HPK1 inhibitor and its use in medicine

Abstract

The present invention relates to a compound represented by the general formula (I), a stereoisomer, a tautomer, a deuteride, or a pharmaceutically acceptable salt thereof, which has cancer therapeutic activity. The present invention also relates to a method for preparing these compounds and a pharmaceutical composition containing the above compounds. TIFF2025519624000144.tif53170

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and specifically to a compound of formula (I), its stereoisomers, tautomers, deuterides or pharmaceutically acceptable salts, methods for preparing the same, pharmaceutical compositions containing the compound, and use as a medicament for treating cancer.

Background Art

[0002] Hematopoietic progenitor kinase 1 (HPK1), also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1), is a member of the serine / threonine kinase subfamily Ste20, and its family members further include MAP4K2 (GCK), MAP4K3 (GLK), MAP4K4 (HGK), MAP4K5 (KHS), and MAP4K6 (MINK). HPK1 is a negative regulator of the activation responses of B cells, T cells, and dendritic cells, and by inhibiting its expression, the antitumor immunity of the living body can be specifically improved. HPK1 is mainly expressed in hematopoietic cells such as T cells, B cells, dendritic cells, macrophages, mast cells, and neutrophils.

[0003] In T cells, HPK1 controls the role of T cell activation through the TCR signaling pathway. After TCR is activated, HPK1 interacts with the T cell receptor protein, is phosphorylated by tyrosine kinases Zap70 and Lck, phosphorylates the SLP-76 receptor protein, and negatively regulates the TCR signal, thereby inhibiting T cell activation and proliferation. Studies have found that HPK1 can be involved in many signal transduction cascades, including the MAPK signaling pathway, the Fas-induced apoptosis pathway, and the NF-κB signaling pathway. And HPK1 can further inhibit AP-1. AP-1 plays a role in promoting cell proliferation, inhibiting differentiation, promoting tumor cell invasion and metastasis, etc. in tumor formation and development.

[0004] Therefore, drugs targeting HPK1 have become one of the fields attracting attention in current drug discovery research, and there are also varieties that have entered the clinical trial stage. However, currently, drugs for the hematopoietic progenitor kinase (HPK1) target are not currently on the market. The present invention provides a novel small molecule HPK1 inhibitor with good antitumor activity.

Summary of the Invention

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

[0006]

Chemical formula

[0007] Ring A is selected from a bicyclic carbocyclic group, a 5- to 14-membered bicyclic heterocyclic group, a C 5-14 bicyclic aryl group, or a 10- to 18-membered bicyclic heteroaryl group, 10-18 and is selected from, L is selected from a bond, NH, O, or S, R1 is H, halogen, C 1-6 alkyl group, C 1-6An alkoxy group, a haloalkyl group, a hydroxyalkyl group, C 2-6 an alkenyl group, C 2-6 an alkynyl group, C 3-14 a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 an aryl group, or a 6- to 18-membered heteroaryl group, and the C 1-6 alkyl group, C 1-6 an alkoxy group, a haloalkyl group, a hydroxyalkyl group, C 3-14 a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 the aryl group or the 6- to 18-membered heteroaryl group is optionally further substituted with one or more R a , and R a is independently H, a hydroxy group, a cyano group, a halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, -C 0-3 alkylene-OR b , -OC(=O)C 1-6 alkyl group, -C 0-3 alkylene-SR b , -C 0-3 alkylene-N(R b )2, -C 0-3 alkylene-S(=O)R b , -C 0-3 alkylene-S(=O)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 group, C 2-6 alkynyl group, -C 0-3 alkylene-C 3-14 cycloalkyl group, -C 0-3 alkylene-(3- to 14-membered heterocyclyl group), -C 0-3 alkylene-C 6-18 aryl group, or -C0-3 Selected from alkylene-(5- to 18-membered heteroaryl group), said C 1-6 alkyl group, C 1-6 haloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, -C 0-3 alkylene-C 3-14 cycloalkyl group, -C 0-3 alkylene-(3- to 14-membered heterocyclyl group), -C 0-3 alkylene-C 6-18 aryl group, or -C 0-3 alkylene-(5- to 18-membered heteroaryl group) is optionally further substituted with one or more R b and each R b is independently H, halogen, hydroxy group, cyano group, C 1-6 alkyl group, -(CH2) 0-3 C 1-6 alkoxy group, C 3-6 cycloalkyl group or C 1-6 haloalkyl group,

[0008] R2 is selected from H, C 1-6 alkyl group, or haloalkyl group, R3 is selected from H, halogen, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, -(CH2) 0-3 N(R b )2, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 aryl group, or -(CH2) 0-3 -5- to 18-membered heteroaryl group, said C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxyalkyl group, C 2-6 alkenyl group, C 2-6Alkynyl group, -(CH2) 0-3 -C 3-14 Cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, - (CH2) 0-3 -C 6-18 Aryl group or -(CH2) 0-3 -5- to 18-membered heteroaryl group is optionally further substituted with one or more R c and R c is independently halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 2-6 alkenyl group, C 2-6 alkynyl group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -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 group, -O(CH2) 0-3 -3- to 14-membered heterocyclyl group, C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-18 aryl group, and one or more substituents selected from the group consisting of 5- to 18-membered heteroaryl groups, R4 or R5 is each independently C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH2) 1-3 N(R b )2, C 2-6 alkenyl group, C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-18 aryl group, or 6- to 18-membered heteroaryl group, and said C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH2) 1-3 N(R b)2. C 2-6 an alkenyl group, C 3-14 a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 an aryl group or a 6- to 18-membered heteroaryl group is optionally further substituted with one or more R d and, R4 or R5 is each independently an atom directly bonded to the A ring and C 3-14 a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 an aryl group or a 6- to 18-membered heteroaryl group, and the C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-18 aryl group or 6- to 18-membered heteroaryl group is optionally further substituted with one or more R d or, R4 and R5 are an atom bonded to the A ring and C 3-14 a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 an aryl group or a 6- to 18-membered heteroaryl group, and the C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-18 aryl group or 6- to 18-membered heteroaryl group is optionally further substituted with one or more R d and, R d is selected from H, halogen, C 1-6 an alkyl group, C 3-6 a cycloalkyl group, C 1-6 a haloalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, or a hydroxyalkyl, X is selected from CR6 or N, R6 is selected from H, halogen, C 1-6 an alkyl group, C 3-6 a cycloalkyl group, or C 1-6 a haloalkyl group, m is selected from 0, 1, 2, 3, or 4, n is selected from 0, 1, or 2.

[0009] In some embodiments, R3 in formula (I) is H, halogen, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, -(CH2) 0-3 N(R b )2, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 aryl group, or -(CH2) 0-3 -5- to 18-membered heteroaryl group, and the C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 aryl group or -(CH2) 0-3 -5- to 18-membered heteroaryl group is optionally further substituted with one or more R c , wherein the R c are independently halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -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 group, -O(CH2) 0-3 -3- to 14-membered heterocyclyl group, C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-18 aryl group, and 5- to 18-membered heteroaryl group, and is substituted with one or more substituents selected from the group consisting of.

[0010] In some embodiments, each R in formula (I) b is independently H, halogen, hydroxy group, cyano group, C 1-6 alkyl group, C 3-6 cycloalkyl group or C 1-6 haloalkyl group, wherein R3 is H, halogen, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, -(CH2) 0-3 N(R b )2, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 aryl group, or -(CH2) 0-3 -5- to 18-membered heteroaryl group, and the C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 aryl group, or -(CH2) 0-3 -5- to 18-membered heteroaryl group may be optionally further substituted with one or more R c s, wherein the R c s are independently halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C 0-3 alkylene-C(=O)R b s, -C 0-3 alkylene-C(=O)N(R b )2, -(CH2) 0-3 N(R b )2, -O(CH2) 0-3 C 3-14A cycloalkyl group, -O(CH2) 0-3 - A 3- to 14-membered heterocyclyl group, C 3-14 A cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 Substituted with one or more substituents selected from the group consisting of an aryl group and a 5- to 18-membered heteroaryl group, n is selected from 1 or 2.

[0011] In some embodiments, each R in formula (I) b is independently H, halogen, a hydroxy group, a cyano group, C 1-6 an alkyl group, C 3-6 a cycloalkyl group or C 1-6 a haloalkyl group, wherein R3 is H, halogen, C 1-6 an alkyl group, C 1-6 an alkoxy group, a haloalkyl group, a hydroxy group, a hydroxyalkyl group, -(CH2) 0-3 N(R b )2, -(CH2) 0-3 -C 3-14 a cycloalkyl group, -(CH2) 0-3 - A 3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 an aryl group, or -(CH2) 0-3 - A 5- to 18-membered heteroaryl group, and the C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 - A 3- to 14-membered heterocyclyl group, -(CH2) 0-3 -C 6-18 aryl group or -(CH2) 0-3 - A 5- to 18-membered heteroaryl group is optionally further substituted with one or more R c , wherein the R c are independently halogen, C 1-6 alkyl group, C 1-6An alkoxy group, a haloalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, -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 group, -O(CH2) 0-3 -a 3- to 14-membered heterocyclyl group, C 3-14 cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 aryl group, and one or more substituents selected from the group consisting of 5- to 18-membered heteroaryl groups, wherein n is selected from 1 or 2.

[0012] In some embodiments, R4 or R5 in formula (I) is each independently an atom directly bonded to ring A and C 3-14 cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 aryl group or a 6- to 18-membered heteroaryl group, and the C 3- 14 cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 aryl group or a 6- to 18-membered heteroaryl group is optionally further substituted with one or more Rd. The R d is selected from H, halogen, C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 haloalkyl group, cyano group, amino group, nitro group, hydroxy group, or hydroxyalkyl.

[0013] In some embodiments, L in formula (I) is selected from a bond or NH, preferably NH.

[0014] In some embodiments, R1 in formula (I) is C 6-18Selected from an aryl group or a 6-18 membered heteroaryl group, said C 6-18 The aryl group or 6-18 membered heteroaryl group is optionally further substituted with one or more R a . R a is independently H, a hydroxy group, a cyano group, a halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, -C 0-3 alkylene-OR b , -OC(=O)C 1-6 alkyl group, -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 group, or C 2-6 alkynyl group, and each R b is independently H, a halogen, a hydroxy group, a cyano group, C 1-6 alkyl group, -(CH2) 0-3 C 1-6 alkoxy group, C 3-6 cycloalkyl group, or C 1-6 haloalkyl group.

[0015] In some embodiments, R1 in formula (I) is

Chemical formula

[0016]

Chemical formula

[0017] is further substituted with one or more R a . R a is independently H, a hydroxy group, a cyano group, a halogen, C 1-6 alkyl group, C1-6 haloalkyl group, -C 0-3 alkylene-OR b , -OC(=O)C 1-6 alkyl group, -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 group, or C 2-6 alkynyl group, and each R b is independently H, halogen, hydroxy group, cyano group, C 1-6 alkyl group, -(CH2) 0-3 C 1-6 alkoxy group, C 3-6 cycloalkyl group, or C 1-6 haloalkyl group.

[0018] In some embodiments, R1 in formula (I) is

Chemical formula

[0019] In some embodiments, R1 in formula (I) is

Chemical formula

[0020] In some embodiments, R2 in formula (I) is preferably H.

[0021] In some embodiments, ring A in formula (I) is C 8-10 bicyclic carbocyclic group, 8- to 10-membered bicyclic heterocycloalkyl group, C 10-12Selected from a bicyclic aryl group or a 10- to 12-membered bicyclic heteroaryl group, preferably,

[0022]

Chemical formula

[0023] In some embodiments, ring A in formula (I) is C 8-10 a bicyclic carbocyclic group, an 8- to 10-membered bicyclic heterocycloalkyl group, C 10-12 a bicyclic aryl group, or a 10- to 12-membered bicyclic heteroaryl group, preferably,

[0024]

Chemical formula

[0025] In some embodiments, R3 in formula (I) is H, halogen, cyano group, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -a 3- to 14-membered heterocyclyl group, or -(CH2) 0-3 N(R b )2, and the C 1-6 alkyl group, C 1-6 alkoxy group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -a 3- to 14-membered heterocyclyl group, haloalkyl group, hydroxyalkyl group, C 2-6 alkenyl group or C 2-6 alkynyl group is optionally further substituted with one or more R c . The R c are independently halogen, C1-6 an alkyl group, C 1-6 an alkoxy group, a haloalkyl group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, C 2-6 an alkenyl group, C 2-6 an alkynyl group, -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 a cycloalkyl group, -O(CH2) 0-3 -a 3- to 14-membered heterocyclyl group, C 3-14 a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 an aryl group, and is substituted with one or more substituents selected from the group consisting of a 5- to 18-membered heteroaryl group. Each R b is, independently, H, a halogen, a hydroxy group, a cyano group, C 1-6 an alkyl group, -(CH2) 0-3 C 1-6 an alkoxy group, C 3-6 a cycloalkyl group, or C 1-6 a haloalkyl group.

[0026] In some embodiments, R3 in formula (I) is H, -(CH2) 0-3 N(R b )2, a cyano group, C 2-6 an alkenyl group, C 2-6 an alkynyl group, -(CH2) 0-3 -a 3- to 14-membered heterocyclyl group or C 1-6 an alkyl group, and each said R b is, independently, H, a halogen, a hydroxy group, a cyano group, C 1-6 an alkyl group, C 3-6 cyclo alkyl group, -(CH2) 0-3 C 1-6 an alkoxy group or C 1-6 a haloalkyl group.

[0027] In some embodiments, R4 in formula (I) is an atom directly bonded to ring A and C 3-14 forms a cycloalkyl group, a 3- to 14-membered heterocyclyl group, C 6-18 an aryl group or a 6- to 18-membered heteroaryl group.

[0028] In some embodiments, formula (I) is formula (IA): [Chemical formula] selected from,

[0029] wherein ring B is C 3-14 selected from a cycloalkyl group, a 3- to 14-membered heterocycloalkyl group, C 6-18 an aryl group, or a 6- to 18-membered heteroaryl group, wherein the definitions of R1, R2, R3, R5, X, L, ring A, R d , m, and n are the same as those described for formula (I).

[0030] In some embodiments, ring A in formula (IA) is C 8-10 selected from a bicyclic carbocyclic group, an 8- to 10-membered bicyclic heterocycloalkyl group, C 10-12 a bicyclic aryl group, or a 10- to 12-membered bicyclic heteroaryl group.

[0031] In some embodiments, ring A in formula (IA) is [Chemical formula] selected from, where D, E, and G are each independently selected from C, N, or O.

[0032] In some embodiments, ring A in formula (IA) is [Chemical formula] selected from.

[0033] In some embodiments, in formula (IA),

Chemical formula

[0034]

Chemical formula

[0035] In some embodiments, in formula (IA),

Chemical formula

[0036]

Chemical formula

[0037] In some embodiments, R3 in formula (IA) is H, halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, or -(CH2) 0-3 N(R b )2, and the C 1-6 alkyl group, C 1-6 alkoxy group, -(CH2) 0-3 -C 3-14 cycloalkyl group, -(CH2) 0-3 -3- to 14-membered heterocyclyl group, haloalkyl group or hydroxy group is optionally further substituted with one or more R c and R c is independently halogen, C 1-6 alkyl group, C 1-6 alkoxy group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -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 group, -O(CH2) 0-3 -3- to 14-membered heterocyclyl group, C 3-14 cycloalkyl group, 3- to 14-membered heterocyclyl group, C 6-18 aryl group, and one or more substituents selected from the group consisting of 5- to 18-membered heteroaryl groups, and each R b is independently H, halogen, hydroxy group, cyano group, C 1-6 alkyl group, -(CH2) 0-3 C 1-6 alkoxy group, C 3-6 cycloalkyl group, or C 1-6 haloalkyl group, and m is selected from 0, 1, 2, or 3.

[0038] In some embodiments, R3 in formula (IA) is H, -(CH2) 0-3 N(R b )2, cyano group, C 2-6 alkenyl group, C 2-6 alkynyl group, -(CH2)0 -3 -3- to 14-membered heterocyclyl group or C 1-6 alkyl group, and each said R b is independently H, halogen, hydroxy group, cyano group, C 1-6 alkyl group, C 3-6 cycloalkyl group, -(CH2) 0-3 C 1-6 alkoxy group or C 1-6 haloalkyl group.

[0039] In some embodiments, R5 in formula (IA) is C 1-6 selected from an alkyl group, and said n is selected from 0 or 1.

[0040] In some embodiments, L in formula (IA) is NH.

[0041] In some embodiments, R1 in formula (IA) is

Chemical formula

[0042]

Chemical formula

[0043] is further substituted with one or more R a , and R a is independently H, a hydroxy group, a cyano group, a halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, -C 0-3 alkylene-OR b , -OC(=O)C 1-6 alkyl group, -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 group, or C 2-6 alkynyl group, and each R b is independently H, a halogen, a hydroxy group, a cyano group, C 1-6 alkyl group, -(CH2) 0-3 C 1-6 alkoxy group, C 3-6 cycloalkyl group or C 1-6 haloalkyl group.

[0044] In some embodiments, R1 in formula (IA) is

Chemical formula

[0045] In some embodiments, R2 in formula (IA) is H.

[0046] In some embodiments,

Chemical formula

[0047]

Chemical formula

[0048]

Chemical formula

[0049]

Chemical formula

[0050] In some embodiments, formula (I) is

Chemical formula

[0051]

Chemical formula

[0052]

Chemical formula

[0053]

Chem.

[0054]

Chem.

[0055] On the other hand, the present invention provides the synthesis of the compound described by formula (I) in the claims or its stereoisomers, tautomers, deuterides, or pharmaceutically acceptable salts, and the intermediate compounds are

[0056]

Chem.

[0057] The compounds according to the present invention can efficiently inhibit the function of the HPK1 protein, induce the secretion of cytokines such as IL2 and IFNγ in T cells, and activate the immune system. On the other hand, such compounds all have excellent oral absorption in animal models of each species and genus, and can significantly inhibit the growth of tumor cells in mouse tumor models, and the drug efficacy is much higher than that of the HPK1 inhibitors currently in the clinical stage. Next, the compounds according to the present invention have the advantages of high selectivity, low toxicity, and a large safety margin, and thus are expected to obtain better clinical drug efficacy in the future.

[0058] The present invention further provides a pharmaceutical composition, which contains a therapeutically effective amount of at least one compound represented by formula (I), its stereoisomers, tautomers, deuterides or pharmaceutically acceptable salts.

[0059] The present invention provides the use of the compound represented by structural formula (I), its stereoisomers, tautomers, deuterides or pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of drugs.

[0060] The present invention further provides a preferred technical solution for the above use.

[0061] Preferably, the above use is for the preparation of a medicament for treating and / or preventing cancer.

[0062] Preferably, the above use is for the preparation of a medicament for treating a disease mediated by HPK1. Preferably, the disease is cancer.

[0063] 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 tumors, intrahepatic cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, squamous cell lung cancer, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

[0064] The present invention further provides a method for treating and / or preventing a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition comprising the same.

[0065] The present invention further provides a method for treating and / or preventing a disease mediated by HPK1, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition comprising the same.

[0066] The present invention further provides a method for treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound represented by structural formula (I) or a pharmaceutical composition comprising the same.

[0067] Preferably, in the above method, the disease mediated by HPK1 is cancer.

[0068] 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 tumors, intrahepatic cholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, squamous cell lung cancer, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

[0069] The general chemical terms used in the general structural formula have general meanings unless otherwise specified.

[0070] For example, unless otherwise specified, the term "halogen" used in the present invention refers to fluorine, chlorine, bromine or iodine.

[0071] In the present invention, unless otherwise specified, the "alkyl group" includes a linear or branched monovalent saturated hydrocarbon group. For example, the alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, a 3-(2-methyl)butyl group, a 2-pentyl group, a 2-methylbutyl group, a neopentyl group, an n-hexyl group, a 2-hexyl group, a 2-methylpentyl group, etc. Similarly, "C 1-6 " in " 1-6 " refers to a group arranged in a linear or branched form containing 1, 2, 3, 4, 5 or 6 carbon atoms.

[0072] The "alkoxy group" refers to the oxyether form of the above linear or branched alkyl group, that is, -O-alkyl group.

[0073] The term "alkylene group" refers to a divalent alkyl bonding group. The alkylene group formally refers to a hydrocarbon in which two C-H bonds are replaced by the bonding sites of the alkylene group and the remaining part of the compound. Similarly, C 1-3 In the alkylene group, "C 1-3The term "alkylene group" 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.

[0074] The term "haloalkyl group" refers to an alkyl group in which one or more H's are substituted by halogen atoms.

[0075] The term "oxo" or "oxo group" refers to an oxygen atom in the form of a divalent substituent, which forms a carbonyl group when bonded to C, and forms a sulfoxide group, a sulfone group, or an N-oxide group when bonded to a heteroatom. When combined with C, a carbonyl group is formed, and when combined with a heteroatom, a sulfoxide group, a sulfone group, or an N-oxide group is formed.

[0076] In the present invention, unless otherwise specified, the terms "aromatic ring", "aromatic group" or "aromatic heterocyclyl" refer to a polyvalent unsaturated ring carbocyclyl or heterocyclyl having aromaticity ((4n + 2) delocalized π electrons, where n is an integer).

[0077] In the present invention, unless otherwise specified, the term "aryl group" refers to an unsubstituted or substituted monocyclic or fused-ring aromatic group containing carbocyclyl atoms. Preferably, it is a C 6-18 aryl group, more preferably, the aryl group is a monocyclic or bicyclic aromatic ring group of C 6-10 Preferably, it is a phenyl group or a naphthalene group. Most preferably, it is a phenyl group. The aryl group ring may be condensed with a heteroaryl group, a heterocyclyl group or a cycloalkyl group, and the ring bonded to the parent structure is an aryl group ring. Non-limiting examples include, but are not limited to, a benzocyclopentyl group.

