The reaction solution was directly concentrated, mixed, and separated by column chromatography (PE:EA = 4:1) to obtain the desired product M9 (218 mg, 48.43% yield). ESI-MS m / z: 29.0 [M+H] + .

[0326] Synthesis of intermediate M10:

[0327]

[0328] Step 1: Synthesis of compound M10-1

[0329] 4-Chloro-7-nitroisoindolin-1-one (3.00 g) and DMAP (3.00 g) were added to THF (30.00 mL) at room temperature. Bocuronium hydroxide (3.89 mL) was added dropwise under an ice-water bath, and the mixture was allowed to react at room temperature for 1 h. The reaction solution was added dropwise to water (200.00 mL), filtered, and the filter cake was washed three times with water and dried to obtain the desired product M10-1 (3.50 g, 79.31% yield). ESI-MS m / z: 313.1 [M+H] + .

[0330] Step 2: M10 synthesis of compound

[0331] Compound M10-1 (4.20 g), ammonium chloride (1.44 g), and water (8.00 mL) were added to ethanol (40.00 mL) at room temperature. Iron powder (3.00 g) was then added portionwise at 70°C. The mixture was reacted at 70°C for 1 h. The reaction mixture was filtered, and the filter cake was washed twice with DCM. The filtrate was concentrated, diluted with water, and filtered. The filter cake was separated by column chromatography (PE:EA = 65:35) to obtain the desired product M10 (3.10 g, purity 81.64%). ESI-MS m / z: 283.1 [M+H] + .

[0332] Synthesis of intermediate M11:

[0333]

[0334] Step 1: Synthesis of compound M11-1

[0335] 2-Bromo-3-iodopyridine (10 g) was dissolved in THF (150 mL), and the reaction system was placed at -20°C. Isopropylmagnesium chloride (4.4 g) was slowly added dropwise under nitrogen protection. After the addition was complete, the reaction was allowed to react at this temperature for 2 h. Tetrahydropyrone (5.3 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was quenched with saturated ammonium chloride solution, concentrated under reduced pressure to remove some of the solvent, and extracted with EA. The organic layers were combined and washed sequentially with 1M HCl, water, and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 70:30-65:35) to obtain compound M11-1 (3.2 g, 35% yield). ESI-MS m / z: 258.0 [M+H] + .

[0336] Step 2: Synthesis of compound M11-2

[0337] Compound M11-1 (3.0 g) was dissolved in DMF (25 mL), and NaH (0.74 g) was added under ice bath. After the addition was complete, the reaction was stirred at room temperature for 30 minutes. Subsequently, a DMF solution of 3-bromopropylene (1.6 g) and TBAI (0.34 g) was added dropwise, and the reaction was stirred at room temperature overnight. The mixture was quenched with water, concentrated under reduced pressure to remove part of the solvent, extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA=70:30-65:35) to obtain compound M11-2 (2.8 g, 80% yield). ESI-MSm / z:298.1[M+H] + .

[0338] Step 3: Synthesis of compound M11-3

[0339] Compound M11-2 (1.5 g), Pd(OAc)2 (0.17 g), XantPhox (0.44 g), and TEA (2.1 ml) were dissolved in ACN (15 mL) and reacted at 90°C under nitrogen for 6 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:30 to 65:35) to obtain compound M11-3 (0.84 g, 77% yield). ESI-MS m / z: 218.1 [M+H] + Step 4: Synthesis of Compound M11-4

[0340] Compound M11-3 (0.34 g) was dissolved in MeOH (5 mL) and DCM (10 mL), and ozone was introduced at -50°C. After 30 min of reaction, dimethyl sulfide (0.34 g) was added. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:40-50:50) to obtain compound M11-4 (0.24 g, 83% yield). ESI-MS m / z: 220.1 [M+H] + Step 5: Synthesis of Compound M11-5

[0341] Under ice bath, sodium borohydride (38.8 mg) was added portionwise to a solution of M11-4 (0.15 g) in MeOH (2.5 mL) and THF (2.5 mL). The ice bath was removed and the reaction was allowed to react at room temperature for 1 hour. The mixture was quenched with water and concentrated under reduced pressure to remove some of the solvent. The mixture was extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M11-5 (112 mg, 74% yield). ESI-MS m / z: 222.1 [M+H] + .

[0342] Step 6: Synthesis of Compound M11-6

[0343] Under ice bath, thionyl chloride (0.18 mL) was added dropwise to a solution of M11-5 (0.11 g) in DCM (5 mL). The ice bath was removed, the temperature was raised to 40°C, and the reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The mixture was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 20:80) to obtain compound M11-6 (115 mg, 96% yield). ESI-MS m / z: 239.0 [M+H] + Step 7: Synthesis of Compound M11-7

[0344] M11-6 (410 mg) was dissolved in DCM (20 mL) at room temperature, and mCPBA (590 mg) was added at room temperature. After 3 h of reaction at room temperature, LC-MS confirmed that the reaction of the raw material was complete. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was stirred at room temperature for 30 min. DCM was used for extraction. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=20:1) to obtain compound M11-7 (428 mg, 98% yield). ESI-MS m / z: 256.1 [M+H] + .

[0345] Step 8: Synthesis of Compound M11-8

[0346] M11-7 (400 mg) and pyridine (1.2 g) were dissolved in DCM (10 mL). Tf2O (1.3 g) was added under ice-cooling and allowed to react at room temperature for 0.5 h. LC-MS confirmed the complete reaction. The mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound M11-8 (472 mg, 96% yield). ESI-MS m / z: 317.1 [M+H] + .

[0347] Step 9: Synthesis of Compound M11-9

[0348] M11-8 (250 mg) was dissolved in dimethylamine tetrahydrofuran solution (15 mL) at room temperature and stirred for 0.5 h, then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=20:1) to obtain compound M11-9 (175 mg, 87% yield). ESI-MS m / z: 255.1 [M+H] + .

[0349] Step 10: Synthesis of Compound M11

[0350] M11-9 (150 mg), KI (12 mg), Cs2CO3 (575 mg), and a methylamine tetrahydrofuran solution (2.4 mL) were dissolved in DMA (5.0 mL) and stirred at 100°C overnight. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give compound M11 (150 mg, 97% yield). ESI-MS m / z: 264.2 [M+H] + .

[0351] Synthesis of intermediate M12

[0352]

[0353] Step 1: Synthesis of compound M12-1

[0354] Methyl 6-chloro-3-methyl-2-pyridinecarboxylate (33.00 g) was dissolved in carbon tetrachloride (400.00 mL) at room temperature. NBS (33.12 g) and AIBN (2.91 g) were then added. Under nitrogen, the reaction was allowed to stand at 80°C for 3 h, after which the reaction was stopped. A suitable amount of water was added to the reaction solution, which was then extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 2:1) to yield the desired product, M12-1 (22.00 g, 46.81% yield). ESI-MS m / z: 186.0 [M+H] + .

[0355] Step 2: Synthesis of compound M12-2

[0356] Compound M12-1 (22.00 g) and K2CO3 (19.50 g) were dissolved in ACN (300.00 mL) at room temperature. TMSCN (12.38 g) was then slowly added dropwise in an ice bath. The reaction was allowed to react at room temperature for 13 h, after which the reaction was stopped. A suitable amount of water was added to the reaction solution, which was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 2:1) to yield the desired product M12-2 (10.00 g, 57.00% yield). ESI-MS m / z: 211.3 [M+H] + .

[0357] Step 3: Synthesis of compound M12-3

[0358] Compound NaH (2.29 g) was dissolved in DMF (65.00 mL) at room temperature. M12-2 (5.23 g) was then slowly added under nitrogen in an ice bath. The mixture was kept warm for 0.5 h, followed by the slow dropwise addition of 2,2'-dibromodiethyl ether (9.20 g). The reaction was allowed to continue at room temperature for 3 h to terminate the reaction. The reaction was quenched with saturated ammonium chloride solution under ice bath conditions, extracted three times with EA, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to yield the desired product M12-3 (4.00 g, 57.38% yield). ESI-MS m / z: 281.2 [M+H] + .

[0359] Step 4: Synthesis of Compound M12

[0360] Compound M12-3 (3.00 g) was dissolved in THF (45.00 mL) at room temperature, and then borane dimethyl sulfide solution (4.3 mL, 10 M) was slowly added dropwise under an ice bath. Under nitrogen protection, the reaction was incubated at 70°C for 16 h before stopping the reaction. The pH was adjusted to 1-2 with 1 M HCl solution, and then heated to 70°C for 1 h before stopping the reaction. The pH was adjusted to 8-9 with 2 M NaOH solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product M12 (750.00 mg, 29.41% yield). ESI-MS m / z: 239.4 [M+H] + .

[0361] Synthesis of intermediate M13

[0362]

[0363] Step 1: Synthesis of intermediate M13-1

[0364] At room temperature, compound 2,2,6,6-tetramethylpiperidine (10.01 g) was added to THF (120.00 mL), and then under N2 protection, the temperature was controlled at -78 ° C, and n-butyl lithium (9.33 mL, 2.5 M / Hexane) was slowly added dropwise in batches. After the addition was completed, the temperature was controlled at -78 ° C for 40 minutes, and then a solution of 2-fluoro-4-pyridinecarboxylic acid (5.00 g) in THF (30.00 mL) was slowly added dropwise to the reaction system, the temperature was controlled at -78 ° C for 2 hours, and tetrahydropyrone (7.10 g) was slowly added at -78 ° C. The temperature was returned to room temperature and the reaction was carried out overnight to stop the reaction. The reaction mixture was quenched by adding 250 mL of ice water, then extracted three times with 100 mL of EA. The organic phase was washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4 to 85:15) to obtain a white solid, the target product M13-1 (5.20 g, 65.75% yield). ESI-MS m / z: 224.23 [M+H] + .

[0365] Step 2: Synthesis of intermediate M13-2

[0366] Compound M13-1 (4.50 g) was added to THF (15.00 mL) and MeOH (45.00 mL) at room temperature. NaBH4 (2.29 g) was then slowly added in portions under N2 protection, maintaining the temperature at 0-5°C. After addition, the ice-water bath was removed and the mixture was allowed to react at room temperature at 25°C for 2 h before stopping the reaction. The reaction solution was quenched with 50 mL of methanol and directly concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4-90:10) to afford the desired product, M13-2 (3.50 g, 77.08% yield), as a white solid. ESI-MS m / z: 226.23 [M+H] + .

[0367] Step 3: Synthesis of intermediate M13-3

[0368] Compound M13-2 (3.50 g) was added to ACN (60.00 mL) at room temperature. Triethylsilane (9.90 mL) was then slowly added under N2 protection, followed by the slow addition of boron trifluoride etherate (3.92 mL). The reaction was allowed to react at room temperature for 2 h at 25°C, after which the reaction was stopped. The reaction solution was quenched with 100 mL of saturated sodium bicarbonate and extracted three times with 60 mL of EA. The organic phase was washed twice with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to obtain the crude product, which was then separated by column chromatography (PE:EA = 10:1 to 1:1) to afford the desired product, M13-3 (3.10 g, 95.34% yield), as a white solid. ESI-MS m / z: 210.21, [M+H] + .

[0369] Step 4: Synthesis of intermediate M13-4

[0370] Compound M13-3 (1.50 g) and NaCN (0.88 g) were added to DMSO (6.00 mL) at room temperature. The reaction was then allowed to react at 150°C under N2 protection for 2.5 h, after which the reaction was stopped. The reaction solution was quenched with 100 mL of saturated sodium bicarbonate and extracted three times with 50 mL of EA. The organic phase was washed twice with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was directly concentrated to dryness to obtain the crude product. The combined aqueous phases were then quenched with sodium hypochlorite solution to quench the sodium cyanide wastewater. The crude product was isolated by column chromatography (PE:EA = 10:1 to 1:1) to obtain the desired product, M13-4, as a white powdery solid (1.41 g, 87.72% yield). ESI-MS m / z: 217.21, [M+H] + .

[0371] Step 5: Synthesis of intermediate M13-5

[0372] Compound M13-4 (1.40 g) was added to DCM (20.00 mL) at room temperature. Under N2 protection, m-chloroperbenzoic acid (2.23 g, 85%) was slowly added in portions. The reaction was allowed to react at 25°C for 24 h, after which the reaction was stopped. The reaction solution was quenched with 100 mL of saturated sodium bicarbonate and extracted three times with 40 mL of DCM. The organic phase was washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was directly concentrated to dryness to obtain the crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 93:7) to afford the desired product, M13-5 (1.17 g, 77.81% yield), as a white solid. ESI-MS m / z: 233.32 [M+H] + .

[0373] Step 6: Synthesis of intermediate M13-6

[0374] Compound M13-5 (1.10 g) was added to DMF (5.00 mL) at room temperature. Under N2 protection, phosphorus oxychloride (5.00 mL) was slowly added in an ice-water bath. The reaction was allowed to react at room temperature for 1 h, then at 50°C for 2.5 h. The reaction was stopped and the reaction solution was quenched with 50 mL of ice water. Saturated sodium bicarbonate was added to adjust the pH to 8-9, and the mixture was extracted four times with 50 mL of EA, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was directly concentrated to dryness to obtain the crude product, which was separated by column chromatography (PE:EA = 95:5-50:50) to obtain the target product M13-6 (0.38 g, 32.00% yield) as a white solid. ESI-MS m / z: 233.32 [M+H] + .

[0375] Step 7: Synthesis of intermediate M13-7

[0376] Compound M13-6 (0.36 g) was added to THF (15.00 mL) at room temperature. Borane dimethyl sulfide (0.43 mL, 10 M) was then slowly added under nitrogen in an ice-water bath. The reaction was incubated at 80°C for 1.5 h, and then stopped. The reaction mixture was cooled to room temperature, and 2 mL of ice water was added. 10 mL of 6M hydrochloric acid (HCl) was then added to the mixture. The reaction was incubated at 80°C for 1 h. Saturated sodium bicarbonate was added to adjust the pH to 8-9. The mixture was then extracted four times with 50 mL of EA, washed twice with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to yield the crude product, which was then separated by column chromatography (DCM:MeOH = 95:5-90:10) to afford the desired product, M13-7 (0.27 g, 73.81% yield), as a colorless oil. ESI-MS m / z: 251.73 [M+H]. + .

[0377] Step 8: Synthesis of intermediate M13

[0378] Compound M13-7 (0.24 g), formic acid (0.22 g), and aqueous formaldehyde (0.23 g, 37%) were added to methanol (3.00 mL) at room temperature. The mixture was then heated at 85°C for 5 h under N₂ protection, after which the reaction was stopped. The reaction solution was quenched with 50 mL of ice water and the pH was adjusted to 8-9 by adding saturated sodium bicarbonate. The mixture was then extracted five times with 25 mL of EA, washed twice with 30 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The organic phase was then concentrated to dryness to yield the crude product, which was then isolated by column chromatography (DCM:MeOH = 95:5-90:10) to afford the desired product M13 (0.20 g, 75.07% yield) as a colorless oil. ESI-MS m / z: 283.72 [M+H]+ .

[0379] Synthesis of intermediate M14:

[0380]

[0381] Step 1: Synthesis of compound M14-1

[0382] 2-Amino-4-fluoropyridine (20.00 g), 2-chloroacetaldehyde (50 ml, 40% / H₂O), and NaHCO₃ (37.47 g) were dissolved in ethanol (200.00 mL) at room temperature and allowed to react at 60°C for 4 h before stopping the reaction. The reaction solution was directly concentrated, mixed, and separated by column chromatography (DCM:MeOH = 19:1) to obtain the desired product M14-1 (22.00 g, 72.47% yield). ESI-MS m / z: 136.95 [M+H] + .

[0383] Step 2: Synthesis of Compound M14

[0384] Compound M14-1 (22.00 g) was dissolved in chloroform (200.00 mL) at room temperature, and the atmosphere was replaced with nitrogen. Nitrogen sulfide (40.00 g) was added under ice-cooling and allowed to react for 3 h at room temperature. The reaction was then stopped. The sample was mixed and separated by column chromatography (DCM:MeOH = 40:1) to obtain the desired product M14 (35.88 g, 84.73% yield). ESI-MS m / z: 263.02 [M+H] + .

[0385] Synthesis of intermediate M15:

[0386]

[0387] Step 1: Synthesis of compound M15-1

[0388] The raw materials 2-chloro-5,6-dihydrocyclopenta[B]pyridin-7-one (27.4 g) and TBSCl (36.96 g) were added to toluene (200 ml). Under ice-bath conditions, the temperature was controlled at 0-5°C, and a toluene solution of DBU (48.85 ml) was added dropwise. The mixture was then allowed to warm to room temperature and allowed to react for 1 hour. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride and extracted three times with EA (300 ml each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The sample was then separated by silica gel column chromatography (PE) to obtain the target product M15-1 (41.0 g, 88.97% yield).

[0389] ESI-MS m / z: 282.10 [M+H] + .

[0390] Step 2: Synthesis of compound M15-2

[0391] Add the raw material M15-1 (41.0 g) to THF (200 ml), replace the N2 gas, add LiHMDS (363.67 ml) dropwise at -50 ° C, heat to -20 ° C and react for 1 hour, add 2,2'-dibromodiethyl ether (18.47 ml) dropwise, then heat to room temperature and react for 16 hours. The reaction solution is quenched with saturated ammonium chloride, then extracted twice with EA (200 ml each time), the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain the crude product of compound M15-2, which is directly reacted in the next step. Step 3: Synthesis of compound M15-3

[0392] Compound M15-2 (51.0 g) was dissolved in THF (300 mL) at room temperature. TBAF (144.91 ml) was added dropwise in an ice bath, and the mixture was allowed to react at room temperature for 0.5 hours. The reaction solution was added to water, and a saturated aqueous sodium bicarbonate solution was added to precipitate a solid. The filter cake was washed with EA to obtain a white solid, the target product M15-3 (9.62 g, 27.93% yield). ESI-MS m / z: 238.06 [M+H] + .

[0393] Step 4: Synthesis of compound M15-4

[0394] Compound M15-3 (4.3 g) was dissolved in DCM (60 mL), and triethylamine (12.57 mL) and Noyori catalyst (ss) (0.46 g, 0.72 mmol) were added. After N2 displacement, formic acid (3.41 mL) was slowly added dropwise in an ice bath, the temperature was controlled at 5-10°C, and the mixture was allowed to react at room temperature for 4 hours. Water was added to the reaction solution, followed by extraction with DCM (80 mL, 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The mixture was mixed and separated by silica gel column chromatography (PE:EA = 2:1-1:1) to obtain the target product M15-4 (3.67 g, 84.63% yield) as a white solid.

[0395] ESI-MS m / z: 240.07 [M+H] + .

[0396] Step 4: Synthesis of Compound M15-5

[0397] Compound M15-4 (1.0 g) was dissolved in DCM (25 mL), and DIEA (2.07 mL) was added. MsCl (0.48 mL) was added dropwise in an ice bath, and the mixture was allowed to react at 10°C for 2 hours. The reaction mixture was quenched with ice water and extracted three times with DCM (25 mL each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and chromatographed on a silica gel column, followed by washing with DCM. The solvent was removed by swirl to obtain a concentrate, which was then slurried with PE:MTBE = 2:1 and filtered to obtain the desired product, M15-5 (1.16 g, 87.49% yield), as a white solid.

[0398] ESI-MS m / z:318.05[M+H] + .

[0399] Step 4: Synthesis of Compound M15

[0400] Compound M15-5 (1.16 g) was dissolved in DMF (10 mL), and a solution of dimethylamine in THF (9.13 mL, 2 M) was added. The mixture was stirred at room temperature overnight. The reaction solution was quenched with ice water, extracted with EA four times (15 mL each time), washed with saturated brine four times (10 mL each time), dried over anhydrous sodium sulfate, and spin-dried. The sample was mixed and separated by silica gel column chromatography (DCM:CH3OH = 97:3-95:5) to obtain the desired product M15 (810 mg, 82.9% yield) as a white solid. ESI-MS m / z: 267.12 [M+H] + .

[0401] Synthesis of intermediate M16:

[0402]

[0403] Step 1: Synthesis of compound M16

[0404] Compound M10 (40.00 g), pinacol diboronate (71.86 g), potassium acetate (41.65 g), Pd2(dba)3 (6.48 g), and Sphos (5.81 g) were dissolved in 1,4-Dioxane (500 mL), the atmosphere was replaced with nitrogen, the temperature was raised to 100°C, and the reaction was allowed to proceed for 17 hours. The mixture was cooled, filtered, and washed with DCM. The filtrate was concentrated under reduced pressure, and EA (40 ml) was then added to the concentrate and sonicated. PE (200 ml) was then slowly added dropwise at room temperature to precipitate a solid. The solid was filtered and further slurried with PE:MTBE = 1:1. The solid was filtered and washed with PE to obtain compound M16 (42.42 g, 80% yield).

[0405] ESI-MS m / z:375.2[M+H] + .

[0406] Example 1: Synthesis of Compound 7-(4-(dimethylamino)-2',3,3',4,5',6'-hexahydro-2H-spiro[naphthalene-1,4'-pyran]-6-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0407]

[0408] Step 1: Synthesis of compound 1-1

[0409] Under N2 protection, raw materials M4 (118 mg), M1 (191.71 mg), Pd2(dba)3 (21.06 mg), XantPhos (26.67 mg), and Cs2CO3 (300.34 mg) were added to 1,4-dioxane (5.00 mL) and heated at 90°C for 2 hours. The reaction mixture was filtered, the filter cake washed with EA, and the filtrate was dried. The concentrate was isolated by column chromatography (DCM:CH3OH = 30:1) to obtain the desired product 1-1 (197 mg, 81.3% yield). ESI-MS m / z: 526.1 [M+H] + .

[0410] Step 2: Synthesis of compound 1-2

[0411] Compound 1-1 (165 mg), pinacol diboronate (159 mg), Pd2(dba)3 (29 mg), Sphos (26 mg), and potassium acetate (93 mg) were added to 1,4-dioxane (7.5 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 18 hours before being stopped. The reaction mixture was filtered while hot, the filtrate was dried, and the concentrate was isolated by column chromatography (DCM:CH3OH = 20:1) to afford the desired product 1-2 (175 mg, 90.0% yield). ESI-MS m / z: 618.6 [M+H] + .

[0412] Step 3: Synthesis of Compound 1-3

[0413] Compound 1-2 (194 mg), M14, [PdCl2(dppf)]CH2Cl2 (26 mg), and Na2CO3 (100 mg) were added to DMF (5 mL) and water (1 mL). The mixture was then reacted at 90°C for 2 h under N2 protection, and the reaction was stopped. Water was added to the reaction solution, and the mixture was extracted three times with 5 mL of EA each time. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried. The concentrate was isolated by column chromatography (DCM:CH3OH = 20:1) to obtain the desired product 1-3 (102 mg, 51.9% yield). ESI-MS m / z: 626.7 [M+H] + .

[0414] Step 4: Synthesis of compound 1

[0415] Compound 1-3 (102 mg) was added to dichloromethane (5.00 mL) at room temperature. Trifluoroacetic acid (0.3 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react for 1 h at room temperature, and the reaction was stopped. The reaction solvent was concentrated to remove the solvent. 10 mL of H2O and 10 mL of DCM were added to the reaction solution, and then NaOH was added to adjust the pH to 9. The solution was then extracted with DCM three times, 15 mL each time. The organic phases were combined, washed with saturated sodium chloride, and concentrated. The concentrate was isolated by column chromatography (DCM:CH3OH = 10:1) to obtain the desired product 1 (67.2 mg, 78.4% yield). ESI-MS m / z: 526.6 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ9.08(s,1H),8.68(s,1H),8.37(t,J=6.7Hz,1H),7.77(s,1 H),7.59(d,J=8.4Hz,1H),7.5507.37(m,3H),7.27(d,J=8.5Hz,1H),7.21(d,J=8.7H z,1H),6.97-6.93(m,1H),4.36-4.28(m,2H),3.78-3.59(m,5H),2.47(s,1H),2.23( s,6H),1.83-1.76(m,2H),1.60-1.54(m,2H),1.48-1.42(m,2H),1.31-1.26(m,2H).

[0416] Example 2: Synthesis and Chiral Resolution of Compound 7-(7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopentyl]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazole[1,2-a]pyridin-3-yl)isoindol-1-one

[0417] Step 1: Synthesis of compound 2-1

[0418] M3 (45 mg), M1 (76 mg), Pd2(dba)3 (17 mg), XantPhos (21 mg), and cesium carbonate (178 mg) were dissolved in 1,4-Dioxane (5 mL), replaced with nitrogen, heated to 90°C, and reacted for 3 hours. The mixture was cooled, filtered, and washed with EA. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=92:8) to obtain compound 2-1 (73 mg, 78% yield). ESI-MS m / z: 513.2 [M+H]+ .

[0419] Step 2: Synthesis of compound 2-2

[0420] Compound 2-1 (73 mg), pinacol diboronate (72 mg), Pd2(dba)3 (13 mg), SPhos (12 mg), and potassium acetate (42 mg) were dissolved in 1,4-Dioxane (5 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for 8 hours. The mixture was cooled, filtered, washed with EA, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 93:7) to obtain compound 2-2 (82 mg, 95% yield). ESI-MS m / z: 605.3 [M+H] + .

[0421] Step 3: Synthesis of compound 2-3

[0422] Compound 2-2 (82 mg), M14 (53 mg), [PdCl2(dppf)]CH2Cl2 (11 mg), and sodium carbonate (43 mg) were dissolved in DMF (4 mL) and water (0.5 mL). The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C for 2 hours. The mixture was cooled, diluted with water, extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=92:8) to obtain compound 2-3 (60 mg, 72% yield). ESI-MS m / z: 613.2 [M+H] + .

[0423] Step 4: Synthesis of compound 2

[0424] 2-3 (60 mg) was dissolved in DCM (1 mL) and MeOH (1 mL), and hydrochloric acid (2 mL, 4M / 1,4-Dioxane) was added. The temperature was raised to 50°C and the reaction was allowed to react for 1 hour. The mixture was cooled, concentrated under reduced pressure, and purified by Pre-HPLC to obtain compound 2 (10 mg, 19.9% ​​yield). ESI-MS m / z: 513.2 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ10.14(s,1H),8.84(s,1H),8.73(d,J=8.5Hz,1H),8.44(dd,J=7.6,5.7H z,1H),7.82(s,1H),7.72(d,J=8.6Hz,1H),7.64(d,J=8.4Hz,1H),7.52(dd,J=10.0,2.7Hz,1H),6 .97(td,J=7.5,2.6Hz,1H),6.87(d,J=8.3Hz,1H),4.39(s,2H),4.26(s,1H),3.90–3.78(m,2H),3 .62–3.50(m,2H),2.39(m,7H),2.02(m,1H),1.90(m,1H),1.68(m,1H),1.45(m,1H),1.34(m,1H).

[0425] Step 5: Chiral resolution of compound 2

[0426] A racemic mixture of compound 2 (120 mg) was dissolved in a mixture of DCM (8 ml), methanol (2 ml), and ethanol (45 ml) and separated on a preparative chiral column [CHIRALPAK IE (DAICEL) 20*250 mm 5 μm, model: GX-271 (GILSON); mobile phase A: n-hexane (AR, Shuanglin Chemical, with 0.1% diethylamine), mobile phase B: ethanol (AR, Shuanglin Chemical, with 0.1% diethylamine); isocratic (95% mobile phase B); flow rate: 10 ml / min, room temperature]. Compound 2A (peak 1): retention time = 38.58 min, recovered amount 37.4 mg; compound 2B (peak 2): retention time = 46.88 min, recovered amount 38.6 mg.