[0078] The term "heterocyclyl group" refers to a ring system having at least one cyclic alkyl group or cyclic alkenyl group containing a heteroatom, and the heteroatom is selected from N, O and / or S. The heterocyclyl group may include a monocyclic or polycyclic ring (for example, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclyl group may be bonded to other parts of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably, it is a 3- to 14-membered heterocyclyl group, and in the 3- to 14-membered heterocyclyl group, "3- to 14-membered" means a heterocyclyl group formed by 3 to 14 ring-forming atoms including C, N, O or S. More preferably, it is a 3- to 8-membered heterocyclyl group, and even more preferably, it is a 3- to 6-membered heterocyclyl group. The nitrogen heteroatom or sulfur heteroatom may be selectively oxidized, and the nitrogen heteroatom may be selectively quaternized. Examples of these heterocyclyl groups include, but are not limited to, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, oxopiperazinyl group, oxopiperidinyl group, tetrahydrofuranyl group, dioxolanyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydrooxazolyl group, tetrahydropyranyl group, morpholinyl group, thiomorpholinyl group, thiomorpholinyl sulfoxide, thiomorpholinyl sulfonyl group and tetrahydrooxadiazolyl group. The heterocyclyl group may be condensed to the ring of an aryl group, heteroaryl group or cycloalkyl group, and the ring bonded to the parent structure is a heterocyclyl group.

[0079] In the present invention, unless otherwise specified, the term "heteroaryl group" refers to an aromatic heterocyclyl having a monocyclic or polycyclic ring (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.) with at least one heteroatom, wherein the heteroatom is selected from N, O, and / or S, the nitrogen heteroatom or sulfur heteroatom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Preferably, it is a 5- to 18-membered heteroaryl group, and "5- to 18-membered" in the 5- to 18-membered heteroaryl group refers to a heteroaryl group formed by ring-forming atoms containing 5 to 18 C, N, O, or S. More preferably, it is a 5- to 10-membered heteroaryl group, and even more preferably, it is a 5- to 6-membered heteroaryl group. Examples of the heteroaryl group include, but are not limited to, thienyl group, furanyl group, imidazolyl group, isoxazolyl group, oxazolyl group, pyrazolyl group, pyrrolyl group, thiazolyl group, thiadiazolyl group, triazolyl group, pyridyl group, pyridazinyl group, indolyl group, azaindolyl group, indazolyl group, benzimidazolyl group, benzofuranyl group, benzothienyl group, benzoisoxazolyl group, benzothiazolyl group, benzothiazolyl group, benzothiadiazolyl group, benzotriazolyl adenine, quinolinyl group, or isoquinolinyl group. The heteroaryl group may be condensed to a ring of an aryl group, a heterocyclyl group, or a cycloalkyl group, and the ring combined with the parent structure is a heteroaryl group ring. The combined ring is a heteroaryl group ring.

[0080] The term "cycloalkyl group" refers to a ring system having at least one cyclic alkyl group. Preferably, it is a C 3-14 cycloalkyl group, and "C 3-14The term "cycloalkyl group" means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring-forming atoms. The cycloalkyl group may include monocyclic and polycyclic rings (e.g., having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes, but is not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, etc. The cycloalkyl group may be condensed to the ring of an aryl group, a heterocyclyl group or a heteroaryl group, and the ring bonded to the parent structure is a cycloalkyl group.

[0081] The term "bicyclic carbocyclic group" refers to a monovalent or polyvalent non-aromatic, saturated or partially unsaturated ring, containing no heteroatoms, including a bicyclic ring of 5-14 carbon atoms, one of which rings may be aromatic, but the bicyclic carbocyclic group is not aromatic as a whole. Preferably, it is a bicyclic carbocyclic group of 7-12 atoms, and the bicyclic carbocyclic group of 7-12 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and the bicyclic carbocyclic group of 9 or 10 atoms may be a bicyclo[5,6] or [6,6] system. Suitable bicyclic carbocyclic groups include, but are not limited to, fused bicyclic groups, spirobicyclic groups and bridged bicyclic groups. Examples further include, but are not limited to, fused bicyclo[3.3.0]octane group, fused bicyclo[3.1.0]hexane group, 1,2,3,4,4a,5,8,8a-octahydronaphthyl group, bicyclo[2.2.1]heptane group, etc. The hydrogen atoms in one or more rings are independently optionally substituted with one or more substituents described in the present invention.

[0082] The term "bicyclic heterocyclyl group" refers to a bicyclic system, where one or more atoms in the ring are independently and optionally substituted with heteroatoms. The ring may be fully saturated or may contain one or more degrees of unsaturation, and one of the rings may be aromatic, but the bicyclic heterocyclyl group as a whole is not aromatic. The heterocyclyl system may form a stable compound by bonding any heteroatom or carbon atom to the main structure. The hydrogen atoms in one or more rings are independently and optionally substituted with one or more substituents described in the present invention. The bicyclic heterocyclyl group includes, but is not limited to, fused heterobicyclic groups, spiro heterobicyclic groups, and bridged heterobicyclic groups. In some embodiments, each ring system in the bicyclic heterocyclyl group is a ring formed by 3-7 atoms, i.e., it contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to obtain groups such as SO, SO2, PO, PO2. In some embodiments, the bicyclic heterocyclyl group includes a heterocyclyl group-fused heterocyclyl group, a heterocyclyl group-fused carbocyclyl group, a heterocyclyl group-fused heteroaryl group, or a heterocyclyl group-fused aryl group, and is bonded to the main structure via a carbocyclyl group, a heteroaryl group, or a heterocyclyl group.

[0083] The term "bicyclic aryl group" is a bicyclic carbocyclic system. The bicyclic aryl ring system forms a ring in a fused form, and the bicyclic aryl group ring system is aromatic as a whole, and each ring system contains 5-9 atoms. It may include a naphthalene group. The hydrogen atoms in one or more rings are independently and optionally substituted with one or more substituents described in the present invention.

[0084] The term "bicyclic heteroaryl group" is a bicyclic system, and the bicyclic heteroaryl ring system forms a ring in a fused form. The bicyclic heteroaryl ring system is aromatic as a whole, and one or more atoms in the ring are independently and optionally substituted with heteroatoms (the heteroatoms are N, O, P , selected from S, and S or P may optionally be substituted with one or more oxygen atoms to give groups such as SO, SO2, PO, PO2.). The bicyclic heteroaryl system may form a stable compound by bonding any heteroatom or carbon atom to the main structure. The bicyclic heteroaryl group may be a bicyclic ring consisting of 7-15 atoms, or may be a bicyclic ring consisting of 7-10 atoms. The bicyclic ring having 7-10 atoms may be a bicyclo[4,5], [5,5], [5,6] or [6,6] system. The hydrogen atoms in one or more rings may independently be optionally substituted with one or more of the substituents described in the present invention.

[0085] The term "substituted" refers to the substitution of one or more hydrogen atoms in the group with the same or different substituents respectively. Typical substituents are halogen (F, Cl, Br or I), C 1-8 alkyl group, C 3-12 cycloalkyl group, -OR 1 , -SR 1 , =O, =S, -C(O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C(O)NR 1 R 2 , cyano group, nitro group, -S(O)2R 1 , -O-S(O2)OR 1 , -O-S(O)2R 1 , -OP(O)(OR 1 )(OR 2 ), including but not limited to these. R 1 and R 2 are independently -H, C 1-6 alkyl group, C 1-6 haloalkyl group, or C 3-6It is selected from a cycloalkyl group. In some embodiments, the substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, t-butoxy group, -SCH3, -SC2H5, formaldehyde group, -C(OCH3), cyano group, nitro group, -CF3, -OCF3, amino group, dimethylamino group, methylthio group, sulfonyl group, or a group containing an acetyl group.

[0086] Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl group, 2-aminoethyl group, 2-hydroxyethyl group, pentachloroethyl group, trifluoromethyl group, methoxymethyl group, pentafluoroethyl group, phenylmethyl group, dioxolylmethyl group and piperazinylmethyl group.

[0087] Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 2-methoxyethoxy group, 2-aminoethoxy group, 2,3-dihydroxypropoxy group, cyclopropylmethoxy group, aminomethoxy group, trifluoromethoxy group, 2-diethylaminoethoxy group, 2-ethoxycarbonylethoxy group, 3-hydroxypropoxy group.

[0088] When the number of a certain connecting group is 0, for example, -(CH2)0- indicates that the connecting group is a bond, (R3)0 indicates that there is no such position and no substitution of R3, and (R5)0 indicates that there is no such position and no substitution of R5.

[0089] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid.

[0090] When the compound provided by the present invention is an acid, the corresponding salt can be easily prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic alkalis include salts such as aluminum, ammonium, calcium, copper (higher and lower valences), ferric, ferrous, lithium, magnesium, manganese (higher and lower valences), potassium, sodium, zinc, etc. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Non-toxic organic bases that can be derived into pharmaceutically acceptable salts include primary amines, secondary amines and tertiary amines, including cycloamines and substituted group-containing amines, such as naturally occurring and synthetic substituted group-containing amines. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N’,N’-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and aminotrimethylolmethane, etc. include

[0091] When the compound provided by the present invention is a base, the corresponding salt can be easily prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclohexylsulfamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharic acid, trifluoroacetic acid, tartaric acid, and p-toluenesulfonic acid, etc. More preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. Even more preferably, formic acid and hydrochloric acid.

[0092] The prodrugs of the compounds according to the present invention are included within the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that can be easily converted into the necessary compound in vivo. For example, any pharmaceutically acceptable salt, ester, salt of ester or other derivative of the compound according to the present invention can directly or indirectly provide the compound according to the present invention, or a metabolite or residue with pharmaceutical activity of the compound according to the present invention when administered to a receptor.

[0093] The compounds according to the present invention can contain one or more asymmetric centers, whereby diastereomers and optical isomers can be generated. The present invention includes all possible diastereomers and their racemic mixtures, their substantially pure separated enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0094] When tautomers exist in the compound represented by formula (I), the present invention includes any possible tautomers and pharmaceutically acceptable salts, and mixtures thereof, unless otherwise specified.

[0095] Substitution of compounds of formula (I) with heavier isotopes (e.g., deuterium) may confer several therapeutic advantages due to greater metabolic stability, for example allowing for increased in vivo half-life or reduced dosage.

[0096] The term "pharmaceutical composition" refers to a mixture consisting of one or more compounds according to the invention or pharma- ceutically acceptable salts thereof, and pharma- ceutically acceptable auxiliary materials, intended to facilitate administration of the compounds according to the invention to an organism.

[0097] As used herein, "a," "one," "the," "at least one," and "one or more" can be used interchangeably. Thus, for example, a mixture comprised of "one" pharma- ceutically acceptable auxiliary ingredient can be interpreted to mean that the pharmaceutical composition contains "one or more" pharma- ceutically acceptable auxiliary ingredients.

[0098] The term "pharmacologically acceptable auxiliary material" refers to a material that has no obvious irritating effect on the organism and does not impair the biological activity and performance of the active compound. Suitable auxiliary materials are well known to those skilled in the art, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers. Coalesce, hydrophilic or hydrophobic materials, gelatin, oil, solvents, water, and the like.

[0099] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharma- ceutically acceptable auxiliary materials, and can be prepared into, for example, solid, semi-solid, liquid or gaseous preparations, such as, for example, tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0100] Typical routes of administration of the compounds of the present invention or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0101] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect. In terms of partially or completely stabilizing or curing a disease and / or side effects associated with the disease, the effect can be therapeutic. As used herein, "treatment" encompasses all treatments of a patient's disease and includes (a) suppression of the symptoms of the disease, i.e., preventing the progression of the disease, or (b) alleviation of the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0102] The term "effective amount" means a dosage of a compound according to the present invention for (i) treating or preventing a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of the compound according to the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the method of administration and the age of the mammal being treated, but can generally be determined by one of ordinary skill in the art based on their own knowledge and the content of the present disclosure.

[0103] Synthesis Scheme 1:

Chemical Formula

[0104] Step I: Compounds I-1 and I-2 underwent a backward coupling reaction under the action of a Pd catalyst such as Pd2(dba)3 to obtain compound I-3.

[0105] Step II: Compound I-3 and

Chemical Formula

[0106] [Chemical formula] Compound I was obtained by introducing R1 through the Suzuki coupling reaction under the action of a metal catalyst such as PdCl2(dppf).CH2Cl2 or PdCl2(dppf). P is Cl, Br or I.

[0107] To make the above content clearer and more definite, in the present invention, the technical solution of the present invention will be further described with reference to 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, and do not limit the protection scope of the present invention. In the specific embodiments of the present invention, technical means or methods not specifically described, etc., are common technical means or methods in the field.

[0108] Unless otherwise specified, all temperatures in the present invention refer to degrees Celsius. In the examples, the following abbreviations were used.

[0109] DMF: N,N-dimethylformamide; NBS: N-bromosuccinimide; THF: Tetrahydrofuran; [PdCl2(dppf)]: Dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II); [PdCl2(dppf)]CH2Cl2: Dichloromethane complex of dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II); EA: Ethyl acetate; PE: Petroleum ether; DCM: Dichloromethane; MeOH: Methanol; Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium; Sphos: 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl; BPO: Dibenzoyl peroxide; DMAP: 4-Dimethylaminopyridine; MsCl: Methanesulfonyl chloride; AIBN: Azobisisobutyronitrile; TMSCN: Trimethylsilyl cyanide; TBAF: Tetrabutylammonium fluoride; LDA: Lithium diisopropylamide; TBAF: Tetrabutylammonium fluoride; LiHMDS: Lithium bis(trimethylsilyl)amide; TMSCl: Trimethylchlorosilane; XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; Dioxane: Dioxane; RT: Room temperature; (Boc)2O: Di-t-butyl dicarbonate; DIBAL-H: Diisobutylaluminum hydride; RuPhos PdG3: Methanesulfonato(2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium(II); i-PrOH: Isopropanol; PPA: Polyphosphoric acid; B2Pin2: Bis(pinacolato)diboron; Noyori catalyst (ss): Chloro(S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine(p-cymene)ruthenium(II) chloride; BocNH2: t-Butyl carbamate; TFA: Trifluoroacetic acid; TFAA: Trifluoroacetic anhydride; MTBE: Methyl t-butyl ether; Ti(OEt)4: Tetraethyl titanate; DMSO: Dimethyl sulfoxide; Solutol / HS15 / SolutolHS15: Polyethylene glycol-15 hydroxystearate.

[0110] Synthesis of Intermediate M1: [Chemical formula]

[0111] Step 1: Synthesis of Compound M1-1 At room temperature, 3-chloro-2-methylbenzoic acid (200.00 g) and potassium carbonate (405.09 g) were added to DMF (1300.00 mL). Methyl iodide (80.28 mL) was added dropwise under an ice-water bath, and the reaction was carried out at room temperature for 16 h. 2000 mL of water was added to the reaction solution, and it was extracted with 1000 mL of EA three times. The organic phases were combined, washed six times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound M1-1 (213.00 g, yield 98.41%).

[0112] Step 2: Synthesis of Compound M1-2 At room temperature, compound M1-1 (103.00 g), NBS (109.22 g), and BPO (2. 70 g) were added to chloroform (700.00 mL), and the reaction was carried out at 90 °C for 16 h. 1000 mL of water was added to the reaction solution, and it was extracted with 1000 mL of DCM three times. The organic phases were combined, washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound M1-2 (145.00 g, yield 98.63%).

[0113] Step 3: Synthesis of Compound M1-3 Under an ice-water bath, compound M1-2 (350.00 g) was added to a methanol solution of ammonia (7 M, 1000.00 mL), and the reaction was carried out under an ice-water bath for 1 h. The reaction solution was concentrated to obtain a solid, and the solid was washed three times with water and dried to obtain the target compound M1-3 (213.80 g, yield 96.05%). ESI-MS m / z: 167.9 [M+H] + .

[0114] Step 4: Synthesis of Compound M1-4 At room temperature, compound M1-3 (100.00 g) was added to concentrated sulfuric acid (600.00 mL). Under the condition of an ice-water bath, concentrated nitric acid (50.00 mL) was added dropwise. The mixture was stirred for 1 h under the ice-water bath and further stirred for 1 h at room temperature. The reaction solution was gradually poured into ice water, filtered, and the filter cake was washed 3 times with water. The filter cake was dried to obtain the target compound M1-4 (116.08 g, yield 91.51%). ESI-MS m / z: 213.0 [M+H] + 。

[0115] Step 5: Synthesis of compound M1-5 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 in several portions at 65 °C, and the mixture was reacted at 65 °C for 2 h. The reaction solution was filtered while it was hot, and the filter cake was washed 6 times with EA. The filtrate was concentrated, water was added, and a solid was precipitated and filtered. The filter cake was washed 3 times with water and dried. Further, it was slurried with PE / EA = 3 / 1, filtered, and dried to obtain the target compound M1-5 (162.00 g, yield 77.29%). ESI-MS m / z: 183.0 [M+H] + 。

[0116] Step 6: Synthesis of compound M1-6 Compound M1-5 (129.00 g) was added to hydrobromic acid (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, and the mixture was reacted at -10 °C for 1 h. CuBr (111.47 g) was added, and the temperature was raised to 80 °C and stirred for 1 h. The reaction solution was poured into ice water, and the product was precipitated and filtered, washed 3 times with water, and the filter cake was dried to obtain the target compound M1-6 (143.00 g, yield 82.12%). ESI-MS m / z: 247.9 [M+H] + 。

[0117] Step 7: Synthesis of compound M1 Compound M1-6 (143.00 g) and DMAP (7.09 g) were added to THF (1300.00 mL). Under an ice-water bath, (Boc)2O (159.94 mL) was added dropwise, and the reaction was carried out at room temperature for 1 h. The reaction solution was quenched by adding it to water (1000.00 mL), extracted with 8000 mL of EA three times repeatedly. The organic phases were combined, washed three times with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, slurried with PE, filtered, and the filter cake was dried to obtain the target compound M1 (185.00 g, yield 92.00%). ESI-MS m / z: 289.9 [M+H] + 。

[0118] Synthesis of intermediate M2:

Chemical formula

[0119] Step 1: Synthesis of compound M2-1 At room temperature, 2-chloro-3-methyl-5-bromopyridine (5.00 g) was dissolved in THF (50 mL). Under N2 protection, LDA (14.53 mL, 2 M) was gradually added dropwise at -78 °C, and the reaction was carried out while maintaining the temperature for 40 min. Then, CO2 was gradually bubbled through, and the temperature was gradually raised to room temperature and the reaction was carried out for 40 min to stop the reaction. It was quenched with a saturated sodium bicarbonate solution, EA was added, and the phases were separated, leaving the aqueous phase. The organic phase was back-extracted twice with water. The aqueous phases were combined, and the pH was adjusted to 4 with HCl. Then, it was extracted five times with DCM / i-PrOH = 3:1. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated to obtain the target compound M2-1 (2.83 g, yield 46.66%). ESI-MS m / z: 250.5 [M+H] + 。

[0120] Step 2: Synthesis of compound M2-2 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 gradually added dropwise under nitrogen gas protection. After that, the reaction was carried out at room temperature for 16 h, and the reaction was stopped. Water was added for quenching, and extraction was performed 3 times with EA. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target compound M2-2 (1.80 g, yield 60.23%). ESI-MS m / z: 265.5 [M+H] + 。

[0121] Step 3: Synthesis of compound M2-3 At room temperature, compound M2-2 (1.50 g) was dissolved in CCl4 (20 mL), NBS (2.02 g) and AIBN (90.00 mg) were added, and the reaction was carried out at 80 °C for 16 h under nitrogen gas protection, and the reaction was stopped. Water was added for quenching, and extraction was performed 3 times with DCM. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target compound M2-3 (1.80 g, yield 92.30%). ESI-MS m / z: 344.4 [M+H] + 。

[0122] Step 4: Synthesis of compound M2-4 At room temperature, compound M2-3 (1.80 g) was dissolved in methanol of ammonia (20 mL), and the reaction was carried out at room temperature for 2 h, and the reaction was stopped. The reaction solution was filtered, the filter cake was 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] + 。

[0123] Step 5: Synthesis of compound M2 At room temperature, compound M2-4 (1.28 g) was dissolved in 1,4-dioxane (60 mL), D After adding MAP (70 mg), di-t-butyl dicarbonate (1.40 g) was gradually added dropwise, and the reaction was carried out at room temperature for 2 h, and then the reaction was stopped. Water was added for quenching, and the mixture was extracted 3 times with EA. The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target compound M2 (1.57 g, yield 87.75%). ESI-MS m / z: 347.3 [M+H] + 。

[0124] Synthesis of Intermediate M3

Chemical Structure

[0125] Step 1: Synthesis of Compound M3-2 Under the protection of nitrogen gas and at -78 °C, LiHMDS (4.95 mL, 1 M / THF) was added dropwise to a solution of M3-1 (1 g) in THF (10 mL) within 30 minutes. After stirring for 30 minutes, TMSCl (0.66 mL) was added, and the mixture was stirred for 5 minutes. Then LiHMDS (9.67 mL, 1 M / THF) was added dropwise within 30 minutes, and the temperature was raised to -30 °C to -20 °C and stirred for 30 minutes. Bis(2-bromoethyl) ether (1.09 g) was added, and 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, the organic layers were combined, washed successively with 1 M 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 M3-2 (246 mg, yield 18%). ESI-MS m / z: 281.99 [M+H] + 。