[0427] Example 2B: Synthesis of Compound (R)-7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopentadienyl[b]pyridin-5'-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

[0428]

[0429] Step 1: Synthesis of compound 2B-1

[0430] Compound M14 (125.00 g), M16 (178.53 g), [PdCl2(dppf)]CH2Cl2 (17.45 g), potassium phosphate (303.79 g), 1,4-dioxane (3000 mL), and water (500 mL) were added to a 5000 ml four-necked flask, the atmosphere was replaced with nitrogen, and the mixture was stirred at 90°C for 2 h. The mixture was cooled to room temperature, filtered through a pad of celite, rinsed with dioxane, and water was added to precipitate a solid. The solid was filtered and the filter cake was slurried with ethanol (300 ml) to obtain a solid. The solid was then slurried with THF (200 ml) / PE (200 ml) to obtain a gray solid, namely compound 2B-1 (130.0 g, 70.8% yield). ESI-MS m / z: 383.2 [M+H] + .

[0431] Step 2: Synthesis of compound 2B-2

[0432] Compound 2B-1 (121.84 g), M15 (85.00 g), palladium acetate (3.58 g), Xphos / 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (15.19 g), cesium carbonate (259.54 g), and 1,4-dioxane (2500 ml) were added to a 5000 four-necked flask. The atmosphere was purged with nitrogen three times, pre-stirred at room temperature for 5 minutes, then heated to an internal temperature of 90°C and stirred for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature, filtered through celite, and rinsed with dioxane (300 ml). Water (5000 ml) was added to precipitate a solid, which was stirred uniformly and filtered with suction. The solid was then slurried with ethanol (500 ml) and then EA (500 ml) to obtain compound 2B-2 (141.00 g, 71.4% yield). ESI-MS m / z: 613.3 [M+H] + .

[0433] Step 3: Synthesis of compound 2B

[0434] Compound 2B-2 (54.00 g) was dissolved in DCM (500 mL) and trifluoroacetic acid (100.00 ml) was added dropwise at room temperature under N2 protection. The reaction was continued at room temperature for 1 hour. The reaction solution was concentrated to dryness, and the crude product was dissolved in DCM (80 ml). Saturated sodium bicarbonate was then slowly added to adjust the pH to 8-9, resulting in the precipitation of a pale yellow solid. Ammonia was added to adjust the pH to 11-12, and the mixture was stirred thoroughly, filtered, and washed with water. Methanol (600 ml) was added to the filter cake, stirred thoroughly, and refluxed for 30 minutes. The mixture was cooled naturally and stirred overnight. The mixture was filtered, and the solid was rinsed with methanol and dried to obtain the desired product 2B (43.20 g, 99.20% purity, 94.5% yield, retention time identical to that of 2B in Example 2). ESI-MS m / z: 513.3 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ10.13(s,1H),8.82(s,1H),8.74(d,J=8.5Hz,1H),8.45-8.42(m,1H),7.82(s,1H) ,7.72(d,J=8.5Hz,1H),7.62(d,J=8.2Hz,1H),7.52(dd,J=10.1,2.7Hz,1H),6.98-6.94(m,1H),6.85(d,J= 8.3Hz,1H),4.39(s,2H),4.22(t,J=7.7Hz,1H),3.88–3.78(m,2H),3.61-3.50(m,2H),2.35(s,6H),2.33-2 .29(m,1H),2.04-1.97(m,1H),1.89-1.84(m,1H),1.71-1.65m,1H),1.46-1.42(m,1H),1.35-1.32(m,1H).

[0435] Example 28: Synthesis of Compound (R)-7-((7-(dimethylamino)-4-methyl-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

[0436] Step 1: Synthesis of compound 28-1

[0437] Under ice-cooling conditions, 2-chloro-4-methyl-5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (6.45 g) and TBSCl (8.03 g) were dissolved in tetrahydrofuran (65 mL). DBU (10.61 mL) was slowly added dropwise and the temperature was slowly raised to room temperature for 12 hours before stopping the reaction. EA was added for extraction, and the organic phase was washed with saturated brine. The sample was mixed and separated by column chromatography (PE:EA = 100:1) to afford the desired product 28-1 (8.30 g, 78.99% yield). ESI-MS m / z: 296.12 [M+H] + .

[0438] Step 2: Synthesis of compound 28-2

[0439] 28-1 (5.0 g) was weighed and dissolved in tetrahydrofuran (50 mL). LiHMDS (50.7 mL, 1 Min THF) was slowly added to the system at -50°C under nitrogen protection. The temperature was slowly raised to -30°C and stirred for 0.5 h. 2,2'-dibromodiethyl ether (4.31 g) was slowly added to the system and the temperature was slowly raised to room temperature for 3 h to stop the reaction. The reaction was quenched with saturated ammonium chloride solution, the solution was spin-dried, and EA was extracted. The organic phase was washed with saturated brine, collected, and spin-dried to obtain crude 28-2 (7.58 g). ESI-MS m / z: 366.17 [M+H] + .

[0440] Step 3: Synthesis of compound 28-3

[0441] At room temperature, crude product 28-2 (8.34 g) was weighed and dissolved in EA (15 mL). Hydrochloric acid solution (60 mL, 1 M) was added and allowed to react for 3 h, after which the reaction was stopped. Sodium carbonate was added to neutralize the mixture, followed by extraction with EA. The organic phase was washed with saturated brine, mixed, and separated by column chromatography (PE:EA = 1:1) to afford the desired product 28-3 (1.94 g, 33.79% yield). ESI-MS m / z: 252.08 [M+H] + .

[0442] Step 4: Synthesis of compound 28-4

[0443] 28-3 (1.88 g), (R)-(+)-tert-butylsulfenamide (2.71 g), and tetraethyl titanate (30 mL) were weighed and reacted at 50°C for 5 h, after which the reaction was stopped. The reaction solution was slowly added dropwise to ice water, EA was added, and the mixture was vigorously stirred. Celite was added and filtered, and EA was extracted. The organic phase was washed with saturated brine, collected, dried, and separated by column chromatography (PE:EA = 3:1) to obtain the desired product 28-4 (2.12 g, 80.19% yield). ESI-MS m / z: 355.12 [M+H] + .

[0444] Step 5: Synthesis of compound 28-5

[0445] 28-4 (2.58 g) was weighed and dissolved in tetrahydrofuran (30 mL). Under nitrogen protection at -78°C, DIBAL-H (25 mL, 1 min THF) was slowly added to the system. The reaction was allowed to react for 6 h, and then stopped. Under nitrogen protection at -78°C, saturated potassium sodium tartrate solution was added to the system, and the temperature was slowly raised to room temperature. After vigorous stirring, the mixture was filtered through celite and extracted with EA. The organic phase was washed with saturated brine, collected, dried, and separated by column chromatography (PE:EA = 2:1) to obtain the desired product 28-5 (2.16 g, 83.25% yield). ESI-MS m / z: 357.14 [M+H] + .

[0446] Step 6: Synthesis of compound 28-6

[0447] Compound 28-5 (2.16 g) was weighed and dissolved in a mixture of DCM (10 mL) and MeOH (5 mL). HCl solution (15.13 mL, 4 M / dioxane) was slowly added under ice-cooling conditions. The mixture was slowly warmed to room temperature and allowed to react for 1 h, after which the reaction was stopped. The solvent was evaporated, and PE and EA were added to precipitate the solid, which was filtered to obtain the hydrochloride salt of the desired product 28-6 (1.23 g, 80.41% yield). ESI-MS m / z: 253.11 [M+H] + .

[0448] Step 7: Synthesis of compound 28-7

[0449] Compound 28-6 (1.33 g) was weighed and dissolved in a mixture of DCE (20 mL) and MeOH (10 mL). Aqueous formaldehyde (1.40 mL, 37%) and AcOH (15 drops) were added and the mixture was allowed to react at room temperature for 0.5 h. Sodium cyanoborohydride (1.32 g) was slowly added to the mixture and allowed to react for 12 h before stopping the reaction. The insoluble material was removed by filtration through Celite, and the organic phase was dried and separated by column chromatography (DCM:MeOH = 50:1) to obtain the desired product 28-7 (1.18 g, 80.13% yield). ESI-MS m / z: 281.14 [M+H] + .

[0450] Step 8: Synthesis of compound 28-8

[0451] 28-7 (893 mg), benzophenone imine (865 mg), Pd2(dba)3 (291 mg), Xantphos (368 mg), and cesium carbonate (3.12 g) were weighed and added to o-xylene (10 mL). The reaction was allowed to proceed at 130°C under nitrogen for 12 h, after which the reaction was terminated. Filtered through celite, the filter cake was washed with ethyl acetate, and the organic phase was collected, dried, and separated by column chromatography (DCM:MeOH = 25:1) to afford the desired product 28-8 (1.30 g, 96.05% yield). ESI-MS m / z: 426.25 [M+H] + .

[0452] Step 9: Synthesis of compound 28-9

[0453] 28-8 (1.30 g) was weighed and dissolved in a mixture of DCM (20 mL) and MeOH (10 mL). HCl solution (15.27 mL, 4 M / dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature for 3 h, after which the reaction was stopped. The solution was dried by rotary evaporation, dissolved in a small amount of methanol, and adjusted to a weakly alkaline state by adding saturated sodium bicarbonate solution. The mixture was extracted with EA, and the organic phase was washed with saturated brine. The organic phase was collected, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 28-9 (530 mg, 66.38% yield). ESI-MS m / z: 262.19 [M+H] + .

[0454] Step 10: Synthesis of compound 28-10

[0455] 28-9 (500 mg), M1 (452 ​​mg), Pd2(dba)3 (132 mg), XantPhos (167 mg), and cesium carbonate (1.41 g) were weighed, and dioxane (10 mL) was added. The reaction was allowed to proceed at 90°C under nitrogen for 2.5 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 33:1) to afford the desired product 28-10 (721 mg, 94.83% yield). ESI-MS m / z: 527.24 [M+H] + .

[0456] Step 11: Synthesis of compound 28-11

[0457] 28-10 (700 mg), diboronic acid pinacol ester (675 mg), Pd2(dba)3 (243 mg), SPhos (218 mg), and KOAC (391 mg) were weighed and dioxane (10 mL) was added. The reaction was allowed to proceed at 90°C under nitrogen for 12 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 28-11 (422 mg, 51.37% yield). ESI-MS m / z: 519.31 [M+H] + .

[0458] Step 12: Synthesis of compound 28-12

[0459] 28-11 (100 mg), M14 (52 mg), [PdCl2(dppf)]CH2Cl2 (13 mg), and sodium carbonate (51 mg) were weighed and added to DMF (4 mL) and water (0.50 mL). The mixture was then reacted at 90°C under nitrogen for 1 h, after which the reaction was terminated. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 12:1) to afford the desired product 28-12 (100 mg, 99% yield). ESI-MS m / z: 627.31 [M+H] + .

[0460] Step 13: Synthesis of compound 28

[0461] Compound 28-12 (100 mg) was weighed and dissolved in dichloromethane (1.5 mL) and MeOH (1.5 mL). HCl solution (3 mL, 4-Min dioxane) was slowly added dropwise in an ice bath. The mixture was slowly warmed to room temperature and allowed to react for 30 minutes before stopping the reaction. The product was concentrated and purified by preparative liquid phase separation to obtain the desired product 28 (22.8 mg, 97.26% purity, 27.13% yield). ESI-MS m / z: 527.41 [M+H] + .

[0462] Example 39: Synthesis of Compound 7-(7-(azetidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0463]

[0464] Step 1: Synthesis of Intermediate 39-1

[0465] Compound M8-10 (1.00 g), KI (0.14 g), potassium carbonate (1.73 g), and azetidinamine (2.38 g) were added to DMF (12.00 mL) at room temperature. The mixture was then incubated at 40°C under N₂ protection for 5 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the desired product 39-1 (0.70 g, 64.45% yield). ESI-MS m / z: 261.32 [M+H] + .

[0466] Step 2: Synthesis of Intermediate 39-2

[0467] Compound 39-1 (0.60 g) and pyridine (0.93 mL) were added to DCM (15.00 mL) at room temperature. Trifluoromethanesulfonic anhydride (0.78 mL) was then slowly added in portions under N2 protection, maintaining the temperature at -50 to -40°C. The reaction was maintained at -50 to -40°C for 1 h, after which the reaction was terminated. The reaction solution was concentrated to dryness to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 75:25) to afford the desired product 39-2 (1.0 g, 92.02% yield). ESI-MS m / z: 322.43 [M+H] + .

[0468] Step 3: Synthesis of Intermediate 39-3

[0469] Compound 39-2 (1.00 g) was added to dimethylamine (15 mL, 2 M in THF) at room temperature. The mixture was then reacted at 25°C under N2 protection for 1 h, after which the reaction was stopped. The reaction solution was concentrated to dryness to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford 0.72 g of the crude target product. The target product 39-3 (0.20 g, 24.86% yield) was then separated by column chromatography (DCM:MeOH (7M-NH3) = 12:1). ESI-MS m / z: 260.36 [M+H] + Step 4: Synthesis of Intermediate 39-4

[0470] Compound 39-3 (200.00 mg), intermediate M1 (320.75 mg), Pd2(dba)3 (70.60 mg), XantPhos (89.22 mg), and cesium carbonate (753.82 mg) were added to 1,4-dioxane (6.00 mL) at room temperature. The mixture was then reacted at 100°C for 5 h under N2 protection, and the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the desired product 39-4 (240.00 mg, 59.27% ​​yield). ESI-MS m / z: 526.05 [M+H] + .

[0471] Step 5: Synthesis of Intermediate 39-5

[0472] Compound 39-4 (240.00 mg), pinacol diboronate (232.15 mg), Pd2(dba)3 (83.70 mg), SPhos (75.09 mg), and potassium acetate (134.58 mg) were added to 1,4-dioxane (8.00 mL) at room temperature. The mixture was then reacted at 100°C for 12 h under N2 protection, and the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the desired product 39-5 (220.00 mg, 78.06% yield). ESI-MS m / z: 617.58 [M+H] + .

[0473] Step 6: Synthesis of Intermediate 39-6

[0474] Compound 39-5 (100.00 mg), M14 (51.02 mg), [PdCl2(dppf)]CH2Cl2 (13.23 mg), and sodium carbonate (51.57 mg) were added to DMF (4.00 mL) and water (0.80 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 1 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 39-6 (80.00 mg, 78.95% yield) as a red solid. ESI-MS m / z: 625.73 [M+H] + .

[0475] Step 7: Synthesis of compound 39

[0476] Compound 39-6 (80.00 mg) was added to dichloromethane (4.00 mL) at room temperature, and trifluoroacetic acid (0.80 mL) was added under N2 protection in an ice-water bath. The reaction was allowed to react for 1 h at room temperature to stop the reaction. The reaction solvent was removed by rotary evaporation, and 5 mL of H2O and 5 mL of DCM were added to the reaction solution. NaOH was then added to adjust the pH to >12. The solution was then extracted with DCM three times, 15 mL each time. The organic phases were combined and washed with saturated sodium chloride. The organic phases were concentrated to obtain a crude product, which was then added to 10.00 mL of methanol for slurrying. The product was filtered and dried to obtain the desired product 39 (34.60 mg, 51.49% yield). ESI-MS m / z: 525.53 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.84(s,1H),8.76(d,J=8.7Hz,1H),8.43(t,J=6.7Hz,1H),7.82(s ,1H),7.71(d,J=8.6Hz,1H),7.62(d,J=8.4Hz,1H),7.53-7.50(m,1H),6.99-6.95(m,1H),6.84(d,J=8.3H z,1H),4.38(d,J=3.3Hz,2H),3.83-3.79(m,2H),3.73(s,1H),3.57–3.49(m,2H),3.44-3.35(m,4H),2.4 9(s,6H),2.18-2.13(m,1H),2.02-1.97(m,2H),1.90-1.75(m,3H),1.56-1.53(m,1H),1.33-1.29(m,1H).

[0477] Example 40: Synthesis of Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(pyrrolidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)isoindolin-1-one

[0478]

[0479] Step 1: Synthesis of compound 40-1

[0480] 2-Chloro-2',3',5',6'-tetrahydrospiro[cyclopenta[b]pyridin-5,4'-pyran]-7(6H)-one (450 mg), pyrrolidine (404 mg), and tetraethyl titanate (216 mg) were weighed and added to DCE (10 mL). The mixture was reacted at room temperature for 1 hour. Sodium cyanoborohydride (357 mg) was slowly added and the temperature was raised to 80°C for 2 hours to terminate the reaction. The organic phase was extracted with DCM and washed with saturated brine. The organic phase was collected, dried, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the desired product 40-1 (540 mg, 97.41% yield). ESI-MS m / z: 293.14 [M+H] + .

[0481] Step 2: Synthesis of compound 40-2

[0482] 40-1 (600 mg), benzophenone imine (557 mg), Pd2(dba)3 (375 mg), Xantphos (474 ​​mg), and cesium carbonate (2.00 g) were weighed and added to o-xylene (10 mL). The reaction was allowed to proceed at 130°C under nitrogen for 12 h, after which the reaction was terminated. The mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic phase was collected, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 40-2 (850 mg, 94.85% yield). ESI-MS m / z: 438.25 [M+H] + .

[0483] Step 3: Synthesis of compound 40-3

[0484] 40-2 (1.20 g) was weighed and dissolved in a mixture of DCM (20 mL) and MeOH (10 mL). HCl solution (13.71 mL, 4 min dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature for 3 h, after which the reaction was stopped. The solution was spin-dried to dryness, dissolved in a small amount of methanol, and adjusted to a weakly alkaline state by adding saturated sodium bicarbonate solution. Extraction was performed with EA, and the organic phase was washed with saturated brine. The organic phase was collected, spin-dried, and separated by column chromatography (DCM:MeOH = 15:1) to afford the desired product 40-3 (750 mg, 99.10% yield). ESI-MS m / z: 274.19 [M+H] + .

[0485] Step 4: Synthesis of compound 40-4

[0486] 40-3 (1.0 g), intermediate M1 (660 mg), Pd2(dba)3 (221 mg), XantPhos (279 mg), and cesium carbonate (2.36 g) were weighed, and dioxane (10 mL) was added. The reaction was allowed to proceed at 90°C under nitrogen for 2.5 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 33:1) to afford the desired product 40-4 (893 mg, 68.61% yield). ESI-MS m / z: 539.24 [M+H] + .

[0487] Step 5: Synthesis of compound 40-5

[0488] 40-4 (883 mg), pinacol diboronate (832 mg), Pd2(dba)3 (300 mg), SPhos (269 mg), and KOAc (482 mg) were weighed and dioxane (10 mL) was added. The reaction was allowed to proceed at 90°C under nitrogen for 12 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 40-5 (905 mg, 87.62% yield). ESI-MS m / z: 631.37 [M+H] + .

[0489] Step 6: Synthesis of compound 40-6

[0490] 40-5 (100 mg), M14 (62 mg), [PdCl2(dppf)]CH2Cl2 (13 mg), and sodium carbonate (51 mg) were weighed and added to dioxane (4 mL) and water (0.50 mL). The mixture was then reacted at 90°C under nitrogen for 1 h, after which the reaction was terminated. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 12:1) to afford the desired product 40-6 (70 mg, 69.10% yield). ESI-MS m / z: 639.31 [M+H] + .

[0491] Step 7: Synthesis of compound 40

[0492] Compound 40-6 (100 mg) was dissolved in dichloromethane (1.5 mL). TFA (1.5 mL) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature for 30 min, after which the reaction was stopped. The solution was concentrated and purified by preparative liquid separation to afford the desired product 40 (16.7 mg, 99.60% purity, 28.29% yield). 1H NMR (500MHz, DMSO) δ10.39(s,1H),10.24(s,1H),8.92(s,1H),8.52(t,J=7.5Hz,2H),8.07(s,1H),7.83(d,J=8.5Hz,1 H),7.77(t,J=9.5Hz,2H),7.23(s,1H),7.13(d,J=8.5Hz,1H),5.11(dd,J=14.6,7.7Hz,1H),4.41(q,J=18.3Hz,2H),3. 98(s,1H),3.92–3.81(m,2H),3.69–3.57(m,1H),3.56–3.50(m,1H),3.49–3.33(m,2H),2.91(dd,J=13.4,8.2Hz,1H),2 .21–1.92(m,6H),1.86(d,J=7.0Hz,1H),1.68(dd,J=12.1,8.6Hz,1H),1.51(d,J=12.9Hz,1H),1.41(d,J=12.5Hz,1H). ESI-MSm / z:539.42[M+H] + .

[0493] Synthesis of compounds 40A and 40B:

[0494]

[0495] Step 1: Synthesis of compounds 40-6A and 40-6B

[0496] 40-6 sample preparation: 70 mg of sample 40-6 was dissolved in 6 ml of a 2:1 ethanol:n-hexane solution. Chromatographic conditions: 1. Chiral preparative column YMC CHIRAL ART Celluose-SB 250*20.0 mm S-5 μm; 2. Instrument model GILSON GX-271; 3. Mobile phase: Mobile phase A:n-hexane, Mobile phase B:0.1% diethylamine in ethanol, isocratic elution with a mobile phase A:mobile phase B ratio of 7:3, flow rate 20 ml / min, wavelength 254 nm, separation at room temperature. Compound 40-6A (peak 1): retention time = 13.035 min, recovered yield 35 mg; Compound 40-6B (peak 2): retention time = 17.645 min, recovered yield 36 mg.

[0497] Step 2: Synthesis of compound 40A

[0498] Compound 40-6A (36 mg) was weighed and dissolved in dichloromethane (1.5 mL) and methanol (1.5 mL). HCl solution (3 mL, 4 M in dioxane) was slowly added dropwise under an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes before stopping the reaction. The organic solvent was removed by concentration to obtain the desired product 40A (21.1 mg, 99.74% purity, 69.46% yield). ESI-MS m / z: 539.40 [M+H] + .

[0499] 1 H NMR(500MHz,DMSO-d6)δ11.64(d,J=5.4Hz,1H),10.25(s,1H),8.95(s,1H),8.73–8.65(m,2H),8.44(s,1H), 8.03(dd,J=8.2,2.3Hz,1H),7.82(dd,J=8.5,3.8Hz,2H),7.54(td,J=7.5,2.5Hz,1H),7.11(d,J=8.5Hz,1H), 5.09(dd,J=14.4,8.0Hz,1H),4.46–4.35(m,2H),3.95–3.81(m,3H),3.63–3.52(m,2H),3.42–3.33(m,2H),2. 89(dd,J=13.4,8.2Hz,1H),2.21–1.84(m,7H),1.74–1.62(m,1H),1.59(d,J=12.4Hz,1H),1.45–1.37(m,1H).

[0500] Step 3: Synthesis of compound 40B

[0501] Compound 40-6B (35 mg) was weighed and dissolved in dichloromethane (1.5 mL) and methanol (1.5 mL). HCl solution (3 mL, 4 M in dioxane) was slowly added dropwise under an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes before stopping the reaction. The organic solvent was removed by concentration to obtain the desired product 40B (22.2 mg, 99.10% purity, 75.21% yield). ESI-MS m / z: 539.40 [M+H] + .

[0502] 1H NMR (500MHz, DMSO-d6) δ11.65(s,1H),10.26(s,1H),8.95(s,1H),8.75–8.62(m,2H),8.45(s,1H),8.04(dd,J=8 .2,2.3Hz,1H),7.82(dd,J=8.5,5.0Hz,2H),7.55(td,J=7.5,2.4Hz,1H),7.11(d,J=8.5Hz,1H),5.09(dd,J=14.4 ,7.9Hz,1H),4.45–4.36(m,2H),3.96–3.80(m,3H),3.57–3.47(m,2H),3.37(dd,J=13.0,6.5Hz,2H),2.93–2.84 (m,1H),2.03(tdd,J=23.7,15.1,9.6Hz,7H),1.70–1.63(m,1H),1.59(d,J=12.4Hz,1H),1.40(d,J=12.5Hz,1H).

[0503] Example 41: Synthesis of Compound 7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-(hydroxymethyl)imidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0504] Step 1: Synthesis of compound 41-1

[0505] At room temperature, 2-aminopyridine-4-methanol (2.00 g), 2-chloroacetaldehyde (6.32 g, 40% / H2O), and NaHCO3 (2.71 g) were dissolved in ethanol (20.00 mL) and water (4.00 mL). The mixture was reacted at 70°C for 2 h, and then the reaction was stopped. The reaction solution was directly concentrated, mixed, and separated by column chromatography (DCM:MeOH = 10:1) to obtain the desired product 41-1 (2.34 g, 98.03% yield). ESI-MS m / z: 149.12 [M+H] + .

[0506] Step 2: Synthesis of compound 41-2

[0507] Compound 41-1 (2.34 g) was dissolved in DMF (20.00 mL) at room temperature. The atmosphere was replaced with N2, and NIS (3.91 g) was added under ice-cooling. The mixture was allowed to react at room temperature for 2 h, after which the reaction was stopped. EA / THF and water were added for extraction three times. The organic phase was washed with saturated brine, mixed, and separated by column chromatography (DCM:MeOH = 13:1) to obtain the desired product 41-2 (3.26 g, 75.32% yield). ESI-MS m / z: 275.10 [M+H] + .

[0508] Step 3: Synthesis of compound 41-3

[0509] Compound 2-2 (80.00 mg), 41-2 (44.00 mg), [PdCl2(dppf)]CH2Cl2 (11.00 mg), and sodium carbonate (42.00 mg) were added to DMF (2.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 1 h, after which the reaction was terminated. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 7:1) to afford the desired product 41-3 (44.00 mg, 53.06% yield). ESI-MS m / z: 625.50 [M+H] + .

[0510] Step 4: Synthesis of compound 41

[0511] Compound 41-3 (44.00 mg) was dissolved in dichloromethane (1.50 mL) at room temperature, and TFA (0.40 mL) was added. The reaction was allowed to react at room temperature for 10 min, and then stopped. The mixture was concentrated, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate to obtain the desired product 41 (15.70 mg, purity 97.16%, yield 41.26%). ESI-MS m / z: 525.51 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.82(s,1H),8.73(d,J=8.5Hz,1H),8.34(d,J=7.1Hz,1H),7.78(s, 1H),7.70(d,J=8.5Hz,1H),7.63(d,J=8.3Hz,1H),7.51(s,1H),6.91-6.83(m,2H),5.42(t,J=5.7Hz,1H),4 .57(d,J=5.7Hz,2H),4.39(s,2H),4.24(s,1H),3.86-3.79(m,2H),3.63-3.50(m,2H),2.37(s,6H),2.34-2 .29(m,1H),2.03-1.97(m,2H),1.89-1.84m,1H),1.71-1.64(m,1H),1.48-1.41(m,1H),1.34-1.31(m,1H).

[0512] Example 43: Synthesis of Compound 4-(7,8-difluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0513]

[0514] Step 1: Synthesis of compound 43-1

[0515] 2-Amino-4-fluoropyridine (2.00 g) and selectfluor (7.58 g) were dissolved in acetonitrile (20.00 mL) and water (10.00 mL). The atmosphere was replaced with nitrogen and the reaction was allowed to proceed at 60°C for 12 h, after which the reaction was stopped. The product was concentrated, dissolved in DCM, mixed, and separated by column chromatography (DCM:MeOH = 16:1) to afford the desired product 43-1 (56.00 mg, 2.41% yield). ESI-MS m / z: 131.06 [M+H] + .

[0516] Step 2: Synthesis of compound 43-2

[0517] Compound 43-1 (56.00 mg), 2-chloroacetaldehyde (169.00 mg, 40% / H2O), and NaHCO3 (72.00 mg) were dissolved in ethanol (3.00 mL) and water (0.60 mL) at room temperature and allowed to react at 70°C for 12 h, after which the reaction was stopped. The reaction solution was directly concentrated, mixed, and separated by column chromatography (DCM:MeOH = 19:1) to afford the desired product 43-2 (53.00 mg, 78.85% yield). ESI-MS m / z: 155.03 [M+H] + .

[0518] Step 3: Synthesis of compound 43-3

[0519] Compound 43-2 (53.00 mg) was dissolved in chloroform (2.00 mL) at room temperature, and the atmosphere was replaced with N2. NIS (84.03 mg) was added under ice-cooling. The reaction was allowed to react at room temperature for 2 h, and then stopped. The sample was mixed and separated by column chromatography (DCM:MeOH = 40:1) to obtain the desired product 43-3 (75.00 mg, 78.33% yield). ESI-MS m / z: 280.92 [M+H] + .