[0126] Step 2: Synthesis of Compound M3-3 Under an ice bath, sodium borohydride (99 mg) was added to a solution of M3-2 in MeOH (6 mL) and THF (2 mL) in several portions. The ice bath was removed, and the reaction was carried out at room temperature for 1 hour. Water was added to quench the reaction, and the mixture was concentrated under reduced pressure to remove a part of the solvent. The residue 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, yield 88%). ESI-MS m / z: 283.98 [M+H] + 。

[0127] Step 3: Synthesis of compound M3-4 Under an ice bath, thionyl chloride (0.28 mL) was added dropwise to a solution of M3-3 in DCM (5 mL). The ice bath was removed, and the temperature was raised to 40 °C and the reaction was carried out for 1 hour. The mixture was concentrated under reduced pressure, a small amount of methanol was added to dissolve it, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (PE:EA = 85:15) gave compound M3-4 (148 mg, yield 64%). ESI-MS m / z: 301.96 [M+H] + 。

[0128] Step 4: Synthesis of compound M3-5 At room temperature, M3-4 (148 mg), potassium carbonate (203 mg) and potassium iodide (16 mg) were dissolved in acetonitrile (5 mL), dimethylamine (2.45 mL, 2 M / THF) was added, the temperature was raised to 80 °C, and the reaction was carried out for 3 hours. After cooling, suction filtration was carried out, the filtrate was concentrated under reduced pressure, and purification by column chromatography (DCM:MeOH = 95:5) gave compound M3-5 (85 mg, yield 56%). ESI-MS m / z: 311.02 [M+H] + 。

[0129] Step 5: Synthesis of compound M3-6 At room temperature, 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), replaced with nitrogen gas, heated to 100 °C and reacted for 6 hours. After cooling, suction filtration was carried out, the filtrate was concentrated under reduced pressure, purified by column chromatography (DCM:MeOH = 92:8), and compound M3-6 (86 mg, yield 77%) was obtained. ESI-MS m / z: 412.25 [M+H] + 。

[0130] Step 6: Synthesis of compound M3 At room temperature, M3-6 (86 mg) was dissolved in MeOH (2 mL), hydrochloric acid (0.52 mL, 4M / 1,4-dioxane) was added, heated to 50 °C and reacted for 1 hour. After cooling, it was concentrated under reduced pressure, a small amount of methanol was added to dissolve it, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by column chromatography (PE:EA = 92:8, 1‰ aqueous ammonia) to obtain compound M3 (45 mg, yield 87%). ESI-MS m / z: 248.15 [M+H] + 。

[0131] Synthesis of intermediate M4:

Chemical formula

[0132] Step 1: Synthesis of compound M4-1 NaH (4.62 g, content 60%) was added to DMSO (200 ml) in several portions, under N2 protection, the temperature was controlled at 15-20 degrees, and a solution of raw material p-bromophenylacetonitrile (10.3 g) and 2,2'-dibromodiethyl ether (12.79 g) in ethyl ether (50 ml) was added dropwise over 2 hours. After the dropwise addition, the temperature was raised to room temperature and reacted for 12 hours. It was detected that the reaction was completely finished. The reaction solution was gradually added dropwise to ice water, a solid was precipitated, filtered, the solid was washed with water, filtered and dried, and the target product M4-1 (14 .0 g, with a yield of 100%) was obtained. ESI-MS m / z: 266.1 [M+H] + .

[0133] Step 2: Synthesis of Compound M4-2 The raw material M4-1 (6.0 g) was dissolved in DCM (100.00 mL). Under N2 protection, it was cooled to -78 °C, and DIBAL-H (27.05 mL) was added dropwise. Then, the temperature was maintained at -65 °C for 2 hours. Subsequently, the temperature was gradually raised to 0 °C and stirred for 5 minutes. The temperature was controlled at 0 °C, and an aqueous solution of 15% HCl (9.6 ml) was added dropwise, and the reaction was carried out at RT for 2 hours. Water and DCM were added to the reaction solution for dilution, and extraction was performed 3 times with DCM (100 ml). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrate was separated by column chromatography (PE:EA = 5:1) to obtain the target product M4-2 (3.26 g, yield 53.7%).

[0134] Step 3: Synthesis of Compound M4-3 Under N2 protection, the raw material triethyl phosphonoacetate (3.30 g) was dissolved in THF (25 mL), and NaH (0.61 g, 60%) was added in several portions and reacted at RT for 1 hour. After cooling to 0 °C, a THF (8 ml) solution of M4-2 (3.30 g) was added dropwise, and the reaction was carried out at RT for 2 hours. Water (30 ml) and EA (25 ml) were added to the reaction solution for dilution, stirred to form layers, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the concentrate was separated by column chromatography (PE:EA = 5:1) to obtain the target product M4-3 (3.73 g, yield 89.7%). ESI-MS m / z: 340.2 [M+H] + .

[0135] Step 4: Synthesis of Compound M4-4 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). Under an ice bath, sodium borohydride (1.78 g) was added in several portions. After the color turned black, the temperature was maintained at 0 °C for 30 minutes, and then naturally warmed to RT and the reaction was carried out for 30 minutes. The reaction solution was quenched by adding water after treatment, extracted twice with EA (50 ml), the organic phase was dried over anhydrous sodium sulfate, and the concentrate was separated by column chromatography (PE:EA = 5:1) to obtain the target product M4-4 (705 mg, yield 17.5%). ESI-MS m / z: 342.2 [M+H] + 。

[0136] Step 5: Synthesis of compound M4-5 Raw material M4-4 (705 mg) was dissolved in THF (6.00 mL) and MeOH (2.00 mL), water (5.00 mL) of sodium hydroxide (0.25 g) was added, and the reaction was carried out at RT for 2 hours. The organic solvent was removed from the reaction solution using a rotary evaporator, diluted HCl was added to adjust the pH to 4, a white solid was precipitated, filtered, washed with water, and dried to obtain the target product M4-5 (545 mg, yield 84.2%). ESI-MS m / z: 314.2 [M+H] + 。

[0137] Step 6: Synthesis of compound M4-6 Raw material M4-5 (520 mg) was added to polyphosphoric acid (5.00 mL), heated to 90 °C and reacted for 0.5 hour, ice water and EA were added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate. The organic phase was separated, dried over anhydrous sodium sulfate, and the concentrate was separated by column chromatography (PE:EA = 3:1) to obtain the target product M4-6 (485 mg, yield 98.9%). ESI-MS m / z: 296.2 [M+H] + 。

[0138] Step 7: Synthesis of compound M4-7 Raw material M4-6 (435.00 mg) was added to methanol (10.00 mL) and tetrahydro Dissolved in Rofluran (3.00 mL), cooled to 0 °C, sodium borohydride (223.00 mg) was added in several portions, and reacted at RT for 0.5 h. For the reaction solution, a part of the solvent was removed with a rotary evaporator, water and EA were added and extracted 3 times (15 ml), dried over anhydrous sodium sulfate, dried with a rotary evaporator, and water was removed 3 times with DCM to obtain the target crude product M4-7, which was directly used in the reaction of the next step (404 mg, yield 92.2%). ESI-MS m / z: 298.2 [M+H] + 。

[0139] Step 8: Synthesis of compound M4-8 The raw material M4-7 (405.00 mg) was dissolved in dichloromethane (12.00 mL), thionyl chloride (0.49 mL) was added dropwise under an ice bath, and heated to 40 °C and reacted for 30 min. The reaction solution was diluted with DCM, water (5 ml) was added and adjusted to pH = 8 - 9 with saturated sodium bicarbonate, extracted 3 times with DCM (15 mL), dried over anhydrous sodium sulfate, and the concentrate was separated by column chromatography (PE:EA = 20:1) to obtain the target product M4-8 (301 mg, yield 70.0%). ESI-MS m / z: 315.1 [M+H] + 。

[0140] Step 9: Synthesis of compound M4-9 The raw material M4-8 (300.00 mg) was dissolved in acetonitrile (7.00 mL), potassium iodide (31.56 mg), potassium carbonate (394.11 mg), dimethylamine (2M) (2571.12 mg) were added, then the tube was sealed and heated to 80 °C and reacted for 8 h. The reaction solution was cooled to room temperature, filtered and washed with EA, the filtrate was dried with a rotary evaporator, and the concentrate was separated by column chromatography (PE:EA = 1:1) to obtain the target product M4-9 (263 mg, yield 85.3%). ESI-MS m / z: 324.2 [M+H] + 。

[0141] Step 10: Synthesis of compound M4-10 Under N2 protection, raw material M4-9 (300.00 mg), benzophenone imine (184.44 mg), cesium carbonate (602.90 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26.79 mg) were added to 1,4-dioxane (8.00 mL), bubbled with N2, heated to 100 °C and reacted for 12 hours. The reaction solution was filtered directly, the filter cake was washed with EA, the filtrate was dried with a rotary evaporator, and the concentrate was separated by column chromatography (DCM:CH3OH = 20:1) to obtain the target product M4-10 (253 mg, yield 64.4%). ESI-MS m / z: 425.6 [M+H] + 。

[0142] Step 11: Synthesis of Compound M4 Raw material M4-10 (304.00 mg, 95%) was dissolved in methanol (5.00 mL), hydrochloric acid (4M dioxane solution) (0.51 mL, 4.00 mol / L) was added, and the reaction was carried out at RT for 1 hour. The reaction solution was dried with a rotary evaporator, then a small amount of methanol (0.5 ml) was added, EA (10 ml) was added to precipitate a solid, filtered, the filter cake was washed with EA, the solid was dissolved in water, saturated sodium bicarbonate was adjusted to pH = 8, and extracted 4 times with DCM:CH3OH = 10:1 (15 ml). The organic phase was dried over anhydrous sodium sulfate and dried with a rotary evaporator to obtain the target product M4 (118 mg, yield 66.6%). ESI-MS m / z: 261.4 [M+H] + 。

[0143] Synthesis of Intermediate M5:

Chemical Structure

[0144] Step 1: Synthesis of Compound M5-2 Under nitrogen gas protection and at -78 °C, LiHMDS (23.25 mL, 1 M / THF) was added dropwise to a solution of M5-1 (4 g) in THF (80 mL) within 30 minutes. After stirring for 30 minutes, TMSCl (3.09 mL) was added, and the mixture was stirred for 5 minutes. Then, LiHMDS (55.36 mL, 1 M / THF) was added dropwise within 30 minutes, the temperature was raised to -30 °C to -20 °C, and the mixture was stirred for 30 minutes. Bis(2-bromoethyl) ether (5.39 g) was added, the temperature was gradually raised to room temperature, and the mixture was stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution, concentrated under reduced pressure to remove part of the solvent, extracted with EA, the organic layers were combined, washed successively with 1 M HCl, water, and saturated brine, 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, yield 29%).

[0145] Step 2: Synthesis of compound M5-3 Under an ice bath, sodium borohydride (0.74 g) was added portionwise to a solution of M5-2 (1.63 g) in MeOH (10 mL) and THF (6 mL). The ice bath was removed, and the reaction was carried out at room temperature for 1 hour. Water was added to quench the reaction, and the mixture was concentrated under reduced pressure to remove part of the solvent. It was extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound M5-3 (1.60 g, yield 97%). 1 H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 7.07 (s, 1H), 5.15 (t, J = 6.3 Hz, 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).

[0146] Step 3: Synthesis of compound M5-4 Under an ice bath, thionyl chloride (2.53 mL) was added dropwise to a DCM (20 mL) solution of M5-3 (1.76 g). The ice bath was removed, and the temperature was raised to 40 °C and reacted for 1 hour. It was concentrated under reduced pressure, a small amount of methanol was added and dissolved, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, 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 M5-4 (1.72 g, yield 91%).

[0147] Step 4: Synthesis of compound M5-5 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, 2 M / THF) was added, the temperature was raised to 80 °C and reacted for 3 hours. It was cooled and suction filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 96:4) to obtain compound M5-5 (1.18 g, yield 66%). ESI-MS m / z: 280.2 [M+H] + 。

[0148] Step 5: Synthesis of compound M5-6 At room temperature, M5-5 (300 mg), benzophenone imine (251 mg), RuPhos PdG3 (77 mg) and cesium carbonate (904 mg) were dissolved in xylene (10 mL), replaced with nitrogen gas, the temperature was raised to 120 °C and reacted for 6 hours. It was cooled and suction filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 93:7) to obtain compound M5-6 (303 mg, yield 77%). ESI-MS m / z: 425.3 [M+H] + 。

[0149] Step 6: Synthesis of compound M5 At room temperature, M5-6 (363 mg) was dissolved in MeOH (5 mL), hydrochloric acid (5 mL, 4 M / 1,4-dioxane) was added, the temperature was raised to 50 °C, and the reaction was carried out for 2 hours. After cooling, it was concentrated under reduced pressure, a small amount of methanol was added and dissolved, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by column chromatography (PE:EA = 92:8, 1‰ aqueous ammonia) to obtain compound M5 (186 mg, yield 83%). ESI-MSm / z: 261.3 [M+H] + 。

[0150] Synthesis of intermediate M6:

Chemical formula

[0151] Step 1: Synthesis of compound M6-1 At room temperature, NaH (2.86 g) was added to DMF (100.00 mL), and replaced with N2. Under the condition of an ice-water bath, a solution of 2-(4-bromo-2-methylphenyl)acetonitrile (5.00 g) dissolved in 10 mL of DMF was added dropwise, and the reaction was continued while maintaining the temperature for 15 min. Then, a solution of 1,2-dibromoethane (6.71 g) dissolved in 10 mL of DMF was added dropwise. The ice-water bath was removed, and the reaction was carried out at room temperature for 2 h. The reaction solution was added to 300 mL of ice water, and extracted 3 times with 150 mL of ice water. The organic phases were combined, washed with saturated sodium chloride, and the organic phase was concentrated. The concentrate was separated and purified by column chromatography (PE:EA = 95:5~90:10) to obtain the target product M6-1 (4.25 g, 75.63%). ESI-MSm / z: 236.0 [M+H] + 。

[0152] Step 2: Synthesis of compound M6-2 At room temperature, compound M6-1 (26.84 g) was dissolved in THF / tetrahydrofuran (270.00 mL), replaced with nitrogen gas, and under the protection of nitrogen gas and the condition of an ice-water bath, BH3.THF (568.38 mL) was gradually added dropwise, and the reaction was continued while maintaining the temperature for 15 min, The ice bath was removed and the reaction was carried out under reflux for 5 h. The reaction solution was cooled, the pH was adjusted to 2 - 3 with 1 M HCl, and the reaction solution was continuously reacted under reflux for 1 h. Then, after adjusting the pH to 8 - 9 with saturated sodium bicarbonate, it was extracted 3 times with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the target product M6-2 (28.80 g) was obtained. ESI-MS m / z: 240.0 [M+H] + 。

[0153] Step 3: Synthesis of compound M6-3 At room temperature, compound M6-2 (25.50 g) was dissolved in dichloromethane (300.00 mL). Under nitrogen gas protection and under the condition of an ice bath, after adding triethylamine (44.28 mL), TFAA (22.14 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 3 h. The reaction solution was added to a certain amount of ice water, extracted 3 times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated to obtain a crude product, the samples were mixed, and the target product (20.60 g, yield 57.71%) was obtained by column chromatography (PE:EA = 95:5 - 91:9). ESI-MS m / z: 336.1 [M+H] + 。

[0154] Step 4: Synthesis of compound M6-4 At room temperature, compound M6-3 (15.60 g) was dissolved in HOAc (206.00 mL). Under nitrogen protection and under the condition of an ice bath, concentrated sulfuric acid (138.00 mL) was slowly added dropwise, and the reaction was carried out while maintaining the temperature for 0.5 h. Then, paraformaldehyde (2.09 g) was added in several portions, the temperature was returned to room temperature, and the reaction was carried out for 16 h. The reaction solution was slowly poured into a certain amount of ice water, extracted 3 times with EA, the organic phases were combined, the organic phase was washed with saturated sodium bicarbonate solution, washed with saturated brine, the organic phase was concentrated to obtain a crude product, the samples were mixed, and separated by column chromatography (PE:EA = 100:0 - 91:9) to obtain the target product M6-4 (6.00 g, yield 37.13%). ESI-MS m / z: 348.0 [M+H] + 。

[0155] Step 5: Synthesis of compound M6-5 At room temperature, compound M6-4 (8.20 g) was dissolved in EtOH (147.00 mL) and H2O (49.00 mL), potassium carbonate (16.28 g) was added, and the mixture was reacted at 80 °C for 1 h. The reaction solution was cooled to room temperature, ethanol was removed by a rotary evaporator, then extracted three times with EA, washed three times with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the target product M6-5 (5.70 g, yield 95.98%) was obtained. ESI-MS m / z: 252.0 [M+H] + 。

[0156] Step 6: Synthesis of compound M6-6 At room temperature, compound M6-5 (5.70 g) was dissolved in methanol (57.00 mL) and HOAc (38.00 mL). Under nitrogen protection and in an ice-water bath, a 37% aqueous solution of formaldehyde (2.75 g) was slowly added dropwise, and the reaction was carried out while maintaining the temperature for 1 h. Then, sodium triacetoxyborohydride (14.37 g) was added in several portions, and the reaction was allowed to proceed at room temperature for 2 h. The pH of the reaction solution was adjusted to 8 - 9 with saturated sodium bicarbonate solution, and then extracted 2 - 3 times with EA. The combined organic phases were washed with saturated sodium bicarbonate and then with saturated brine, and the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM:MeOH = 100:0 - 95:5) to obtain the target product M6-6 (4.80 g, 79.77%). ESI-MS m / z: 266.1 [M+H] + 。

[0157] Step 7: Synthesis of compound M6-7 At room temperature, 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), and the reaction was carried out at 90 °C for 24 h under N2 protection, and then the reaction was stopped. The reaction solution was directly concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4 - 90:10) to obtain the target product M6-7 (0.72 g, yield 59.43%). ESI-MS m / z: 323.26 [M+H] +。

[0158] Step 8: Synthesis of Compound M6 At room temperature, compound M6-7 (720.00 mg) was added to dichloromethane (20.00 mL), and under N2 protection conditions, trifluoroacetic acid (5.0 mL) was added in an ice-water bath, and the reaction was carried out under reflux for 1 h, and then the reaction was stopped. The reaction solvent was removed by a rotary evaporator, 10 mL of H2O and 10 mL of DCM were added to the reaction solution, and NaOH was added to adjust the pH>12, and then extracted 3 times with 25 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and the organic phase was concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4~90:10) to obtain the target product M6 (350.00 mg, yield 77.49%). ESI-MS m / z: 203.22 [M+H] + 。

[0159] Synthesis of Intermediate M7:

Chemical formula

[0160] Step 1: Synthesis of Intermediate M7-1 At room temperature, compound 2-bromo-3-pyridinecarboxaldehyde (15.00 g) was added to MeOH (200.00 mL), and under N2 protection conditions, the temperature was controlled at 0~5 °C. After sodium borohydride (3.66 g) was gradually added in several portions, the ice-water bath was removed, and the reaction was carried out at room temperature of 25 °C for 1 h. 150 mL of water was added to the reaction solution to quench it, methanol was removed, and then extracted 5 times with 100 mL of EA, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated as it was, dried, to obtain the target product M7-1 (14.20 g, yield 93.67%). ESI-MS m / z: 188.0 [M+H] + 。

[0161] Step 2: Synthesis of Intermediate M7-2 At room temperature, compound M7-1 (14.20 g) was added to DCM (350.00 mL), and then Under N₂ protection conditions, the temperature was controlled at 0 - 5 °C, and PBr₃ (6.40 mL) was gradually added in several portions. After that, the ice-water bath was removed, and the reaction was carried out at room temperature (25 °C) for 18 h. The reaction solution was quenched by adding it to 500 mL of ice water, 30% NaOH was added to adjust the pH to 12 - 13, and then it was extracted 3 times with 250 mL of DCM, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was directly concentrated and dried to obtain the target product M7-2 (18.00 g, yield 94.99%). ESI-MS m / z: 250.9 [M + H] + 。

[0162] Step 3: Synthesis of intermediate M7-3 At room temperature, compound M7-2 (18.00 g), TMSCN (12.81 g), and potassium carbonate (19.83 g) were added to THF (200.00 mL). Under N₂ protection conditions, the temperature was controlled at 0 - 5 °C, and TBAF (7.17 mL, 1 M - THF) was gradually added in several portions. After that, the ice-water bath was removed, and the reaction was carried out at room temperature (25 °C) for 14 h. The reaction solution was quenched by adding it to 500 mL of ice water, and then it was extracted 4 times with 150 mL of EA, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was directly concentrated. The concentrate was separated by column chromatography (PE:EA = 10:1 - 60:40) to obtain the target product M7-3 (12.10 g, yield 85.61%). ESI-MS m / z: 197.0 [M + H] + 。

[0163] Step 4: Synthesis of intermediate M7-4 At room temperature, compound NaH (60%) was added to DMSO (240.00 mL), and under N2 protection conditions, the temperature was controlled at 18 - 25 °C. A solution of M7-3 (12.10 g) and 2,2'-dibromodiethyl ether dissolved in ethyl ether (60.00 mL) and DMSO (15.00 mL) was gradually added dropwise to the reaction system in several portions and dissolved, and the reaction was carried out at room temperature (25 °C) for 3 h. The reaction solution was quenched by adding it to 500 mL of ice water, and then extracted 4 times with 150 mL of EA, washed 5 times with 150 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was directly concentrated. The concentrate was separated by column chromatography (PE:EA = 10:1 - 60:40) to obtain the target product M7-4 (13.20 g, yield 77.89%). ESI-MS m / z: 267.2 [M + H] + 。

[0164] Step 5: Synthesis of intermediate M7-5 At room temperature, compound M7-4 (6.00 g) was added to anhydrous DCM (100.00 mL), and under N2 protection conditions, the temperature was controlled at -78 °C. DIBAL-H (24.33 mL, 1 M / hexane) was gradually added dropwise in several portions, the temperature was controlled at -70 - -60 °C, and the reaction was carried out for 3 h to stop the reaction. The temperature was raised to room temperature, 10 mL of 15% HCl was added to the reaction solution to quench it, saturated sodium bicarbonate was added to adjust the pH to 8 - 9, and then extracted 4 times with 60 mL of DCM, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was directly concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (PE:EA = 10:1 - 40:60) to obtain the target product M7-5 (4.00 g, yield 65.93%). ESI-MS m / z: 270.2 [M + H] + 。

[0165] Step 6: Synthesis of intermediate M7-6 At room temperature, 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). Then, under reflux conditions, water was separated from toluene using a water separator, and the reaction was carried out for 3 h before stopping the reaction. After cooling to room temperature, the reaction solution was directly concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (PE:EA = 10:1 - 40:60) to obtain the target product M7-6 (4.50 g, yield 52.58%). ESI-MS m / z: 314.2 [M+H] + .