[0520] Step 4: Synthesis of compound 43-4

[0521] Compound 2-2 (70.00 mg), 43-3 (65.00 mg), [PdCl2(dppf)]CH2Cl2 (9.00 mg), and sodium carbonate (37.00 mg) were added to DMF (2.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 1 h, after which the reaction was terminated. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product 43-4 (17.00 mg, 23.27% yield). ESI-MS m / z: 630.45 [M+H] + .

[0522] Step 5: Synthesis of compound 43

[0523] Compound 43-4 (17.00 mg) was dissolved in dichloromethane (2 mL) at room temperature, and TFA (0.50 mL) was added. The reaction was allowed to react at room temperature for 10 min, and then stopped. The mixture was concentrated, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, and extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate to obtain the desired product 43 (6.84 mg, 97.40% purity, 46.51% yield). ESI-MS m / z: 531.21 [M+H] + .

[0524] 1H NMR(500MHz,DMSO-d6)δ10.96(s,1H),10.28(s,1H),8.92(s,1H),8.76(d,J=8.5Hz,1H),8.32-8.29(m,1 H),8.05(s,1H),7.81(d,J=8.5Hz,1H),7.73(d,J=8.5Hz,1H),7.33-7.28(m,1H),7.09(d,J=8.5Hz,1H),5 .11-5.07(m,1H),4.39(s,2H),3.62-3.50(m,3H),2.93(d,J=4.8Hz,3H),2.82(d,J=4.9Hz,3H),2.77-2.7 2(m,1H),2.16-2.08(m,2H),2.02-1.95(m,1H),1.71-1.65(m,1H),1.55-1.51(m,1H),1.45-1.37(m,1H).

[0525] Example 46: Synthesis of Compound 4-(6-chloro-7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)isoindolin-1-one

[0526]

[0527] Step 1: Synthesis of compound 46-1

[0528] Compound 2-2 (70.00 mg), M9 (40.00 mg), [PdCl2(dppf)]CH2Cl2 (11.00 mg), and sodium carbonate (37.00 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 85°C for 40 min under nitrogen protection, and the reaction was stopped. A certain amount of water was added to the reaction solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 13:1) to obtain the desired product 46-1 (30.00 mg, 60.05% yield). ESI-MS m / z: 647.2 [M+H] + .

[0529] Step 2: Synthesis of compound 46

[0530] Compound 46-1 (30.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (396.22 mg) was added. The reaction was allowed to react at room temperature for 0.5 h, and then the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried to obtain the target product 46 (27.30 mg, purity 98.45%, yield 70.69%). ESI-MS m / z: 547.1 [M+H] + .

[0531] 1 H NMR (500MHz, DMSO-d6) δ10.15(s,1H),8.83(s,1H),8.73(d,J=8.5Hz,1H),8.66(d,J=6.9Hz,1 H),7.87(s,1H),7.81(d,J=9.9Hz,1H),7.75(d,J=8.5Hz,1H),7.65(d,J=8.3Hz,1H),6.89(d, J=8.4Hz,1H),4.37(s,2H),3.87-3.80(m,2H),3.63-3.51(m,2H),2.40(s,3H),2.36(s,3H),2 .06–1.97(m,2H),1.91-1.85(m,1H),1.69-1.64(m,2H),1.46-1.44(m,1H),1.35-1.32(m,1H).

[0532] Example 49: Compound 7-((8'-(dimethylamino)-2,3,5,6,7',8'-hexahydrospiro[pyran-4,5'-pyrano[4,3-b]pyridin]-2'-yl)amino)-4-(7-fluoroimidazole[1,2-a]pyridin-3-yl)isoindol-1-one

[0533]

[0534] Step 1: Synthesis of compound 49-1

[0535] 2-Bromo-3-iodopyridine (10 g, 35.2 mmol) was dissolved in THF (150 mL). The reaction system was then placed at -20°C and slowly added dropwise with isopropylmagnesium chloride (4.4 g, 42.3 mmol) under nitrogen. After complete addition, the mixture was allowed to react at this temperature for 2 h. Tetrahydropyrone (5.3 g, 52.8 mmol) was then added and stirred at room temperature overnight. The reaction solution was quenched with saturated ammonium chloride solution and concentrated under reduced pressure to remove some of the solvent. The mixture was extracted with EA. The combined organic layers were washed sequentially with 1M HCl, water, and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 70:30 to 65:35) to obtain compound 49-1 (3.2 g, 35% yield). ESI-MS m / z: 258.0 [M+H] + .

[0536] Step 2: Synthesis of compound 49-2

[0537] Compound 49-1 (3.0 g, 9.3 mmol) was dissolved in DMF (25 mL) and NaH (0.74 g, 18.6 mmol) was added under ice-cooling. After completion of the addition, the mixture was stirred at room temperature for 30 min. Subsequently, a DMF solution of allyl bromide (1.6 g, 13.0 mmol) and TBAI (0.34 g, 0.93 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was quenched with water, concentrated under reduced pressure to remove some of the solvent, and extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 70:30-65:35) to obtain compound 49-2 (2.8 g, 80% yield). ESI-MS m / z: 298.1 [M+H] + .

[0538] Step 3: Synthesis of compound 49-3

[0539] Compound 49-2 (1.5 g, 5.0 mmol), Pd(OAc)2 (0.17 g, 0.75 mmol), XantPhox (0.44 g, 0.75 mmol), and TEA (2.1 ml, 15 mmol) were dissolved in ACN (15 mL) and reacted at 90°C under nitrogen for 6 h. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:30 to 65:35) to obtain compound 49-3 (0.84 g, 77% yield). ESI-MS m / z: 218.1 [M+H] + .

[0540] Step 4: Synthesis of compound 49-4

[0541] Compound 49-3 (0.34 g, 5.5 mmol) was dissolved in MeOH (5 mL) and DCM (10 mL). Ozone was introduced at -50°C for 30 min, and then dimethyl sulfide (0.34 g, 5.5 mmol) was added. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:40-50:50) to obtain compound 49-4 (0.24 g, 83% yield). ESI-MS m / z: 220.1 [M+H] + .

[0542] Step 5: Synthesis of compound 49-5

[0543] Under ice-cooling, sodium borohydride (38.8 mg, 1.0 mmol) was added portionwise to a solution of 49-4 (0.15 g, 0.68 mmol) in MeOH (2.5 mL) and THF (2.5 mL). The ice-cooling was removed and the reaction was allowed to proceed at room temperature for 1 hour. The mixture was quenched with water and concentrated under reduced pressure to remove some of the solvent. The mixture was extracted with EA, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound 49-5 (112 mg, 74% yield). ESI-MS m / z: 222.1 [M+H] + .

[0544] Step 6: Synthesis of compound 49-6

[0545] To a solution of 49-5 (0.11 g, 0.50 mmol) in DCM (5 mL) was added dropwise thionyl chloride (0.18 mL) under an ice bath. The ice bath was removed, the temperature was raised to 40°C, and the reaction was allowed to proceed for 1 hour. The solution was concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The solution was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 20:80) to afford compound 49-6 (115 mg, 96% yield). ESI-MS m / z: 239.0 [M+H] + .

[0546] Step 7: Synthesis of compound 49-7

[0547] At room temperature, 49-6 (410 mg, 1.71 mmol) was dissolved in DCM (20 mL). mCPBA (590 mg, 3.43 mmol) was added at room temperature and allowed to react for 3 h. LC-MS confirmed the complete reaction. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was extracted with DCM. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to afford compound 49-7 (428 mg, 98% yield). ESI-MS m / z: 256.1 [M+H]+ .

[0548] Step 8: Synthesis of compound 49-8

[0549] Compound 49-7 (400 mg, 1.56 mmol) and pyridine (1.2 g, 15.6 mmol) were dissolved in DCM (10 mL). Tf2O (1.3 g, 4.68 mmol) was added under ice-cooling. The mixture was allowed to react at room temperature for 0.5 h. LC-MS confirmed the complete reaction. The mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to afford compound 49-8 (472 mg, 96% yield). ESI-MS m / z: 317.1 [M] + .

[0550] Step 9: Synthesis of compound 49-9

[0551] Compound 49-8 (250 mg, 0.79 mmol) was dissolved in dimethylamine tetrahydrofuran solution (15 mL) at room temperature and stirred for 0.5 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give compound 49-9 (175 mg, 87% yield). ESI-MS m / z: 255.1 [M+H] + .

[0552] Step 10: Synthesis of compound 49-10

[0553] 49-9 (150 mg, 0.59 mmol), KI (12 mg, 0.12 mmol), Cs2CO3 (575 mg, 1.78 mmol), and dimethylamine tetrahydrofuran solution (2.4 mL) were dissolved in DMA (5.0 mL) and stirred at 100°C overnight. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give compound 49-10 (150 mg, 97% yield). ESI-MS m / z: 264.2 [M+H] + .

[0554] Step 11: Synthesis of compound 49-11

[0555] 49-10 (300 mg, 1.14 mmol), intermediate M1 (434 mg, 1.25 mmol), Pd2(dba)3 (104 mg, 0.11 mmol), XantPhos (132 mg, 0.23 mmol), and Cs2CO3 (1.11 g, 3.42 mmol) were dissolved in 1,4-dioxane (8.0 mL). The mixture was sealed under nitrogen and stirred at 90°C for 4 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 49-11 (480 mg, 80% yield). ESI-MS m / z: 529.3 [M+H] + .

[0556] Step 12: Synthesis of compound 49-12

[0557] 49-11 (250 mg, 0.47 mmol), Pd2(dba)3 (86.5 mg, 0.09 mmol), pinacol diboronate (240 mg, 0.95 mmol), SPhos (77.6 mg, 0.19 mmol), and AcOK (139 mg, 1.42 mmol) were dissolved in 1,4-dioxane (4.0 mL). The mixture was sealed under nitrogen and stirred at 90°C for 16 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give compound 49-12 (293 mg, 72% yield). ESI-MS m / z: 621.5 [M+H] + .

[0558] Step 13: Synthesis of compound 49-13

[0559] Compound 49-12 (100 mg, 0.47 mmol), M14 (54.9 mg, 0.21 mmol), PdCl2(dppf)·CH2Cl2 (86.5 mg, 0.09 mmol), and Na2CO3 (51.2 mg, 0.48 mmol) were dissolved in DMF (5.0 mL) and H2O (0.5 mL). The mixture was sealed under nitrogen and stirred at 90°C for 0.5 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=10:1) to give compound 49-13 (60 mg, 59% yield). ESI-MS m / z: 629.5 [M+H] + .

[0560] Step 14: Synthesis of compound 49

[0561] 49-13 (50 mg, 0.47 mmol) was dissolved in CH2Cl2 (5.0 mL), and then TFA (0.5 mL) was added and stirred at room temperature for 15 minutes. The reaction was complete. The residue was washed with saturated sodium bicarbonate and then extracted with dichloromethane. The crude product was slurried with ethyl acetate and n-hexane to obtain compound 49 (25 mg, 60% yield). ESI-MS m / z: 529.5 [M+H] + . 1 H NMR (500MHz, DMSO) δ10.11(s,1H),8.85(s,1H),8.79(d,J=8.6Hz,1H),8.45–8.40(m,1H),7.71(d,J=8.6Hz,1H),7 .66(d,J=8.6Hz,1H),7.53–7.47(m,1H),6.97(td,J=7.5,2.6Hz,1H),6.94(d,J=8.6Hz,1H),4.45–4.34(m,2H),4.0 9(dd,J=12.3,2.3Hz,1H),3.95(dd,J=12.3,3.8Hz,1H),3.77–3.58(m,4H),3.54–3.42(m,1H),2.41(s,6H),2.37(d ,J=6.7Hz,1H),2.17–2.06(m,1H),2.04–1.95(m,1H),1.78(ddd,J=19.4,18.8,8.8Hz,2H),1.58(d,J=12.6Hz,1H).

[0562] Example 50: Synthesis of Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7′-methyl-2,3,5,6,7′,8′-hexahydro-6′-spiro[pyran-4,5′-[1,7]naphthyridine]-2′-yl)amino)isoindol-1-one

[0563]

[0564] Step 1: Synthesis of compound 50-1

[0565] Methyl 6-chloro-3-methyl-2-pyridinecarboxylate (5.00 g) was dissolved in carbon tetrachloride (60.00 mL) at room temperature, followed by the addition of NBS (5.00 g) and AIBN (440.00 mg). The reaction was allowed to proceed at 80°C for 3 h under nitrogen protection, after which the reaction was stopped. A suitable amount of water was added to the reaction solution, which was then extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (PE:EA = 2:1) to afford the desired product 50-1 (5.43 g, 80.00% yield). ESI-MS m / z: 186.0 [M+H] + .

[0566] Step 2: Synthesis of compound 50-2

[0567] Compound 50-1 (5.00 g) and K2CO3 (5.23 g) were dissolved in ACN (70.00 mL) at room temperature. TMSCN (3.00 g) was then slowly added dropwise in an ice bath. The reaction was allowed to react at room temperature for 13 h, after which the reaction was stopped. A certain amount of water was added to the reaction solution, which was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 2:1) to afford the desired product 50-2 (2.15 g, 54.00% yield). ESI-MS m / z: 211.3 [M+H] + .

[0568] Step 3: Synthesis of compound 50-3

[0569] Compound NaH (520.00 mg) was dissolved in DMF (30.00 mL) at room temperature. 50-2 (2.00 g) was then slowly added under nitrogen in an ice bath. The reaction was incubated for 0.5 h, followed by the slow dropwise addition of 2,2'-dibromodiethyl ether (3.52 g). The reaction was allowed to stand for 3 h at room temperature to terminate the reaction. The reaction was quenched with saturated ammonium chloride solution under ice bath conditions and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to afford the desired product 50-3 (1.20 g, 45.02% yield). ESI-MS m / z: 281.2 [M+H] + .

[0570] Step 4: Synthesis of compound 50-4

[0571] Compound 50-3 (1.20 g) was dissolved in THF (30.00 mL) at room temperature, and then borane dimethyl sulfide solution (1.6 mL, 10 M) was slowly added dropwise under an ice bath. Under nitrogen protection, the reaction was incubated at 70°C for 16 h, and then stopped. The pH was adjusted to 1-2 with 1 M HCl solution, and the reaction was continued at 70°C for 1 h, and then stopped. The pH was adjusted to 8-9 with 2 M NaOH solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 50-4 (250.00 mg, 30.00% yield). ESI-MS m / z: 239.4 [M+H] + .

[0572] Step 5: Synthesis of compound 50-5

[0573] Compound 50-4 (250.00 mg) was dissolved in MeOH (10.00 mL) at room temperature, and glacial acetic acid (1.00 mL) was added. Then, in an ice bath, under nitrogen, aqueous formaldehyde solution (127.00 mg, 37% in water) was slowly added. The reaction was incubated for 1 h. NaBH(OAc)3 (665.00 mg) was then slowly added dropwise. The reaction was continued at room temperature for 1 h to terminate the reaction. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to afford the desired product 50-5 (208.00 mg, 79.00% yield). ESI-MS m / z: 253.4 [M+H] + .

[0574] Step 6: Synthesis of compound 50-6

[0575] Compound 50-5 (208.00 mg), M10 (267.00 mg), Pd2(dba)3 (76.00 mg), XantPhos (94.00 mg), and cesium carbonate (800.00 mg) were added to 1,4-dioxane (6.00 mL) at room temperature. The mixture was then reacted at 100°C for 3 h under N2 protection, after which the reaction was terminated. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 13:1) to afford the desired product 50-6 (200.00 mg, 49.00% yield). ESI-MS m / z: 499.3 [M+H]+.

[0576] The subsequent synthetic steps were carried out according to the synthesis of Example 2 to prepare compound 50. 1H NMR (500MHz, DMSO-d6) δ10.06(s,1H),8.84(s,1H),8.72(d,J=8.6Hz,1H),8.45(dd,J=7.6 ,5.7Hz,1H),7.83(s,1H),7.78(d,J=8.6Hz,1H),7.72(d,J=8.5Hz,1H),7.53(dd,J=10.0,2 .7Hz,1H),6.99-6.95(m,1H),6.87(d,J=8.6Hz,1H),4.40(s,2H),3.76-3.71(m,2H),3.64- 3.58(m,2H),3.53(s,2H),2.74(s,2H),2.43(s,3H),1.96-1.89(m,2H),1.59-1.54(m,2H).

[0577] Example 58: Synthesis of Compound 7-((7-(dimethylamino)-4',5',6,7-tetrahydro-2'H-spiro[cyclopenta[b]pyridin-5,3'-furan]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0578] Step 1: Synthesis of compound 58-1

[0579] NaH (2.03 g, 60%, 50.75 mmol) was dissolved in DMF (80 mL). A 10 mL DMF solution of 2-(2-bromopyridin-3-yl)acetonitrile (10.00 g, 50.75 mmol) (3.0 g, 9.3 mmol) was added under ice-cooling. After completion of the addition, the reaction was stirred at 0°C for 30 min. Subsequently, a 20 mL DMF solution of allyl bromide (6.14 g, 50.75 mmol) was added dropwise, and the reaction was stirred at room temperature overnight. The reaction was quenched with water, concentrated under reduced pressure to remove some of the solvent, and extracted with EA. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 8:1-3:1) to afford compound 58-1 (9.6 g, 80% yield). ESI-MS m / z: 236.9 [M+H] + .

[0580] Step 2: Synthesis of compound 58-2

[0581] Compound 58-1 (9.46 g, 39.90 mmol), palladium acetate (0.18 g, 0.80 mmol), XantPhox (0.46 g, 0.80 mmol), and TEA (16.64 mL, 119.70 mmol) were dissolved in ACN (150 mL) and reacted at 90°C under nitrogen for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:30 to 65:35) to obtain compound 58-2 (4.1 g, 66% yield). ESI-MS m / z: 157.1 [M+H] + .

[0582] Step 3: Synthesis of compound 58-3

[0583] Compound 58-2 (4.12 g, 26.38 mmol) was dissolved in THF (200 mL). LDA (19.78 mL, 2.00 mol / L, 39.57 mmol) was added at -78°C and stirred at 0°C for 15 min. Subsequently, a 10 mL THF solution of (2-bromoethoxy)-tert-butyldimethylsilane (9.47 g, 39.57 mmol) was added at -78°C, and the reaction was stirred at room temperature for 8 hours. The mixture was quenched with saturated ammonium chloride and extracted with EA. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1 to 5:1) to afford compound 58-3 (9.6 g, 80% yield). ESI-MS m / z: 315.4 [M+H]+.

[0584] Step 4: Synthesis of compound 58-4

[0585] Compound 58-3 (4.0 g, 12.7 mmol) was dissolved in EtOH (50 mL), and 50 mL of 20% aqueous sodium hydroxide solution was added. The mixture was heated at 100°C for 1 hour. After the reaction was complete, 4N hydrochloric acid was added to adjust the pH to 2-3, and the reaction was stirred at room temperature overnight. Saturated sodium bicarbonate was added to adjust the pH to 7-8, and the mixture was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1-3:1) to obtain compound 58-4 (2.0 g, 78% yield). ESI-MS m / z: 202.2 [M+H]+.

[0586] Step 5: Synthesis of compound 58-5

[0587] To a solution of 58-4 (2.0 g, 9.94 mmol) in MeOH (90 mL) and THF (30 mL) was added sodium borohydride (1.13 g, 29.8 mmol) in an ice bath. The ice bath was removed and the reaction was allowed to react at room temperature for 1 hour. The mixture was quenched with saturated ammonium chloride, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 10:1) to afford compound 58-5 (2.0 g, 98% yield). ESI-MS m / z: 206.1 [M+H] + .

[0588] Step 6: Synthesis of compound 58-6

[0589] Compound 58-5 (2.00 g, 9.74 mmol) and TEA (1.63 mL, 11.69 mmol) were dissolved in 50 mL of DCM. p-Toluenesulfonyl chloride (1.86 g, 9.74 mmol) was added at 0°C. The mixture was allowed to react overnight at room temperature, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 10:1-3:1) to obtain compound 58-6 (0.70 g, 37% yield). ESI-MS m / z: 188.1 [M+H]+.

[0590] Step 7: Synthesis of compound 58-7

[0591] Compound 58-6 (0.9 g, 4.81 mmol) was dissolved in a mixed solvent of MeOH (20 mL) and DCM (40 mL). Ozone was then introduced at -40°C to -20°C. After completion of the reaction, Me2S (1.49 g, 24.03 mmol) was added, and the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 4:1 to 1:1) to obtain compound 58-7 (0.72 g, 79% yield). ESI-MS m / z: 190.2 [M+H]+.

[0592] Step 8: Synthesis of compound 58-8

[0593] To a solution of 58-7 (0.71 g, 3.75 mmol) in MeOH (15 mL) and THF (15 mL) was added sodium borohydride (0.21 g, 5.63 mmol) in an ice bath. The ice bath was removed and the mixture was allowed to react at room temperature for 1 hour. The mixture was quenched with water and concentrated under reduced pressure to remove some of the solvent. The mixture was extracted with EA. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound 58-8 (0.69 g, 96% yield). ESI-MS m / z: 192.2 [M+H]+.

[0594] Step 9: Synthesis of compound 58-9

[0595] To a solution of 58-8 (0.69 g, 3.61 mmol) in DCM (25 mL) was added dropwise thionyl chloride (1.3 mL) under an ice bath. The ice bath was removed, the temperature was raised to 40°C, and the reaction was allowed to proceed for 1 hour. The solution was concentrated under reduced pressure, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The solution was extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (PE:EA = 20:80) to afford compound 58-9 (0.69 g, 91% yield). ESI-MS m / z: 209.1 [M+H] + .

[0596] Step 10: Synthesis of compound 58-10

[0597] At room temperature, 58-9 (0.60 g, 2.85 mmol) was dissolved in DCM (20 mL). mCPBA (0.98 g, 5.70 mmol) was added at room temperature and allowed to react for 3 h. LC-MS confirmed the complete reaction. Saturated sodium bicarbonate solution (30 mL) was added and stirred at room temperature for 30 min. Extraction was performed with DCM. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to afford compound 58-10 (450 mg, 69% yield). ESI-MS m / z: 225.1 [M] + .

[0598] Step 11: Synthesis of compound 58-11

[0599] 58-10 (450 mg, 2.0 mmol) was dissolved in DCM (15 mL) and POCl3 (1.5 g, 10.0 mmol) was added under ice-cooling. The mixture was allowed to react at room temperature for 16 h. LC-MS confirmed the complete reaction. The pH was adjusted to 7-8 with saturated sodium bicarbonate. The mixture was extracted with EA. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to afford compound 58-11 (300 mg, 61% yield). ESI-MS m / z: 244.1 [M] + Step 12: Synthesis of compound 58-12

[0600] 58-11 (300 mg, 1.25 mmol), KI (20 mg, 0.10 mmol), K2CO3 (509 mg, 3.70 mmol), and a methylamine tetrahydrofuran solution (5 mL) were dissolved in ACN (5.0 mL). The mixture was stirred at 80°C overnight, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to give compound 58-12 (200 mg, 64% yield). ESI-MS m / z: 253.1 [M+H]+ .

[0601] Step 13: Synthesis of compound 58-13

[0602] 58-12 (200 mg, 0.80 mmol), compound M10 (257 mg, 0.90 mmol), Pd2(dba)3 (72.4 mg, 0.10 mmol), XantPhos (94.5 mg, 0.15 mmol), and Cs2CO3 (0.70 g, 2.35 mmol) were dissolved in 1,4-dioxane (8.0 mL). The mixture was sealed under nitrogen and stirred at 90°C for 4 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 58-13 (300 mg, 79% yield). ESI-MS m / z: 499.3 [M+H] + .

[0603] Step 14: Synthesis of compound 58-14

[0604] 58-13 (300 mg, 0.60 mmol), Pd2(dba)3 (110 mg, 0.10 mmol), pinacol diboronate (305 mg, 1.2 mmol), SPhos (98.7 mg, 0.25 mmol), and AcOK (177 mg, 1.8 mmol) were dissolved in 1,4-dioxane (8.0 mL). The mixture was sealed under nitrogen and stirred at 90°C for 16 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to give compound 58-14 (300 mg, 84% yield). ESI-MS m / z: 591.5 [M+H] + .

[0605] Step 15: Synthesis of compound 58-15

[0606] Compound 58-14 (100 mg, 0.17 mmol), 7-fluoro-3-iodoimidazo[1,2-a]pyridine (48.6 mg, 0.18 mmol), PdCl2(dppf)·CH2Cl2 (13.8 mg, 0.02 mmol), and Na2CO3 (54 mg, 0.5 mmol) were dissolved in DMF (4 mL) and H2O (0.4 mL). The mixture was sealed under nitrogen and stirred at 90°C for 0.5 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (DCM:MeOH=10:1) to give compound 58-15 (58 mg, 57% yield). ESI-MS m / z: 599.4 [M+H] + .

[0607] Step 16: Synthesis of compound 58

[0608] 58-15 (35 mg, 0.47 mmol) was dissolved in CH2Cl2 (5.0 mL), and then TFA (0.5 mL) was added at room temperature and stirred for 15 minutes. The reaction was complete. The mixture was spin-dried and reverse-phase prepared to give compound 58 (16.2 mg, 55% yield). ESI-MS m / z: 499.3 [M+H] + . 1 H NMR (500MHz, DMSO) δ10.32(s,2H),8.94(s,1H),8.64(d,J=8.5Hz,1H),8.55(s,1H),8.14(s,1H),7.89–7.65(m,3H),7.29(s,1H),7.14(d,J=8.6Hz ,1H),5.20–5.01(m,1H),4.41(s,2H),3.97(dd,J=30.7,22.7Hz,4H),2.9 6(s,3H),2.84(s,3H),2.35(d,J=18.2Hz,2H),2.14(s,1H),1.99(s,1H).

[0609] Example 59: Synthesis of Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-(7-morpholin-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0610]

[0611] Step 1: Synthesis of compound 59-1

[0612] Intermediate M8 (200.00 mg), morpholine (202.00 mg), and potassium carbonate (321.00 mg) were dissolved in DMF (3.00 mL) and reacted at 80°C for 4 h. After completion of the reaction, ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, and the sample was mixed and separated by silica gel column chromatography (PE:EA = 1:4) to obtain the desired product 59-1 (173.00 mg, 72.31% yield). ESI-MS m / z: 309.18 [M+H] + .

[0613] Step 2: Synthesis of compound 59-2

[0614] 59-1 (173.00 mg), M10 (190.00 mg), Pd2(dba)3 (51.00 mg), Xantphos (65.00 mg), and Cs2CO3 (547 mg) were dissolved in 1,4-dioxane (5.00 mL) and reacted at 100°C for 3 h. After completion of the reaction, the mixture was filtered, the filter cake was washed with dichloromethane, concentrated, and the sample was mixed. The desired product 59-2 (164.00 mg, 52.74% yield) was isolated by silica gel column chromatography (PE:EA = 1:4). ESI-MS m / z: 555.35 [M+H] + .

[0615] Step 3: Synthesis of compound 59-3

[0616] 59-2 (164.00 mg), B2Pin2 (150.00 mg), Pd2(dba)3 (54.00 mg), Sphos (49.00 mg), and AcOK (87.00 mg) were dissolved in 1,4-dioxane (5.00 mL) and reacted at 100°C for 14 h. After completion of the reaction, the mixture was filtered, the filter cake washed with dichloromethane, concentrated, and the sample was mixed and separated by silica gel column chromatography (PE:EA = 1:5) to obtain the desired product 59-3 (147.00 mg, 76.94% yield). ESI-MS m / z: 647.53 [M+H] + .

[0617] Step 4: Synthesis of compound 59-4

[0618] Compound 59-3 (147.00 mg), M14 (77.00 mg), [PdCl2(dppf)]CH2Cl2 (19.00 mg), and sodium carbonate (72.00 mg) were added to DMF (5.00 mL) and water (1.00 mL) at room temperature. The mixture was then reacted at 85°C for 1 h under nitrogen protection, and the reaction was stopped. A certain amount of water was added to the reaction solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 13:1) to obtain the desired product 59-4 (77.00 mg, 51.74% yield). ESI-MS m / z: 655.31 [M+H] + .

[0619] Step 5: Synthesis of compound 59

[0620] Compound 59-4 (77.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (1.00 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a preparative plate to obtain the desired product 59 (20.40 mg, 97.29% purity, 30.43% yield). 1 H NMR (500MHz, DMSO-d6) δ10.11(s,1H),8.83(s,1H),8.76(d,J=8.6Hz,1H),8.42(t,J=6.7Hz,1H),7.82(s,1H),7.72( d,J=8.5Hz,1H),7.63(d,J=8.3Hz,1H),7.52(d,J=8.6Hz,1H),7.01-6.95(m,1H),6.86(d,J=8.3Hz,1H),4.44-4.32( m,2H),4.22(t,J=7.8Hz,1H),3.83(t,J=11.3Hz,2H),3.61(s,4H),3.58-3.50(m,2H),2.88(d,J=9.7Hz,2H),2.57(s ,2H),2.41-2.36(m,1H),2.01(d,J=7.7Hz,1H),1.93-1.86(m,1H),1.68(s,1H),1.46(s,1H),1.35(d,J=13.1Hz,1H). ESI-MSm / z:555.43[M+H] + .

[0621] Example 60: Synthesis of Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(methylamino)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0622]

[0623] Step 1: Synthesis of compound 60-1

[0624] Intermediate M3-2 (300.00 mg), methylamine tetrahydrofuran solution (1.59 mL, 2.0 mol / L), and tetraethyl titanate (242.55 mg) were added to DCE (10.00 mL) at room temperature. After reacting at room temperature for 1 hour, sodium cyanoborohydride (200.45 mg) was added, and the temperature was raised to 60°C for 1 hour. The reaction solution was added with 50 mL of H2O and filtered. The filter cake was washed three times with DCM and then extracted three times with 30 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and separated by column chromatography (DCM:MeOH = 95:5) to obtain the desired product 60-1 (160.00 mg, 50.63% yield). ESI-MS m / z: 297.2 [M+H] + .

[0625] Step 2: Synthesis of compound 60-2

[0626] At room temperature, 60-1 (160.00 mg) and DMAP (6.57 mg) were added to DCM (5.00 mL). BoccO (0.19 mL) was added dropwise under an ice-water bath, and the mixture was allowed to react at room temperature for 1 h. The reaction solution was added dropwise to water (30.00 mL) and extracted three times with 30 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and separated by column chromatography (PE:EA = 60:40) to obtain the desired product 60-2 (155.00 mg, 72.46% yield). ESI-MS m / z: 397.1 [M+H] + .

[0627] Step 3: Synthesis of compound 60-3

[0628] Compound 60-2 (120.00 mg), M10 (85.38 mg), Pd2(dba)3 (27.65 mg), XantPhos / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.95 mg), and cesium carbonate (295.19 mg) were added to 1,4-dioxane (5.00 mL) at room temperature. The reaction was then carried out at 100°C for 1 h under N2 protection. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 70:30) to obtain the desired product 60-3 (150.00 mg, 82.90% yield). ESI-MS m / z: 599.3 [M+H] + .

[0629] Step 4: Synthesis of compound 60-4

[0630] Compound 60-3 (180.00 mg), B2Pin2 (152.57 mg), Pd2(dba)3 (55.03 mg), SPhos (49.35 mg), and potassium acetate (88.44 mg) were added to 1,4-dioxane (5.00 mL) at room temperature. The mixture was then reacted at 100°C for 6 h under N2 protection. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 67:33) to obtain the desired product 60-4 (190.00 mg, 91.58% yield). ESI-MS m / z: 691.4 [M+H] + .

[0631] Step 5: Synthesis of compound 60-5

[0632] Compound 60-4 (180.00 mg), M14 (86.49 mg), [PdCl2(dppf)]CH2Cl2 (22.46 mg), and sodium carbonate (87.47 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 100°C under N2 protection for 2 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 97:3) to obtain the desired product 60-5 (150.00 mg, 78.03% yield). ESI-MS m / z: 699.5 [M+H] + .

[0633] Step 6: Synthesis of compound 60

[0634] Compound 60-5 (150.00 mg) and TFA (1.00 mL) were added to DCM (2.00 mL) at room temperature and allowed to react for 30 min. The reaction solution was concentrated, adjusted to pH 9 with saturated sodium bicarbonate aqueous solution, and extracted three times with 30 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and separated by column chromatography (DCM:MeOH = 90:10) to obtain the desired product 60 (19.50 mg, 17.37% yield). ESI-MS m / z: 499.3 [M+H] + . 1H NMR (500MHz, DMSO) δ10.16(s,1H),8.85(s,1H),8.76(d,J=8.5Hz,1H),8.44(t,J=6.6Hz,1H),7.83(s,1 H),7.72(d,J=8.6Hz,1H),7.66(d,J=8.3Hz,1H),7.53(d,J=9.9Hz,1H),6.98(t,J=6.3Hz,1H),6.89(d,J =8.3Hz,1H),4.40(s,2H),4.17(d,J=6.6Hz,1H),3.84(t,J=10.5Hz,2H),3.64–3.48(m,2H),3.17(s,1H ),2.65–2.58(m,1H),2.56(s,3H),2.06–1.96(m,1H),1.81–1.66(m,2H),1.42(dd,J=42.1,12.9Hz,2H).

[0635] Example 61: Compound 7-((7-(cyclopropyl(methyl)amino)-2',3',5',6,6',7-hexahydrospiro[cyclopentyl[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazole[1,2-a]pyridin-3-yl)isoindol-1-one

[0636] Step 1: Synthesis of compound 61-1

[0637] M8 (300 mg), N-methylcyclopropylamine (248 mg), potassium carbonate (482 mg), and potassium iodide (39 mg) were weighed and added to ACN (10 mL). The reaction was allowed to proceed at 80°C for 12 h, after which the reaction was stopped. The insoluble material was filtered off, the residue was washed with DCM, and the filtrate was concentrated. The target product 61-1 (230 mg, 67.59% yield) was isolated by column chromatography (PE:EA = 2:1). ESI-MS m / z: 293.14 [M+H] + .

[0638] Step 2: Synthesis of compound 61-2

[0639] 61-1 (265 mg), M10 (307 mg), Pd2(dba)3 (83 mg), XantPhos (105 mg), and cesium carbonate (885 mg) were weighed, and dioxane (10 mL) was added. The reaction was allowed to proceed at 120°C under nitrogen for 4 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 33:1) to afford the desired product 61-2 (679 mg, 139.18% yield). ESI-MS m / z: 539.41 [M+H]+ .

[0640] Step 3: Synthesis of compound 61-3

[0641] 61-2 (670 mg), pinacol diboronate (631 mg), Pd2(dba)3 (341 mg), SPhos (306 mg), and KOAc (366 mg) were weighed and dioxane (10 mL) was added. The reaction was allowed to proceed at 120°C under nitrogen for 8 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 61-3 (290 mg, 37.00%). ESI-MS m / z: 631.39 [M+H] + .

[0642] Step 4: Synthesis of compound 61-4

[0643] 61-3 (290 mg), M14 (145 mg), [PdCl2(dppf)]CH2Cl2 (38 mg), and sodium carbonate (146 mg) were weighed and added to DMF (8 mL) and water (2 mL). The mixture was then reacted at 90°C for 2 h under N2 protection, and the reaction was stopped. The insoluble material was filtered off, the residue was washed with DCM, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 8:1) to obtain the desired product 61-4 (120 mg, 40.85% yield). ESI-MS m / z: 639.39 [M+H] + .

[0644] Step 5: Synthesis of compound 61

[0645] Compound 61-4 (120 mg) was weighed and dissolved in dichloromethane (1.5 mL) and methanol (1.5 mL). A solution of hydrogen chloride in dioxane (3 mL, 4 M in dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes before stopping the reaction. The product was concentrated and purified by preparative liquid phase separation to obtain the desired product 61 (41.9 mg, 41.40% yield). ESI-MS m / z: 539.41 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ10.24(s,2H),8.93(s,1H),8.63–8.53(m,1H),8.50(s,1H),8.18(s,1H),7.86(t ,J=9.0Hz,2H),7.76(d,J=8.5Hz,1H),7.34(s,1H),7.16(d,J=7.7Hz,1H),5.28(s,1H),4.40(s,2H),3.9 3–3.84(m,3H),3.63–3.49(m,2H),2.98(s,3H),2.82–2.73(m,1H),2.28(s,1H),2.17–2.07(m,1H),1.72 (t,J=10.6Hz,1H),1.57(d,J=13.0Hz,1H),1.45(d,J=11.7Hz,1H),1.05(d,J=39.3Hz,2H),0.87(s,2H).

[0646] Example 62: Compound 7-((7-(cyclopropylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopentyl[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazole[1,2-a]pyridin-3-yl)isoindol-1-one

[0647]

[0648] Step 1: Synthesis of compound 62-1

[0649] M3-2 (700 mg), M10 (842 mg), Pd2(dba)3 (227 mg), XantPhos (287 mg), and cesium carbonate (2.43 g) were weighed, and dioxane (15 mL) was added. The reaction was allowed to proceed at 120°C under nitrogen for 4 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 40:1) to afford the desired product 62-1 (1.20 g, 84.12% yield). ESI-MS m / z: 484.16 [M+H] + .

[0650] Step 2: Synthesis of compound 62-2

[0651] 62-1 (1.01 g), pinacol diboronate (1.06 g), Pd2(dba)3 (573 mg), SPhos (514 mg), and KOAC (615 mg) were weighed and dioxane (25 mL) was added. The reaction was allowed to proceed at 120°C under nitrogen for 8 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 62-2 (1.10 g, 91.59%). ESI-MS m / z: 576.29 [M+H] + .

[0652] Step 3: Synthesis of compound 62-3

[0653] 62-2 (2.20 g), M14 (1.20 g), [PdCl2(dppf)]CH2Cl2 (312 mg), and sodium carbonate (1.22 g) were weighed and added to DMF (40 mL) and water (10 mL). The mixture was then reacted at 90°C for 2 h under N2 protection, and the reaction was stopped. The insoluble material was filtered off, the residue was washed with DCM, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 8:1) to obtain the desired product 62-3 (1.63 g, 73.06% yield). ESI-MS m / z: 584.26 [M+H] + .

[0654] Step 4: Synthesis of compound 62-4

[0655] 62-3 (150 mg), cyclopropylamine (73 mg), and tetraethyl titanate (176 mg) were weighed, and DCE (5 mL) and MeOH (2 mL) were added. The mixture was reacted at room temperature for 1 h. Sodium cyanoborohydride (48 mg) was slowly added, and the temperature was raised to 80°C for 2 h to stop the reaction. The organic phase was extracted with DCM, washed with saturated brine, and collected, dried, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the desired product 62-4 (175 mg, 109.00% yield). ESI-MS m / z: 625.34 [M+H] + .

[0656] Step 5: Synthesis of compound 62

[0657] Compound 62-4 (350 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). A solution of hydrogen chloride in dioxane (6 mL, 4 M in dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes before stopping the reaction. The product was concentrated and purified by preparative liquid phase separation to obtain the desired product 62 (51.40 mg, 17.49% yield). ESI-MS m / z: 525.48 [M+H] + .

[0658] 1 H NMR (500MHz, DMSO-d6) δ10.28(s,1H),9.78(s,1H),9.34(s,1H),8.93(s,1H),8.72(d,J=8.5Hz,1H),8.54(dd,J=7.3,5.6H z,1H),8.15(s,1H),7.83(dd,J=14.7,5.3Hz,2H),7.74(d,J=8.5Hz,1H),7.31–7.27(m,1H),7.11(d,J=12.2Hz,1H),5.01(t ,J=7.5Hz,1H),4.50–4.33(m,2H),3.93–3.83(m,2H),3.55(dt,J=38.8,11.2Hz,2H),3.10(s,1H),2.88(dd,J=13.4,8.2Hz ,1H),2.16–2.03(m,2H),1.71(td,J=12.9,4.4Hz,1H),1.52–1.44(m,2H),1.02(dt,J=15.9,7.3Hz,1H),0.96–0.80(m,3H).

[0659] Example 67: Synthesis of Compound 7-(7-(3-fluoroazetidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

[0660]

[0661] Step 1: Synthesis of Intermediate 67-1

[0662] Compound M8 (300.00 mg), KI (39.60 mg), potassium carbonate (963.70 mg), and 3-fluoroazetidine hydrochloride (648.10 mg) were added to DMF (6.00 mL) at room temperature. The mixture was then incubated at 80°C under N₂ protection for 2 h, after which the reaction was terminated. The reaction solution was directly concentrated to obtain a crude product, which was then separated by column chromatography (PE:EA = 95:5 to 65:35) to afford the desired product 67-1 (250.00 mg, 72.49% yield). ESI-MS m / z: 297.78 [M+H] + .

[0663] Step 2: Synthesis of Intermediate 67-2

[0664] Compound 67-1 (250.00 mg), intermediate M10 (274.35 mg), Pd2(dba)3 (74.08 mg), XantPhos (93.56 mg), and cesium carbonate (790.47 mg) were added to 1,4-dioxane (6.00 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 2 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 67-2 (250.00 mg, 56.93% yield). ESI-MS m / z: 544.05 [M+H] + .

[0665] Step 3: Synthesis of Intermediate 67-3

[0666] Compound 67-2 (250.00 mg), pinacol diboronate (233.83 mg), Pd2(dba)3 (84.34 mg), SPhos (75.62 mg), and potassium acetate (135.55 mg) were added to 1,4-dioxane (8.00 mL) at room temperature. The mixture was then reacted at 100°C for 12 h under N2 protection, and the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the desired product 67-3 (160.00 mg, 54.77% yield). ESI-MS m / z: 634.55 [M+H] + .

[0667] Step 4: Synthesis of Intermediate 67-4

[0668] Compound 67-3 (100.00 mg), M14 (49.57 mg), [PdCl2(dppf)]CH2Cl2 (12.82 mg), and sodium carbonate (50.11 mg) were added to DMF (4.00 mL) and water (0.80 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 1 hour, after which the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 67-4 (80.00 mg, 78.98% yield). ESI-MS m / z: 643.71 [M+H] + .

[0669] Step 5: Synthesis of compound 67

[0670] Compound 67-4 (80.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (0.80 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react for 1 h at room temperature to stop the reaction. The solvent was removed by rotary evaporation, and the reaction solution was added with 5 mL of H2O and 5 mL of DCM. NaOH was then added to adjust the pH to >12. The solution was then extracted three times with 15 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) and slurried in 5.00 mL of methanol. The product was then filtered and dried to obtain the desired product 67 (37.50 mg, 55.51% yield). ESI-MS m / z: 543.53 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ10.14(s,1H),8.84(s,1H),8.71(d,J=8.6Hz,1H),8.43(dd,J=7.5,5.8Hz,1H),7.8 2(s,1H),7.74(d,J=8.5Hz,1H),7.64(d,J=8.4Hz,1H),7.52(dd,J=10.1,2.7Hz,1H),699-6.95(m,1H),6.8 6(d,J=8.3Hz,1H),5.28–5.23(m,1H),5.17–5.11(m,1H),4.39(d,J=5.3Hz,2H),3.89–3.75(m,4H),3.55-3 .50(m,2H),3.43-3.35(m,2H),2.29-2.24(m,1H),1.93-1.77(m,3H),1.53-1.49(m,1H),1.35-1.31(m,1H).

[0671] Example 71: 4-(7-Fluoroimidazolo[1,2-a]pyridin-3-yl)-7-((7-((R)-3-fluoropyrrolidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[cyclopentyl[b]pyridin-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0672] Step 1: Synthesis of compound 71-1

[0673] M8 (300.00 mg), 3(R)-fluoropyrrolidine hydrochloride (310 mg), and potassium carbonate (481 mg) were dissolved in acetonitrile (10 mL) and reacted at 80°C for 12 h. After completion of the reaction, ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, and the sample was mixed. The target product 71-1 (280 mg, 77.53% yield) was isolated by silica gel column chromatography (PE:EA = 1:1). ESI-MS m / z: 311.14 [M+H] + .

[0674] Step 2: Synthesis of compound 71-2

[0675] 71-1 (280 mg), M10 (306 mg), Pd2(dba)3 (82 mg), Xantphos (104 mg), and Cs2CO3 (880 mg) were dissolved in 1,4-dioxane (10 mL) and reacted at 110°C for 5 h. After completion of the reaction, the mixture was filtered, the filter cake washed with dichloromethane, concentrated, and the sample was mixed and separated by silica gel column chromatography (DCM:MeOH = 50:1) to obtain the desired product 71-2 (200 mg, 39.85% yield). ESI-MS m / z: 557.37 [M+H] + .

[0676] Step 3: Synthesis of compound 71-3

[0677] 71-2 (200 mg), B2Pin2 (182 mg), Pd2(dba)3 (65 mg), Sphos (59 mg), and AcOK (105 mg) were dissolved in 1,4-dioxane (10 mL) and reacted at 100°C for 6 h. After completion of the reaction, the mixture was filtered, the filter cake washed with dichloromethane, concentrated, and the sample was mixed and isolated by silica gel column chromatography (DCM:MeOH = 30:1) to obtain the desired product 71-3 (171 mg, 73.44% yield). ESI-MS m / z: 649.31 [M+H] + .

[0678] Step 4: Synthesis of compound 71-4

[0679] Compound 71-3 (171 mg), M14 (104 mg), [PdCl2(dppf)]CH2Cl2 (21 mg), and sodium carbonate (83 mg) were added to DMF (4.5 mL) and water (0.5 mL) at room temperature. The mixture was then reacted at 90°C for 2 h under N2 protection, and the reaction was stopped. A certain amount of water was added to the reaction solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 71-4 (138 mg, 79.69% yield). ESI-MS m / z: 657.30 [M+H] + .

[0680] Step 5: Synthesis of compound 71

[0681] Compound 71-4 (138 mg) was dissolved in dichloromethane (5 mL) at room temperature, and TFA (1 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product was isolated by silica gel column chromatography (DCM:MeOH = 17:1). The product was dissolved in 2M HCl to obtain the hydrochloride salt of the target product 71 (47.60 mg, 39.84% yield). ESI-MS m / z: 557.19 [M+H] + .

[0682] 1H NMR(500MHz,DMSO-d6)δ12.27(s,1H),10.31–10.15(m,1H),8.95(d,J=6.3Hz,1H),8.84–8.47(m,2 H),8.44(s,1H),8.04(dd,J=8.2,2.6Hz,1H),7.84–7.80(m,2H),7.57–7.53(m,1H),7.20–7.06(m, 1H),5.70–5.35(m,1H),5.18–5.13(m,1H),4.48–4.12(m,3H),4.00–3.79(m,7H),3.02–2.90(m,1H) ),2.42–2.26(m,1H),2.25–1.98(m,3H),1.67–1.58(m,1H),1.66–1.55(m,1H),1.43–1.40(m,1H).

[0683] Synthesis of compounds 71A and 71B:

[0684]

[0685] Step 1: Synthesis of compounds 71-4A and 71-4B

[0686] 71-4 sample preparation: 200 mg of sample 71-4 was dissolved in 6 ml of a 3:2 dichloromethane:methanol solution. Chromatographic conditions: 1. Chiral preparative column YMC CHIRAL ART Celluose-SB 250*20.0 mm S-5 μm; 2. Instrument model GILSON GX-271; 3. Mobile phase: Mobile phase A: n-hexane, Mobile phase B: 0.1% diethylamine in ethanol, isocratic elution with a mobile phase A:mobile phase B ratio of 6:4, flow rate 20 ml / min, wavelength 254 nm, separation at room temperature. Compound 71-4A (peak 1): retention time = 13.566 min, recovered amount 70 mg; Compound 71-4B (peak 2): retention time = 20.645 min, recovered amount 55 mg.

[0687] Step 2: Synthesis of compound 71A

[0688] Compound 71-4A (70 mg) was dissolved in dichloromethane (2 mL) at room temperature, and TFA (0.5 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product 71A (25.90 mg, 98.09% purity, 42.82% yield) was isolated and purified on a preparative plate (DCM:MeOH = 15:1). ESI-MS m / z: 557.39 [M+H] + .

[0689] Step 3: Synthesis of Compound 71B

[0690] Compound 71-4B (55 mg) was dissolved in dichloromethane (2 mL) at room temperature, and TFA (0.5 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product 71B (21.80 mg, 99.44% purity, 46.53% yield) was isolated and purified on a preparative plate (DCM:MeOH = 15:1). ESI-MS m / z: 557.39 [M+H] + .

[0691] Example 72: Compound 7-((7-(3,3-difluoropyrrolidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-fluoroimidazole[1,2-a]pyridin-3-yl)isoindol-1-one

[0692]

[0693] Step 1: Synthesis of compound 72-1

[0694] Compound 62-3 (300 mg), 3,3-difluoropyrrolidine (165 mg), and tetraethyl titanate (117 mg) were weighed, and DCE (5 mL) and MeOH (2 mL) were added. The mixture was reacted at room temperature for 1 hour. Sodium cyanoborohydride (97 mg) was slowly added, and the temperature was raised to 80°C for 2 hours to terminate the reaction. The mixture was extracted with DCM, and the organic phase was washed with saturated brine. The organic phase was collected, dried, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the desired product 72-1 (290 mg, 83.62% yield). ESI-MS m / z: 675.39 [M+H] + .

[0695] Step 2: Synthesis of compound 72

[0696] Compound 72-1 (100 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). A solution of hydrogen chloride in dioxane (6 mL, 4 M in dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes before stopping the reaction. The product was concentrated and purified by preparative liquid phase separation to obtain the desired product 72 (26.20 mg, 30.77% yield). ESI-MS m / z: 575.44 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ10.19(s,1H),8.91(s,1H),8.66–8.58(m,1H),8.56(d,J=8.5Hz,1H),8 .24(s,1H),7.91(d,J=7.3Hz,1H),7.76(dd,J=14.8,8.5Hz,2H),7.38(t,J=6.3Hz,1H),7.06(d ,J=8.4Hz,1H),4.71(s,1H),4.40(dd,J=33.7,18.3Hz,2H),4.25–3.47(m,11H),2.66(d,J=23. 5Hz,1H),2.15–1.96(m,2H),1.77–1.65(m,1H),1.51(d,J=12.5Hz,1H),1.38(d,J=12.6Hz,1H).

[0697] Example 85: 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(isopropyl(methyl)amino)-2',3',5',6,6',7-hexahydrospiro[cyclopentyl[b]pyridin-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0698]

[0699] Step 1: Synthesis of compound 85-1

[0700] M8 (300 mg), N-methylisopropylamine (255 mg), potassium carbonate (482 mg), and potassium iodide (39 mg) were weighed and added to ACN (10 mL). The mixture was reacted at 80°C for 12 h, after which the reaction was stopped. The insoluble material was filtered off, the residue was washed with DCM, and the filtrate was concentrated. The target product 85-1 (400 mg, 116.75% yield) was isolated by column chromatography (PE:EA = 2:1). ESI-MS m / z: 295.17 [M+H] + .

[0701] Step 2: Synthesis of compound 85-2

[0702] 85-1 (380 mg), M10 (437 mg), Pd2(dba)3 (118 mg), XantPhos (149 mg), and cesium carbonate (1.26 g) were weighed, and dioxane (15 mL) was added. The reaction was allowed to proceed at 120°C under nitrogen for 4 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 33:1) to afford the desired product 85-2 (729 mg, 104.53% yield). ESI-MS m / z: 541.28 [M+H] + .

[0703] Step 3: Synthesis of compound 85-3

[0704] 85-2 (719 mg), pinacol diboronate (675 mg), Pd2(dba)3 (365 mg), SPhos (327 mg), and KOAC (391 mg) were weighed and dioxane (15 mL) was added. The reaction was allowed to proceed at 120°C under nitrogen for 8 h, after which the reaction was terminated. The organic phase was collected by filtration through celite, dried, and separated by column chromatography (DCM:MeOH = 20:1) to afford the desired product 85-3 (324 mg, 38.54%). ESI-MS m / z: 633.41 [M+H] + .

[0705] Step 4: Synthesis of compound 85-4

[0706] 85-3 (324 mg), M14 (161 mg), [PdCl2(dppf)]CH2Cl2 (42 mg), and sodium carbonate (163 mg) were weighed and added to DMF (8 mL) and water (2 mL). The mixture was then reacted at 90°C for 2 h under N2 protection, and the reaction was stopped. The insoluble material was filtered off, the residue was washed with DCM, and the filtrate was concentrated. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 8:1) to obtain the desired product 85-4 (300 mg, 91.41% yield). ESI-MS m / z: 641.36 [M+H] + .

[0707] Step 5: Synthesis of compound 85

[0708] Compound 85-4 (300 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). A solution of hydrogen chloride in dioxane (6 mL, 4 M in dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes before stopping the reaction. The product was concentrated and purified by preparative liquid phase separation to obtain the desired product 85 (133.60 mg, 52.78% yield). ESI-MS m / z: 541.50 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ10.23(d,J=5.9Hz,1H),9.97(d,J=39.3Hz,1H),8.95(s,1H),8.69–8.56(m,1H),8.44(dd, J=14.5,8.5Hz,1H),8.33(s,1H),8.01(dd,J=8.4,1.9Hz,1H),7.88–7.77(m,2H),7.47(dd,J=6.8,4.3Hz,1H),7.1 6(t,J=8.0Hz,1H),5.24–5.13(m,1H),4.81–4.01(m,3H),3.94–3.83(m,2H),3.67–3.46(m,2H),3.02(d,J=4.4Hz, 1H),2.93–2.82(m,1H),2.74(d,J=4.3Hz,2H),2.24–2.03(m,2H),1.64(dd,J=12.1,8.4Hz,1H),1.58–1.33(m,8H).

[0709] Example 87: Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((2,3,5,6,7',8'-hexahydro-6'H-spiro[pyran-4,5'-[1,7]naphthyridine]-2'-yl)amino)isoindol-1-one

[0710]

[0711] Step 1: Synthesis of compound 87-1

[0712] Compound M12 (250.00 mg) and DMAP (64.00 mg) were added to THF (6.00 mL) at room temperature, and di-tert-butyl dicarbonate (457.00 mg) was slowly added dropwise. The reaction was allowed to react at room temperature for 3 h, after which the reaction was stopped. A suitable amount of water was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to afford the desired product 87-1 (136.00 mg, 38.41% yield). ESI-MS m / z: 339.2 [M+H] + Step 2: Synthesis of compound 87-2

[0713] Compound 87-1 (130.00 mg), M10 (130.17 mg), Pd2(dba)3 (35.16 mg), XantPhos (44.38 mg), and cesium carbonate (375.05 mg) were added to 1,4-dioxane (6.00 mL) at room temperature. The mixture was then reacted at 100°C for 3 h under nitrogen protection, after which the reaction was terminated. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 1.5:1) to afford the desired product 87-2 (85.00 mg, 37.86% yield). ESI-MS m / z: 585.3 [M+H]+.

[0714] Step 3: Synthesis of compound 87-3

[0715] Compound 87-2 (85.00 mg), B2Pin2 (73.79 mg), Pd2(dba)3 (26.65 mg), SPhos (23.85 mg), and potassium acetate (42.78 mg) were added to 1,4-dioxane (5.00 mL) at room temperature. The mixture was then reacted at 100°C for 6 h under N2 protection. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 24:1) to obtain the desired product 87-3 (80.00 mg, 81.37% yield). ESI-MS m / z: 677.4 [M+H]+.

[0716] Step 4: Synthesis of compound 87-4

[0717] Compound 87-3 (80.00 mg), M14 (37.18 mg), [PdCl2(dppf)]CH2Cl2 (10.00 mg), and sodium carbonate (37.58 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was reacted at 85°C under nitrogen for 40 min, after which the reaction was terminated. A suitable amount of water was added to the reaction solution, which was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 24:1) to afford the desired product 87-4 (50.00 mg, 61.78% yield). ESI-MS m / z: 685.2 [M+H]+.