[0166] Step 7: Synthesis of intermediate M7-7 At room temperature, compound M7-6 (4.50 g), tributyl(1-ethoxyvinyl)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). Then, under N2 protection conditions, the reaction was carried out for 14 h while maintaining the temperature at 110 °C before stopping the reaction. After cooling to room temperature, 200 mL of 5% KF aqueous solution was added to the reaction solution for quenching for 0.5 h. Then, extraction was performed 5 times with 60 mL of DCM, washing was carried out 2 times with 100 mL of saturated sodium chloride, drying was performed with anhydrous sodium sulfate, filtration was carried out, and the organic phase was directly concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (PE:EA = 10:1 - 40:60) to obtain the target product M7-7 (2.30 g, yield 52.58%). ESI-MS m / z: 306.4 [M+H] + .

[0167] Step 8: Synthesis of intermediate M7-8 At room temperature, compound M7-7 (2.30 g) was added to 6 M HCl (10.00 mL) and DCM (10.00 mL), and under N2 protection conditions, the reaction was carried out for 1 h while maintaining the temperature at 50 °C, and the reaction was stopped. The reaction solution was added to 100 mL of ice water for quenching, 30% NaOH was added to adjust the pH to 12 - 13, and then extracted 3 times with 50 mL of DCM, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4 - 90:10) to obtain the target product M7-8 (0.9 g, yield 55.51%). ESI-MS m / z: 216.3 [M+H] + 。

[0168] Step 9: Synthesis of intermediate M7-9 At room temperature, compound M7-8 (1.80 g) and 10% palladium on carbon (0.18 g) were added to methanol (40.00 mL), and under H2 conditions, the reaction was carried out for 34 h while maintaining the temperature at 25 °C, and the reaction was stopped. Celite was added to filter off the palladium on carbon, and then washed 5 times with 20 mL of methanol. The reaction solutions were combined and concentrated as it was and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:EA = 10:1 - 50:50) to obtain the target product M7-9 (1.70 g, yield 52.58%). ESI-MS m / z: 220.3 [M+H] + 。

[0169] Step 10: Synthesis of intermediate M7-10 At room temperature, compound M7-9 (1.70 g) was added to DCM (40.00 mL), and under N2 protection conditions, the temperature was controlled at 0 - 5 °C. SOCl2 (2.48 mL) was gradually added in several portions. After that, the ice-water bath was removed, and the reaction was carried out at room temperature (25 °C) for 2 h, and then the reaction was stopped. The reaction solution was quenched by adding it to 50 mL of ice water, saturated sodium bicarbonate was added to adjust the pH to 8 - 9, and then it was extracted 3 times with 50 mL of DCM, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5 - 93:7) to obtain the target product M7-10 (1.40 g, yield 86.09%). ESI-MS m / z: 238.7 [M+H] + .

[0170] Step 11: Synthesis of intermediate M7-11 At room temperature, compound M7-10 (1.43 g) was added to DCM (50.00 mL), and under N2 protection conditions, m-chloroperbenzoic acid (2.44 g, 85%) was gradually added in several portions. The reaction was carried out at room temperature (25 °C) for 1 h, and then the reaction was stopped. The reaction solution was quenched by adding it to 100 mL of saturated sodium bicarbonate, and then it was extracted 4 times with 30 mL of DCM, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5 - 93:7) to obtain the target product M7-11 (1.50 g, yield 98 .28%). ESI-MS m / z: 254.7 [M+H] + .

[0171] Step 12: Synthesis of intermediate M7-12 At room temperature, compound M7-11 (1.30 g) and pyridine (2.06 mL) were added to DCM (40.00 mL), and under N2 protection conditions, trifluoromethanesulfonic anhydride (1.72 mL) was gradually added in several portions. The reaction was carried out at room temperature (25 °C) for 1 h and then stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was slurried with 10 mL of ethyl ether, filtered, and the solid was dried as it was to obtain the target product M7-12 (2.0 g, yield 123.59%). ESI-MS m / z: 254.7 [M+H] + 。

[0172] Step 13: Synthesis of intermediate M7-13 At room temperature, compound M7-12 (2.00 g) and ethanolamine (11.91 mL) were added to ethanol (15.00 mL), and under N2 protection conditions, the reaction was carried out at room temperature (25 °C) for 3 h and then stopped. The reaction solution was quenched by adding it to 20 mL of saturated sodium bicarbonate, a large amount of pale yellow solid was precipitated and filtered, and the solid was dried as it was to obtain the target product M7-13 (1.10 g, yield 68.72%). ESI-MS m / z: 253.8 [M+H] + 。

[0173] Step 14: Synthesis of intermediate M7 At room temperature, 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), and under N2 protection conditions, the reaction was carried out at 100 °C for 4 h while maintaining the temperature, and then the reaction was stopped. The reaction solution was concentrated as it was to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~90:10) to obtain the target product M7 (1.05 g, yield 96.70%). ESI-MS m / z: 262.1 [M+H] + 。

[0174] Synthesis of intermediate M8:

Chemical Structure

[0175] Step 1: Synthesis of Compound M8-1 Control the temperature at 15 - 30 °C in an ice-water bath. Add mCPBA (490. 7 g, 85%) to the DCM solution (1500 mL) of compound 6,7-dihydro-5H-cyclopenta[b]pyridine (240.0 g) in several portions, and then stir at room temperature for 1.5 hours for reaction. Purify the reaction solution directly by column chromatography to obtain compound M8-1 (143.60 g, yield 52%). ESI-MS m / z: 136.05 [M+H] + 。

[0176] Step 2: Synthesis of Compound M8-2 Under the protection of nitrogen gas, react the solution of M8-1 (41.0 g) in acetic anhydride (200 mL) at 110 - 120 °C for 1.5 hours while maintaining the temperature. Concentrate under reduced pressure to remove part of the solvent, add water, extract with EA, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify by column chromatography (PE / EA = 100 - 3 / 1) to obtain compound M8-2 (37.7 g, yield 71%). ESI-MS m / z: 178.12 [M+H] + 。

[0177] Step 3: Synthesis of Compound M8-3 Under an ice bath, dropwise add the aqueous solution (400 mL) of NaOH (40.3 g) to the EtOH solution (400 mL) of M8-2 (89.2), remove the ice bath, warm up to room temperature, and react for 1 hour. Concentrate under reduced pressure, add water, extract with DCM, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain compound M8-3 (59.8 g, yield 88%). ESI-MS m / z: 136.08 [M+H] + 。

[0178] Step 4: Synthesis of Compound M8-4 The temperature was controlled at 15 - 30 °C in an ice bath. Dess-Martin oxidant (206.4 g) was added to M8-3 (59.8 g) in DCM (400 mL) in several portions, and then stirred at room temperature for 2 hours for reaction. The reaction solution was quenched by adding it to a 10% aqueous sodium carbonate solution, filtered, and the filtrate was extracted with DCM. The organic layer was washed with a 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 (47.8 g, yield 81%). ESI-MS m / z: 134.11 [M+H] + 。

[0179] Step 5: Synthesis of compound M8-5 At room temperature, DBU (132.4 mL) was added to M8-4 (59.0 g) in THF (700 mL). The temperature was controlled below 25 °C in an ice bath, and t-butyldimethylchlorosilane (80.1 g) was added dropwise. Then, it was stirred at room temperature for 2 hours for reaction. The reaction solution was quenched by adding it to a saturated ammonium chloride aqueous solution, 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, yield 94%).

[0180] Step 6: Synthesis of compound M8-6 Under nitrogen gas protection, M8-5 (56.0 g) was dissolved in THF (700 mL), cooled to -70 °C in a dry ice - ethanol bath, and LiHMDS (679 mL, 1.0 mol / L) was added dropwise. Then, the temperature was gradually raised to -30 to -20 °C, and the reaction was carried out while maintaining the temperature for 2 hours. After 2,2'-dibromodiethyl ether (57.7) was added dropwise, the temperature was naturally raised to room temperature, and it was stirred for 3 hours for reaction. The reaction solution was quenched by adding it to a saturated ammonium chloride aqueous solution, extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product of compound M8-6 (88.2 g), which was directly used in the next step of the reaction. ESI-MS m / z: 318.33 [M+H] + 。

[0181] Step 7: Synthesis of Compound M8-7 Dissolve M8-6 (88.0 g, crude product) in THF (400 mL), cool it in an ice-water bath, and add dropwise a solution of hydrochloric acid (92 mL) in water (90 mL). Then stir at room temperature for 4 hours to react. Concentrate and remove THF, add water to dissolve, extract with EA to remove impurities , and neutralize the acid and water layer with sodium carbonate to a pH of about 9, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain Compound M8-7 (40.5 g, yield 72%). ESI-MS m / z: 204.16 [M+H] + .

[0182] Step 8: Synthesis of Compound M8-8 Dissolve Compound M8-7 (24.3 g) in THF (100 mL) and MeOH (300 mL), cool it in an ice-water bath, add sodium borohydride (6.8 g) in several portions, then stir at room temperature for 1.5 hours to react. Concentrate the reaction solution, add the concentrate to saturated ammonium chloride, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate by column chromatography, purify (DCM / MeOH = 100~100 / 5) to obtain Compound M8-8 (17.0 g, yield 69%). ESI-MS m / z: 206.25 [M+H] + .

[0183] Step 9: Synthesis of Compound M8-9 Dissolve Compound M8-8 (17.0 g) in DCM (350 mL), cool it in an ice-water bath, add thionyl chloride (29.6 g) dropwise, then stir at room temperature for 3 hours to react. Add the reaction solution to a cold aqueous sodium bicarbonate solution to quench, add sodium carbonate to adjust the pH to about 7 - 8, extract with DCM, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain Compound M8-9 (18.5 g, yield 99%). ESI-MS m / z: 224.20 [M+H] + .

[0184] Step 10: Synthesis of Compound M8-10 Compound M8-9 (18.1 g) was dissolved in DCM (250 mL), cooled in an ice-water bath, the temperature was controlled at 15 - 30 °C, mCPBA (36 g) was added in several portions, and then stirred at room temperature for 4 hours for reaction. The reaction solution was cooled to below 5 °C, the temperature was controlled below 10 °C, an aqueous sodium carbonate solution was added dropwise to quench it until the pH was about 8 - 9, extracted with DCM, the organic phases were combined, washed with a 5% aqueous sodium sulfite solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated and purified by column chromatography to obtain compound M8-10 (12.6 g, yield 65%). ESI-MS m / z: 240.08 [M+H] + 。

[0185] Step 11: Synthesis of Compound M8 Compound M8-10 (6.8 g) was dissolved in DMF (100 mL), cooled in an ice-water bath, the temperature was controlled at 0 - 10 °C, phosphorus oxychloride (21.8 g) was added dropwise, and then stirred at room temperature for 9 hours for reaction. The reaction solution was added to an ice-water mixture, filtered to collect the filter cake, dissolved in DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound M8 (5.4 g, yield 71%). ESI-MS m / z: 258.14 [M+H] + 。

[0186] Synthesis of Intermediate M9:

Chemical Structure

[0187] Step 1: Synthesis of Compound M9-1 At room temperature, 2-amino-4-fluoropyridine (3.00 g) was added to acetonitrile (30.0 Dissolved in (0 mL), and NCS (3.93 g) was added in portions several times, and reacted at room temperature for 3 h, then the reaction was stopped. Quenched with saturated sodium thiosulfate solution, extracted 3 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 target product M9-1 (1.00 g, yield 25.50%). ESI-MS m / z: 113.0 [M+H] + 。

[0188] Step 2: Synthesis of compound M9-2 At room temperature, compound M9-1 (986.00 mg), chloroacetaldehyde (4.00 g, 40% aqueous solution), and NaHCO3 (1.13 g) were dissolved in ethanol (20.00 mL), reacted at 80 °C for 13 h, and then the reaction was stopped. The reaction solution was concentrated directly, the samples were mixed, and separated by column chromatography (PE:EA = 3:1) to obtain the target product M9-2 (259 mg, yield 22.57%). ESI-MS m / z: 171.0 [M+H] + 。

[0189] Step 3: Synthesis of compound M9 At room temperature, compound M9-2 (259.00 mg) was dissolved in chloroform (5.00 mL), then NCS (3.93 g) was added in portions several times, reacted at room temperature for 7 h, and then the reaction was stopped. The reaction solution was concentrated directly, the samples were mixed, and separated by column chromatography (PE:EA = 4:1) to obtain the target product M9 (218 mg, yield 48.43%). ESI-MS m / z: 29.0 [M+H] + 。

[0190] Synthesis of intermediate M10:

Chemical formula

[0191] Step 1: Synthesis of compound M10-1 4-Chloro-7-nitroisoindolin-1-one (3.00 g) and DMAP (3.00 g) were added to THF (30.00 mL) at room temperature. Under an ice-water bath, Boc2O (3.89 mL) was added dropwise, and the mixture was reacted 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, dried to obtain the target product M10-1 (3.50 g, yield 79.31%). ESI-MS m / z: 313.1 [M+H] + 。

[0192] Step 2: Synthesis of compound M10 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, and iron powder (3.00 g) was added in several portions at 70 °C. The mixture was reacted at 70 °C for 1 h. The reaction solution was filtered, and the filter cake was washed twice with DCM. The filtrate was concentrated, diluted with water, filtered, and the filter cake was separated by column chromatography (PE:EA = 65:35) to obtain the target product M10 (3.10 g, purity 81.64%). ESI-MS m / z: 283.1 [M+H] + 。

[0193] Synthesis of intermediate M11:

Chemical formula

[0194] Step 1: Synthesis of compound M11-1 After dissolving 2-bromo-3-iodopyridine (10 g) in THF (150 mL), the reaction system was placed at -20 °C. Under nitrogen gas protection, isopropylmagnesium chloride (4.4 g) was gradually added dropwise. After that, the reaction was carried out at this temperature for 2 h. Then, tetrahydro-4H-pyran-4-one (5.3 g) was added, and the mixture was stirred overnight at room temperature. 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. The combined organic layers were washed successively with 1 M 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, yield 35%). ESI-MS m / z: 258.0 [M + H] + 。

[0195] Step 2: Synthesis of compound M11-2 Compound M11-1 (3.0 g) was dissolved in DMF (25 mL). Under an ice bath, NaH (0.74 g) was added, and then the mixture was stirred at room temperature for 30 min to react. Then, a DMF solution of 3-bromopropylene (1.6 g) and TBAI (0.34 g) was added dropwise, and the mixture was stirred overnight at room temperature to react. Water was added to quench the reaction. The mixture was concentrated under reduced pressure to remove part of the solvent, extracted with EA, and the organic layers were combined. 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 = 70:30 - 65:35) to obtain compound M11-2 (2.8 g, yield 80%). ESI-MS m / z: 298.1 [M + H] + 。

[0196] Step 3: Synthesis of compound M11-3 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). Under nitrogen gas protection, the reaction was carried out at 90 °C for 6 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:30 - 65:35) to obtain compound M11-3 (0.84 g, yield 77%). ESI-MS m / z: 218.1 [M + H] + 。

[0197] Step 4: Synthesis of Compound M11-4 Compound M11-3 (0.34 g) was dissolved in MeOH (5 mL) and DCM (10 mL), ozone was bubbled through the solution at -50 °C, and after reacting for 30 min, dimethyl sulfide (0.34 g) was added. After complete reaction, the solution was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:40 - 50:50) to obtain Compound M11-4 (0.24 g, yield 83%). ESI-MS m / z: 220.1 [M+H] + 。

[0198] Step 5: Synthesis of Compound M11-5 Under an 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 proceed at room temperature for 1 h. Water was added to quench the reaction, and the solution was concentrated under reduced pressure to remove part of the solvent. The residue was extracted with EA, 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, yield 74%). ESI-MS m / z: 222.1 [M+H] + 。

[0199] Step 6: Synthesis of Compound M11-6 Under an 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, and the temperature was raised to 40 °C and the reaction was allowed to proceed for 1 h. The solution was concentrated under reduced pressure, a small amount of methanol was added to dissolve the residue, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, the residue was extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:80) to obtain Compound M11-6 (115 mg, yield 96%). ESI-MS m / z: 239.0 [M+H] + 。

[0200] Step 7: Synthesis of Compound M11-7 At room temperature, M11-6 (410 mg) was dissolved in DCM (20 mL), mCPBA (590 mg) was added at room temperature, and the mixture was reacted at room temperature for 3 h. Then, LC-MS was used to confirm that the raw materials had completely reacted. Saturated sodium bicarbonate solution (10 mL) was added, and the mixture was stirred at room temperature for 30 min. Then, it 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 obtain compound M11-7 (428 mg, yield 98%). ESI-MS m / z: 256.1 [M+H] + 。

[0201] Step 8: Synthesis of compound M11-8 M11-7 (400 mg) and pyridine (1.2 g) were dissolved in DCM (10 mL). Under an ice bath, Tf2O (1.3 g) was added, and the mixture was reacted at room temperature for 0.5 h. Then, LC-MS was used to confirm that the raw materials had completely reacted. It was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound M11-8 (472 mg, yield 96%). ESI-MS m / z: 317.1 [M+H] + 。

[0202] Step 9: Synthesis of compound M11-9 M11-8 (250 mg) was dissolved in dimethylamine tetrahydrofuran solution (15 mL) at room temperature and stirred at room temperature for 0.5 h. Then, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound M11-9 (175 mg, yield 87%). ESI-MS m / z: 255.1 [M+H] + 。

[0203] Step 10: Synthesis of compound M11 M11 - 9 (150 mg), KI (12 mg), Cs2CO3 (575 mg), and methylamine tetrahydrofuran solution (2.4 mL) were dissolved in DMA (5.0 mL), stirred overnight at 100 °C, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound M11 (150 mg, yield 97%). ESI-MS m / z: 264.2 [M + H] + 。

[0204] Synthesis of Intermediate M12

Chemical Structure

[0205] Step 1: Synthesis of Compound M12 - 1 At room temperature, methyl 6-chloro-3-methylpyridine-2-carboxylate (33.00 g) was dissolved in carbon tetrachloride (400.00 mL), then NBS (33.12 g) and AIBN (2.91 g) were added. Under nitrogen gas protection, the reaction was carried out at 80 °C for 3 h and then stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 obtain the target product M12 - 1 (22.00 g, yield 46.81%). ESI-MS m / z: 186.0 [M + H] + 。

[0206] Step 2: Synthesis of Compound M12 - 2 At room temperature, compound M12 - 1 (22.00 g) and K2CO3 (19.50 g) were dissolved in ACN (300.00 mL). Under ice bath conditions, TMSCN (12.38 g) was slowly added dropwise, and the reaction was carried out at room temperature for 13 h and then stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 obtain the target product M12 - 2 (10.00 g, yield 57.00%). ESI-MS m / z: 211.3 [M + H] + 。

[0207] Step 3: Synthesis of compound M12-3 Compound NaH (2.29 g) was dissolved in DMF (65.00 mL) at room temperature, and then slowly added to M12-2 (5.23 g) under nitrogen gas protection conditions and reacted while maintaining the temperature for 0.5 h, then 2,2'-dibromodiethyl ether (9.20 g) was slowly added dropwise and reacted at room temperature for 3 h to stop the reaction. Under ice bath conditions, it was quenched with saturated ammonium chloride solution, extracted with EA three times, the organic phase was combined, washed with saturated saline, dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by silica gel column chromatography (PE:EA=3:1) to obtain the target product M12-3 (4.00 g, yield 57.38%). ESI-MS m / z: 281.2 [M+H] + .

[0208] Step 4: Synthesis of compound M12 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 ice bath conditions, and the mixture was reacted at 70 °C for 16 h under nitrogen gas protection conditions, and the reaction was stopped. The pH was adjusted to 1-2 with 1 M HCl solution, and the mixture was heated to 70 °C and reacted for 1 h, and the reaction was stopped. The pH was adjusted to 8-9 with 2 M NaOH solution, and the mixture was extracted three times with EA, and the organic phases were combined and saturated sodium chloride solution was added. The mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated 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] + .