[0718] Step 5: Synthesis of Compound 87

[0719] Compound 87-4 (50.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (396.22 mg) was added. The reaction was allowed to react at room temperature for 0.5 h, and then the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried to obtain the target product 87 (30.40 mg, purity 99.40%, yield 85.94%). ESI-MS m / z: 585.1 [M+H] + .

[0720] 1 H NMR (500MHz, DMSO-d6) δ10.03(s,1H),8.83(s,1H),8.69(d,J=8.5Hz,1H),8.45(dd,J=7 .6,5.7Hz,1H),7.82(s,1H),7.76(d,J=8.5Hz,1H),7.72(d,J=8.5Hz,1H),7.52(dd,J=1 0.1, 2.7Hz, 1H), 6.98-6.94 (m, 1H), 6.85 (d, J = 8.5Hz, 1H), 4.39 (s, 2H), 3.86 (s, 2H), 3. 75-3.70(m,2H),3.59-3.54(m,2H),3.08(s,2H),1.95-3.86(m,2H),1.60-1.55(m,2H).

[0721] Example 89: 7-((7'-cyclopropyl-2,3,5,6,7',8'-hexahydro-6'H-spiro[pyran-4,5'-[1,7]naphthyridine]-2'-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0722]

[0723] Step 1: Synthesis of compound 89-1

[0724] Compound M12 (250.00 mg), cyclopropylboronic acid (180.00 mg), copper acetate (190.00 mg), 2,2'-bipyridine (163.00 mg), and sodium carbonate (222.00 mg) were added to DCE (6.00 mL) at room temperature and allowed to react at 70°C for 4 h. The reaction was then stopped. A suitable amount of aqueous ammonia was added, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 5:1) to afford the desired product 89-1 (130.00 mg, 45.44% yield). ESI-MS m / z: 279.2 [M+H] + .

[0725] Step 2: Synthesis of compound 89-2

[0726] Compound 89-1 (130.00 mg), M10 (145.17 mg), Pd2(dba)3 (41.02 mg), XantPhos / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (51.90 mg), and cesium carbonate (438.29 mg) were added to 1,4-dioxane (6.00 mL) at room temperature. The mixture was then reacted at 100°C for 3 h under N2 protection, after which the reaction was terminated. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 4:1) to afford the desired product 89-2 (67.00 mg, 28.46% yield). ESI-MS m / z: 525.3 [M+H]+.

[0727] Step 3: Synthesis of compound 89-3

[0728] Compound 89-2 (67.00 mg), B2Pin2 / pinacol diboronate (62.88 mg), Pd2(dba)3 (22.71 mg), SPhos / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (20.32 mg), and potassium acetate (36.45 mg) were added to 1,4-dioxane (5.00 mL) at room temperature. The mixture was then reacted at 100°C for 6 h under N2 protection. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to obtain the desired product 89-3 (70.00 mg, 91.71% yield). ESI-MS m / z: 617.4 [M+H]+.

[0729] Step 4: Synthesis of compound 89-4

[0730] Compound 89-3 (70.00 mg), M14 (35.69 mg), [PdCl2(dppf)]CH2Cl2 (10.00 mg), and sodium carbonate (37.58 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 85°C under nitrogen for 40 min, after which the reaction was stopped. A suitable amount of water was added to the reaction solution, which was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 24:1) to afford the desired product 89-4 (50.00 mg, 70.52% yield). ESI-MS m / z: 625.2 [M+H]+.

[0731] Step 5: Synthesis of compound 89

[0732] Compound 89-4 (50.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (396.22 mg) was added. The reaction was allowed to react at room temperature for 0.5 h, and then the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried to obtain the target product 89 (28.00 mg, purity 99.22%, yield 55.17%). ESI-MS m / z: 525.1 [M+H] + .

[0733] Example 100: Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7'-(methyl-d3)-2,3,5,6,7',8'-hexahydro-6'H-spiro[pyran-4,5'-[1,7]naphthyridine]-2'-yl)amino)isoindol-1-one

[0734]

[0735] Step 1: Synthesis of compound 100-1

[0736] At room temperature, compound M12 (250.00 mg) and potassium carbonate (283.69 mg) were added to ethanol (10.00 mL), and deuterated iodomethane (223.17 mg) was slowly added dropwise. The reaction was allowed to react at room temperature for 16 h, after which the reaction was stopped. A certain amount of water was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 100-1 (207.00 mg, 78.86% yield). ESI-MS m / z: 256.2 [M+H] + Step 2: Synthesis of compound 100-2

[0737] Compound 100-1 (207.00 mg), M10 (256.17 mg), Pd2(dba)3 (72.02 mg), XantPhos / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (91.90 mg), and cesium carbonate (772.29 mg) were added to 1,4-dioxane (6.00 mL) at room temperature. The mixture was then reacted at 100°C for 3 h under nitrogen protection, after which the reaction was terminated. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 19:1) to afford the desired product 100-2 (149.00 mg, 36.69% yield). ESI-MS m / z: 502.3 [M+H]+.

[0738] Step 3: Synthesis of compound 100-3

[0739] Compound 100-2 (149.00 mg), B2Pin2 / pinacol diboronate (151.88 mg), Pd2(dba)3 (55.71 mg), SPhos / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (49.32 mg), and potassium acetate (87.45 mg) were added to 1,4-dioxane (5.00 mL) at room temperature. The mixture was then reacted at 100°C for 6 h under N2 protection. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 100-3 (76.00 mg, 43.18% yield). ESI-MS m / z: 594.4 [M+H]+.

[0740] Step 4: Synthesis of compound 100-4

[0741] Compound 100-3 (76.00 mg), M14 (40.69 mg), [PdCl2(dppf)]CH2Cl2 (11.00 mg), and sodium carbonate (41.58 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 85°C under nitrogen for 40 min, after which the reaction was terminated. A suitable amount of water was added to the reaction solution, which was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to afford the desired product 100-4 (50.00 mg, 64.93% yield). ESI-MS m / z: 602.2 [M+H]+.

[0742] Step 5: Synthesis of Compound 100

[0743] Compound 100-4 (50.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (396.22 mg) was added. The reaction was allowed to react at room temperature for 0.5 h, and then the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and slurried to obtain the target product 100 (30.7.00 mg, purity 96.46%, yield 59.21%). ESI-MS m / z: 502.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ10.06(s,1H),8.84(s,1H),8.71(d,J=8.5Hz,1H),8.44(dd,J= 7.5,5.8Hz,1H),7.83(s,1H),7.77(d,J=8.6Hz,1H),7.72(d,J=8.6Hz,1H),7.53(dd,J= 10.0,2.6Hz,1H),6.98-6.94(m,1H),6.86(d,J=8.6Hz,1H),4.39(s,2H),3.75-3.71(m, 2H),363-3.57(m,2H),3.52(s,2H),2.73(s,2H),1.95-1.88(m,2H),1.58-1.54(m,2H).

[0744] Example 123: Synthesis of Compound 4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((2,3,5,6,7',8'-hexahydro-6'H-spiro[pyran-4,5'-[1,7]naphthyridine]-2'-yl)amino)isoindol-1-one

[0745]

[0746] Step 1: Synthesis of compound 123-1

[0747] At room temperature, 2-amino-4-hydroxypyridine (2.00 g) and chloroacetaldehyde (10.69 g, 40% aqueous solution) were added to ethanol (15.00 mL). The mixture was then heated to 80°C under nitrogen for 18 hours before being stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 123-1 (2.2 g, 90.30% yield). ESI-MS m / z: 135.15 [M+H] + .

[0748] Step 2: Synthesis of compound 123-2

[0749] Compound 123-1 (1.00 g), sodium difluorochloroacetate (5.68 g), and potassium carbonate (2.06 g) were added to water (7.5 mL) and acetonitrile (37.50 mL) at room temperature. The mixture was then heated at 110°C for 24 h under N₂ protection, after which the reaction was stopped. The solid was directly filtered from the reaction solution and washed with 10 mL of DCM:MeOH (10:1) three times. The combined mother liquors were concentrated to dryness to afford the crude product, which was then separated by column chromatography (DCM:MeOH = 97:3 to 90:10) to afford the desired crude product, 123-2 (1.4 g, 101.98% yield). ESI-MS m / z: 185.20 [M+H] + .

[0750] Step 3: Synthesis of compound 123-3

[0751] Crude compound 123-2 (500.00 mg) was added to acetonitrile (10.00 mL) at room temperature. NIS (733.10 mg) was then slowly added in portions in an ice-water bath. The mixture was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The reaction solution was quenched by adding 50 mL of water, then extracted three times with 10 mL of DCM and washed with saturated sodium chloride. The organic phase was concentrated to dryness to afford the crude product, which was then separated by column chromatography (DCM:MeOH = 97:3 to 90:10) to afford the desired product 123-3 (75 mg, 8.91% yield). ESI-MS m / z: 311.10 [M+H] + .

[0752] Step 4: Synthesis of compound 123-4

[0753] Compound 123-3 (25.20 mg), compound 87-3 (50.00 mg), [PdCl2(dppf)]CH2Cl2 (6.04 mg), and sodium carbonate (23.50 mg) were added to DMF (2.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 4 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 123-4 (30.00 mg, 55.40% yield). ESI-MS m / z: 733.71 [M+H] + .

[0754] Step 5: Synthesis of compound 123

[0755] Compound 123-4 (30.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react for 1 h at room temperature, and then stopped. The solvent was removed by rotary evaporation, and the desired product 123 (2.20 mg, 99.42% purity, 10.04% yield) was obtained by preparative isolation. ESI-MS m / z: 533.53 [M+H] + . 1 H NMR (500MHz, DMSO) δ10.27(s,1H),9.31(s,2H),8.98(s,1H),8.77(d,J=8.6Hz,1H),8.67(d,J=7.6Hz,1 H),8.32(s,1H),7.96(d,J=8.8Hz,1H),7.82(s,1H),7.80(d,J=8.6Hz,1H),7.75(d,J=1.9Hz,1H),7.68 (s,1H),7.53(s,1H),7.29(dd,J=7.4,2.2Hz,1H),7.08(d,J=8.7Hz,1H),4.42(s,2H),4.29(s,2H),3.8 0(dd,J=11.4,4.5Hz,2H),3.65(d,J=11.7Hz,4H),2.02(td,J=13.6,4.9Hz,2H),1.69(d,J=13.2Hz,2H).

[0756] Example 133: Synthesis of Compound 7-((7',8'-dihydro-6'H-spiro[cyclopropane-1,5'-[1,7]naphthyridine]-2'-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0757]

[0758] Step 1: Synthesis of compound 133-1

[0759] Compound NaH (2.18 g) was dissolved in DMF (40.00 mL) at room temperature. Then, under nitrogen protection and in an ice bath, 50-2 (5.00 g) dissolved in DMF (10.00 mL) was slowly added. The reaction was incubated for 0.5 h. 1,2-dibromoethane (3.52 g) was then slowly added dropwise. The reaction was continued at room temperature for 3 h to terminate the reaction. The reaction was quenched with saturated ammonium chloride solution under ice bath conditions and extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (PE:EA = 3:1) to afford the desired product 133-1 (1.28 g, 22.78% yield). ESI-MS m / z: 236.78 [M+H]+ .

[0760] Step 2: Synthesis of compound 133-2

[0761] Compound 133-1 (1.28 g) was dissolved in THF (20.00 mL) at room temperature, and then borane dimethyl sulfide solution (2.16 mL, 10 M) was slowly added dropwise under an ice bath. Under nitrogen protection, the reaction was incubated at 70°C for 20 h before stopping the reaction. The pH was adjusted to 1-2 with 1 M HCl solution, and the reaction was incubated at 70°C for 1 h before stopping the reaction. The pH was adjusted to 8-9 with 2 M NaOH solution, and the mixture was extracted three times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 133-2 (240.00 mg, 22.79% yield). ESI-MS m / z: 237.65 [M+H] + .

[0762] Step 3: Synthesis of compound 133-3

[0763] Compound 133-2 (240.00 mg) and 4-DMAP (150.00 mg) were added to THF (8.00 mL) at room temperature, and di-tert-butyl dicarbonate (670.00 mg) was slowly added dropwise. The reaction was allowed to react at room temperature for 5 h, after which the reaction was stopped. 8 mL of water was added, and the mixture was extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to afford the desired product 133-3 (310.00 mg, 85.31% yield). ESI-MS m / z: 295.80 [M+H] + .

[0764] Step 4: Synthesis of compound 133-4

[0765] Compound 133-3 (310.00 mg), M10 (327.05 mg), Pd2(dba)3 (96.33 mg), XantPhos / 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (121.63 mg), and cesium carbonate (1027.90 mg) were added to 1,4-dioxane (8.00 mL) at room temperature. The mixture was then reacted at 100°C for 8 h under N2 protection, after which the reaction was terminated. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 1.5:1) to afford the desired product 133-4 (330.00 mg, 37.86% yield). ESI-MS m / z: 542.08 [M+H]+.

[0766] Step 5: Synthesis of compound 133-5

[0767] Compound 133-4 (330.00 mg), B2Pin2 / pinacol diboronate (309.80 mg), Pd2(dba)3 (111.70 mg), SPhos / 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (100.20 mg), and potassium acetate (179.60 mg) were added to 1,4-dioxane (8.00 mL) at room temperature. The reaction was then carried out at 100°C under N2 protection for 8 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA:DCM = 10:1:1 to 5:1:1 to 3:1:1) to obtain the desired product 133-5 (150.00 mg, 38.88% yield). ESI-MS m / z: 633.62 [M+H]+.

[0768] Step 6: Synthesis of compound 133-6

[0769] Compound 133-5 (80.00 mg), M14 (41.01 mg), [PdCl2(dppf)]CH2Cl2 (11.60 mg), and sodium carbonate (45.25 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 85°C under nitrogen for 30 min, after which the reaction was terminated. The reaction solution was directly spin-dried to obtain the crude product. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 97:3 to 88:12) to afford the desired product 133-6 (70.00 mg, 76.78% yield). ESI-MS m / z: 641.63 [M+H]+.

[0770] Step 7: Synthesis of compound 133

[0771] Compound 133-6 (70.00 mg) was dissolved in dichloromethane (4.00 mL) at room temperature, and TFA (1.00 mL) was added. The reaction was allowed to react at room temperature for 1.5 h, after which the reaction was terminated. The reaction solution was concentrated to obtain the crude product, which was then isolated and prepared to afford the desired product 133 (34.10 mg, 99.80% purity, 70.69% yield). ESI-MS m / z: 441.16 [M+H] + . Trifluoroacetate 1H NMR (500MHz, DMSO) δ=10.19(s,1H),9.53(s,2H),8.93(s,1H),8.74(d,J=8.5,1H),8.68–8.60(m,1H),8.22(s,1H),7.89(d,J=7.7,1H),7.78(d ,J=8.5,1H),7.33(d,J=7.0,1H),7.30–7.25(m,1H),7.10(d,J=51.0,1 H),6.98(d,J=8.6,1H),4.41(s,4H),1.19(d,J=48.0,2H),1.10(s,4H).

[0772] Example 146: Synthesis of Compound 3-(7-((2,3,5,6,7',8'-hexahydro-6'-H-spiro[pyran-4,5'-[1,7]naphthyridine]-2'-yl)amino)-1-oxoisoindol-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile

[0773]

[0774] Step 1: Synthesis of Intermediate 146-1

[0775] At room temperature, 2-amino-4-cyanopyridine (2.00 g), chloroacetaldehyde (6.59 g, 40% aqueous solution), and sodium bicarbonate (4.23 g) were added to ethanol (30.00 mL). The mixture was then heated to 80°C under nitrogen for 8 h, after which the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the desired product 146-1 (1.64 g, 68.24% yield). ESI-MS m / z: 144.15 [M+H] + .

[0776] Step 2: Synthesis of Intermediate 146-2

[0777] Compound 146-1 (1.64 g) was added to DMF (40.00 mL) at room temperature. NIS (3.09 g) was then slowly added in portions in an ice-water bath. The reaction was allowed to react at room temperature for 2 h, after which the reaction was stopped. The reaction solution was directly added to 50 mL of ice water to quench the reaction. A large amount of white solid precipitated, which was filtered and dried to obtain the desired product 146-2 (2.30 g, 74.62% yield). ESI-MS m / z: 270.12 [M+H] + .

[0778] Step 3: Synthesis of Intermediate 146-3

[0779] Compound 146-2 (43.80 mg), intermediate 87-3 (100.00 mg), [PdCl2(dppf)]CH2Cl2 (12.00 mg), and sodium carbonate (47.00 mg) were added to DMF (4.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 1 hour, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 146-3 (80.00 mg, 78.24% yield). ESI-MS m / z: 692.73 [M+H] + .

[0780] Step 4: Synthesis of compound 146

[0781] Compound 146-3 (80.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react at room temperature for 1.5 h, after which the reaction was terminated. The solvent was removed by rotary evaporation, and the desired product 146 (55.50 mg, 99.67% purity, 97.67% yield) was obtained. ESI-MS m / z: 491.53 [M+H] + . Trifluoroacetate 1 H NMR(500MHz,DMSO)δ10.27(s,1H),9.27(s,2H),8.95(s,1H),8.75(d,J=8.6Hz,1H) ,8.57(d,J=7.2Hz,1H),8.50(s,1H),8.21(s,1H),7.94(d,J=8.8Hz,1H),7.80(d,J= 8.6Hz,1H),7.27(dd,J=7.2,1.3Hz,1H),7.06(d,J=8.7Hz,1H),4.44(s,2H),4.30( s,2H),3.83-3.78(m,2H),3.71-3.58(m,4H),2.05-1.98(m,2H),1.71-1.68(m,2H).

[0782] Example 147: Synthesis of Compound 7-((2,3,5,6,7',8'-hexahydro-6'-H-pyrano[4,5'-[1,7]naphthyridin]-2'-yl)amino)-4-(7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0783]

[0784] Step 1: Synthesis of Intermediate 147-1

[0785] At room temperature, 2-amino-4-trifluoromethylpyridine (1.00 g), chloroacetaldehyde (2.42 g, 40% aqueous solution), and sodium bicarbonate (1.55 g) were added to ethanol (15.00 mL). The mixture was then incubated at 80°C under nitrogen for 4 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 90:10) to afford the desired product 147-1 (1.00 g, 87.09% yield). ESI-MS m / z: 187.15 [M+H] + .

[0786] Step 2: Synthesis of Intermediate 147-2

[0787] Compound 147-1 (1.00 g) was added to DMF (15.00 mL) at room temperature. NIS (1.05 g) was then slowly added in portions in an ice-water bath. The reaction was allowed to react at room temperature for 1 h, after which the reaction was stopped. The reaction solution was directly added to 50 mL of ice water to quench the reaction. A large amount of light yellow solid precipitated, which was filtered and dried to obtain the desired product 147-2 (0.70 g, 41.76% yield). ESI-MS m / z: 313.12 [M+H] + .

[0788] Step 3: Synthesis of Intermediate 147-3

[0789] Compound 147-2 (40.56 mg), intermediate 87-3 (80.00 mg), [PdCl2(dppf)]CH2Cl2 (9.60 mg), and sodium carbonate (37.60 mg) were added to DMF (4.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 1 hour, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (PE:EA = 95:5 to 50:50) to afford the desired product 147-3 (70.00 mg, 80.60% yield). ESI-MS m / z: 735.73 [M+H] + .

[0790] Step 4: Synthesis of compound 147

[0791] Compound 147-3 (70.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react at room temperature for 1.5 h, after which the reaction was terminated. The solvent was removed by rotary evaporation, and the desired product 147 (50.80 mg, 99.77% purity, 99.49% yield) was obtained. ESI-MS m / z: 534.53 [M+H] + . Trifluoroacetate 1H NMR (500MHz, DMSO) δ10.26(s,1H),9.20(s,2H),8.94(s,1H),8.75(d,J=8.5Hz,1H),8.61(d,J=7.3Hz,1H),8.24(s ,1H),8.16(s,1H),7.94(d,J=8.8Hz,1H),7.81(d,J=8.6Hz,1H),7.23(dd,J=7.3,1.8Hz,1H),7.06(d,J=8.7Hz,1H ), 4.44 (s, 2H), 4.29 (s, 2H), 3.82-3.78 (m, 2H), 3.66-3.61 (m, 4H), 2.04-1.98 (m, 2H), 1.70-1.65 (m, 2H). Example 149: Synthesis of compound 4-(8-fluoro-7-methylimidazo[1,2-a]pyridin-3-yl)-7-((2,3,5,6,7',8'-hexahydro-6'H-spiro[pyran-4,5'-[1,7]naphthyridine]-2'-yl)amino)isoindol-1-one

[0792]

[0793] Step 1: Synthesis of compound 149-1

[0794] 2-Bromo-3-fluoro-4-methylpyridine (3.00 g), benzophenone imine (4.29 g), Pd2(dba)3 (1.45 g), XantPhos (1.83 g), and cesium carbonate (15.43 g) were added to 1,4-dioxane (40.00 mL) at room temperature. The mixture was then reacted at 110°C under nitrogen for 20 h before being stopped. The reaction mixture was filtered to remove salt, and the filter cake was washed with EA three times (30 mL each time). The combined filtrates were concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 90:10 to 75:25) to obtain the desired product 149-1 (4.20 g, 91.63% yield). ESI-MS m / z: 291.41 [M+H] + .

[0795] Step 2: Synthesis of compound 149-2

[0796] Compound 149-1 (4.20 mg) was added to dichloromethane (15.00 mL) at room temperature, followed by the addition of HCl (10.00 mL, 4 M in Dioxane) in an ice-water bath. The reaction was allowed to react at room temperature for 1 h, and the reaction was stopped. The solvent was removed by rotary evaporation to yield the crude product, which was then extracted with EA (30 mL H₂O and 30 mL EA) to remove impurities. The remaining aqueous phase was adjusted to pH 8-9 by adding saturated sodium bicarbonate. The product was then extracted with DCM (3 times, 50 mL each), washed with saturated sodium chloride, and separated by column chromatography (PE:EA = 90:10 to 50:50) to afford the desired product 149-2 (1.20 g, 65.77% yield) as a pale yellow solid. ESI-MS m / z: 127.13 [M+H] + .

[0797] Step 3: Synthesis of Intermediate 149-3

[0798] Compound 149-2 (1.24 g) and 2-bromo-1,1-diethoxyethane (3.75 g) were added to ethanol (8.00 mL) at room temperature. HBr (1.5 mL, 40% H2O) was then slowly added under N2 protection in an ice-water bath. The reaction was incubated at 80°C for 36 h before being stopped. Aqueous NaOH was added to the reaction solution to adjust the pH to >10. The solution was then extracted with 4DCM (50 mL each time) for four times, washed with saturated sodium chloride, and isolated by column chromatography (PE:EA = 90:10 to 50:50) to afford the desired product 149-3 as a pale yellow solid (0.62 g, 43.40% yield). ESI-MS m / z: 151.13 [M+H] + .

[0799] Step 4: Synthesis of Intermediate 149-4

[0800] Compound 149-3 (0.62 g) was added to DMF (10.00 mL) at room temperature. NIS (1.11 g) was then slowly added in portions in an ice-water bath. The reaction was allowed to react at room temperature for 2 h, after which the reaction was stopped. The reaction solution was directly added to 50 mL of ice water to quench the reaction. A large amount of light yellow solid precipitated, which was filtered and dried to obtain the desired product 149-4 (0.90 g, 78.96% yield) as a light yellow solid. ESI-MS m / z: 277.10 [M+H] + .

[0801] Step 5: Synthesis of Intermediate 149-5

[0802] Compound 149-4 (35.90 mg), intermediate 87-3 (80.00 mg), [PdCl2(dppf)]CH2Cl2 (9.60 mg), and sodium carbonate (37.60 mg) were added to DMF (4.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 90°C for 1 h under N2 protection, and the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:EA = 95:5 to 50:50) to afford the desired product 149-5 (70.00 mg, 84.75% yield) as a pale yellow solid. ESI-MS m / z: 699.80 [M+H] + .

[0803] Step 6: Synthesis of compound 149

[0804] Compound 149-5 (70.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react at room temperature for 1.5 h, after which the reaction was terminated. The solvent was removed by rotary evaporation, and the desired product 149 (4.50 mg, 99.86% purity, 9.00% yield) was obtained as a white solid. ESI-MS m / z: 499.81 [M+H] + . Trifluoroacetate 1 H NMR(500MHz,DMSO)δ10.24(s,1H),9.22(s,2H),8.93(s,1H),8.73(d,J=8.6H z,1H),8.21(d,J=6.9Hz,1H),7.93(d,J=8.8Hz,2H),7.74(d,J=8.5Hz,1H),7. 05(d,J=8.7Hz,1H),6.95(s,1H),4.41(s,2H),4.28(s,2H),3.84-3.77(m,2H ),3.64(d,J=11.5Hz,4H),2.37(s,3H),2.04-1.98(m,2H),1.70-1.65(m,2H).

[0805] Example 152: Synthesis of Compound 4-(7-chloroimidazo[1,2-a]pyridin-3-yl)-7-((7',8'-dihydro-6'H-spiro[cyclopropane-1,5'-[1,7]naphthyridine]-2'-yl)amino)isoindol-1-one

[0806]

[0807] Step 1: Synthesis of Intermediate 152-1

[0808] At room temperature, 3-bromo-7-chloroimidazo[1,2-A]pyridine (18.10 mg), intermediate 133-5 (45.00 mg), [PdCl2(dppf)]CH2Cl2 (5.80 mg), and sodium carbonate (22.61 mg) were added to DMF (2.00 mL) and water (0.40 mL). The mixture was then reacted at 90°C under nitrogen for 0.5 h before being stopped. The reaction solution was concentrated to obtain the crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 152-1 as a white solid (40.00 mg, 85.60% yield). ESI-MS m / z: 657.22 [M+H] + .

[0809] Step 2: Synthesis of compound 152

[0810] Compound 152-1 (40.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react at room temperature for 1.5 h, after which the reaction was terminated. The solvent was removed by rotary evaporation, and the desired product 152 (31.60 mg, 99.57% purity, 90.49% yield) was obtained as a white solid. ESI-MS m / z: 457.23 [M+H] + . Trifluoroacetate 1 H NMR (500MHz, DMSO) δ10.18(s,1H),9.45(s,2H),8.91(s,1H),8.72(d,J=8.5Hz,1H),8.48(d,J=7.4Hz,1H),8.05(s,1H),7.99 (s,1H),7.76(d,J=8.5Hz,1H),7.27(d,J=8.7Hz,1H),7.15(d,J=7.3Hz,1H),6.97(d,J=8.6Hz,1H),4.41(s,4H),1.10(s,4H).

[0811] Example 157: Synthesis of Compound 3-(7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)-1-oxoisoindol-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile

[0812] Step 1: Synthesis of Intermediate 157-1

[0813] Compound 146-2 (48.94 mg), intermediate 2-2 (100.00 mg), [PdCl2(dppf)]CH2Cl2 (13.50 mg), and sodium carbonate (52.60 mg) were added to DMF (4.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 90°C under nitrogen for 0.5 h, after which the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 157-1 (90.00 mg, 87.80% yield). ESI-MS m / z: 620.71 [M+H] + .

[0814] Step 2: Synthesis of compound 157

[0815] Compound 157-1 (90.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react at room temperature for 1.5 h, after which the reaction was stopped. The reaction solvent was removed by rotary evaporation, and the crude product was added with 10 mL of H2O. Saturated sodium bicarbonate was then added to adjust the pH to 8-9. A pale yellow solid precipitated, which was then filtered. The filter cake was slurried in 10 mL of methanol, filtered, and dried to obtain the desired product 157 (46.80 mg, purity 99.28%, yield 61.58%). ESI-MS m / z: 520.23 [M+H] + .