[0209] Synthesis of intermediate M13 [ka]

[0210] Step 1: Synthesis of intermediate M13-1 At room temperature, 2,2,6,6-tetramethylpiperidine (10.01 g) was added to THF (120.00 mL), and under N2 protection conditions, the temperature was controlled to -78 °C. n-Butyllithium (9.33 mL, 2.5 M / hexane) was gradually added dropwise in several portions. After that, the temperature was controlled at -78 °C and reacted for 40 min. Then, a solution of 2-fluoro-4-pyridinecarboxylic acid (5.00 g) in THF (30.00 mL) was gradually added dropwise to the reaction system. The temperature was controlled at -78 °C and reacted for 2 h. Tetrahydro-4H-pyran-4-one (7.10 g) was gradually added at -78 °C, and the temperature was returned to room temperature and reacted overnight, then the reaction was stopped. The reaction solution was added to 250 mL of ice water for quenching, and extracted 3 times with 100 mL of EA. The organic phase was washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated as it was to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4~85:15) to obtain the target product M13-1 (5.20 g, yield 65.75%) as a white solid. ESI-MS m / z: 224.23 [M+H] + 。

[0211] Step 2: Synthesis of Intermediate M13-2 At room temperature, compound M13-1 (4.50 g) was added to THF (15.00 mL) and MeOH (45.00 mL), and under N2 protection conditions, the temperature was controlled to 0~5 °C. NaBH4 (2.29 g) was gradually added in several portions. After that, the ice bath was removed and reacted at room temperature (25 °C) for 2 h, then the reaction was stopped. The reaction solution was added to 50 mL of methanol for quenching, concentrated as it was to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 96:4~90:10) to obtain the target product M13-2 (3.50 g, yield 77.08%) as a white solid. ESI-MS m / z: 226.23 [M+H] + 。

[0212] Step 3: Synthesis of Intermediate M13-3 At room temperature, compound M13-2 (3.50 g) was added to ACN (60.00 mL), and under N2 protection conditions, triethylsilane (9.90 mL) was gradually added. Subsequently, boron trifluoride diethyl etherate (3.92 mL) was gradually added, and the reaction was carried out at room temperature (25 °C) for 2 h, and then the reaction was stopped. The reaction solution was added to 100 mL of saturated sodium bicarbonate for quenching, and then extracted 3 times with 60 mL of EA. The organic phase was washed 2 times with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was and dried to obtain a crude product and the crude product was separated by column chromatography (PE:EA = 10:1~1:1) to obtain the target product M13-3 (3.10 g, yield 95.34%) as a white solid. ESI-MS m / z: 210.21, [M+H] + .

[0213] Step 4: Synthesis of intermediate M13-4 At room temperature, compound M13-3 (1.50 g) and NaCN (0.88 g) were added to DMSO (6.00 mL), and under N2 protection conditions, the temperature was controlled at 150 °C and the reaction was carried out for 2.5 h, and then the reaction was stopped. The reaction solution was added to 100 mL of saturated sodium bicarbonate for quenching, and then extracted 3 times with 50 mL of EA. The organic phase was washed 2 times with 50 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was and dried to obtain a crude product. The aqueous phases were combined, sodium hypochlorite solution was added to quench the sodium cyanide waste liquid, and the crude product was separated by column chromatography (PE:EA = 10:1~1:1) to obtain the target product M13-4 (1.41 g, yield 87.72%) as a white powdery solid. ESI-MS m / z: 217.21, [M+H] + .

[0214] Step 5: Synthesis of intermediate M13-5 At room temperature, compound M13-4 (1.40 g) was added to DCM (20.00 mL), and under N2 protection conditions, m-chloroperbenzoic acid (2.23 g, 85%) was gradually added in several portions. The reaction was carried out at room temperature (25 °C) for 24 h, and then the reaction was stopped. The reaction solution was quenched by adding it to 100 mL of saturated sodium bicarbonate, and then extracted 3 times with 40 mL of DCM. The organic phase was washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was, dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5~93:7) to obtain the target product M13-5 (1.17 g, yield 77.81%) as a white solid. ESI-MS m / z: 233.32 [M+H] + 。

[0215] Step 6: Synthesis of intermediate M13-6 At room temperature, compound M13-5 (1.10 g) was added to DMF (5.00 mL). Under N2 protection and ice-water bath conditions, phosphorus oxychloride (5.00 mL) was gradually added. The reaction was carried out at room temperature for 1 h, and then the reaction was carried out while maintaining the temperature at 50 °C for 2.5 h. The reaction was stopped, and the reaction solution was quenched by adding it to 50 mL of ice water. Saturated sodium bicarbonate was added to adjust the pH to 8-9, and then extracted 4 times with 50 mL of EA. It was washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was, dried to obtain a crude product. The crude product was separated by column chromatography (PE:EA = 95:5~50:50) to obtain the target product M13-6 (0.38 g, yield 32.00%) as a white solid. ESI-MS m / z: 233.32 [M+H] + 。

[0216] Step 7: Synthesis of intermediate M13-7 At room temperature, compound M13-6 (0.36 g) was added to THF (15.00 mL), and under the protection of nitrogen gas, borane dimethyl sulfide (0.43 mL, 10 M) was gradually added under the condition of an ice-water bath, and the reaction was carried out for 1.5 h while maintaining the temperature at 80 °C, and then the reaction was stopped. After cooling to room temperature, 2 mL of ice water was added to the reaction solution, and then 10 mL of hydrochloric acid (6 M-HCl) was added to the reaction solution, and the reaction was carried out for 1 h while maintaining the temperature at 80 °C. Saturated sodium bicarbonate was added to adjust the pH to 8-9, and then extracted 4 times with 50 mL of EA, washed 2 times with 100 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was, dried to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~90:10) to obtain the target product M13-7 (0.27 g, yield 73.81%) as a colorless oil. ESI-MS m / z: 251.73 [M+H] + 。

[0217] Step 8: Synthesis of Intermediate M13 At room temperature, compound M13-7 (0.24 g), formic acid (0.22 g), and aqueous formaldehyde solution (0.23 g, 37%) were added to methanol (3.00 mL), and under N2 protection conditions, the reaction was carried out for 5 h while maintaining the temperature at 85 °C, and then the reaction was stopped. The reaction solution was quenched by adding it to 50 mL of ice water, saturated sodium bicarbonate was added to adjust the pH to 8-9, and then extracted 5 times with 25 mL of EA, washed 2 times with 30 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated as it was, dried to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~90:10) to obtain the target product M13 (0.20 g, yield 75.07%) as a colorless oil. ESI-MS m / z: 283.72 [M+H] + 。

[0218] Synthesis of Intermediate M14:

Chemical Structure

[0219] Step 1: Synthesis of Compound M14-1 At room temperature, 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), reacted at 60 °C for 4 h, and the reaction was stopped. The reaction solution was concentrated as it was, the samples were mixed, and separated by column chromatography (DCM:MeOH = 19:1) to obtain the target product M14-1 (22.00 g, yield 72.47%). ESI-MS m / z: 136.95 [M+H] + 。

[0220] Step 2: Synthesis of Compound M14 At room temperature, compound M14-1 (22.00 g) was dissolved in chloroform (200.00 mL), replaced with N2, under an ice bath, NIS (40.00 g) was added, reacted at room temperature for 3 h, and the reaction was stopped. The samples were mixed and separated by column chromatography (DCM:MeOH = 40:1) to obtain the target product M14 (35.88 g, yield 84.73%). ESI-MS m / z: 263.02 [M+H] + 。

[0221] Synthesis of Intermediate M15:

Chemical formula

[0222] Step 1: Synthesis of Compound M15-1 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 the condition of an ice bath, the temperature was controlled at 0 - 5 °C, and a toluene solution of DBU (48.85 ml) was added dropwise. Then the temperature was raised to room temperature and reacted for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride, and then extracted with EA three times (300 ml each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, dried with a rotary evaporator, the samples were mixed, separated by silica gel column chromatography (PE), and the target product M15-1 (41.0 g, yield 88.97%) was obtained. ESI-MS m / z: 282.10 [M+H] + 。

[0223] Step 2: Synthesis of compound M15-2 The raw material M15-1 (41.0 g) was added to THF (200 ml), replaced with N2 gas, LiHMDS (363.67 ml) was added dropwise at -50 °C, the temperature was raised to -20 °C and reacted for 1 hour, 2,2'-dibromodiethyl ether (18.47 ml) was added dropwise, and then the temperature was raised to room temperature and reacted for 16 hours. The reaction solution was quenched with saturated ammonium chloride, and then extracted with EA twice (200 ml each time). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, dried with a rotary evaporator to obtain the crude product of compound M15-2, which was directly used for the reaction in the next step.

[0224] Step 3: Synthesis of compound M15-3 At room temperature, compound M15-2 (51.0 g) was dissolved in THF (300 mL). Under the condition of an ice bath, TBAF (144.91 ml) was added dropwise, and then reacted at room temperature for 0.5 hour. The reaction solution was added to water, saturated aqueous sodium bicarbonate solution was added, a solid was precipitated, the filter cake was washed with EA, and the target product M15-3 (9.62 g, yield 27.93%), a white solid, was obtained. ESI-MS m / z: 238.06 [M+H] + 。

[0225] Step 4: Synthesis of Compound M15-4 Dissolve Compound M15-3 (4.3 g) in DCM (60 mL), add triethylamine (12.57 ml) and Noyori catalyst (ss) (0.46 g, 0.72 mmol). After purging with N2, under the condition of an ice bath, gradually add formic acid (3.41 ml), control the temperature at 5 - 10 °C. After dropping, react at room temperature for 4 hours. Add water, then extract with DCM (80 ml, 30 ml). Combine the organic phases, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, dry with a rotary evaporator, mix the samples, and separate by silica gel column chromatography (PE:EA = 2:1 - 1:1) to obtain the target product M15-4 (3.67 g, yield 84.63%) as a white solid. ESI-MS m / z: 240.07 [M+H] + 。

[0226] Step 4: Synthesis of Compound M15-5

[0227] Dissolve Compound M15-4 (1.0 g) in DCM (25 mL), add DIEA (2.07 ml). Under the condition of an ice bath, dropwise add MsCl (0.48 ml), then react at 10 °C for 2 hours. Quench the reaction solution with ice water and extract 3 times with DCM (25 ml each time). Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, pass through silica gel column chromatography, wash with DCM, remove the solvent with a rotary evaporator to obtain a concentrate, then slurry with PE:MTBE = 2:1 and filter to obtain the target product M15-5 (1.16 g, yield 87.49%) as a white solid. ESI-MS m / z: 318.05 [M+H] + 。

[0228] Step 4: Synthesis of Compound M15 Compound M15-5 (1.16 g) was dissolved in DMF (10 mL), a solution of dimethylamine in THF (9.13 mL, 2 M) was added, and the mixture was stirred overnight at room temperature to allow the reaction to proceed. The reaction mixture was quenched with ice water and extracted 4 times (15 mL each time) with EA, washed 4 times (10 mL each time) with saturated brine, dried over anhydrous sodium sulfate, dried using a rotary evaporator, the samples were combined, separated by silica gel column chromatography (DCM:CH3OH = 97:3 - 95:5), and the target product M15, a white solid (810 mg, yield 82.9%), was obtained. ESI-MS m / z: 267.12 [M+H] + 。

[0229] Synthesis of Intermediate M16:

Chemical Structure

[0230] Step 1: Synthesis of Compound M16 Compound M10 (40.00 g), bis(pinacolato)diboron (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), purged with nitrogen gas, heated to 100 °C and reacted for 17 hours. After cooling, suction filtration was carried out, washed with DCM, the filtrate was concentrated under reduced pressure, and EA (40 mL) was added to the concentrated solution and dissolved by ultrasonic treatment. Then, PE (200 mL) was slowly added dropwise at RT, a solid was precipitated and the solid was filtered. Subsequently, the solid was slurried with PE:MTBE = 1:1, the solid was filtered and washed with PE to obtain compound M16 (42.42 g, yield 80%). ESI-MS m / z: 375.2 [M+H] + 。

[0231] Example 1: Synthesis of 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)isoindole-1-one [Chemistry]

[0232] Step 1: Synthesis of Compound 1-1 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), heated to 90 °C and reacted for 2 hours. The reaction solution was filtered, the filter cake was washed with EA, the filtrate was dried with a rotary evaporator, and the concentrate was separated by column chromatography (DCM:CH3OH = 30:1) to obtain the target product 1-1 (197 mg, yield 81.3%). ESI-MS m / z: 526.1 [M+H] + .

[0233] Step 2: Synthesis of Compound 1-2 At room temperature, compound 1-1 (165 mg), bis(pinacolato)diboron (159 mg), Pd2(dba)3 (29 mg), Sphos (26 mg), and potassium acetate (93 mg) were added to 1,4-dioxane (7.5 mL), and then reacted at 90 °C for 18 h under N2 protection conditions to stop the reaction. The reaction solution was filtered while it was hot, the filtrate was dried with a rotary evaporator, and the concentrate was separated by column chromatography (DCM:CH3OH = 20:1) to obtain the target product 1-2 (175 mg, yield 90.0%). ESI-MS m / z: 618.6 [M+H] + .

[0234] Step 3: Synthesis of Compound 1-3 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), and the reaction was carried out at 90 °C for 2 h under N2 protection conditions. The reaction was stopped. Water was added to the reaction solution, and extraction was performed 3 times with EA, 5 mL each time. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, dried with a rotary evaporator, and the concentrate was separated by column chromatography (DCM:CH3OH = 20:1) to obtain the target product 1-3 (102 mg, yield 51.9%). ESI-MS m / z: 626.7 [M+H] + 。

[0235] Step 4: Synthesis of Compound 1 At room temperature, compound 1-3 (102 mg) was added to dichloromethane (5.00 mL), and under N2 protection conditions, trifluoroacetic acid (0.3 mL) was added in an ice-water bath, and the reaction was carried out at room temperature for 1 h. The reaction was stopped. The reaction solvent was removed by concentration, 10 mL of H2O and 10 mL of DCM were added to the reaction solution, and NaOH was added to adjust the pH to 9. Then, extraction was performed 3 times with DCM, 15 mL each time. The organic phases were combined, washed with saturated sodium chloride, and the organic phase was Concentrated, and the concentrate was separated by column chromatography (DCM:CH3OH = 10:1) to obtain the target product 1 (67.2 mg, yield 78.4%). ESI-MS m / z: 526.6 [M+H] + 。 1 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.68 (s, 1H), 8.37 (t, J = 6.7 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.5507.37 (m, 3H), 7.27 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.7 Hz, 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).

[0236] Example 2: Synthesis and Chiral Resolution of 7-(7-(Dimethylamino)-2’,3’,5’,6,6’,7-Hexahydrospiro[Cyclopentyl]Pyridine-5,4’-Pyran)-2-Ylamino)-4-(7-Fluoroimidazo[1,2-a]Pyridin-3-Yl)Isoindole-1-One

Chemical Structure

[0237] Step 1: Synthesis of Compound 2-1 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 gas, heated to 90 °C and reacted for 3 hours. After cooling, suction filtration was carried out, washed with EA, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 92:8) to obtain Compound 2-1 (73 mg, yield 78%). ESI-MS m / z: 513.2 [M+H] + .

[0238] Step 2: Synthesis of Compound 2-2 Compound 2-1 (73 mg), bis(pinacolato)diboron (72 mg), Pd2(dba)3 (13 mg), SPhos (12 mg) and potassium acetate (42 mg) were dissolved in 1,4-dioxane (5 mL), replaced with nitrogen gas, heated to 90 °C and reacted for 8 hours. After cooling, suction filtration was carried out, 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, yield 95%). ESI-MS m / z: 605.3 [M+H] + .

[0239] Step 3: Synthesis of Compound 2-3 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), replaced with nitrogen gas, heated to 90 °C and reacted for 2 hours. After cooling Add water for dilution, extract with EA, combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography (DCM:MeOH = 92:8) to obtain compound 2-3 (60 mg, yield 72%). ESI-MS m / z: 613.2 [M+H] + 。

[0240] Step 4: Synthesis of Compound 2 Dissolve 2-3 (60 mg) in DCM (1 mL) and MeOH (1 mL), add hydrochloric acid (2 mL, 4 M / 1,4-dioxane), heat to 50 °C and react for 1 hour. Cool and concentrate under reduced pressure, and purify by Pre-HPLC to obtain compound 2 (10 mg, yield 19.9%). ESI-MS m / z: 513.2 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.84 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.44 (dd, J = 7.6, 5.7 Hz, 1H), 7.82 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 10.0, 2.7 Hz, 1H), 6.97 (td, J = 7.5, 2.6 Hz, 1H), 6.87 (d, J = 8.3 Hz, 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).

[0241] Step 5: Chiral Resolution of Compound 2 A racemic mixture of Compound 2 (120 mg) was dissolved in a mixed solution of DCM (8 ml), methanol (2 ml) and ethanol (45 ml), and separated by a preparative chiral column [CHIRALPAK IE (DAICEL) 20×250 mm 5um, model: GX-271 (GILSON); mobile phase A: n-hexane (AR, Shuanglin Chemical, add 0.1% diethylamine.), mobile phase B: ethanol (AR, Shuanglin Chemical, add 0.1% diethylamine.); isocratic (95% mobile phase B); flow rate: 10 ml / min, room temperature]. Compound 2A (Peak 1): retention time = 38.58 min, recovery amount 37.4 mg; Compound 2B (Peak 2): retention time = 46.88 min, recovery amount 38.6 mg.

[0242] Example 2B: Synthesis of Compound (R)-7-((7-(dimethylamino)-2’,3’,5’,6,6’,7-hexahydrospiro[cyclopentadiene[b]pyridine-5,4’-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

Chemical Structure

[0243] Step 1: Synthesis of Compound 2B-1 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, replaced with nitrogen gas, and stirred at an internal temperature of 90 °C for 2 h. Cooled to room temperature, diatomaceous earth was spread and filtered, washed with dioxane, water was added to precipitate a solid, and filtered to obtain a filter cake Slurried with ethanol (300 ml) to obtain a solid, and further slurried with THF (200 ml) / PE (200 ml) to obtain Compound 2B-1 (130.0 g, yield 70.8%) as a gray solid. ESI-MS m / z: 383.2 [M+H] + 。

[0244] Step 2: Synthesis of Compound 2B-2 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), and cesium carbonate (259.54 g) were added to a 5000 mL four-necked flask, replaced with nitrogen gas three times, pre-stirred at room temperature for 5 minutes, the internal temperature was raised to 90 °C, and stirred for 16 h. It was confirmed by LCMS that the reaction was complete. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, washed with dioxane (300 mL), water was added (5000 mL) to precipitate solids, stirred uniformly and suction filtered. The solids were slurried successively with ethanol (500 mL) and EA (500 mL) to obtain Compound 2B-2 (141.00 g, yield 71.4%). ESI-MS m / z: 613.3 [M+H] + .

[0245] Step 3: Synthesis of Compound 2B Compound 2B-2 (54.00 g) was dissolved in DCM (500 mL). Under N2 protection, trifluoroacetic acid (100.00 mL) was added dropwise at room temperature, and then the reaction was continued at room temperature for 1 h. The reaction solution was concentrated to dryness, the crude product was added and dissolved in DCM (80 mL), saturated sodium bicarbonate was gradually added to adjust the pH to 8 - 9, a pale yellow solid was precipitated, ammonia water was added to adjust the pH = 11 - 12, stirred uniformly, suction filtered and washed with water. The filter cake was added to methanol (600 mL), stirred uniformly, refluxed for 30 minutes, cooled naturally, stirred overnight, suction filtered, and the solid was washed with methanol and dried to obtain the target product 2B (43.20 g, purity 99.20%, yield 94.5%, retention time was the same as that of 2B in Example 2). ESI-MS m / z: 513.3 [M+H] + . 11H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (s, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.45 - 8.42 (m, 1H), 7.82 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 10.1, 2.7 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.39 (s, 2H), 4.22 (t, J = 7.7 Hz, 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 - 1.65 m, 1H), 1.46 - 1.42 (m, 1H), 1.35 - 1.32 (m, 1H).

[0246] Example 28: Synthesis of Compound (R)-7-((7-(Dimethylamino)-4-methyl-2’,3’,5’,6,6’,7-hexahydrospiro[b]pyridine-5,4’-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

Chemical Structure

[0247] Step 1: Synthesis of Compound 28-1 Under ice bath 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), and DBU (10.61 mL) was slowly added dropwise. The temperature was gradually raised to room temperature and reacted for 12 h, then the reaction was stopped. EA was added for extraction, and the organic phase was washed with saturated brine. The samples were combined and separated by column chromatography (PE:EA = 100:1) to obtain the target product 28-1 (8.30 g, yield 78.99%). ESI-MS m / z: 296.12 [M+H] + .

[0248] Step 2: Synthesis of Compound 28-2 Weighed 28-1 (5.0 g) and dissolved it in tetrahydrofuran (50 mL). At -50 °C, under nitrogen gas protection, slowly added LiHMDS (50.7 mL, 1 M THF solution) to the reaction system, slowly warmed up to -30 °C, stirred for 0.5 h, slowly added 2,2'-dibromodiethyl ether (4.31 g) to the reaction system, slowly warmed up to room temperature and reacted for 3 h, then stopped the reaction. Quenched with saturated ammonium chloride solution, dried the solution with a rotary evaporator, extracted with EA, washed the organic phase with saturated brine, collected the organic phase and dried it with a rotary evaporator to obtain 28-2 crude product (7.58 g). ESI-MS m / z: 366.17 [M+H] + 。

[0249] Step 3: Synthesis of compound 28-3 Weighed the 28-2 crude product (8.34 g) at room temperature and dissolved it in EA (15 mL), added hydrochloric acid solution (60 mL, 1 M), reacted for 3 h, then stopped the reaction. Added sodium carbonate to adjust the reaction system to neutral, extracted with EA, washed the organic phase with saturated brine, mixed the samples, and separated by column chromatography (PE:EA = 1:1) to obtain the target product 28-3 ( 1.94 g, yield 33.79%). ESI-MS m / z: 252.08 [M+H] + 。

[0250] Step 4: Synthesis of compound 28-4 Weighed 28-3 (1.88 g), (R)-(+)-t-butylsulfinamide (2.71 g), and tetraethyl titanate (30 mL), reacted under the condition of 50 °C for 5 h, then stopped the reaction. Slowly dropped the reaction solution into ice water, added EA and stirred vigorously, added diatomaceous earth and filtered by suction, extracted with EA, washed the organic phase with saturated brine, collected the organic phase and dried it with a rotary evaporator, and separated by column chromatography (PE:EA = 3:1) to obtain the target product 28-4 (2.12 g, yield 80.19%). ESI-MS m / z: 355.12 [M+H] + 。

[0251] Step 5: Synthesis of compound 28-5 Weighed 28-4 (2.58 g) and dissolved it in tetrahydrofuran (30 mL). Under the protection of nitrogen gas and at -78 °C, slowly added DIBAL-H (25 mL, 1 M THF solution) to the reaction system and reacted for 6 h, then stopped the reaction. Under the protection of nitrogen gas and at -78 °C, added saturated potassium sodium tartrate solution to the reaction system, slowly warmed up to room temperature, stirred vigorously, filtered by suction through diatomaceous earth, extracted with EA, washed the organic phase with saturated brine, collected the organic phase, dried it with a rotary evaporator, and separated it by column chromatography (PE:EA = 2:1) to obtain the target product 28-5 (2.16 g, yield 83.25%). ESI-MS m / z: 357.14 [M+H] + 。

[0252] Step 6: Synthesis of compound 28-6 Weighed 28-5 (2.16 g) and dissolved it in a mixed solution of DCM (10 mL) and MeOH (5 mL). Under the condition of an ice bath, slowly added it to HCl solution (15.13 mL, 4 M / dioxane), slowly warmed up to room temperature and reacted for 1 h, then stopped the reaction. Dried the solvent with a rotary evaporator, added PE and EA to precipitate the solid, filtered by suction to obtain the hydrochloride salt of the target product 28-6 (1.23 g, yield 80.41%). ESI-MS m / z: 253.11 [M+H] + 。

[0253] Step 7: Synthesis of compound 28-7 Weighed 28-6 (1.33 g) and dissolved it in a mixed solution of DCE (20 mL) and MeOH (10 mL). Added aqueous formaldehyde solution (1.40 mL, concentration 37%) and AcOH (15 drops), reacted at room temperature for 0.5 h, slowly added sodium cyanoborohydride (1.32 g) to the reaction system, reacted for 12 h, then stopped the reaction. Filtered by suction through diatomaceous earth to remove insoluble substances, dried the organic phase with a rotary evaporator, and separated it by column chromatography (DCM:MeOH = 50:1) to obtain the target product 28-7 (1.18 g, yield 80.13%). ESI-MS m / z: 281.14 [M+H] + 。

[0254] Step 8: Synthesis of compound 28-8 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 o-xylene (10 mL) was added. The mixture was reacted for 12 h under nitrogen gas protection at 130 °C, and the reaction was stopped. The mixture was filtered through diatomaceous earth with suction, and the filter cake was washed with ethyl acetate. The organic phase was collected and dried on a rotary evaporator, and the product was separated by column chromatography (DCM:MeOH = 25:1) to obtain the desired product 28-8 (1.30 g, 96.05% yield). ESI-MS m / z: 426.25 [M + H] + .

[0255] Step 9: Synthesis of compound 28-9 28-8 (1.30 g) was weighed out and dissolved in a mixture of DCM (20 mL) and MeOH (10 mL). The mixture was dissolved in the above mixture, and under ice bath conditions, HCl solution (15.27 mL, 4 M / dioxane) was gradually added dropwise, and the mixture was gradually warmed to room temperature and reacted for 3 h, after which the reaction was stopped. The solution was dried in a rotary evaporator, dissolved by adding a small amount of methanol, and the solution was adjusted to a weak alkalinity by adding saturated sodium bicarbonate, extracted with EA, and the organic phase was washed with saturated saline, and the organic phase was collected and dried in a rotary evaporator. The product was separated by column chromatography (DCM:MeOH=20:1) to obtain the target product 28-9 (530 mg, yield 66.38%). ESI-MS m / z: 262.19 [M+H] + .

[0256] Step 10: Synthesis of compound 28-10 28-9 (500 mg), M1 (452 mg), Pd2(dba)3 (132 mg), XantPhos (167 mg), and cesium carbonate (1.41 g) were weighed and added to dioxane (10 mL). Under nitrogen gas protection, the reaction was carried out at 90 °C for 2.5 h, and then the reaction was stopped. The mixture was suction filtered through diatomaceous earth, and the organic phase was collected and dried with a rotary evaporator. It was separated by column chromatography (DCM:MeOH = 33:1) to obtain the target product 28-10 (721 mg, yield 94.83%). ESI-MS m / z: 527.24 [M+H] + 。

[0257] Step 11: Synthesis of compound 28-11 28-10 (700 mg), bis(pinacolato)diboron (675 mg), Pd2(dba)3 (243 mg), SPhos (218 mg), and KOAC (391 mg) were weighed and added to dioxane (10 mL). Under nitrogen gas protection, the reaction was carried out at 90 °C for 12 h, and then the reaction was stopped. The mixture was suction filtered through diatomaceous earth, and the organic phase was collected and dried with a rotary evaporator. It was separated by column chromatography (DCM:MeOH = 20:1) to obtain the target product 28-11 (422 mg, yield 51.37%). ESI-MS m / z: 519.31 [M+H] + 。

[0258] Step 12: Synthesis of compound 28-12 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). Then, under N2 protection conditions, the reaction was carried out at 90 °C for 1 h, and then the reaction was stopped. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 12:1) to obtain the target product 28-12 (100 mg, yield 99%). ESI-MS m / z: 627.31 [M+H] + 。

[0259] Step 13: Synthesis of compound 28 Compound 28-12 (100 mg) was weighed and dissolved in dichloromethane (1.5 mL) and MeOH (1.5 mL). Under the condition of an ice bath, HCl solution (3 mL, 4 M dioxane solution) was gradually added dropwise, and the temperature was gradually raised to room temperature and reacted for 30 min, then the reaction was stopped. It was concentrated to prepare a liquid phase, separated and purified to obtain the target product 28 (22.8 mg, purity 97.26%, yield 27.13%). ESI-MS m / z: 527.41 [M+H] + 。

[0260] Example 39: Synthesis of 7-(7-(azetidin-1-yl)-2’,3’,5’,6,6’,7-hexahydrospiro[b]pyridine-5,4’-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

Chemical Structure

[0261] Step 1: Synthesis of Intermediate 39-1 At room temperature, compound M8-10 (1.00 g), KI (0.14 g), potassium carbonate (1.73 g), and azetidineamine (2.38 g) were added to DMF (12.00 mL), and under N2 protection conditions, the reaction was carried out at 40 °C while maintaining the temperature for 5 h, then the reaction was stopped. The reaction solution was directly concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~90:10) to obtain the target product 39-1 (0.70 g, yield 64.45%). ESI-MS m / z: 261.32 [M+H] + 。

[0262] Step 2: Synthesis of Intermediate 39-2 At room temperature, compound 39-1 (0.60 g) and pyridine (0.93 mL) were added to DCM (15.00 mL), and under N2 protection conditions, the temperature was controlled to -50 to -40 °C. Trifluoromethanesulfonic anhydride (0.78 mL) was gradually added in several portions, and the reaction was carried out for 1 h while maintaining the temperature at -50 to -40 °C. The reaction was stopped. The reaction solution was concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5 to 75:25) to obtain the target product 39-2 (1.0 g, yield 92.02%). ESI-MS m / z: 322.43 [M+H] + 。

[0263] Step 3: Synthesis of intermediate 39-3 At room temperature, compound 39-2 (1.00 g) was added to dimethylamine (15 mL, 2M THF solution), and under N2 protection conditions, the reaction was carried out at room temperature (25 °C) for 1 h. The reaction was stopped. The reaction solution was concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15). The total amount of the target crude product was 0.72 g, and it was separated by a chromatography plate (DCM:MeOH(7M-NH3) = 12:1) to obtain the target product 39-3 (0.20 g, yield 24.86%). ESI-MS m / z: 260.36 [M+H] + 。

[0264] Step 4: Synthesis of intermediate 39-4 At room temperature, 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), and under N2 protection conditions, the reaction was carried out at 100 °C for 5 h. The reaction was stopped. The reaction solution was concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the target product 39-4 (240.00 mg, yield 59.27%). ESI-MS m / z: 526.05 [M+H] + 。

[0265] Step 5: Synthesis of Intermediate 39-5 At room temperature, compound 39-4 (240.00 mg), bis(pinacolato)diboron (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), and the reaction was carried out at 100 °C for 12 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the target product 39-5 (220.00 mg, yield 78.06%). ESI-MS m / z: 617.58 [M+H] + 。

[0266] Step 6: Synthesis of Intermediate 39-6 At room temperature, 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), and the reaction was carried out at 90 °C for 1 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the target product 39-6, a red solid (80.00 mg, yield 78.95%). ESI-MS m / z: 625.73 [M+H] + 。

[0267] Step 7: Synthesis of Compound 39 At room temperature, compound 39-6 (80.00 mg) was added to dichloromethane (4.00 mL), and under N2 protection conditions, trifluoroacetic acid (0.80 mL) was added in an ice-water bath, and the reaction was carried out at room temperature for 1 h, and then the reaction was stopped. The reaction solvent was removed by a rotary evaporator, 5 mL of H2O and 5 mL of DCM were added to the reaction solution, and NaOH was added to adjust the pH>12, and then extracted 3 times with DCM, 15 mL each time. The organic phases were combined, washed with saturated sodium chloride, and the organic phase was concentrated to obtain a crude product. The crude product was added to 10.00 mL of methanol to form a slurry, filtered and dried to obtain the target product 39 (34.60 mg, yield 51.49%). ESI-MSm / z: 525.53 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.84 (s, 1H), 8.76 (d, J = 8.7 Hz, 1H), 8.43 (t, J = 6.7 Hz, 1H), 7.82 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.53 - 7.50 (m, 1H), 6.99 - 6.95 (m, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.38 (d, J = 3.3 Hz, 2H), 3.83 - 3.79 (m, 2H), 3.73 (s, 1H), 3.57 - 3.49 (m, 2H), 3.44 - 3.35 (m, 4H), 2.49 (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).

[0268] 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]pyridine-5,4’-pyran]-2-yl)amino)isoindolin-1 -one

Chemical Structure

[0269] Step 1: Synthesis of compound 40-1 2-Chloro-2’,3’,5’,6’-tetrahydrospiro[cyclopenta[b]pyridine-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 reaction was carried out at room temperature for 1 h. Sodium cyanoborohydride (357 mg) was gradually added, and the temperature was raised to 80 °C and reacted for 2 h. The reaction was stopped. It was extracted with DCM, the organic phase was washed with saturated brine, the organic phase was collected and dried with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the target product 40-1 (540 mg, yield 97.41%). ESI-MS m / z: 293.14 [M+H] + 。

[0270] Step 2: Synthesis of compound 40-2 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). Under the protection of nitrogen gas, the reaction was carried out at 130 °C for 12 h. The reaction was stopped. It was suction filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the organic phase was collected and dried with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 20:1) to obtain the target product 40-2 (850 mg, yield 94.85%). ESI-MS m / z: 438.25 [M+H] + 。

[0271] Step 3: Synthesis of compound 40-3 Weighed 40-2 (1.20 g) and dissolved it in a mixed solution of DCM (20 mL) and MeOH (10 mL). Under the condition of an ice bath, HCl solution (13.71 mL, 4 M dioxane solution) was slowly added dropwise. Then, the temperature was gradually raised to room temperature and reacted for 3 h, and the reaction was stopped. The solution was dried with a rotary evaporator, a small amount of methanol was added to dissolve it, saturated sodium bicarbonate was added to adjust the solution to be weakly alkaline, extracted with EA, the organic phase was washed with saturated brine, the organic phase was collected and dried with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 15:1) to obtain the target product 40-3 (750 mg, yield 99.10%). ESI-MS m / z: 274.19 [M+H] + 。

[0272] Step 4: Synthesis of compound 40-4 Weighed 40-3 (1.0 g), intermediate M1 (660 mg), Pd2(dba)3 (221 mg), XantPhos (279 mg), and cesium carbonate (2.36 g), added them to dioxane (10 mL), reacted under nitrogen gas protection at 90 °C for 2.5 h, and stopped the reaction. Filtered with suction through diatomaceous earth, collected the organic phase and dried it with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the target product 40-4 (893 mg, yield 68.61%). ESI-MS m / z: 539.24 [M+H] + 。

[0273] Step 5: Synthesis of compound 40-5 Weighed 40-4 (883 mg), bis(pinacolato)diboron (832 mg), Pd2(dba)3 (300 mg), SPhos (269 mg), and KOAc (482 mg), added them to dioxane (10 mL), reacted under nitrogen gas protection at 90 °C for 12 h, and stopped the reaction. Filtered with suction through diatomaceous earth, collected the organic phase and dried it with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 20:1) to obtain the target product 40-5 (905 mg, yield 87.62%). ESI-MS m / z: 631.37 [M+H] + 。

[0274] Step 6: Synthesis of Compound 40-6 Weighed 40-5 (100 mg), M14 (62 mg), [PdCl2(dppf)]CH2Cl2 (13 mg), and sodium carbonate (51 mg), added them to dioxane (4 mL) and water (0.50 mL), and reacted them at 90 °C for 1 h under N2 protection conditions, then stopped the reaction. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 12:1) to obtain the target product 40-6 (70 mg, yield 69.10%). ESI-MS m / z: 639.31 [M+H] + 。

[0275] Step 7: Synthesis of Compound 40 Weighed Compound 40-6 (100 mg), dissolved it in dichloromethane (1.5 mL), slowly added dropwise TFA (1.5 mL) under ice bath conditions, gradually warmed up to room temperature and reacted for 30 min, then stopped the reaction. Concentrated and separated and purified by preparative liquid chromatography to obtain the target product 40 (16.7 mg, purity 99.60%, yield 28.29%). 1 1H NMR (500 MHz, DMSO) δ 10.39 (s, 1H), 10.24 (s, 1H), 8.92 (s, 1H), 8.52 (t, J = 7.5 Hz, 2H), 8.07 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.77 (t, J = 9.5 Hz, 2H), 7.23 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.11 (dd, J = 14.6, 7.7 Hz, 1H), 4.41 (q, J = 18.3 Hz, 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, 8.2 Hz, 1H), 2.21 - 1.92 (m, 6H), 1.86 (d, J = 7.0 Hz, 1H), 1.68 (dd, J = 12.1, 8.6 Hz, 1H), 1.51 (d, J = 12.9 Hz, 1H), 1.41 (d, J = 12.5 Hz, 1H) was obtained. ESI-MS m / z: 539.42 [M+H] + 。

[0276] Synthesis of Compounds 40A and 40B [Chemical formula]

[0277] Step 1: Synthesis of Compounds 40-6A and 40-6B Preparation of 40-6 sample: 70 mg of sample 40-6 was dissolved in 6 mL of ethanol:n-hexane (2:1) solution. Chromatography conditions: 1. Chiral resolution column YMC CHIRAL ART Celluose-SB 250×20.0 mm S-5um; 2. Instrument type GILSON GX-271; 3. Mobile phase, mobile phase A was n-hexane, mobile phase B was an ethanol solution of 0.1% dihexylamine, isocratic elution with mobile phase A:mobile phase B = 7:3, flow rate was 20 mL / min, wavelength was 254 nm, and separation was performed at room temperature. Compound 40-6A (peak 1): retention time = 13.035 min, recovery amount 35 mg; Compound 40-6B (peak 2): retention time = 17.645 min, recovery amount 36 mg.

[0278] Step 2: Synthesis of Compound 40A Compound 40-6A (36 mg) was weighed and dissolved in dichloromethane (1.5 mL) and methanol (1.5 mL). Under the conditions of an ice bath, HCl solution (3 mL, 4M dioxane solution) was slowly added dropwise, and the temperature was slowly raised to room temperature and reacted for 30 min, then the reaction was stopped. It was concentrated to remove the organic solvent to obtain the target product 40A (21.1 mg, purity 99.74%, yield 69.46%). ESI-MS m / z: 539.40 [M+H] + .

[0279] 11H NMR (500 MHz, DMSO-d6) δ 11.64 (d, J = 5.4 Hz, 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, 2.3 Hz, 1H), 7.82 (dd, J = 8.5, 3.8 Hz, 2H), 7.54 (td, J = 7.5, 2.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.09 (dd, J = 14.4, 8.0 Hz, 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, 8.2 Hz, 1H), 2.21 - 1.84 (m, 7H), 1.74 - 1.62 (m, 1H), 1.59 (d, J = 12.4 Hz, 1H), 1.45 - 1.37 (m, 1H).

[0280] Step 3: Synthesis of Compound 40B Compound 40 - 6B (35 mg) was weighed and dissolved in dichloromethane (1.5 mL) and methanol (1.5 mL). Under ice bath conditions, HCl solution (3 mL, 4 M dioxane solution) was slowly added dropwise, and the temperature was gradually raised to room temperature and reacted for 30 min, then the reaction was stopped. The organic solvent was concentrated and removed to obtain the target product 40B (22.2 mg, purity 99.10%, yield 75.21%). ESI-MS m / z: 539.40 [M + H] + 。

[0281] 11H NMR (500 MHz, DMSO-d6) δ 11.65 (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, 2.3 Hz, 1H), 7.82 (dd, J = 8.5, 5.0 Hz, 2H), 7.55 (td, J = 7.5, 2.4 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.09 (dd, J = 14.4, 7.9 Hz, 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, 6.5 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.03 (tdd, J = 23.7, 15.1, 9.6 Hz, 7H), 1.70 - 1.63 (m, 1H), 1.59 (d, J = 12.4 Hz, 1H), 1.40 (d, J = 12.5 Hz, 1H).

[0282] Example 41: Synthesis of 7 - ((7 - (dimethylamino)-2’,3’,5’,6,6’,7 - hexahydrospiro[b]pyridine - 5,4’ - pyran]-2 - yl)amino)-4-(7 - (hydroxymethyl)imidazo[1,2 - a]pyridin - 3 - yl)isoindol - 1 - one

Chemical Structure

[0283] Step 1: Synthesis of Compound 41 - 1 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), and reacted at 70 °C for 2 h. The reaction was stopped. The reaction solution was concentrated as it was, the samples were mixed, and separated by column chromatography (DCM:MeOH = 10:1) to obtain the target product 41 - 1 (2.34 g, yield 98.03%). ESI - MS m / z: 149.12 [M + H] + .

[0284] Step 2: Synthesis of Compound 41 - 2 At room temperature, compound 41-1 (2.34 g) was dissolved in DMF (20.00 mL), replaced with N2, and under an ice bath, NIS (3.91 g) was added. The reaction was carried out at room temperature for 2 h and then stopped. EA / THF and water were added for extraction three times. The organic phase was washed with saturated brine, and the samples were combined and separated by column chromatography (DCM:MeOH = 13:1) to obtain the target product 41-2 (3.26 g, yield 75.32%). ESI-MS m / z: 275.10 [M+H] + 。

[0285] Step 3: Synthesis of compound 41-3 At room temperature, 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), and under N2 protection conditions the reaction was carried out at 90 °C for 1 h and then stopped. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 7:1) to obtain the target product 41-3 (44.00 mg, yield 53.06%). ESI-MS m / z: 625.50 [M+H] + 。

[0286] Step 4: Synthesis of compound 41 At room temperature, compound 41-3 (44.00 mg) was dissolved in dichloromethane (1.50 mL), TFA (0.40 mL) was added, and the reaction was carried out at room temperature for 10 min and then stopped. It was concentrated, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted three times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and purified by preparative plate to obtain the target product 41 (15.70 mg, purity 97.16%, yield 41.26%). ESI-MS m / z: 525.51 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 7.1 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.51 (s, 1H), 6.91 - 6.83 (m, 2H), 5.42 (t, J = 5.7 Hz, 1H), 4.57 (d, J = 5.7 Hz, 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 - 1.84 m, 1H), 1.71 - 1.64 (m, 1H), 1.48 - 1.41 (m, 1H), 1.34 - 1.31 (m, 1H).

[0287] 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]pyridine-5,4’-pyran]-2-yl)amino)isoindole-1-one

Chemical Structure

[0288] Step 1: Synthesis of Compound 43-1 2-Amino-4-fluoropyridine (2.00 g) and Selectfluor (7.58 g) were dissolved in acetonitrile (20.00 mL) and water (10.00 mL), purged with N2 and reacted at 60 °C for 12 h, then the reaction was stopped. The reaction mixture was concentrated and dissolved in DCM, and the sample was mixed and separated by column chromatography (DCM:MeOH = 16:1) to obtain the target product 43-1 (56.00 mg, yield 2.41%). ESI-MS m / z: 131.06 [M+H] + .