[0816] 1 H NMR (500MHz, DMSO-d6) δ10.17(s,1H),8.87(s,1H),8.77(d,J=8.5Hz,1H),8.56(d,J=7.1Hz,1H),8.45(s, 1H),8.16(s,1H),7.77(d,J=8.6Hz,1H),7.64(d,J=8.4Hz,1H),7.20(dd,J=7.2,1.8Hz,1H),6.86(d,J=8. 3Hz,1H),4.42(s,2H),4.22(t,J=7.8Hz,1H),3.87-3.80(m,2H),3.61-3.52(m,2H),2.35(s,6H),2.34–2. 27(m,1H),2.01-1.96(m,2H),1.89-1.84(m,1H),1.73–1.64(m,1H),1.46-1.42(m,1H),1.35-1.32m,1H).

[0817] Example 158: Synthesis of Compound 4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-(methylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0818]

[0819] Step 1: Synthesis of Intermediate 158-1

[0820] Compound 123-3 (56.40 mg), intermediate 2-2 (100.00 mg), [PdCl2(dppf)]CH2Cl2 (13.47 mg), and sodium carbonate (52.59 mg) were added to DMF (4.00 mL) and water (0.50 mL) at room temperature. The mixture was then reacted at 80°C under nitrogen for 3 h, after which the reaction was terminated. The reaction solution was concentrated to obtain a crude product, which was then separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to afford the desired product 158-1 (80.00 mg, 73.21% yield). ESI-MS m / z: 661.75 [M+H] + .

[0821] Step 2: Synthesis of compound 158

[0822] Compound 158-1 (80.00 mg) was added to dichloromethane (4.00 mL) at room temperature. Trifluoroacetic acid (1.00 mL) was then added under N2 protection in an ice-water bath. The reaction was allowed to react for 1 h at room temperature, and then stopped. The solvent was removed by rotary evaporation, and the desired product 158 ​​(43.70 mg, 99.59% purity, 64.11% yield) was obtained by preparative isolation. ESI-MS m / z: 561.56 [M+H] + . Trifluoroacetate 1H NMR (500MHz, DMSO) δ10.34(d,J=19.9Hz,2H),8.98(s,1H),8.68(d,J=8.6Hz,1H),8.60(d,J=7.6Hz,1H),8.28(s,1H) ,7.84(d,J=8.5Hz,1H),7.81(s,1H),7.79-7.72(m,2H),7.66(s,1H),7.52(s,1H),7.27(d,J=5.6Hz,1H),7.13(d,J= 8.5Hz,1H),5.16-5.11(m,1H),4.42(s,2H),3.93-3.85(m,2H),3.63-3.51(m,2H),2.99(d,J=4.7Hz,3H),2.81(d,J= 4.8Hz,3H),2.77-2.71(m,1H),2.17-2.06(m,2H),1.73-1.64(m,1H),1.52(d,J=12.1Hz,1H),1.41(d,J=11.9Hz,1H).

[0823] Chiral separation of Example 158:

[0824]

[0825] A racemic mixture of compound 158-1 (2800 mg) was dissolved in a mixed solution of DCM (22 ml) and ethanol (10 ml) and separated on a preparative chiral column [CHIRAL ART Cellulose IC (YMC) 30*250 mm 5 μm, model: GX-271 (GILSON); mobile phase A: n-hexane (AR, Shuanglin Chemical, with 0.1% diethylamine), mobile phase B: ethanol (AR, Shuanglin Chemical, with 0.1% diethylamine); isocratic (65% mobile phase B); flow rate: 40 ml / min, room temperature. Compound 158A-1 (peak 1): retention time = 21.00 min, recovered amount 1200 mg; compound 158B-1 (peak 2): retention time = 28.70 min, recovered amount 1020 mg].

[0826] Step 2: Synthesis of Compound 158A

[0827] Compound 158A-1 (1200.00 mg) was added to dichloromethane (40.00 mL) at room temperature, and trifluoroacetic acid (5.00 mL) was added under N2 protection in an ice-water bath. The reaction was allowed to react at room temperature for 0.5 h, and the reaction was stopped. The reaction solvent was removed by rotary evaporation, and the concentrate was dissolved in 5 ml of DCM. Saturated sodium bicarbonate was then slowly added to adjust the pH to 8-9, resulting in the precipitation of a pale yellow solid. Ammonia was added to adjust the pH to 11-12, and the aqueous phase was decanted. 40 ml of water was then added to the slurry, and the mixture was allowed to stand and the aqueous phase was decanted. 20 ml of methanol was added to the remaining solid, and the slurry was filtered. The solid was washed with methanol and dried to obtain the desired product 158A (872.2 mg, purity 99.24%, yield 85.01%). ESI-MS m / z: 561.56 [M+H] + .

[0828] Step 3: Synthesis of compound 158B

[0829] Compound 158B-1 (1040.00 mg) was added to dichloromethane (40.00 mL) at room temperature. Trifluoroacetic acid (5.00 mL) was then added under N protection in an ice-water bath. The reaction was allowed to react at room temperature for 0.5 h, and the reaction was stopped. The reaction solvent was removed by rotary evaporation, and the concentrate was dissolved in 5 mL of DCM. Saturated sodium bicarbonate was then slowly added to adjust the pH to 8-9, resulting in the precipitation of a pale yellow solid. Ammonia was added to adjust the pH to 11-12, and the aqueous phase was decanted. 40 mL of water was then added for pulping, and the mixture was allowed to stand and the aqueous phase was decanted. 20 mL of methanol was added to the remaining solid for pulping, and the mixture was filtered, washed with methanol, and dried to obtain the desired product 158B (797.50 mg, 99.12% purity, 89.69% yield).

[0830] ESI-MS m / z:561.56[M+H] + .

[0831] Example 158A: Synthesis of Compound (R)-4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopentadienyl[b]pyridin-5'-pyran]-2-yl)amino)isoindolin-1-one

[0832]

[0833] Step 1: Synthesis of compound 158A-1

[0834] Compound 123-3 (6.74 g), 158A-1 (7.40 g), [PdCl2(dppf)]CH2Cl2 (1.61 g), and potassium carbonate (8.2 g) were dissolved in 1,4-Dioxane (80 mL) and water (20 mL). The atmosphere was replaced with nitrogen, and the temperature was raised to 100°C for 4 hours. The mixture was cooled, filtered, washed with DCM, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:EA = 95:5-50:50) to obtain compound 158A-1 (5.75 g, 67% yield). ESI-MS m / z: 431.2 [M+H] + .

[0835] Step 2: Synthesis of compound 158A-2

[0836] Compound 158A-1 (3.70 g), M15 (2.41 g), palladium acetate (97.00 mg), XantPhos (497 mg), and cesium carbonate (7.00 g) were dissolved in 1,4-Dioxane (60 mL), replaced with nitrogen, and heated to 90°C for 4 hours. The mixture was cooled, filtered, and washed with EA. The filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 93:7 to 90:10) to obtain compound 158A-2 (5.05 g, 88% yield). ESI-MS m / z: 661.3 [M+H] + .

[0837] Step 3: Synthesis of Compound 158A

[0838] Compound 158A-2 (4.30 g) was dissolved in DCM (60 mL) and trifluoroacetic acid (10.00 ml) was added dropwise at room temperature under N2 protection. The reaction was continued at room temperature for 1 hour. The reaction solution was concentrated to dryness, and the crude product was dissolved in DCM (8 ml). Saturated sodium bicarbonate was then slowly added to adjust the pH to 8-9, resulting in the precipitation of a pale yellow solid. Ammonia was added to adjust the pH to 11-12, and the aqueous phase was decanted. 50 ml of water was then added for pulping, and the mixture was allowed to stand and the aqueous phase was decanted. 100 ml of methanol was added to the remaining solid for pulping, and the mixture was filtered. The solid was washed three times with methanol (5 ml / times), and then dried to obtain the desired product 158A (3.158 g, 99.20% purity, 85.88% yield, retention time identical to that of 158A in Example 158).

[0839] ESI-MS m / z:561.56[M+H] + .

[0840] 1H NMR (500MHz, DMSO-d6) δ10.13(s,1H),8.83(s,1H),8.74(d,J=8.5Hz,1H),8.43(d,J=7.5Hz,1H),7.83(s, 1H),7.71(d,J=8.5Hz,1H),7.63(d,J=8.3Hz,1H),7.43(t,J=73.5Hz,1H),7.41(d,J=2.5Hz,1H),6.88–6.8 1(m,2H),4.39(s,2H),4.22(t,J=7.8Hz,1H),3.92–3.77(m,2H),3.61-3.51(m,2H),2.35(s,6H),2.33–2. 29(m,1H),2.03-1.98(m,1H),1.89-1.84(m,1H),1.70-1.65(m,1H),1.46-1.42(m,1H),1.36-1.31(m,1H).

[0841] Example 160: Synthesis of Compound 4-(7-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)-7-((7-(methylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0842] Step 1: Synthesis of compound 160-1

[0843] 4-(Difluoromethyl)pyridin-2-amine (100.00 mg), 40% aqueous chloroacetaldehyde solution (272.00 mg), and sodium bicarbonate (116.00 mg) were dissolved in ethanol (5.00 mL) and water (1.00 mL) and reacted at 70°C for 2 h. After completion of the reaction, the mixture was concentrated, stirred, and isolated by silica gel column chromatography (DCM:MeOH = 24:1) to obtain the desired product 160-1 (110.00 mg, 94.28% yield). ESI-MS m / z: 169.03 [M+H] + .

[0844] Step 2: Synthesis of compound 160-2

[0845] 160-1 (110.00 mg) was dissolved in DMF (5.00 mL), and NIS (162.00 mg) was added under ice-cooling. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, EA / THF and water were added for extraction. The organic phase was separated and washed with saturated brine, concentrated, and the sample was separated by silica gel column chromatography (DCM:MeOH = 25:1) to obtain the desired product 160-2 (150.00 mg, 77.98% yield). ESI-MS m / z: 295.05 [M+H] + .

[0846] Step 3: Synthesis of compound 160-3

[0847] 160-2 (58.00 mg), 2-2 (100.00 mg), Pd(dppf)Cl2CH2Cl2 (13.00 mg), and sodium carbonate (52.00 mg) were dissolved in DMF (2.00 mL) and water (0.30 mL) and reacted at 90°C for 1 h. After the reaction, the mixture was concentrated, mixed, and isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 160-3 (49.00 mg, 45.95% yield). ESI-MS m / z: 645.45 [M+H] + .

[0848] Step 4: Synthesis of compound 160

[0849] Compound 160-3 (49.00 mg) was dissolved in dichloromethane (4.00 mL) at room temperature, and TFA (1.00 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, and then the reaction was stopped. The product was concentrated and purified by RP-HPLC to obtain the trifluoroacetate salt of the product 160 (32.60 mg, 99.9% purity, 78.69% yield). ESI-MS m / z: 545.20 [M+H] + .

[0850] 1H NMR (500MHz, DMSO-d6) δ10.36(s,1H),10.32(s,1H),8.96(s,1H),8.68(d,J=8.4Hz,1H),8.58(d,J=7.2 Hz,1H),8.22(s,1H),8.11(s,1H),7.84(d,J=8.5Hz,1H),7.77(d,J=8.5Hz,1H),7.36–7.09(m,3H),5.16 –5.12(m,1H),4.43(s,2H),3.92–3.86(m,2H),3.70–3.46(m,2H),2.99(d,J=4.6Hz,3H),2.82(d,J=4.7 Hz,3H),2.76–2.72(m,1H),2.23–2.03(m,2H),1.73–1.66(m,1H),1.53–1.51(m,1H),1.43–1.40(m,1H).

[0851] Example 163: Synthesis of Compound 7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(7-isopropylimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0852] Step 1: Synthesis of compound 163-1

[0853] 4-Bromopyridin-2-amine (1.00 g), 4,4,5,5-tetramethyl-2-(propyl-1-en-2-yl)-1,3,2-dioxaborolane (1.17 g), Pd(dppf)Cl2CH2Cl2 (470.00 mg), and potassium carbonate (2.40 g) were dissolved in 1,4-dioxane (10.00 mL) and water (2.00 mL) and reacted at 90°C for 4 h. After completion of the reaction, the mixture was filtered, washed with dichloromethane, concentrated, and the sample was separated by silica gel column chromatography (DCM:MeOH = 30:1) to obtain the desired product 163-1 (510.00 mg, 65.76% yield). ESI-MS m / z: 135.11 [M+H] + .

[0854] Step 2: Synthesis of compound 163-2

[0855] 163-1 (510.00 mg) and Pd / C (161.00 mg) were dissolved in methanol (10.00 mL), replaced with H2, and allowed to react at room temperature overnight. After completion of the reaction, the mixture was filtered, and the filtrate was mixed with a sample and separated by silica gel column chromatography (DCM:MeOH = 15:1) to obtain the desired product 163-2 (252.00 mg, 48.68% yield). ESI-MS m / z: 137.10 [M+H] + .

[0856] Step 3: Synthesis of compound 163-3

[0857] 2-Chloroacetaldehyde (252.00 mg), 40% aqueous chloroacetaldehyde solution (726.00 mg), and sodium bicarbonate (310.00 mg) were dissolved in ethanol (5.00 mL) and water (1.00 mL) and reacted at 70°C for 2 h. After completion of the reaction, the mixture was concentrated, mixed, and isolated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the desired product 163-3 (290.00 mg, 97.83% yield). ESI-MS m / z: 161.19 [M+H] + .

[0858] Step 4: Synthesis of compound 163-4

[0859] 163-3 (290.00 mg) was dissolved in DMF (5.00 mL), and NIS (448.00 mg) was added under ice-cooling. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, EA / THF and water were added for extraction. The organic phase was separated and washed with saturated brine, concentrated, and the mixture was separated by silica gel column chromatography (DCM:MeOH = 15:1) to obtain the desired product 163-4 (298.00 mg, 57.54% yield). ESI-MS m / z: 287.07 [M+H] + .

[0860] Step 5: Synthesis of compound 163-5

[0861] 163-4 (56.00 mg), 2-2 (100.00 mg), Pd(dppf)Cl2CH2Cl2 (13.00 mg), and sodium carbonate (52.00 mg) were dissolved in DMF (2.00 mL) and water (0.30 mL) and reacted at 90°C for 1 h. After the reaction, the mixture was concentrated, mixed, and isolated by silica gel column chromatography (DCM:MeOH = 15:1) to obtain the desired product 163-5 (65.00 mg, 61.71% yield). ESI-MS m / z: 637.30 [M+H] + .

[0862] Step 6: Synthesis of compound 163

[0863] Compound 163-5 (65.00 mg) was dissolved in dichloromethane (4.00 mL) at room temperature, and TFA (1.00 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The mixture was concentrated, the pH adjusted to alkaline with saturated sodium bicarbonate solution, and extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The product 163 (11.50 mg, 98.73% purity, 20.72% yield) was isolated by preparative plate purification (DCM:MeOH = 18:1). ESI-MS m / z: 537.20 [M+H] + .

[0864] 1 H NMR (500MHz, DMSO-d6) δ10.43(s,1H),10.32(s,1H),8.97(s,1H),8.68(d,J=8.5Hz,1H),8.54(d,J=7.1Hz,1H),8.38(s, 1H),7.89–7.83(m,2H),7.79(d,J=8.5Hz,1H),7.45(dd,J=7.2,1.7Hz,1H),7.14(d,J=8.5Hz,1H),5.15–5.12(m,1H),4.4 2(s,2H),3.92–3.88(m,2H),3.66–3.49(m,2H),3.24–3.17(m,1H),2.98(d,J=4.6Hz,3H),2.82(d,J=4.7Hz,3H),2.75(dd ,J=13.7,8.5Hz,1H),2.16–2.11(m,2H),1.72–1.67(m,1H),1.54–1.51(m,1H),1.42–1.40(m,1H),1.31(d,J=6.8Hz,6H).

[0865] Example 164: Synthesis of Compound 4-(7-cyclopropylimidazo[1,2-a]pyridin-3-yl)-7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0866]

[0867] Step 1: Synthesis of compound 164-1

[0868] At room temperature, 7-bromoimidazo[1,2-a]pyridine (1.00 g), cyclopropylboronic acid (566.70 mg), palladium acetate (113.90 mg), tricyclohexylphosphine (284.70 mg), and potassium phosphate (3.23 g) were dissolved in toluene (10 mL) and water (1 mL). The mixture was heated to 100°C and reacted for 15 hours. The reaction solution was cooled, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 97:3) to obtain compound 164-1 (707.00 mg, 88% yield). ESI-MS m / z: 159.2 [M+H] + .

[0869] Step 2: Synthesis of compound 164-2

[0870] At room temperature, 164-1 (707.00 mg) was dissolved in DMF (8 mL), and NIS (1.21 g) was added. The mixture was reacted at room temperature for 3 hours, diluted with water, extracted with DCM, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=97:3) to obtain compound 164-2 (1.15 g, 91% yield). ESI-MS m / z: 285.0 [M+H] + .

[0871] Step 3: Synthesis of compound 164-3

[0872] At room temperature, 2-2 (100.00 mg), 164-2 (56.39 mg), [PdCl2(dppf)]CH2Cl2 (13.47 mg), and potassium carbonate (68.58 mg) were dissolved in DMF (4 mL) and water (0.5 mL). The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C for 2 hours. The mixture was cooled, filtered through celite, and the filtrate was diluted with water and extracted with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 95:5) to give compound 164-3 (86.00 mg, 82% yield). ESI-MS m / z: 635.4 [M+H] + .

[0873] Step 4: Synthesis of compound 164

[0874] At room temperature, 164-3 (86.00 mg) was dissolved in DCM (4 mL), trifluoroacetic acid (1 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated, dissolved in a small amount of methanol, and the pH was adjusted to alkaline with saturated sodium bicarbonate. The mixture was extracted with DCM, and the organic layers were combined, washed with saturated brine, dried, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=92:8) to obtain compound 164 (16.20 mg, 21% yield). ESI-MS m / z: 535.3 [M+H]+ .

[0875] 1 H NMR (500MHz, DMSO-d6) δ10.12(s,1H),8.84(s,1H),8.73(d,J=8.6Hz,1H),8.26(d,J=7.2Hz,1H),7.74(s,1H ),7.69(d,J=8.6Hz,1H),7.62(d,J=8.3Hz,1H),7.37(s,1H),6.85(d,J=8.3Hz,1H),6.65(dd,J=7.3,1.9Hz, 1H),4.39(s,2H),4.23(s,1H),3.83(t,J=13.2Hz,2H),3.56(dt,J=24.2,12.0Hz,2H),2.36(s,6H),2.32(m, 1H),2.07–1.97(m,2H),1.87(m,1H),1.66(m,1H),1.44(m,1H),1.36–1.31(m,1H),1.02(m,2H),0.80(m,2H)

[0876] Example 165: Synthesis of Compound 4-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-3-yl)-7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0877]

[0878] Step 1: Synthesis of compound 165-1

[0879] 3-Morpholinone (1.00 g) and aminoacetaldehyde dimethyl acetal (2.08 g) were added to a reaction flask at room temperature, followed by the slow dropwise addition of SnCl₄ (0.35 mL). The mixture was then reacted at 150°C for 3 h under N₂ protection to terminate the reaction. 50 mL of water was added to the reaction mixture to quench the reaction, followed by filtration through celite. The filter cake was washed with water and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with EA, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (DCM:MeOH = 9:1) to afford the desired product 165-1 (840.00 mg, 68.41% yield). ESI-MS m / z: 125.2 [M+H] + .

[0880] Step 2: Synthesis of compound 165-2

[0881] At room temperature, 165-1 (840.00 mg) was dissolved in ACN (15.00 mL) and, under an ice-water bath, NBS (1.20 g) was added portionwise. The reaction was allowed to react at room temperature for 1 h, after which the reaction was stopped. The reaction solution was poured into 50 mL of water and extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was isolated by silica gel column chromatography (PE:EA = 20:80) to afford the desired product 165-2 (840.00 mg, 61.14% yield). ESI-MS m / z: 203.2 [M+H] + .

[0882] Step 3: Synthesis of compound 165-3

[0883] Compound 2-2 (80.00 mg), 165-2 (31.00 mg), [PdCl2(dppf)]CH2Cl2 (11.00 mg), and sodium carbonate (42.00 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 95°C under N2 protection for 6 h, after which the reaction was terminated. The reaction solution was directly concentrated. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product 165-3 (60.00 mg, 75.47% yield). ESI-MS m / z: 601.2 [M+H] + .

[0884] Step 4: Synthesis of compound 165

[0885] Compound 165-3 (60.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (396.22 mg) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The reaction solution was directly concentrated. The concentrate was separated by preparative liquid phase to afford the desired product 165 (31.50 mg, 63.00% yield). ESI-MS m / z: 501.2 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ10.28(s,1H),8.98(s,1H),8.60(d,J=8.5Hz,1H),7.91(s,1H),7.83(d,J=8.5H z,1H),7.69(d,J=8.5Hz,1H),7.10(d,J=8.4Hz,1H),5.11(s,3H),4.46(s,2H),4.10(s,4H),3.95–3.82( m,2H),3.57(ddd,J=32.3,12.8,10.6Hz,2H),2.98(d,J=4.4Hz,3H),2.81(d,J=4.5Hz,3H),2.74(dd,J=1 3.8,8.6Hz,1H),2.22–2.05(m,2H),1.69(td,J=12.8,4.7Hz,1H),1.56–1.47(m,1H),1.44–1.35(m,1H).

[0886] Example 166: Synthesis of Compound 7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridin-5,4'-pyran]-2-yl)amino)-4-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

[0887] Step 1: Synthesis of compound 166-1

[0888] 5,6,7,8-Tetrahydro-imidazole[1,2-A]pyridine (300.00 mg) was dissolved in ACN (8.00 mL) at room temperature, and NBS (480.76 mg) was added portionwise. The mixture was allowed to react at room temperature for 1 h, after which the reaction was stopped. The reaction solution was directly concentrated. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 19:1) to afford the desired product 166-1 (200.00 mg, 40.51% yield). ESI-MS m / z: 201.2 [M+H] + .

[0889] Step 2: Synthesis of compound 166-2

[0890] Compound 2-2 (80.00 mg), 166-1 (32.18 mg), [PdCl2(dppf)]CH2Cl2 (11.00 mg), and sodium carbonate (42.00 mg) were added to DMF (4.00 mL) and water (0.40 mL) at room temperature. The mixture was then reacted at 95°C under nitrogen for 6 h, after which the reaction was terminated. The reaction solution was directly concentrated. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 10:1) to afford the desired product 166-2 (60.00 mg, 75.59% yield). ESI-MS m / z: 599.2 [M+H] + .

[0891] Step 3: Synthesis of compound 166

[0892] Compound 166-2 (60.00 mg) was dissolved in dichloromethane (5.00 mL) at room temperature, and TFA (396.22 mg) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The reaction solution was directly concentrated. The concentrate was separated by preparative liquid phase to afford the desired product 166 (22.40 mg, 44.80% yield). ESI-MS m / z: 499.2 [M+H] + .

[0893] 1 H NMR (500MHz, DMSO-d6) δ10.26(s,1H),8.96(s,1H),8.58(d,J=8.5Hz,1H),7.87–7.80(m,2H),7.63(d,J=8.6Hz, 1H),7.11(d,J=8.5Hz,1H),5.12(t,J=7.4Hz,1H),4.42(s,2H),3.96(s,2H),3.89(t,J=13.2Hz,2H),3.65–3.50 (m,2H),3.07(d,J=5.4Hz,2H),2.98(d,J=4.5Hz,3H),2.81(d,J=4.7Hz,3H),2.74(dd,J=13.8,8.5Hz,1H),2.12 (dt,J=13.0,6.8Hz,2H),1.95(s,4H),1.69(td,J=12.9,4.7Hz,1H),1.51(d,J=12.9Hz,1H),1.43–1.37(m,1H).

[0894] Example 168: Synthesis of 3-(1-oxo-7-((7-(pyrrolidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)isoindol-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile

[0895] Step 1: Synthesis of compound 168-1

[0896] Compound 40-5 (300.00 mg), 146-2 (128.01 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (38.87 mg), sodium carbonate (151.29 mg), and water (1.00 mL) were added to 1,4-dioxane (6.00 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 90°C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain the target product 168-1 (200.00 mg, 65.09% yield). ESI-MS m / z: 646.5 [M+H] + .

[0897] Step 2: Synthesis of compound 168

[0898] Compound 168-1 (200.00 mg) was added to DCM (5.00 mL), followed by TFA (1.00 mL), and the mixture was allowed to react at room temperature for 0.5 h. The reaction solution was concentrated and the target product 168 (81.30 mg, 46.77% yield) was obtained by preparative isolation. ESI-MS m / z: 546.3 [M+H] + . Trifluoroacetate 1 H NMR (500MHz, DMSO) δ10.50(d,J=5.5Hz,1H),10.26(s,1H),8.94(s,1H),8.58–8.46(m,3H),8.19(s,1H),7. 82(t,J=8.6Hz,2H),7.27(d,J=7.1Hz,1H),7.12(d,J=8.5Hz,1H),5.12(dd,J=14.5,7.8Hz,1H),4.44(d,J=1 2.2Hz,2H),3.92–3.84(m,2H),3.70–3.32(m,6H),2.91(dd,J=13.2,8.1Hz,1H),2.10(dtd,J=21.8,13.2,6 .6Hz,4H),1.99–1.80(m,2H),1.68(dd,J=12.3,8.6Hz,1H),1.52(d,J=12.7Hz,1H),1.41(d,J=12.1Hz,1H).

[0899] Example 169: Synthesis of Compound 4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-(pyrrolidin-1-yl)-2',3',5',6,6',7-hexahydrospiro[cyclopenta[b]pyridine-5,4'-pyran]-2-yl)amino)isoindol-1-one

[0900]

[0901] Step 1: Synthesis of compound 169-1

[0902] Compound 40-5 (150 mg), 123-3 (82 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (17.4 mg), and aqueous sodium carbonate (0.357 mL, 2 M) were added to DMF (10 mL). The atmosphere was replaced with nitrogen and the reaction was carried out at 95°C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM / MeOH = 90 / 10) to obtain the desired product 169-1 (110 mg, 67.3% yield). ESI-MS m / z: 687.3 [M+H]+.

[0903] Step 2: Synthesis of compound 169

[0904] Compound 169-1 (110 mg) was added to DCM (3 mL) and MeOH (3 mL), followed by a solution of hydrogen chloride in dioxane (6 mL). The mixture was allowed to react at room temperature for 2 h. The reaction solution was concentrated and the desired product 169 (17.8 mg, 20.8% yield) was obtained by preparative isolation. ESI-MS m / z: 587.4 [M+H] + . Hydrochloride 1 H NMR(500MHz,DMSO)δ11.26(s,1H),10.25(s,1H),8.96(s,1H),8.67–8.54(m ,2H),8.31(s,1H),7.82(dd,J=8.3,4.4Hz,2H),7.70(d,J=17.2Hz,2H),7.2 9(s,1H),7.12(d,J=8.5Hz,1H),5.10(d,J=6.6Hz,1H),4.48–4.35(m,2H),4 .00–3.80(m,3H),3.69–3.30(m,4H),3.00-2.80(m,1H),2.21–1.20(m,10H).

[0905] Example 172 Synthesis of Compound 4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-(methylamino)-4',5',6,7-tetrahydro-2'-H-pyrido[cyclopentyl[b]pyridin-5,3'-furan]-2-yl)amino)isoindolin-1-one

[0906] Step 1: Synthesis of compound 172-1

[0907] Compounds 58-14 (260 mg), 123-3 (164 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (36 mg), and sodium carbonate (140 mg) were added to DMF (10 mL) and water (2 mL). The atmosphere was replaced with nitrogen and the mixture was reacted at 95°C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM / MeOH = 92 / 8) to obtain the desired product 172-1 (221 mg, 77.6% yield).

[0908] ESI-MS m / z: 647.30 [M+H] + .

[0909] Step 2: Synthesis of the hydrochloride salt of compound 172

[0910] Compound 172-1 (221 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). A solution of hydrogen chloride in dioxane (6 mL, 4 M in dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 minutes, after which the reaction was stopped. The reaction solution was concentrated and purified by preparative liquid phase separation to obtain the hydrochloride salt of the desired product 172 (87.50 mg, 99.27% ​​purity, 46.85% yield). ESI-MS m / z: 547.38 [M+H] + .