[0289] Step 2: Synthesis of Compound 43-2 At room temperature, 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), and reacted at 70 °C for 12 h. The reaction was stopped. The reaction solution was concentrated as it was, the samples were mixed, and separated by column chromatography (DCM:MeOH = 19:1) to obtain the target product 43-2 (53.00 mg, yield 78.85%). ESI-MS m / z: 155.03 [M+H] + 。

[0290] Step 3: Synthesis of compound 43-3 At room temperature, compound 43-2 (53.00 mg) was dissolved in chloroform (2.00 mL), replaced with N2, and under an ice bath, NIS (84.03 mg) was added and reacted at room temperature for 2 h. The reaction was stopped. The samples were mixed and separated by column chromatography (DCM:MeOH = 40:1) to obtain the target product 43-3 (75.00 mg, yield 78.33%). ESI-MS m / z: 280.92 [M+H] + 。

[0291] Step 4: Synthesis of compound 43-4 At room temperature, 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), and under N2 protection conditions, reacted at 90 °C for 1 h. The reaction was stopped. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the target product 43-4 (17.00 mg, yield 23.27%). ESI-MS m / z: 630.45 [M+H] + 。

[0292] Step 5: Synthesis of compound 43 At room temperature, compound 43-4 (17.00 mg) was dissolved in dichloromethane (2 mL), TFA (0.50 mL) was added, and the reaction was carried out at room temperature for 10 min. The reaction was stopped. It was concentrated, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted 3 times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and purified by preparative plate to obtain the target product 43 (6.84 mg, purity 97.40%, yield 46.51%). ESI-MS m / z: 531.21 [M+H] + 。

[0293] 1 H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 10.28 (s, 1H), 8.92 (s, 1H), 8.76 (d, J = 8.5 Hz, 1H), 8.32 - 8.29 (m, 1H), 8.05 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.11 - 5.07 (m, 1H), 4.39 (s, 2H), 3.62 - 3.50 (m, 3H), 2.93 (d, J = 4.8 Hz, 3H), 2.82 (d, J = 4.9 Hz, 3H), 2.77 - 2.72 (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).

[0294] 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]pyridine-5,4’-pyran]-2-yl)amino)isoind lin-1-one

Chemical formula

[0295] Step 1: Synthesis of compound 46-1 At room temperature, 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), and then reacted at 85 °C for 40 min under N2 protection conditions. The reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 (DCM:MeOH = 13:1) to obtain the target product 46-1 (30.00 mg, yield 60.05%). ESI-MS m / z: 647.2 [M+H] + .

[0296] Step 2: Synthesis of compound 46 At room temperature, compound 46-1 (30.00 mg) was dissolved in dichloromethane (5.00 mL), TFA (396.22 mg) was added, and the reaction was carried out at room temperature for 0.5 h. The reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and it was extracted 3 times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and 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] + .

[0297] 1 H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.83 (s, 1H), 8.73 (d, J = 8.5 Hz, 1H), 8.66 (d, J = 6.9 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J = 9.9 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.4 Hz, 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).

[0298] Example 49: Compound 7-((8'-(dimethylamino)-2,3,5,6,7',8'-hexahydrospiro[pyran-4,5'-pyrano[4,3-b]pyridine]-2'-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

Chemical Structure

[0299] Step 1: Synthesis of Compound 49-1 2-Bromo-3-iodopyridine (10 g, 35.2 mmol) was dissolved in THF (150 mL), and the reaction system was placed at -20 °C. Under nitrogen gas protection, isopropylmagnesium chloride (4.4 g, 42.3 mmol) was gradually added dropwise. After reacting at this temperature for 2 h, tetrahydro-4H-pyran-4-one (5.3 g, 52.8 mmol) was added, and the mixture was stirred overnight at room temperature. 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 successively with 1 M 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 49-1 (3.2 g, yield 35%). ESI-MS m / z: 258.0 [M+H] + 。

[0300] Step 2: Synthesis of Compound 49-2 Compound 49-1 (3.0 g, 9.3 mmol) was dissolved in DMF (25 mL). Under an ice bath, NaH (0.74 g, 18.6 mmol) was added, and then the mixture was stirred at room temperature for 30 min for reaction. 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 overnight at room temperature for reaction Water was added for quenching, and it was concentrated under reduced pressure to remove a part of the solvent. It 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 = 70:30 - 65:35) to obtain Compound 49-2 (2.8 g, yield 80%). ESI-MS m / z: 298.1 [M+H] + 。

[0301] Step 3: Synthesis of Compound 49-3 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 for 6 h under nitrogen gas protection. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:30 - 65:35) to obtain Compound 49-3 (0.84 g, yield 77%). ESI-MS m / z: 218.1 [M+H] + 。

[0302] Step 4: Synthesis of Compound 49-4 Compound 49-3 (0.34 g, 5.5 mmol) was dissolved in MeOH (5 mL) and DCM (10 mL), ozone was bubbled through at -50 °C, and after reacting for 30 min, dimethyl sulfide (0.34 g, 5.5 mmol) was added. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:40 - 50:50) to obtain Compound 49-4 (0.24 g, yield 83%). ESI-MS m / z: 220.1 [M+H] + 。

[0303] Step 5: Synthesis of Compound 49-5 Under an ice bath, 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 bath was removed, and the reaction was allowed to proceed at room temperature for 1 hour. Water was added to quench the reaction, and the mixture was concentrated under reduced pressure to remove a portion of the solvent. The residue 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 afford compound 49-5 (112 mg, yield 74%). ESI-MS m / z: 222.1 [M+H] + 。

[0304] Step 6: Synthesis of compound 49-6 Under an ice bath, thionyl chloride (0.18 mL) was added dropwise to a solution of 49-5 (0.11 g, 0.50 mmol) in DCM (5 mL). The ice bath was removed, and the temperature was raised to 40 °C and the reaction was allowed to proceed for 1 hour. The mixture was concentrated under reduced pressure, a small amount of methanol was added to dissolve the residue, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The residue was extracted with EA, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 20:80) to afford compound 49-6 (115 mg, yield 96%). ESI-MS m / z: 239.0 [M+H] + 。

[0305] Step 7: Synthesis of compound 49-7 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 the reaction was allowed to proceed at room temperature for 3 h. After confirmation by LC-MS that the starting material had completely reacted, 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, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 20:1) to afford compound 49-7 (428 mg, yield 98%). ESI-MS m / z: 256.1 [M+H] + 。

[0306] Step 8: Synthesis of compound 49-8 49-7 (400 mg, 1.56 mmol) and pyridine (1.2 g, 15.6 mmol) were dissolved in DCM (10 mL). Under an ice bath, Tf2O (1.3 g, 4.68 mmol) was added, and after reacting at room temperature for 0.5 h, it was confirmed by LC-MS that the raw materials had completely reacted. It was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 49-8 (472 mg, yield 96%). ESI-MS m / z: 317.1 [M] + .

[0307] Step 9: Synthesis of compound 49-9 49-8 (250 mg, 0.79 mmol) was dissolved in dimethylamine tetrahydrofuran solution (15 mL) at room temperature. After stirring at room temperature for 0.5 h, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 49-9 (175 mg, yield 87%). ESI-MS m / z: 255.1 [M + H] + .

[0308] Step 10: Synthesis of compound 49-10 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). After stirring at 100 °C overnight, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 49-10 (150 mg, yield 97%). ESI-MS m / z: 264.2 [M + H] + .

[0309] Step 11: Synthesis of compound 49-11 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). Then, under nitrogen gas protection, the tube was sealed and stirred at 90 °C for 4 h to react. After that, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 49-11 (480 mg, yield 80%). ESI-MS m / z: 529.3 [M+H] + 。

[0310] Step 12: Synthesis of compound 49-12 49-11 (250 mg, 0.47 mmol), Pd2(dba)3 (86.5 mg, 0.09 mmol), bis(pinacolato)diboron (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). Then, under nitrogen gas protection, the tube was sealed and stirred at 90 °C for 16 h to react. After that, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain compound 49-12 (293 mg, yield 72%). ESI-MS m / z: 621.5 [M+H] + 。

[0311] Step 13: Synthesis of compound 49-13 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). Then, under nitrogen gas protection, the tube was sealed and stirred at 90 °C for 0.5 h to react. After that, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 49-13 (60 mg, yield 59%). ESI-MS m / z: 629.5 [M+H] + 。

[0312] Step 14: Synthesis of Compound 49 49-13 (50 mg, 0.47 mmol) was dissolved in CH2Cl2 (5.0 mL), and TFA (0.5 mL) was added at room temperature. After stirring for 15 minutes to allow the reaction to proceed, the reaction was complete. It was washed with saturated sodium bicarbonate and extracted with dichloromethane. The crude product was slurried with ethyl acetate and n-hexane to obtain Compound 49 (25 mg, yield 60%). ESI-MS m / z: 529.5 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 10.11 (s, 1H), 8.85 (s, 1H), 8.79 (d, J = 8.6 Hz, 1H), 8.45 - 8.40 (m, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.53 - 7.47 (m, 1H), 6.97 (td, J = 7.5, 2.6 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 4.45 - 4.34 (m, 2H), 4.09 (dd, J = 12.3, 2.3 Hz, 1H), 3.95 (dd, J = 12.3, 3.8 Hz, 1H), 3.77 - 3.58 (m, 4H), 3.54 - 3.42 (m, 1H), 2.41 (s, 6H), 2.37 (d, J = 6.7 Hz, 1H), 2.17 - 2.06 (m, 1H), 2.04 - 1.95 (m, 1H), 1.78 (ddd, J = 19.4, 18.8, 8.8 Hz, 2H), 1.58 (d, J = 12.6 Hz, 1H).

[0313] Example 50: Synthesis of 4-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7’-methyl-2,3,5,6,7’,8’-hexahydro-6’-spiro[pyrazolo-4,5’-[1,7]naphthyridin]-2’-yl)amino)isoindol-1-one

Chemical Structure

[0314] Step 1: Synthesis of Compound 50-1 Methyl 6-chloro-3-methylpyridine-2-carboxylate (5.00 g) was dissolved in carbon tetrachloride (60.00 mL) at room temperature, and NBS (5.00 g) and AIBN (440.00 mg) were added. The reaction was carried out at 80 °C for 3 h under nitrogen gas protection, and then the reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 obtain the target product 50-1 (5.43 g, yield 80.00%). ESI-MS m / z: 186.0 [M+H] + .

[0315] Step 2: Synthesis of compound 50-2 Compound 50-1 (5.00 g) and K2CO3 (5.23 g) were dissolved in ACN (70.00 mL) at room temperature, and under the condition of an ice bath, TMSCN (3.00 g) was slowly added dropwise and reacted at room temperature for 13 h, and then the reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 obtain the target product 50-2 (2.15 g, yield 54.00%). ESI-MS m / z: 211.3 [M+H] + .

[0316] Step 3: Synthesis of compound 50-3 NaH (520.00 mg) was dissolved in DMF (30.00 mL) at room temperature, and under the condition of an ice bath and under nitrogen gas protection, 50-2 (2.00 g) was slowly added. After reacting for 0.5 h while maintaining the temperature, 2,2'-dibromodiethyl ether (3.52 g) was slowly added dropwise, and the reaction was carried out at room temperature for 3 h, and then the reaction was stopped. Under the condition of an ice bath, it was quenched with saturated ammonium chloride solution, extracted 3 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 target product 50-3 (1.20 g, yield 45.02%). ESI-MS m / z: 281.2 [M+H]+ 。

[0317] Step 4: Synthesis of Compound 50-4 Dissolve Compound 50-3 (1.20 g) in THF (30.00 mL) at room temperature, and slowly add dropwise a borane dimethyl sulfide solution (1.6 mL, 10 M) under the condition of an ice bath. React at 70 °C for 16 h under the protection of nitrogen gas, and then stop the reaction. Adjust the pH to 1-2 with 1 M HCl solution and react at 70 °C for 1 h, then stop the reaction. Adjust the pH to 8-9 with 2 M NaOH solution, extract three times with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate and concentrate. Separate the concentrate by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the target product 50-4 (250.00 mg, yield 30.00%). ESI-MS m / z: 239.4 [M+H] + 。

[0318] Step 5: Synthesis of Compound 50-5 Dissolve Compound 50-4 (250.00 mg) in MeOH (10.00 mL) at room temperature, add glacial acetic acid (1.00 mL), and slowly add an aqueous formaldehyde solution (127.00 mg, 37% aqueous solution) under the condition of an ice bath and under the protection of nitrogen gas. React while maintaining the temperature for 1 h, then slowly add dropwise NaBH(OAc)3 (665.00 mg) and react at room temperature for 1 h, then stop the reaction. Adjust the pH to 8-9 with saturated sodium bicarbonate solution, extract three times with EA, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate and concentrate. Separate the concentrate by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the target product 50-5 (208.00 mg, yield 79.00%). ESI-MS m / z: 253.4 [M+H] + 。

[0319] Step 6: Synthesis of Compound 50-6 At room temperature, 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). Then, under N2 protection, the reaction was carried out at 100 °C for 3 h and the reaction was stopped. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 13:1) to obtain the target product 50-6 (200.00 mg, yield 49.00%). ESI-MS m / z: 499.3 [M+H]+.

[0320] The next synthetic step was to obtain compound 50 with reference to the synthetic preparation method of Example 2. 1 H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.84 (s, 1H), 8.72 (d, J = 8.6 Hz, 1H), 8.45 (dd, J = 7.6, 5.7 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.72 (d , J = 8.5 Hz, 1H), 7.53 (dd, J = 10.0, 2.7 Hz, 1H), 6.99 - 6.95 (m, 1H), 6.87 (d, J = 8.6 Hz, 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).

[0321] Example 58: Synthesis of 7 - ((7-(dimethylamino)-4’,5’,6,7-tetrahydro-2’H-spiro[cyclopenta[b]pyridine-5,3’-furan]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindole-1-one

Chemical Structure

[0322] Step 1: Synthesis of compound 58-1 NaH (2.03 g, 60%, 50.75 mmol) was dissolved in DMF (80 mL). Under an ice bath, 10 mL of a DMF solution of compound 2-(2-bromopyridin-3-yl)acetonitrile (10.00 g, 50.75 mmol) was added, and then the mixture was stirred at 0 °C for 30 min for reaction. Then, 20 mL of a DMF solution of allyl bromide (6.14 g, 50.75 mmol) was added dropwise, and the mixture was stirred overnight at room temperature for reaction. Water was added to quench the reaction, and the mixture was concentrated under reduced pressure to remove part of the solvent. It 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 = 8:1 - 3:1) to obtain compound 58-1 (9.6 g, yield 80%). ESI-MS m / z: 236.9 [M+H] + 。

[0323] Step 2: Synthesis of compound 58-2 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). Under nitrogen gas protection, the mixture was reacted at 90 °C for 16 h. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography (PE:EA = 70:30 - 65:35) to obtain compound 58-2 (4.1 g, yield 66%). ESI-MS m / z: 157.1 [M+H] + 。

[0324] Step 3: Synthesis of compound 58-3 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 then the mixture was stirred at 0 °C for 15 min for reaction. Then, 10 mL of a THF solution of (2-bromoethoxy)-t-butyldimethylsilane (9.47 g, 39.57 mmol) was added at -78 °C, and the mixture was stirred at room temperature for 8 h for reaction. Saturated ammonium chloride was added for quenching, 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 - 5:1) to obtain Compound 58-3 (9.6 g, yield 80%). ESI-MS m / z: 315.4 [M+H]+.

[0325] Step 4: Synthesis of Compound 58-4 Compound 58-3 (4.0 g, 12.7 mmol) was dissolved in EtOH (50 mL). 50 mL of 20% aqueous sodium hydroxide solution was added, and the mixture was heated at 100 °C for 1 h for reaction. After the raw material reaction was completed, the pH was adjusted to 2 - 3 with 4N hydrochloric acid, and then 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, yield 78%). ESI-MS m / z: 202.2 [M+H]+.

[0326] Step 5: Synthesis of Compound 58-5 Under an ice bath, sodium borohydride (1.13 g, 29.8 mmol) was added portionwise to a solution of 58-4 (2.0 g, 9.94 mmol) in MeOH (90 mL) and THF (30 mL). The ice bath was removed, and the mixture was reacted at room temperature for 1 h. Water and saturated ammonium chloride were added for quenching, and the mixture was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 10:1) to obtain Compound 58-5 (2.0 g, yield 98%). ESI-MS m / z: 206.1 [M+H] + 。

[0327] Step 6: Synthesis of Compound 58-6 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, and the mixture was reacted at room temperature overnight. It was concentrated under reduced pressure and purified by column chromatography (PE:EA = 10:1 - 3:1) to obtain Compound 58-6 (0.70 g, yield 37%). ESI-MS m / z: 188.1 [M+H]+.

[0328] Step 7: Synthesis of Compound 58-7 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 bubbled through at -40 °C to -20 °C. After the reaction was completed, Me2S (1.49 g, 24.03 mmol) was added. It was concentrated under reduced pressure and purified by column chromatography (PE:EA = 4:1 - 1:1) to obtain Compound 58-7 (0.72 g, yield 79%). ESI-MS m / z: 190.2 [M+H]+.

[0329] Step 8: Synthesis of Compound 58-8 Under an ice bath, sodium borohydride (0.21 g, 5.63 mmol) was added portionwise to a solution of 58-7 (0.71 g, 3.75 mmol) in MeOH (15 mL) and THF (15 mL). The ice bath was removed, and the mixture was reacted at room temperature for 1 hour. Water was added to quench the reaction. It was concentrated under reduced pressure to remove part of the solvent, extracted with EA, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Compound 58-8 (0.69 g, yield 96%). ESI-MS m / z: 192.2 [M+H]+.

[0330] Step 9: Synthesis of Compound 58-9 Under an ice bath, thionyl chloride (1.3 mL) was added dropwise to a DCM (25 mL) solution of 58-8 (0.69 g, 3.61 mmol). The ice bath was removed, and the temperature was raised to 40 °C and reacted for 1 hour. It was concentrated under reduced pressure, a small amount of methanol was added and dissolved, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, 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 58-9 (0.69 g, yield 91%). ESI-MS m / z: 209.1 [M+H] + 。

[0331] Step 10: Synthesis of compound 58-10 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 after reacting at room temperature for 3 h, it was confirmed by LC-MS that the raw material had completely reacted. Saturated sodium bicarbonate solution (30 mL) was added, stirred at room temperature for 30 min, 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 obtain compound 58-10 (450 mg, yield 69%). ESI-MS m / z: 225.1 [M] + 。

[0332] Step 11: Synthesis of compound 58-11 58-10 (450 mg, 2.0 mmol) was dissolved in DCM (15 mL), under an ice bath, POCl3 (1.5 g, 10.0 mmol) was added, and after reacting at room temperature for 16 h, it was confirmed by LC-MS that the raw material had completely reacted. Saturated sodium bicarbonate was added to adjust the pH to 7-8, 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 = 20:1) to obtain compound 58-11 (300 mg, yield 61%). ESI-MS m / z: 244.1 [M] + 。

[0333] Step 12: Synthesis of Compound 58-12 58-11 (300 mg, 1.25 mmol), KI (20 mg, 0.10 mmol), K2CO3 (509 mg, 3.70 mmol), and methylamine in tetrahydrofuran solution (5 mL) were dissolved in ACN (5.0 mL), stirred at 80 °C overnight, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 20:1) to obtain Compound 58-12 (200 mg, yield 64%). ESI-MS m / z: 253.1 [M+H] + 。

[0334] Step 13: Synthesis of Compound 58-13 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), and the tube was sealed under nitrogen gas protection and stirred at 90 °C for 4 h. After the reaction, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain Compound 58-13 (300 mg, yield 79%). ESI-MS m / z: 499.3 [M+H] 。 + 。

[0335] Step 14: Synthesis of Compound 58-14 58-13 (300 mg, 0.60 mmol), Pd2(dba)3 (110 mg, 0.10 mmol), bis(pinacolato)diboron (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), and the tube was sealed under nitrogen gas protection and stirred at 90 °C for 16 h. After the reaction, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 20:1) to obtain Compound 58-14 (300 mg, yield 84%). ESI-MS m / z: 591.5 [M+H] + 。

[0336] Step 15: Synthesis of Compound 58-15 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), and then the tube was sealed under nitrogen gas protection and stirred at 90 °C for 0.5 h. After the reaction, it was concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 10:1) to obtain Compound 58-15 (58 mg, yield 57%). ESI-MS m / z: 599.4 [M+H] + 。

[0337] Step 16: Synthesis of Compound 58 58-15 (35 mg, 0.47 mmol) was dissolved in CH2Cl2 (5.0 mL), and TFA (0.5 mL) was added at room temperature and stirred for 15 min to react. After the reaction was complete, it was dried with a rotary evaporator and Compound 58 (16.2 mg, yield 55%) was obtained by reverse-phase preparative separation. ESI-MS m / z: 499.3 [M+H] + 。 1 H NMR (500 MHz, DMSO) δ10.32 (s, 2H), 8.94 (s, 1H), 8.64 (d, J = 8.5 Hz, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.89 - 7.65 (m, 3H), 7.29 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 5.20 - 5.01 (m, 1H), 4.41 (s, 2H), 3.97 (dd, J = 30.7, 22.7 Hz, 4H), 2.96 (s, 3H), 2.84 (s, 3H), 2.35 (d, J = 18.2 Hz, 2H), 2.14 (s, 1H), 1.99 (s, 1H).