[0911] 1 H NMR (500MHz, DMSO) δ11.58(s,1H),10.32(s,1H),8.95(d,J=41.9Hz,2H),8.68(s,1H),8.46(s,1H),7.94–7.58(m,4H),7.39(s,1H),7.1 1(s,1H),5.13(s,1H),4.42(s,2H),4.15–3.33(m,4H),2.85(d,J=17.5Hz,6H),2.45-2.25(m,2H),2.20-2.05(m,1H),2.05–1.85(m,1H).

[0912] Example 174: Synthesis of Compound 174 4-(7-aminoimidazo[1,2-a]pyridin-3-yl)-7-((7-(dimethylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopentadienyl[b]pyridin-5'-pyran]-2-yl)amino)isoindol-1-one

[0913] Step 1: Synthesis of compound 174-1

[0914] 7-Bromoimidazo[1,2-A]pyridine (1.00 g), BocNH2 (890.00 mg), Pd2(dba)3 (460.00 mg), XantPhos (590.00 mg), and cesium carbonate (4.96 g) were dissolved in 1,4-dioxane (10.00 mL), replaced with nitrogen, and reacted at 100°C for 8 h. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated and isolated by silica gel column chromatography (DCM:MeOH = 32:1) to obtain the desired product 174-1 (980.00 mg, 82.78% yield).

[0915] Step 2: Synthesis of compound 174-2

[0916] 174-1 (960.00 mg) was dissolved in DMF (10.00 mL), and NIS (1.11 g) was added under ice-cooling. The reaction was allowed to react at room temperature for 5 h. After completion of the reaction, the reaction system was poured into ice water. The product precipitated and was filtered and dried to obtain the desired product 174-2 (1.32 g, 89.30% yield).

[0917] Step 3: Synthesis of compound 174-3

[0918] 174-2 (300.00 mg), 2-2 (214.00 mg), Pd(dppf)Cl2CH2Cl2 (40.00 mg), and sodium carbonate (158.00 mg) were dissolved in DMF (3.00 mL) and water (0.40 mL) and reacted at 100°C for 2 h. After completion of the reaction, water was added and the mixture was extracted with EA / THF (1:1). The organic phase was washed with saturated brine, separated, concentrated, and mixed. The mixture was then isolated by silica gel column chromatography (DCM:MeOH = 13:1) to afford the desired product 174-3 (160.00 mg, 45.43% yield).

[0919] ESI-MS m / z:710.49[M+H] + .

[0920] Step 4: Synthesis of compound 174

[0921] At room temperature, compound 174-3 (160.00 mg) was dissolved in dichloromethane (4.00 mL), TFA (1.00 mL) was added, and the reaction was carried out at room temperature for 0.5 h. The reaction was stopped, and the reaction solution was concentrated and purified by RP-HPLC to obtain the trifluoroacetate salt of compound 174 (86.90 mg, purity 99.32%, yield 75.14%).

[0922] ESI-MS m / z:510.40[M+H] + .

[0923] 1 H NMR(500MHz,DMSO-d6)δ13.50(s,1H),10.82(s,1H),10.31(s,1H),8.97(s,1H),8.69(d,J=8.5Hz,1H),8.1 6(d,J=7.5Hz,1H),7.95(s,1H),7.82(d,J=8.5Hz,1H),7.69(d,J=8.5Hz,1H),6.81(dd,J=7.5,2.2Hz,1H),6 .68(d,J=2.1Hz,1H),5.16–5.12(m,1H),4.42(s,2H),3.91–3.85(m,2H),3.63–3.52(m,2H),2.97(s,3H),2 .82(s,3H),2.77–2.72(m,1H),2.17–2.10(m,2H),1.72–1.66(m,1H),1.54–1.51(m,1H),1.43–1.40(m,1H).

[0924] Example 177: Synthesis of Compound 177 4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-morpholin-2',3',5',6,6',7-hexahydrospiro[b]pyridin-5'-pyran]-2-yl)amino)isoindol-1-one:

[0925]

[0926] Step 1: Synthesis of compound 177-1

[0927] Compound 62-2 (835.00 mg), 123-3 (300.00 mg), Pd(dppf)Cl2CH2Cl2 (79.00 mg), and sodium carbonate (307.00 mg) were dissolved in DMF (10.00 mL) and water (2.00 mL) and reacted at 95°C for 2 h. After completion of the reaction, the insoluble material was removed by filtration, water was added, and the mixture was extracted with EA / THF (1:1). The organic phase was washed with saturated brine, separated, concentrated, and mixed. The mixture was then separated by silica gel column chromatography (PE:EA = 1:99) to obtain the target compound 177-1 (176.00 mg, 28.80% yield).

[0928] ESI-MS m / z: 632.23 [M+H] + .

[0929] Step 2: Synthesis of compound 177-2

[0930] Compound 177-1 (176.00 mg), morpholine (121.00 mg), and Ti(OEt)4 (63.00 mg) were dissolved in DCE (10.00 mL) and methanol (2.00 mL) and reacted at 40°C overnight. NaBH3CN (60.00 mg) was then added and the mixture was allowed to react at 40°C for 2 h. After completion of the reaction, the mixture was quenched with water. The reaction solution was concentrated and separated by silica gel column chromatography (DCM:MeOH = 13:1) to afford the target compound 177-2 (35.00 mg, 17.88% yield).

[0931] ESI-MS m / z:703.24[M+H] + .

[0932] Step 3: Synthesis of compound 177

[0933] Compound 177-2 (35.00 mg) was dissolved in dichloromethane (4.00 mL) at room temperature, and TFA (1.00 mL) was added. The reaction was allowed to react at room temperature for 0.5 h, after which the reaction was stopped. The reaction solution was concentrated, the pH adjusted to alkaline with saturated sodium bicarbonate solution, and extracted three times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 177 (24.10 mg, purity 95.23%, yield 76.47%). ESI-MS m / z: 603.43 [M+H] + .

[0934] 1H NMR (500MHz, DMSO-d6) δ10.19(s,1H),8.92(s,1H),8.50–8.45(m,2H),7.99(s,1H),7.82(d,J=8.4Hz,1H),7.77(d,J=8.5Hz,1H),7.66–7.37(m 3H),7.01(d,J=7.5Hz,1H),5.11(s,1H),4.42–4.41(m,2H),4.10–4.01(m,4H),3.91–3.86(m,4H),2.80–2.75(m,2H) ,2.65–2.63(m,1H),2.19–2.10(m,2H),2.06–1.94(m,2H),1.71–1.66(m,1H),1.53–1.50(m,1H),1.43–1.40(m,2H).

[0935] Example 178: Synthesis of Compound 178 7-((7-(cyclopropylamino)-2',3',5',6,6',7-hexahydrospiro[cyclopentadienyl[b]pyridin-5'-pyran]-2-yl)amino)-4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

[0936]

[0937] Step 1: Synthesis of compound 178-1

[0938] Compound 62-2 (700 mg), 123-3 (245 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (99 mg), and sodium carbonate (387 mg) were added to DMF (20 mL) and water (4 mL). The atmosphere was replaced with nitrogen and the mixture was reacted at 95°C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM / MeOH = 95 / 5) to obtain the desired product 178-1 (615 mg, 80.1% yield).

[0939] ESI-MS m / z: 632.29 [M+H] + .

[0940] Step 2: Synthesis of compound 178-2

[0941] Compound 178-1 (615 mg), cyclopropylamine (405 mL), and tetraethyl titanate (222 mg) were weighed, and DCE (5 mL) and MeOH (2 mL) were added. The mixture was reacted at 40°C for 4 h. Sodium cyanoborohydride (184 mg) was slowly added, and the temperature was raised to 80°C for 1 h, after which the reaction was stopped. The reaction solution was extracted with DCM, and the organic phase was washed with saturated brine. The organic phase was collected, dried, and separated by column chromatography (DCM:MeOH = 90:10) to obtain the target compound 178-2 (655 mg, 99.8% yield). ESI-MS m / z: 673.35 [M+H] + .

[0942] Step 3: Synthesis of the hydrochloride salt of compound 178

[0943] Compound 178-2 (655 mg) was dissolved in dichloromethane (5 mL) and methanol (5 mL). A solution of hydrogen chloride in dioxane (10 mL, 4 M in dioxane) was slowly added dropwise in an ice bath. The temperature was slowly warmed to room temperature and the reaction was allowed to proceed for 30 minutes, after which the reaction was terminated. The solution was concentrated and purified by preparative liquid phase separation to afford the hydrochloride salt of the desired product 178 (83.40 mg, 96.37% purity, 14.96% yield).

[0944] ESI-MS m / z:573.40[M+H] + .

[0945] 1 H NMR (500MHz, DMSO) δ10.29(s,1H),9.69(s,1H),9.21(s,1H),8.96(s,1H),8.71(t,J=12.0Hz,1H),8.56(d,J=7.5Hz,1H),8.23(s,1H),7 .83(t,J=11.9Hz,1H),7.79–7.75(m,1H),7.72(s,1H),7.57(d,J=72.4Hz,1H),7.23(d,J=5.5Hz,1H),7.14(d,J=8.5Hz,1H),5.02(s,1H ),4.49–4.35(m,2H),3.95–3.81(m,2H),3.57(dt,J=39.2,11.5Hz,2H),3.09(s,1H),2.89(dd,J=13.3,8.2Hz,1H),2.15(dd,J=12.1,8. 5Hz,1H),2.08–1.97(m,1H),1.80–1.63(m,1H),1.54–1.41(m,2H),1.10–0.96(m,1H),0.87(dd,J=23.2,7.1Hz,2H),0.64–0.49(m,1H).

[0946] Example 180: Synthesis of Compound 7-((7-(dimethylamino)-4',5',6,7-tetrahydro-2'H-spiro[cyclopentadienyl[b]pyridin-5,3'-furan]-2-yl)amino)-4-(7-methoxyimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

[0947] Step 1: Synthesis of compound 180-1

[0948] Compound 58-14 (347 mg), 7-methoxy H-imidazo[1,2-a]pyridine (193 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (48 mg), and sodium carbonate (187 mg) were added to DMF (10 mL) and water (2 mL). The atmosphere was replaced with nitrogen and the mixture was reacted at 95°C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM / MeOH = 92 / 8) to obtain the target compound 180-1 (85 mg, 23.7% yield).

[0949] ESI-MS m / z: 611.32 [M+H] + .

[0950] Step 2: Synthesis of Compound 180 Hydrochloride

[0951] Compound 180-1 (85 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). A solution of hydrogen chloride in dioxane (6 mL, 4 min dioxane) was slowly added dropwise in an ice bath. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 30 min, after which the reaction was stopped. The solution was concentrated and purified by preparative liquid phase separation to obtain the hydrochloride salt of the desired product 180 (4.50 mg, 95.01% purity, 5.38% yield). ESI-MS m / z: 511.42 [M+H] + .

[0952] The following compounds were synthesized by the above methods or similar methods using corresponding intermediates.

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960] Compound 3: 1 H NMR (500MHz, DMSO-d6) δ10.00(s,1H),9.94(s,1H),8.92(s,1H),8.60(t,J=6.5Hz,1H),8.30(d,J=8.5Hz,1 H),8.21(s,1H),8.00(d,J=8.8Hz,1H),7.83(d,J=8.8Hz,1H),7.79(d,J=8.5Hz,1H),7.35-7.31(m,1H),7. 26(d,J=8.7Hz,1H),4.68-4.64(m,1H),4.42(s,2H),3.79-3.74(m,2H),3.68-3.62(m,2H),2.94(s,3H),2. 73(s,3H),2.54-2.53(m,1H),2.21-2.02(m,3H),1.83-1.81(m,1H),1.75–1.65(m,2H),1.34-1.31(m,1H).

[0961] Compound 14: 1 H NMR(500MHz,DMSO-d6)δ9.06(s,1H),8.79(s,1H),8.71(s,1H),8.33(d,J=5.0Hz,1H),7.5 4(d,J=3.4Hz,1H),7.35(d,J=5.0Hz,1H),7.02(d,J=2.6Hz,1H),6.96(d,J=2.4Hz,1H),6. 90(d,J=3.4Hz,1H),4.69(s,2H),3.86(s,3H),3.79-3.75(m,2H),3.62-3.56(m,2H),3.50 (s,2H),2.71(s,2H),2.59(s,3H),2.47-2.39(m,2H),2.35(s,3H),1.50(d,J=13.8Hz,2H).

[0962] Compound 15: 11H NMR (500 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.77 (s, 1H), 8.51 (t, J = 6.6 Hz, 1H), 8.07 (s, 1H), 7.80–7.74 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.18 (s, 1H), 7.06 (s, 1H), 4.43–4.24 (m, 6H), 3.84 (s, 2H), 3.50 - 3.46 (m, 1H), 3.20 - 3.16 (m, 1H), 3.00 (s, 3H), 2.78 - 3.71 (m, 1H), 2.63 (s, 3H), 2.31 - 2.24 (m, 2H), 1.33 - 1.29 (m, 1H). Compound 16: 1 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.67 (s, 1H), 8.37 (dd, J = 7.6, 5.7 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 10.1, 2.7 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 6.96 (td, J = 7.5, 2.7 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 4.34 (s, 2H), 3.63 (s, 2H), 2.34 (s, 1H), 2.29 (s, 3H), 2.22 (s, 3H), 1.50 - 1.48 (m, 2H), 0.68 - 0.64 (m, 2H). Compound 29: 1 1H NMR (500 MHz, DMSO) δ 10.17 (d, J = 22.3 Hz, 2H), 9.09 (s, 1H), 8.89 (s, 1H), 8.58 (d, J = 8.3 Hz, 1H), 8.38 (s, 1H), 7.88–7.77 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.45 (t, J = 8.7 Hz, 1H), 6.87 (s, 1H), 5.04 (s, 1H), 4.52 (s, 2H), 3.89 (s, 2H), 3.65 (t, J = 11.4 Hz, 1H), 3.54 (t, J = 11.7 Hz, 1H), 2.97 (s, 3H), 2.81 (s, 4H), 2.46 (s, 3H), 2.06 (dd, J = 26.5, 17.3 Hz, 3H), 1.54 (d, J = 12.8 Hz, 1H), 1.34 (d, J = 12.9 Hz, 1H).

[0963] Compound 31: 11H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.88–8.80 (m, 2H), 8.39 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 4.38 (s, 1H), 3.76 - 3.71 (m, 2H), 3.66 - 3.58 (m, 3H), 3.39 - 3.36 (m, 1H), 2.29 (s, 6H), 2.17 - 2.11 (m, 1H), 1.97 - 1.90 (m, 3H), 1.88 - 1.82 (m, 1H), 1.75 - 1.70 (m, 1H), 1.46 - 1.42 (m, 1H), 1.36 - 1.32 (m, 1H).

[0964] Compound 32: 1 1H NMR (500 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.66 (s, 1H), 9.10 (dd, J = 4.8, 2.2 Hz, 1H), 8.88 (s, 1H), 8.39 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.86 (dd, J = 9.8, 5.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.48 - 7.43 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 4.68–4.60 (m, 1H), 4.53 (s, 2H), 3.78 - 3.74 (m, 2H), 3.68 - 3.61 (m, 2H), 2.95 (s, 3H), 2.70 (s, 3H), 2.58–2.52 (m, 1H), 2.23 - 2.13 (m, 2H), 2.04 - 1.97 (m, 1H), 1.81 - 17.5 (m, 1H), 1.69 - 1.62 (m, 2H), 1.33 - 1.30 (m, 1H).

[0965] Compound 33: 1¹H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.81 (s, 1H), 8.75 (d, J = 7.0 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 8.15 (s, 2H), 7.83 - 7.80 (m, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.35 – 7.28 (m, 1H), 6.99 - 6.95 (m, 2H), 4.51 (s, 2H), 3.76 - 3.72 (m, 2H), 3.67 - 3.59 (m, 2H), 2.45 (s, 6H), 2.28 - 2.22 (m, 1H), 2.04 – 1.85 (m, 5H), 1.82 - 1.72 (m, 1H), 1.51 - 1.47 (m, 1H), 1.35 - 1.32 (m, 1H).

[0966] Compound 34: 1 ¹H NMR (500 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.73 (s, 1H), 8.88 (s, 1H), 8.37 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 3.5 Hz, 1H), 7.36 (d, J = 5.2 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.54 (d, J = 3.5 Hz, 1H), 4.67 - 4.62 (m, 1H), 4.49 (s, 2H), 3.92 (s, 3H), 3.79 - 3.74 (m, 2H), 3.69 - 3.60 (m, 2H), 2.95 (d, J = 4.9 Hz, 3H), 2.71 (d, J = 4.9 Hz, 3H), 2.56 – 2.54 (m, 1H), 2.24 – 2.11 (m, 2H), 2.06 - 1.99 (m, 1H), 1.82 - 1.76 (m, 1H), 1.72 – 1.63 (m, 2H), 1.34 - 1.31 (m, 1H).

[0967] Compound 35: 11H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.95 (s, 1H), 8.67 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 7.0 Hz, 1H), 8.30 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.84 - 7.81 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.35 (t, J = 6.9 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.13 (t, J = 8.5 Hz, 1H), 4.42 (s, 2H), 3.93 - 3.86 (m, 2H), 3.65–3.51 (m, 2H), 2.99 (d, J = 3.8 Hz, 3H), 2.82 (d, J = 4.0 Hz, 3H), 2.78 - 2.71 (m, 1H), 2.16 - 2.10 (m, 2H), 1.77–1.65 (m, 1H), 1.54 - 1.50 (m, 1H), 1.44 - 1.38 (m, 1H). Compound 36: 1 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.06 (dd, J = 4.8, 2.2 Hz, 1H), 8.82 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.36 (s, 1H), 7.90 (dd, J = 9.9, 5.6 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.41 - 7.36 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.50 (s, 2H), 4.21 - 4.17 (m, 1H), 3.88–3.78 (m, 2H), 3.60 - 3.50 (m, 2H), 2.37 (s, 6H), 2.34–2.29 (m, 1H), 2.00 - 1.97 (m, 2H), 1.87 - 1.84 (m, 1H), 1.71 - 1.63 (m, 1H), 1.46 - 1.41 (m, 1H), 1.34 - 1.31 (m, 1H).

[0968] Compound 37: 11H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.89 (s, 1H), 8.77 (d, J = 7.0 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 7.79 (dd, J = 8.7, 2.2 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.35 - 7.31 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 7.00 - 6.97 (m, 1H), 5.13 - 5.08 (m, 1H), 4.54 (s, 2H), 3.91 - 3.85 (m, 2H), 3.65–3.52 (m, 2H), 3.00 (d, J = 4.6 Hz, 3H), 2.85 (d, J = 4.7 Hz, 3H), 2.75 - 2.71 (m, 1H), 2.17–2.07 (m, 2H), 1.77–1.64 (m, 1H), 1.53 - 1.49 (m, 1H), 1.43–1.38 (m, 1H).

[0969] Compound 38: 1 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.21 (d, J = 7.0 Hz, 1H), 8.94 (s, 1H), 8.67 - 8.63 (m, 2H), 8.58 (s, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.24–7.10 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 5.17–5.09 (m, 1H), 4.69 (d, J = 5.2 Hz, 2H), 3.94–3.84 (m, 2H), 3.63–3.52 (m, 2H), 3.01 (d, J = 3.9 Hz, 3H), 2.80 (d, J = 4.1 Hz, 3H), 2.74 - 2.71 (m, 1H), 2.14 - 2.09 (m, 2H), 1.71 - 1.65 (m, 1H), 1.52 - 1.48 (m, 1H), 1.43 - 1.39 (m, 1H).

[0970] Compound 42: 11H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.85 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.40 (d, J = 7.4 Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.74 - 7.67 (m, 2H), 6.99 (d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 4.49 - 4.44 (m, 1H), 4.40 (s, 2H), 3.89–3.80 (m, 2H), 3.62 - 3.51 (m, 2H), 2.48 (s, 6H), 2.47 - 2.43 (m, 1H) 2.08–1.99 (m, 2H), 1.71 - 1.64 (m, 1H), 1.48 - 1.44 (m, 1H), 1.37 - 1.33 (m, 1H).

[0971] Compound 44: 1 1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.89–8.84 (m, 2H), 8.75 (d, J = 8.5 Hz, 1H), 8.59 (dd, J = 4.1, 1.9 Hz, 1H), 8.02 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 6.9, 4.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.43 (s, 2H), 4.30 - 4.21 (m, 1H), 3.88 - 3.81 (m, 2H), 3.56 (dt, J = 24.0, 11.7 Hz, 2H), 2.38 (s, 6H), 2.05 - 1.98 (m, 1H), 1.90 - 1.85 (m, 1H), 1.71 - 1.65 (m, 1H), 1.46 - 1.41 (m, 1H), 1.35 - 1.32 (m, 1H).

[0972] Compound 45: 1 1H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.36 (s, 1H), 9.21 (d, J = 7.0 Hz,

[0973] 1H), 8.90 (s, 1H), 8.68 (d, J = 4.0 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 1H), 7.17 - 7.14 (m, 1H), 4.68 (s, 2H), 4.66 - 4.64 (m, 1H), 3.78 - 3.73 (m, 2H), 3.68 - 3.60 (m, 2H), 3.02 (s, 3H), 2.64 (s, 3H), 2.59–2.52 (m, 1H), 2.22 - 2.15 (m, 2H), 2.02 - 1.95 (m, 1H), 1.80 - 1.75 (m, 1H), 1.67 - 1.59 (m, 2H), 1.32 - 1.28 (m, 1H).

[0974] Compound 47: 1 H NMR (500 MHz, DMSO) δ 10.37 (s, 1H), 10.26 (s, 1H), 8.95 (s, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.57 (d, J = 6.8 Hz, 1H), 8.34 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.92–7.83 (m, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.39 (t, J = 6.8 Hz, 1H), 6.94 (s, 1H), 5.07 (t, J = 8.7 Hz, 1H), 4.39 (d, J = 18.8 Hz, 2H), 3.90 (dd, J = 13.6, 6.8 Hz, 2H), 3.66 (t, J = 11.7 Hz, 1H), 3.55 (t, J = 11.6 Hz, 1H), 2.97 (s, 3H), 2.86–2.71 (m, 4H), 2.48 (s, 3H), 2.12–1.97 (m, 3H), 1.55 (d, J = 13.0 Hz, 1H), 1.35 (d, J = 13.1 Hz, 1H).

[0975] Compound 48: 1H NMR (500MHz, DMSO) δ10.14(s,1H),10.08(s,1H),8.88(s,1H),8.77(d,J=7.0Hz,1H),8.57(d,J=8.4Hz,1H),8.36(s,1H),7 .79(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.36–7.29(m,1H),6.99(t,J=6.8Hz,1H),6.87(s,1H),5.04(t,J=8.6Hz,1H), 4.51(d,J=18.9Hz,2H),3.89(t,J=8.2Hz,2H),3.65(t,J=11.4Hz,1H),3.54(t,J=11.6Hz,1H),2.98(d,J=4.3Hz,3H),2.80 (dd,J=14.4,6.8Hz,4H),2.46(s,3H),2.03(ddd,J=23.6,14.8,7.3Hz,3H),1.54(d,J=12.8Hz,1H),1.34(d,J=13.1Hz,1H).

[0976] Trifluoroacetate of compound 54: δ10.12 (s, 1H), 9.52 (s, 1H), 8.93 (s, 1H), 8.58 (dd, J = 7.6, 5.3 Hz, 1H), 8.28–8.22 (m, 2H), 7.92 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 7.4 Hz,1H),7.26(s,1H),5.03(s,2H),4.60(d,J=5.4Hz,2H),4.41(s,2H),3.87-3.84( m,2H),3.77-3.71(m,2H),2.99(s,4H),2.23-2.16(m,2H),1.62(d,J=13.0Hz,2H).

[0977] Compound 67: 11H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.84 (s, 1H), 8.71 (d, J = 8.6 Hz, 1H), 8.44 - 8.40 (m, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 10.1, 2.7 Hz, 1H), 6.98 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.28–5.23 (m, 1H), 5.17–5.11 (m, 1H), 4.43 - 4.34 (m, 2H), 3.89–3.75 (m, 5H), 3.53 (t, J = 11.9 Hz, 2H), 3.44–3.36 (m, 1H), 2.30 - 2.24 (m, 1H), 1.91 - 1.85 (m, 1H), 1.83 - 1.78 (m, 2H), 1.52 - 1.49 (m, 1H), 1.35 - 1.31 (m, 1H). Compound 70: 1 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.84 (s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.41 (t, J = 6.7 Hz, 1H), 7.81 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.53 - 7.50 (m, 1H), 6.99 - 6.94 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.38 (d, J = 25.2 Hz, 3H), 3.85 - 3.78 (m, 2H), 3.56–3.49 (m, 2H), 3.41–3.34 (m, 2H), 3.29 - 3.26 (m, 2H), 3.22 - 3.19 (m, 1H), 3.12 (s, 3H), 2.26 - 2.21 (m, 1H), 1.91 - 1.86 (m, 1H), 1.85–1.78 (m, 2H), 1.55 - 1.50 (m, 1H), 1.36 (s, 3H), 1.33 - 1.31 (m, 1H).

[0978] Compound 73: 11H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.84 (s, 1H), 8.70 (d, J = 8.1 Hz, 1H), 8.40 (t, J = 6.5 Hz, 1H), 7.82 (s, 1H), 7.72–7.60 (m, 2H), 7.53 (dd, J = 10.0, 2.1 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 4.39 (dt, J = 31.6, 11.1 Hz, 2H), 3.92 (d, J = 22.1 Hz, 2H), 3.83 (t, J = 9.2 Hz, 2H), 3.57 (dd, J = 22.1, 10.7 Hz, 2H), 3.16 (d, J = 8.7 Hz, 3H), 2.88 (dd, J = 98.3, 40.7 Hz, 4H), 2.36 (s, 1H), 2.05–1.91 (m, 4H), 1.72 (dd, J = 34.0, 21.7 Hz, 2H), 1.52 (d, J = 13.2 Hz, 1H), 1.35 (d, J = 12.7 Hz, 1H).

[0979] Compound 74: 1 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.84 (s, 1H), 8.70 (t, J = 5.8 Hz, 1H), 8.42 (t, J = 6.7 Hz, 1H), 7.83 (s, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.54 - 7.52 (m, 1H), 7.00 - 6.96 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.39 (d, J = 15.1 Hz, 2H), 4.23 - 4.19 (m, 1H), 4.00 - 3.95 (m, 1H), 3.86 - 3.79 (m, 2H), 3.61 - 3.52 (m, 2H), 3.01 - 2.84 (m, 3H), 2.08–1.92 (m, 4H), 1.76 - 1.71 (m, 1H), 1.57 - 1.52 (m, 1H), 1.38 - 1.34 (m, 1H).

[0980] Compound 75: 11H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.84 (s, 1H), 8.66 (d, J = 8.6 Hz, 1H), 8.42–8.40 (m, 1H), 7.82 (s, 1H), 7.67 (dd, J = 19.5, 8.4 Hz, 2H), 7.52 (d, J = 9.9 Hz, 1H), 6.98–6.87 (m, 2H), 5.36–5.14 (m, 1H), 4.38 (q, J = 18.2 Hz, 2H), 4.08–3.97 (m, 1H), 3.85–3.81 (m, 2H), 3.65–3.53 (m, 2H), 3.13–3.01 (m, 2H), 2.66–2.62 (m, 1H), 2.40–2.36 (m, 2H), 2.02–1.96 (m, 3H), 1.76–1.74 (m, 1H), 1.55–1.51 (m, 1H), 1.48–1.44 (m, 1H), 1.37–1.35 (m, 1H).

[0981] Compound 76: 1 1H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.84 (s, 1H), 8.70 (d, J = 8.1 Hz, 1H), 8.40 (t, J = 6.5 Hz, 1H), 7.82 (s, 1H), 7.72–7.59 (m, 2H), 7.53 (dd, J = 10.0, 2.1 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 4.39 (dt, J = 31.6, 11.1 Hz, 2H), 3.92 (d, J = 22.1 Hz, 2H), 3.83 (t, J = 9.2 Hz, 2H), 3.57 (dd, J = 22.1, 10.7 Hz, 2H), 3.16 (d, J = 8.7 Hz, 3H), 2.98 (d, J = 15.9 Hz, 2H), 2.85 (s, 1H), 2.72 (s, 1H), 2.36 (s, 1H), 2.04–1.93 (m, 3H), 1.75 (t, J = 12.3 Hz, 1H), 1.66 (s, 1H), 1.52 (d, J = 13.2 Hz, 1H), 1.35 (d, J = 12.7 Hz, 1H).

[0982] Compound 84: 11H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.83 (s, 1H), 8.62 (d, J = 24.3 Hz, 1H), 8.41 (t, J = 6.5 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 36.7 Hz, 2H), 7.52 (d, J = 9.6 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 4.38 (q, J = 17.8 Hz, 3H), 4.13 - 3.70 (dt, J = 108.1, 22.1 Hz, 5H), 3.65 - 3.51 (m, 2H), 3.28–2.90 (m, 2H), 2.39–2.06 (m, 2H), 2.00 (dd, J = 13.2, 5.7 Hz, 1H), 1.87 (s, 1H), 1.75 (s, 1H), 1.70 - 1.52 (m, 2H), 1.49–1.28 (m, 2H).

[0983] Compound 86: 1 1H NMR (500 MHz, DMSO) δ 10.12 (s, 1H), 8.86 (s, 1H), 8.80 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 25.9 Hz, 2H), 7.69 (dd, J = 25.9, 8.6 Hz, 2H), 7.06–6.89 (m, 2H), 4.46–4.35 (m, 2H), 4.07 (t, J = 16.2 Hz, 1H), 3.95 (dd, J = 12.3, 3.6 Hz, 1H), 3.69 (ddd, J = 33.2, 20.1, 8.7 Hz, 4H), 3.49 (s, 1H), 2.41 (s, 6H), 2.16–2.08 (m, 1H), 2.05–1.93 (m, 1H), 1.78 (ddd, J = 19.6, 18.6, 8.9 Hz, 2H), 1.58 (d, J = 12.6 Hz, 1H).

[0984] Compound 88: 11H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.84 (s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.43 (t, J = 6.8 Hz, 1H), 7.85–7.77 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 10.2 Hz, 1H), 7.01 - 6.95 (m, 1H), 6.85 (d, J = 8.5 Hz, 1H), 4.64 - 4.60 (m, 4H), 4.39 (d, J = 26.7 Hz, 2H), 3.85–3.79 (m, 2H), 3.72–3.68 (m, 1H), 3.60 - 3.48 (m, 6H), 2.20 - 2.16 (m, 1H), 1.89–1.73 (m, 3H), 1.51 - 1.46 (m, 1H), 1.32 - 1.27 (m, 1H).

[0985] Compound 90: 1 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.84 - 8.81 (m, 2H), 8.41 (dd, J = 7.6, 5.7 Hz, 1H), 7.81 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 10.1, 2.7 Hz, 1H), 6.99 - 6.95 (m, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.37 (d, J = 22.1 Hz, 2H), 4.26 (t, J = 8.1 Hz, 1H), 3.87–3.78 (m, 2H), 3.63–3.48 (m, 2H), 2.84–2.78 (m, 2H), 2.54 - 2.52 (m, 2H), 2.39 - 2.35 (m, 1H), 2.04 - 1.99 (m, 1H), 1.83 - 1.81 (m, 1H), 1.66 - 1.60 (m, 1H), 1.54 - 1.50 (m, 4H), 1.42 - 1.38 (m, 3H), 1.36 - 1.32 (m, 1H).

[0986] Compound 91: 1H NMR (500MHz, DMSO-d6) δ10.09(s,1H),8.83(s,1H),8.76(d,J=8.6Hz,1H),8.41(dd,J=7.6,5.8Hz,1H),7.82(s,1H),7.65( dd,J=23.9,8.5Hz,2H),7.53(dd,J=10.0,2.7Hz,1H),6.99-6.95(m,1H),6.86(d,J=8.3Hz,1H),4.37(d,J=27.2Hz,2H),4. 22(t,J=7.7Hz,1H),3.87–3.79(m,2H),3.63–3.49(m,2H),2.90-2.84(m,1H),2.58-2.54(m,1H),2.39-2.32(m,3H),2.16- 2.13(m,2H),2.05–1.95(m,2H),1.89-1.84(m,1H),1.70-1.64(m,1H),1.47-1.42(m,1H),1.36-1.32(m,1H),1.24(s,3H).

[0987] Trifluoroacetate salt of compound 94: 1 H NMR(500MHz,DMSO-d6)δ10.23(s,1H),9.97(s,1H),8.92(s,1H),8.55-8.50(m,2H),8.16(s,1H),7.86-7.81(m,2H),7.7 5(d,J=8.5Hz,1H),7.34-7.30(m,1H),7.13(d,J=8.5Hz,1H),5.14–5.07(m,1H),4.39(d,J=12.1Hz,2H),3.91-3.85(m,2 H),3.76-3.72(m,2H),3.61-3.48(m,2H),3.40-3.35(m,1H),3.09-3.07(m,1H),3.04(s,3H),2.84-2.79(m,1H),2.17-2 .07(m,2H),2.03-1.98(m,1H),1.81-1.73(m,2H),1.70–1.62(m,1H),1.56-1.53(m,1H),1.43-1.40(m,1H),1.14(s,3H).

[0988] Trifluoroacetate salt of compound 95: 1H NMR (500MHz, DMSO) δ10.22(s,1H),9.80(s,1H),8.91(s,1H),8.56(d,J=8.6Hz,1H),8.54–8.47(m,1H),8.11(s,1H),7.86–7.72(m, 3H),7.27(s,1H),7.12(d,J=8.5Hz,1H),5.11(s,1H),4.38(d,J=11.9Hz,2H),3.88(d,J=12.3Hz,3H),3.74(s,2H),3.60(d,J=11.9 Hz, 1H), 3.51 (d, J = 11.6 Hz, 1H), 3.34 (dd, J = 30.3, 11.3 Hz, 2H), 2.84 (dd, J = 13.1, 8.2 Hz, 1H), 2.19–2.03 (m, 2H), 2.02–1.95 (m, 1H), 1.80 (dd, J = 32.8, 15.9 Hz, 3H), 1.66 (t, J = 10.5 Hz, 1H), 1.54 (d, J = 12.2 Hz, 1H), 1.43 (d, J = 12.4 Hz, 1H), 1.20 (s, 3H). Trifluoroacetic acid salt of compound 96: 1 H NMR (500MHz, DMSO) δ10.23–9.99(m,1H),8.93(s,1H),8.71(s,1H),8.47(s,1H),8.18(s,1H),7.84(s, 2H),7.69(d,J=7.8Hz,1H),7.35(s,1H),5.16(s,1H),4.40(d,J=4.4Hz,2H),3.91(d,J=11.4Hz,5H),3 .79(s,1H),3.60(d,J=11.1Hz,1H),3.53(d,J=12.2Hz,1H),3.20(d,J=62.4Hz,3H),2.78(s,1H),2.09 (d,J=61.6Hz,2H),2.04–1.93(m,1H),1.68(s,1H),1.52(d,J=13.4Hz,1H),1.24(s,3H),1.19(s,3H).

[0989] Compound 97: 1H NMR (500MHz, DMSO-d6) δ10.11(d,J=1.8Hz,1H),8.83(s,1H),8.76(d,J=8.5Hz,1H),8.41-8.38(m,1H),7.81(s,1H),7.72–7.6 5(m,1H),7.65–7.60(m,1H),7.54-7.50(m,1H),6.99-6.95(m,1H),6.86(d,J=8.3Hz,1H),4.45–4.31(m,2H),4.26–4.17(m,1H ),3.85-3.72(m,2H),3.64–3.48(m,4H),3.05-3.02(m,1H),2.85-2.82(m,1H),2.80–2.71(m,1H),2.64-2.60(m,1H),2.44–2. 36(m,2H),2.13–1.97(m,2H),1.89-1.84(m,1H),1.71–1.62(m,1H),1.46-1.42(m,1H),1.37-1.32(m,1H),1.06-1.02(m,3H).

[0990] Compound 98: 1 H NMR (500MHz, DMSO-d6) δ10.24(s,1H),8.95(s,1H),8.66(dd,J=7.6,5.1Hz,1H),8.47(d,J=8.5Hz,1H),8.39 (s,1H),8.06(dd,J=8.4,2.6Hz,1H),7.86(d,J=8.5Hz,1H),7.80(d,J=8.5Hz,1H),7.55-7.51(m,1H),7.17( d,J=8.5Hz,1H),5.24(t,J=8.6Hz,1H),4.40(d,J=13.4Hz,2H),3.92-3.86(m,2H),3.63-3.50(m,2H),2.86- 2.80(m,1H),2.44-2.32(m,5H),2.21-2.13(m,2H),1.69-1.63(m,1H),1.54-1.52(m,1H),1.45-1.40(m,1H).

[0991] Trifluoroacetate salt of compound 99: 1H NMR(500MHz,DMSO)δ10.13(s,1H),8.88(s,1H),8.64(s,1H),8.53(s,2H),8.05(s,1H),7.73 (dd,J=20.7,8.4Hz,3H),7.21(s,2H),6.98(s,1H),6.66(s,1H),5.32(t,J=5.0Hz,1H),4.43 (d,J=18.2Hz,1H),4.35(d,J=18.4Hz,1H),3.84(d,J=12.5Hz,2H),3.60(s,2H),2.64(s,1H) ,2.36(s,1H),2.03–1.98(m,3H),1.46(d,J=8.5Hz,3H),1.35(s,1H),0.85(d,J=7.1Hz,2H).

[0992] Trifluoroacetate salt of compound 101: 1 H NMR (500MHz, DMSO-d6) δ10.22(s,1H),8.91(s,1H),8.66(s,1H),8.62(d,J=8.6Hz,1H),8.52–8. 43(m,2H),8.13(s,1H),7.82(t,J=7.6Hz,2H),7.73(d,J=8.5Hz,1H),7.30(s,1H),7.15(d,J=8.4 Hz,1H),4.99(s,1H),4.39(d,J=11.9Hz,2H),3.92-3.84(m,2H),3.63–3.57(m,1H),3.60-3.50( m,1H),2.76-2.70(m,1H),2.33-2.28(m,1H),2.06-2.00(m,1H),1.83-1.77(m,1H),1.49(s,9H).

[0993] Trifluoroacetate salt of compound 102: 11H NMR (500 MHz, DMSO) δ 10.32 (s, 1H), 10.22 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 8.50 (d, J = 8.2 Hz, 1H), 8.20 (s, 1H), 7.94–7.81 (m, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.36 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 5.15 (s, 1H), 5.00 (t, J = 43.7 Hz, 1H), 4.46–4.30 (m, 2H), 3.95–3.81 (m, 3H), 3.59 (dd, J = 23.5, 11.9 Hz, 1H), 3.58–3.46 (m, 2H), 3.27 (s, 1H), 2.81 (d, J = 7.9 Hz, 1H), 2.12 (t, J = 39.7 Hz, 5H), 1.68 (dd, J = 12.6, 8.4 Hz, 1H), 1.54 (d, J = 12.2 Hz, 1H), 1.43 (d, J = 12.8 Hz, 1H).

[0994] Compound 103: 1 1H NMR (500 MHz, DMSO-d6) δ 10.43 (d, J = 5.7 Hz, 1H), 10.24 (s, 1H), 8.93 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.45 (d, J = 7.3 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 9.8, 4.2 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 14.6, 8.0 Hz, 1H), 4.41 (q, J = 18.3 Hz, 2H), 4.02–3.82 (m, 3H), 3.66–3.31 (m, 4H), 2.91 (dd, J = 13.4, 8.2 Hz, 1H), 2.20–1.92 (m, 6H), 1.84 (dd, J = 12.8, 6.7 Hz, 1H), 1.68 (td, J = 12.8, 4.4 Hz, 1H), 1.51 (d, J = 12.4 Hz, 1H), 1.41 (d, J = 12.6 Hz, 1H).

[0995] Compound 104: 1H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.41 (t, J = 6.8 Hz, 1H), 7.82 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J = 9.6 Hz, 1H), 6.98 (d, J = 7.4Hz,1H),6.87(s,1H),4.39(d,J=9.1Hz,2H),4.22(m,1H),3.86–3.81(m,2H),3.61 –3.51(m,2H),2.20–1.96(m,3H),1.70–1.66(m,2H),1.46–1.42(m,2H),1.24(s,6H).

[0996] Compound 105: 1 H NMR (500MHz, DMSO-d6) δ10.11(s,1H),8.83(s,1H),8.68(d,J=8.6Hz,1H),8.40(dd,J=7.6,5.8Hz,1H),7.82(s,1 H),7.65(dd,J=8.4,5.7Hz,2H),7.53(dd,J=10.0,2.6Hz,1H),6.98(td,J=7.5,2.7Hz,1H),6.89(d,J=8.3Hz,1H) ,6.24–5.92(m,1H),4.38(d,J=5.4Hz,2H),4.23–4.21(m,1H),3.86–3.81(m,2H),3.61–3.51(m,2H),3.20–3.17( m,1H),2.63–2.59(m,1H),2.07–1.93(m,2H),1.78–1.63(m,2H),1.46(d,J=12.6Hz,1H),1.37(d,J=13.6Hz,1H).

[0997] Compound 106: 11H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.84 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.44–8.39 (m, 1H), 7.82 (s, 1H), 7.65 (dd, J = 17.2, 8.4 Hz, 2H), 7.52 (dd, J = 10.0, 2.4 Hz, 1H), 6.98 (td, J = 7.5, 2.5 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.47–4.31 (m, 2H), 4.15 (t, J = 7.1 Hz, 1H), 3.83 (t, J = 10.7 Hz, 2H), 3.65–3.40 (m, 4H), 3.28 (s, 3H), 3.06 (dt, J = 11.8, 5.9 Hz, 1H), 2.92–2.84 (m, 1H), 2.57 (dd, J = 12.8, 7.6 Hz, 1H), 2.22 (s, 1H), 2.01 (td, J = 12.8, 4.4 Hz, 1H), 1.71 (dd, J = 12.6, 7.0 Hz, 2H), 1.45 (d, J = 12.5 Hz, 1H), 1.37 (d, J = 12.7 Hz, 1H).

[0998] Compound 107: 1 1H NMR (500 MHz, DMSO-d6) δ 10.10 (d, J = 5.6 Hz, 1H), 8.84 (s, 1H), 8.69 (d, J = 8.6 Hz, 1H), 8.41 (dd, J = 7.6, 5.7 Hz, 1H), 7.82 (s, 1H), 7.69 (dd, J = 8.6, 4.2 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 10.0, 2.7 Hz, 1H), 7.04–6.94 (m, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.46–4.31 (m, 2H), 4.19–4.17 (m, 1H), 3.85–3.80 (m, 4H), 3.75–3.64 (m, 1H), 3.64–3.44 (m, 3H), 2.68–2.55 (m, 1H), 2.24–2.22 (s, 1H), 2.13–2.09 (m, 1H), 2.06–1.96 (m, 1H), 1.86–1.63 (m, 3H), 1.51–1.35 (m, 2H).

[0999] Compound 108: 11H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.77 (s, 1H), 9.50 (s, 1H), 8.96 (s, 1H), 8.72–8.54 (m, 2H), 8.43 (s, 1H), 8.05 (d, J = 6.9 Hz, 1H), 7.81 (dd, J = 15.5, 8.5 Hz, 2H), 7.54 (s, 1H), 7.14 (d, J = 7.7 Hz, 1H), 5.04 (s, 1H), 4.41 (q, J = 18.9 Hz, 2H), 4.08–3.82 (m, 6H), 3.37 (d, J = 22.4 Hz, 2H), 2.89 (s, 1H), 2.24–1.81 (m, 7H), 1.68 (s, 1H), 1.57 (d, J = 12.4 Hz, 1H), 1.49 (d, J = 12.4 Hz, 1H).

[1000] Compound 109: 1 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.23 (d, J = 5.2 Hz, 1H), 9.13 (s, 1H), 8.94 (s, 1H), 8.53 (dd, J = 10.6, 7.2 Hz, 2H), 8.17 (s, 1H), 7.85 (dd, J = 14.3, 8.8 Hz, 2H), 7.75 (t, J = 11.0 Hz, 1H), 7.33 (t, J = 6.3 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.95–4.85 (m, 1H), 4.47–4.33 (m, 2H), 4.29–4.20 (m, 1H), 3.94–3.83 (m, 2H), 3.64–3.55 (m, 1H), 3.53–3.44 (m, 1H), 2.88 (dd, J = 13.3, 8.2 Hz, 1H), 2.21–2.07 (m, 3H), 1.93 (dd, J = 13.2, 8.0 Hz, 1H), 1.84–1.56 (m, 7H), 1.49 (d, J = 13.1 Hz, 2H).

[1001] Compound 110: 11H NMR (500 MHz, DMSO-d6) δ 10.19 (dd, J = 28.7, 18.4 Hz, 1H), 8.92 (s, 1H), 8.59 (s, 1H), 8.38 (ddd, J = 23.8, 16.1, 8.4 Hz, 1H), 8.19 (s, 1H), 7.92–7.75 (m, 3H), 7.34 (s, 1H), 7.24–7.04 (m, 1H), 4.79–4.65 (m, 1H), 4.48–4.31 (m, 2H), 4.17 (dd, J = 29.3, 8.9 Hz, 1H), 4.00–3.74 (m, 4H), 3.58 (d, J = 27.0 Hz, 2H), 3.30–3.09 (m, 2H), 3.05–2.86 (m, 1H), 2.25–1.93 (m, 5H), 1.64 (s, 1H), 1.54–1.35 (m, 2H).

[1002] Compound 112: 1 1H NMR (500 MHz, DMSO-d6) δ 10.13 (d, J = 6.7 Hz, 1H), 8.94 (d, J = 8.5 Hz, 1H), 8.85–8.83 (m, 1H), 8.44–8.34 (m, 1H), 7.82 (d, J = 4.6 Hz, 1H), 7.66–7.62 (m, 2H), 7.53 (dd, J = 10.1, 2.6 Hz, 1H), 7.07–6.96 (m, 1H), 6.85–6.83 (m, 1H), 4.48–4.29 (m, 2H), 4.24–4.14 (m, 1H), 3.95–3.91 (m, 2H), 3.85–3.81 (m, 2H), 3.61–3.51 (m, 2H), 2.83–3.81 (m, 1H), 2.63 (d, J = 4.5 Hz, 1H), 2.41–2.36 (m, 1H), 2.32–2.21 (m, 2H), 2.02–1.92 (m, 2H), 1.74–1.62 (m, 1H), 1.45 (d, J = 12.7 Hz, 1H), 1.34 (d, J = 13.1 Hz, 1H), 1.17–1.14 (m, 6H).

[1003] Compound 113: 11H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.25 (s, 1H), 8.93 (s, 1H), 8.51 (d, J = 5.9 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.93–7.79 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 7.16 (d, J = 8.5 Hz, 1H), 5.07 (s, 1H), 4.48–4.33 (m, 2H), 4.11 (d, J = 11.4 Hz, 1H), 3.99–3.10 (m, 7H), 2.86–2.73 (m, 2H), 2.21–2.09 (m, 2H), 2.03–1.93 (m, 1H), 1.69 (t, J = 10.6 Hz, 1H), 1.53 (d, J = 12.5 Hz, 1H), 1.40 (d, J = 12.7 Hz, 1H), 1.16 (dd, J = 13.7, 6.1 Hz, 6H).

[1004] Compound 114: 1 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.93 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.64 (dd, J = 7.4, 5.3 Hz, 1H), 8.33 (s, 1H), 8.00 (dd, J = 8.5, 2.4 Hz, 1H), 7.76 (dd, J = 15.9, 8.5 Hz, 2H), 7.47 (td, J = 7.5, 2.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.42 (t, J = 54.8 Hz, 1H), 4.91 (s, 1H), 4.46–4.33 (m, 2H), 3.86 (dd, J = 19.9, 8.0 Hz, 2H), 3.75–3.30 (m, 4H), 2.79 (s, 3H), 2.69 (dt, J = 27.2, 13.7 Hz, 1H), 2.11 (td, J = 12.9, 4.6 Hz, 1H), 2.02–1.93 (m, 1H), 1.66 (td, J = 12.8, 4.5 Hz, 1H), 1.49 (d, J = 12.3 Hz, 1H), 1.40 (d, J = 12.2 Hz, 1H).

[1005] Compound 115: 11H NMR (500 MHz, DMSO-d6) δ 10.60 (d, J = 7.9 Hz, 1H), 10.13 (s, 1H), 8.92 (s, 1H), 8.64–8.57 (m, 1H), 8.27–8.20 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 7.3, 5.2 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 5.33 (d, J = 6.2 Hz, 1H), 4.84 (q, J = 8.4 Hz, 1H), 4.41 (q, J = 18.4 Hz, 2H), 4.17 (d, J = 6.2 Hz, 1H), 4.09–3.77 (m, 6H), 3.66 (dd, J = 18.0, 6.6 Hz, 1H), 3.53 (t, J = 11.9 Hz, 1H), 3.00 (dd, J = 12.6, 7.7 Hz, 1H), 2.49–2.45 (m, 1H), 2.32 (d, J = 9.7 Hz, 1H), 2.27–2.15 (m, 3H), 2.00–1.92 (m, 1H), 1.62 (td, J = 12.6, 4.1 Hz, 1H), 1.49 (dd, J = 26.7, 12.6 Hz, 2H).

[1006] Compound 116: 1 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.18 (s, 1H), 8.92 (s, 1H), 8.58 (dd, J = 17.0, 11.5 Hz, 2H), 8.24 (s, 1H), 7.91 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.40 (t, J = 6.3 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 5.06 (s, 1H), 4.56 (s, 2H), 4.40 (q, J = 18.3 Hz, 2H), 3.88 (t, J = 11.3 Hz, 4H), 3.54 (dt, J = 34.8, 11.5 Hz, 2H), 3.39 (s, 1H), 3.23 (s, 1H), 2.80 (s, 1H), 2.12 (s, 4H), 1.98 (d, J = 16.2 Hz, 2H), 1.66 (td, J = 12.8, 4.5 Hz, 1H), 1.51 (d, J = 13.0 Hz, 1H), 1.40 (d, J = 13.0 Hz, 1H).

[1007] Compound 118: 11H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.96–8.85 (m, 1H), 8.70 (d, J = 8.5 Hz, 1H), 8.66–8.56 (m, 1H), 8.26 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.80–7.63 (m, 2H), 7.42 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.55–4.32 (m, 3H), 3.98–3.26 (m, 5H), 2.70 (dd, J = 13.1, 7.9 Hz, 1H), 2.11–1.93 (m, 3H), 1.81 (dd, J = 12.9, 7.3 Hz, 1H), 1.71 (td, J = 12.9, 4.5 Hz, 1H), 1.49 (d, J = 12.9 Hz, 1H), 1.40 (d, J = 11.9 Hz, 1H).

[1008] Compound 119: 1 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.83 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.45 (dd, J = 7.6, 5.7 Hz, 1H), 7.83 (s, 1H), 7.73 (dd, J = 12.3, 8.6 Hz, 2H), 7.53 (dd, J = 10.0, 2.7 Hz, 1H), 6.97 (td, J = 7.5, 2.7 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 4.39 (s, 2H), 3.77 - 3.72 (m, 2H), 3.69 (s, 2H), 3.61 (t, J = 11.8 Hz, 2H), 2.99 - 2.92 (m, 1H), 2.79 (s, 2H), 1.91 (td, J = 13.1, 5.0 Hz, 2H), 1.58 (d, J = 13.2 Hz, 2H), 1.10 (d, J = 6.5 Hz, 6H).

[1009] Compound 121: 1H NMR(500MHz,DMSO-d6)δ10.02(s,1H),8.81(s,1H),8.68(d,J=8.5Hz,1H),8.30(d,J =7.1Hz,1H),7.78–7.72(m,2H),7.70(d,J=8.6Hz,1H),7.42(s,1H),6.84(d,J=8.5H z,1H),6.78(d,J=7.2Hz,1H),4.38(s,2H),3.86(s,2H),3.76-3.71(m,2H),3.57(t, J=12.0Hz,2H),3.08(s,2H),2.38(s,3H),1.95-1.87(m,2H),1...

Claims

1. A compound represented by general formula (IA), its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts: in, Ring A is selected from The D or G are each independently selected from C or N, and the E are each independently selected from C, N or O; Ring B is selected from C 3-14 Cycloalkyl or 3-14 membered heterocyclic group; L is NH; X is selected from N or CH; R1 is selected from 6-18 membered heteroaryl, said 6-18 membered heteroaryl optionally further substituted with one or more R a Replacement; R a are independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, -C 0-3 Alkylene-OR b or -C 0-3 Alkylene-N(R b )2; R2 is H, C 1-6 Alkyl or C 1-6 alkyl halide; R3 is selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxy, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 N(R b )2、-(CH2) 0-3 -C 3-14 Cycloalkyl or -(CH2) 0-3 -3-14 membered heterocyclic group, said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -C 3-14 Cycloalkyl or -(CH2) 0-3 -3-14 membered heterocyclic group optionally further substituted with one or more R c replaced by; Each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 alkyl halide; The R c independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, cyano, amino, nitro, hydroxyl, C 1-6 Hydroxyalkyl, -C 0-3 Alkylene-C(=O)R b 、-C 0-3 Alkylene-C(=O)N(R b )2、-(CH2) 0-3 N(R b )2、-O(CH2) 0-3 C 3-14 Cycloalkyl, -O(CH2) 0-3 -3-14 membered heterocyclic group, C 3-14 Cycloalkyl, 3-14 membered heterocyclic group, C 6-18 Aryl or 5-18 membered heteroaryl; R5 is selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 1-6 alkyl halide; R d Selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, hydroxy or halogen; m is selected from 0, 1 or 2; n is selected from 0 or 1.

2. The compound of formula (IA) according to claim 1, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: The ring A is selected from 3. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: described Selected from The D or G is each independently selected from C or N, and the E or Z is each independently selected from C, N or O.

4. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: described Selected from 5. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: R3 is H, -(CH2) 0-3 N(R b )2, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, -(CH2) 0-3 -3-14 membered heterocyclic group or C 1-6 Alkyl, each R b are independently H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, -(CH2) 0-3 C 1-6 Alkoxy or C 1-6 Halogenated alkyl.

6. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: The R5 is selected from C 1-6 Alkyl, wherein n is selected from 0 or 1.

7. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: R1 is selected from described further by one or more R a Replacement; R a are independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-3 Alkylene-OR b or -C 0-3 Alkylene-N(R b )2, each R b are independently H, halogen, cyano, C 1-6 Alkyl, -(CH2) 0-3 C 1-6 Alkoxy, C 3-6 Cycloalkyl or C 1-6 Halogenated alkyl.

8. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: R1 is selected from 9. The compound of formula (IA) according to claim 1 or 2, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: R2 is H.

10. The compound according to claim 1, its stereoisomers, tautomers, deuterated substances or pharmaceutically acceptable salts, characterized in that: Selected from 11. A compound, a stereoisomer, a tautomer, a deuterated compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

12. An intermediate compound selected from:

13. A pharmaceutical composition, characterized in that The pharmaceutical composition contains a therapeutically effective amount of the compound according to any one of claims 1 to 11 or a stereoisomer, tautomer, deuterated substance or pharmaceutically acceptable salt thereof.

14. Use of the compound according to any one of claims 1 to 11 or its stereoisomers, tautomers or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 13, in the preparation of a medicament for treating and / or preventing cancer.

15. The use according to claim 14, characterized in that The medicine is used in preparing medicine for treating and / or preventing diseases mediated by HPK1.

16. The use according to claim 14 or 15, characterized in that The cancer or disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck cancer, cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.

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