[0338] Example 59: Synthesis of Compound 4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)-7-(7-morpholine-2’,3’,5’,6,6’,7-hexahydrospiro[b]pyridine-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0339] Step 1: Synthesis of Compound 59-1 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 the reaction was completed, ethyl acetate and water were added for extraction. The organic phase was washed with saturated brine, separated, dried over anhydrous sodium sulfate, filtered, the samples were mixed, and separated by silica gel column chromatography (PE:EA = 1:4) to obtain the target product 59-1 (173.00 mg, yield 72.31%). ESI-MS m / z: 309.18 [M+H] + 。

[0340] Step 2: Synthesis of Compound 59-2 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 the reaction was completed, it was filtered, the filter cake was washed with dichloromethane, concentrated, the samples were mixed, and separated by silica gel column chromatography (PE:EA = 1:4) to obtain the target product 59-2 (164.00 mg, yield 52.74%). ESI-MS m / z: 555.35 [M+H] + 。

[0341] Step 3: Synthesis of Compound 59-3 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 the reaction was completed, it was filtered, the filter cake was washed with dichloromethane, concentrated, the samples were mixed, separated by silica gel column chromatography (PE:EA = 1:5), and the target product 59-3 (147.00 mg, yield 76.94%) was obtained. ESI-MS m / z: 647.53 [M+H] + 。

[0342] Step 4: Synthesis of compound 59-4 At room temperature, 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), and then reacted at 85 °C for 1 h under N2 protection conditions to stop the reaction. A certain amount of water was added to the reaction solution, extracted 3 times with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The concentrated product was separated by silica gel column chromatography (DCM:MeOH = 13:1), and the target product 59-4 (77.00 mg, yield 51.74%) was obtained. ESI-MS m / z: 655.31 [M+H] + 。

[0343] Step 5: Synthesis of compound 59 At room temperature, compound 59-4 (77.00 mg) was dissolved in dichloromethane (5.00 mL), TFA (1.00 mL) was added, and the reaction was carried out at room temperature for 0.5 h to stop the reaction. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted 3 times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and purified by preparative plate to obtain the target product 59 (20.40 mg, purity 97.29%, yield 30.43%). 1 H NMR (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.83 (s, 1H), 8.76 (d, J = 8.6 Hz, 1H), 8.42 (t, J = 6.7 Hz, 1H), 7.82 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.01 - 6.95 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.44 - 4.32 (m, 2H), 4.22 (t, J = 7.8 Hz, 1H), 3.83 (t, J = 11.3 Hz, 2H), 3.61 (s, 4H), 3.58 - 3.50 (m, 2H), 2.88 (d, J = 9.7 Hz, 2H), 2.57 (s, 2H), 2.41 - 2.36 (m, 1H), 2.01 (d, J = 7.7 Hz, 1H), 1.93 - 1.86 (m, 1H), 1.68 (s, 1H), 1.46 (s, 1H), 1.35 (d, J = 13.1 Hz, 1H) was obtained. ESI-MS m / z: 555.43 [M + H] + 。

[0344] Example 60: Synthesis of 4-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(methylamino)-2’,3’,5’,6,6’,7-hexahydrospiro[b]pyridine-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0345] Step 1: Synthesis of Compound 60-1 At room temperature, 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). After reacting at room temperature for 1 h, sodium cyanoborohydride (200.45 mg) was further added, and the temperature was raised to 60 °C and reacted for 1 h. 50 mL of H2O was added to the reaction solution and filtered, and the filter cake was washed 3 times with DCM, Then, it was extracted three times with 30 mL of DCM, the organic phases were combined, washed with saturated sodium chloride, separated by column chromatography (DCM:MeOH = 95:5), and the target product 60-1 (160.00 mg, yield 50.63%) was obtained. ESI-MS m / z: 297.2 [M+H] + 。

[0346] Step 2: Synthesis of Compound 60-2 At room temperature, 60-1 (160.00 mg) and DMAP (6.57 mg) were added to DCM (5.00 mL), Boc2O (0.19 mL) was added dropwise under an ice-water bath, and the mixture was reacted at room temperature for 1 h. The reaction solution was added dropwise to water (30.00 mL), 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 (PE:EA = 60:40) to obtain the target product 60-2 (155.00 mg, yield 72.46%). ESI-MS m / z: 397.1 [M+H] + 。

[0347] Step 3: Synthesis of Compound 60-3 At room temperature, 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). Then, under N2 protection, the mixture was reacted at 100 °C for 1 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 70:30) to obtain the target product 60-3 (150.00 mg, yield 82.90%). ESI-MS m / z: 599.3 [M+H] + 。

[0348] Step 4: Synthesis of Compound 60-4 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 100 °C for 6 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 67:33) to obtain the target product 60-4 (190.00 mg, yield 91.58%). ESI-MS m / z: 691.4 [M+H] + 。

[0349] Step 5: Synthesis of compound 60-5 At room temperature, 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), and then, under N2 protection conditions, the reaction was carried out at 100 °C 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 target product 60-5 (150.00 mg, yield 78.03%). ESI-MS m / z: 699.5 [M+H] + 。

[0350] Step 6: Synthesis of compound 60 At room temperature, compound 60-5 (150.00 mg) and TFA (1.00 mL) were added to DCM (2.00 mL), and the reaction was carried out at room temperature for 30 min. The reaction solution was concentrated, adjusted to pH = 9 with saturated aqueous sodium bicarbonate solution, and further extracted 3 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 target product 60 (19.50 mg, yield 17.37%). ESI-MS m / z: 499.3 [M+H] + 。 11H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 8.85 (s, 1H), 8.76 (d, J = 8.5 Hz, 1H), 8.44 (t, J = 6.6 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 9.9 Hz, 1H), 6.98 (t, J = 6.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.40 (s, 2H), 4.17 (d, J = 6.6 Hz, 1H), 3.84 (t, J = 10.5 Hz, 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, 12.9 Hz, 2H).

[0351] Example 61: Compound 7 - ((7 - (Cyclopropyl(methyl)amino)-2’,3’,5’,6,6’,7 - hexahydrospiro[cyclopenta[b]pyridine - 5,4’ - pyran]-2 - yl)amino)-4-(7 - fluoroisoimidazo[1,2 - a]pyridin - 3 - yl)isoindol - 1 - one

Chemical Structure

[0352] Step 1: Synthesis of Compound 61 - 1 M8 (300 mg), N - methylcyclopropylamine (248 mg), potassium carbonate (482 mg), and potassium iodide (39 mg) were weighed, ACN (10 mL) was added, and the reaction was carried out at 80 °C for 12 h, and then the reaction was stopped. The insoluble matter was filtered off, the residue was washed with DCM, and the filtrate was concentrated and separated by column chromatography (PE:EA = 2:1) to obtain the target product 61 - 1 (230 mg, yield 67.59%). ESI - MS m / z: 293.14 [M + H] + 。

[0353] Step 2: Synthesis of Compound 61 - 2 Weighed 61-1 (265 mg), M10 (307 mg), Pd2(dba)3 (83 mg), XantPhos (105 mg), and cesium carbonate (885 mg), added dioxane (10 mL), reacted under nitrogen gas protection at 120 °C for 4 h, and then stopped the reaction. Filtered by suction with diatomaceous earth, collected the organic phase, dried it with a rotary evaporator, and separated it by column chromatography (DCM:MeOH = 33:1) to obtain the target product 61-2 (679 mg, yield 139.18%). ESI-MS m / z: 539.41 [M+H] + 。

[0354] Step 3: Synthesis of compound 61-3 Weighed 61-2 (670 mg), bis(pinacolato)diboron (631 mg), Pd2(dba)3 (341 mg), SPhos (306 mg), and KOAc (366 mg), added dioxane (10 mL), reacted under nitrogen gas protection at 120 °C for 8 h, and then stopped the reaction. Filtered by suction with diatomaceous earth, collected the organic phase, dried it with a rotary evaporator, and separated it by column chromatography (DCM:MeOH = 20:1) to obtain the target product 61-3 (290 mg, 37.00%), ESI-MS m / z: 631.39 [M+H] + 。

[0355] Step 4: Synthesis of compound 61-4 Weighed 61-3 (290 mg), M14 (145 mg), [PdCl2(dppf)]CH2Cl2 (38 mg), and sodium carbonate (146 mg), added them to DMF (8 mL) and water (2 mL), and reacted at 90 °C for 2 h under N2 protection conditions, then stopped the reaction. Filtered off the insoluble matter, washed the residue with DCM, concentrated the filtrate, and separated the concentrate by silica gel column chromatography (DCM:MeOH = 8:1) to obtain the target product 61-4 (120 mg, yield 40.85%). ESI-MS m / z: 639.39 [M+H] + 。

[0356] Step 5: Synthesis of compound 61 Compound 61-4 (120 mg) was weighed and dissolved in dichloromethane (1.5 mL) and methanol (1.5 mL). Under the conditions of an ice bath, a dioxane solution of hydrogen chloride (3 mL, 4 M dioxane solution) was slowly added dropwise. The temperature was gradually raised to room temperature and reacted for 30 min, and then the reaction was stopped. It was concentrated and separated and purified by preparative liquid chromatography to obtain the target product 61 (41.9 mg, yield 41.40%). ESI-MS m / z: 539.41 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 2H), 8.93 (s, 1H), 8.63 - 8.53 (m, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 7.86 (t, J = 9.0 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.34 (s, 1H), 7.16 (d, J = 7.7 Hz, 1H), 5.28 (s, 1H), 4.40 (s, 2H), 3.93 - 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 = 10.6 Hz, 1H), 1.57 (d, J = 13.0 Hz, 1H), 1.45 (d, J = 11.7 Hz, 1H), 1.05 (d, J = 39.3 Hz, 2H), 0.87 (s, 2H).

[0357] Example 62: 7 - ((7 - (Cyclopropylamino)-2’,3’,5’,6,6’,7 - hexahydrospiro[cyclopenta[b]pyridine - 5,4’ - pyran]-2 - yl)amino)-4-(7 - fluoroimidazo[1,2 - a]pyridin - 3 - yl)isoindole - 1 - one

Chemical Structure

[0358] Step 1: Synthesis of Compound 62-1 Weighed M3-2 (700 mg), M10 (842 mg), Pd2(dba)3 (227 mg), XantPhos (287 mg), and cesium carbonate (2.43 g), added dioxane (15 mL), reacted under nitrogen gas protection at 120 °C for 4 h, and then stopped the reaction. Filtered by suction with diatomaceous earth, collected the organic phase, dried it with a rotary evaporator, and separated it by column chromatography (DCM:MeOH = 40:1) to obtain the target product 62-1 (1.20 g, yield 84.12%). ESI-MS m / z: 484.16 [M+H] + 。

[0359] Step 2: Synthesis of compound 62-2 Weighed 62-1 (1.01 g), bis(pinacolato)diboron (1.06 g), Pd2(dba)3 (573 mg), SPhos (514 mg), and KOAC (615 mg), added dioxane (25 mL), reacted under nitrogen gas protection at 120 °C for 8 h, and then stopped the reaction. Filtered by suction with diatomaceous earth, collected the organic phase, dried it with a rotary evaporator, and separated it by column chromatography (DCM:MeOH = 20:1) to obtain the target product 62-2 (1.10 g, 91.59%). ESI-MS m / z: 576.29 [M+H] + 。

[0360] Step 3: Synthesis of compound 62-3 Weighed 62-2 (2.20 g), M14 (1.20 g), [PdCl2(dppf)]CH2Cl2 (312 mg), and sodium carbonate (1.22 g), added them to DMF (40 mL) and water (10 mL), and reacted at 90 °C for 2 h under N2 protection, then stopped the reaction. Filtered off the insoluble matter, washed the residue with DCM, concentrated the filtrate, and separated the concentrate by silica gel column chromatography (DCM:MeOH = 8:1) to obtain the target product 62-3 (1.63 g, yield 73.06%). ESI-MS m / z: 584.26 [M+H] + 。

[0361] Step 4: Synthesis of compound 62-4 62-3 (150 mg), cyclopropylamine (73 mg), and tetraethyl titanate (176 mg) were weighed, DCE (5 mL) and MeOH (2 mL) were added, and the reaction was carried out at room temperature for 1 h. Then it was gradually added to sodium cyanoborohydride (48 mg), the temperature was raised to 80 °C and the reaction was carried out for 2 h, and the reaction was stopped. It was extracted with DCM, the organic phase was washed with saturated brine, the organic phase was collected and dried with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the target product 62-4 (175 mg, yield 109.00%). ESI-MS m / z: 625.34 [M+H] + 。

[0362] Step 5: Synthesis of Compound 62 Compound 62-4 (350 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). Under the condition of an ice bath, a dioxane solution of hydrogen chloride (6 mL, 4 M dioxane solution) was gradually added dropwise, and the temperature was gradually raised to room temperature and reacted for 30 min, and the reaction was stopped. It was concentrated and separated and purified by preparative liquid chromatography to obtain the target product 62 (51.40 mg, yield 17.49%). ESI-MS m / z: 525.48 [M+H] + 。

[0363] 1 H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.78 (s, 1H), 9.34 (s, 1H), 8.93 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.54 (dd, J = 7.3, 5.6 Hz, 1H), 8.15 (s, 1H), 7.83 (dd, J = 14.7, 5.3 Hz, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.31 - 7.27 (m, 1H), 7.11 (d, J = 12.2 Hz, 1H), 5.01 (t, J = 7.5 Hz, 1H), 4.50 - 4.33 (m, 2H), 3. 93 - 3.83 (m, 2H), 3.55 (dt, J = 38.8, 11.2 Hz, 2H), 3.10 (s, 1H), 2.88 (dd, J = 13.4, 8.2 Hz, 1H), 2.16 - 2.03 (m, 2H), 1.71 (td, J = 12.9, 4.4 Hz, 1H), 1.52 - 1.44 (m, 2H), 1.02 (dt, J = 15.9, 7.3 Hz, 1H), 0.96 - 0.80 (m, 3H).

[0364] Example 67: Synthesis of 7-(7-(3-Fluoroazetidin-1-yl)-2’,3’,5’,6,6’,7-hexahydrospiro[b]pyridine-5,4’-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

Chemical Structure

[0365] Step 1: Synthesis of Intermediate 67-1 At room temperature, 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), and then, under N2 protection conditions, the reaction was carried out for 2 h while maintaining the temperature at 80 °C, and the reaction was stopped. The reaction solution was concentrated directly to obtain a crude product, and the crude product was separated by column chromatography (PE:EA = 95:5~65:35) to obtain the target product 67-1 (250.00 mg, yield 72.49%). ESI-MS m / z: 297.78 [M + H] + 。

[0366] Step 2: Synthesis of Intermediate 67-2 At room temperature, 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), and then reacted at 90 °C for 2 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the target product 67-2 (250.00 mg, yield 56.93%). ESI-MS m / z: 544.05 [M+H] + .

[0367] Step 3: Synthesis of intermediate 67-3 At room temperature, compound 67-2 (250.00 mg), bis(pinacolato)diboron (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), and then reacted at 100 °C for 12 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the target product 67-3 (160.00 mg, yield 54.77%). ESI-MS m / z: 634.55 [M+H] + .

[0368] Step 4: Synthesis of intermediate 67-4 At room temperature, 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), and then reacted at 90 °C for 1 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 to 85:15) to obtain the target product 67-4 (80.00 mg, yield 78.98%). ESI-MS m / z: 643.71 [M+H] + .

[0369] Step 5: Synthesis of Compound 67 At room temperature, compound 67-4 (80.00 mg) was added to dichloromethane (4.00 mL), and under N2 protection conditions, trifluoroacetic acid (0.80 mL) was added in an ice-water bath, and the reaction was carried out at room temperature for 1 h, and then the reaction was stopped. The reaction solvent was removed by a rotary evaporator. 5 mL of H2O and 5 mL of DCM were added to the reaction solution, and NaOH was added to adjust the pH>12. Then, it was extracted 3 times with 15 mL of DCM. The organic phases were combined, washed with saturated sodium chloride, and the organic phase was concentrated to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 95:5~85:15), and the crude product was obtained and slurried in 5.00 mL of methanol, filtered and dried to obtain the target product 67 (37.50 mg, yield 55.51%). ESI-MS m / z: 543.53 [M+H] + 。 1 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.84 (s, 1H), 8.71 (d, J = 8.6 Hz, 1H), 8.43 (dd, J = 7.5, 5.8 Hz, 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), 6.99 - 6.95 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 5.28 - 5.23 (m, 1H), 5.17 - 5.11 (m, 1H), 4.39 (d, J = 5.3 Hz, 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).

[0370] Example 71: 4-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-((R)-3-fluoropyrrolidin-1-yl)-2’,3’,5’,6,6’,7-hexahydrospiro[cyclopenta[b]pyridine-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0371] Step 1: Synthesis of Compound 71-1 M8 (300.00 mg), (R)-3-fluoropyrrolidine hydrochloride (310 mg), and potassium carbonate (481 mg) were dissolved in acetonitrile (10 mL) and reacted at 80 °C for 12 h. After the reaction was completed, 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 samples were combined. They were separated by silica gel column chromatography (PE:EA = 1:1) to obtain the target product 71-1 (280 mg, yield 77.53%). ESI-MS m / z: 311.14 [M+H] + 。

[0372] Step 2: Synthesis of Compound 71-2 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 the reaction was completed, the mixture was filtered, and the filter cake was washed with dichloromethane, concentrated, and the samples were combined. They were separated by silica gel column chromatography (DCM:MeOH = 50:1) to obtain the target product 71-2 (200 mg, yield 39.85%). ESI-MS m / z: 557.37 [M+H] + 。

[0373] Step 3: Synthesis of Compound 71-3 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 the reaction was completed, the mixture was filtered, and the filter cake was washed with dichloromethane, concentrated, and the samples were combined. They were separated by silica gel column chromatography (DCM:MeOH = 30:1) to obtain the target product 71-3 (171 mg, yield 73.44%). ESI-MS m / z: 649.31 [M+H] + 。

[0374] Step 4: Synthesis of Compound 71-4 At room temperature, 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), and then reacted at 90 °C for 2 h under N2 protection conditions. The reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 (DCM:MeOH = 19:1) to obtain the target product 71-4 (138 mg, yield 79.69%). ESI-MS m / z: 657.30 [M+H] 。 + 。

[0375] Step 5: Synthesis of Compound 71 At room temperature, Compound 71-4 (138 mg) was dissolved in dichloromethane (5 mL), and TFA (1 mL) was added. The reaction was carried out at room temperature for 0.5 h and then stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and it was extracted 3 times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. It was separated by silica gel column chromatography (DCM:MeOH = 17:1) to obtain the product, which was dissolved in 2 M HCl aqueous solution to form a salt, and the hydrochloride salt of the target product 71 (47.60 mg, yield 39.84%) was obtained. ESI-MS m / z: 557.19 [M+H] + 。

[0376] 11H NMR (500 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.31 - 10.15 (m, 1H), 8.95 (d, J = 6.3 Hz, 1H), 8.84 - 8.47 (m, 2H), 8.44 (s, 1H), 8.04 (dd, J = 8.2, 2.6 Hz, 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).

[0377] Synthesis of Compounds 71A and 71B:

Chem.

[0378] Step 1: Synthesis of Compounds 71-4A and 71-4B Preparation of 71-4 sample: 200 mg of sample 71-4 was dissolved in 6 ml of dichloromethane:methanol (3:2) solution. Chromatography conditions: 1. Chiral resolution column YMC CHIRAL ART Celluose-SB 250×20.0 mm S-5um; 2. Instrument type GILSON GX-271; 3. Mobile phase, mobile phase A was n-hexane, mobile phase B was an ethanol solution of 0.1% dihexylamine, isocratic elution with mobile phase A:mobile phase B being 6:4, flow rate was 20 ml / min, wavelength was 254 nm, and separation was carried out at room temperature. Compound 71-4A (peak 1): retention time = 13.566 mi n, recovery amount 70 mg; Compound 71-4B (peak 2): retention time = 20.645 min, recovery amount 55 mg.

[0379] Step 2: Synthesis of Compound 71A At room temperature, compound 71-4A (70 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 0.5 h. 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 (DCM:MeOH = 15:1) to separate the product 71A (25.90 mg, purity 98.09%, yield 42.82%). ESI-MS m / z: 557.39 [M+H] + 。

[0380] Step 3: Synthesis of compound 71B At room temperature, compound 71-4B (55 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted at room temperature for 0.5 h. 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 (DCM:MeOH = 15:1) to separate the product 71B (21.80 mg, purity 99.44%, yield 46.53%). ESI-MS m / z: 557.39 [M+H] + 。

[0381] Example 72: 7-((7-(3,3-Difluoropyrrolidin-1-yl)-2’,3’,5’,6,6’,7-hexahydrospiro[b]pyridine-5,4’-pyran]-2-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindole-1-one

Chemical Structure

[0382] Step 1: Synthesis of compound 72-1 Weighed 62-3 (300 mg), 3,3-difluoropyrrolidine (165 mg), and tetraethyl titanate (117 mg), added DCE (5 mL) and MeOH (2 mL), reacted at room temperature for 1 h, gradually added sodium cyanoborohydride (97 mg), heated to 80 °C and reacted for 2 h, then stopped the reaction. Extracted with DCM, washed the organic phase with saturated brine, collected the organic phase and dried it with a rotary evaporator, separated by column chromatography (DCM:MeOH = 33:1) to obtain the target product 72-1 (290 mg, yield 83.62%). ESI-MS m / z: 675.39 [M+H] + 。

[0383] Step 2: Synthesis of compound 72 Weighed 72-1 (100 mg) and dissolved it in dichloromethane (3 mL) and methanol (3 mL). Under the condition of an ice bath, gradually added a dioxane solution of hydrogen chloride (6 mL, 4 M dioxane solution), gradually warmed to room temperature and reacted for 30 min, then stopped the reaction. Concentrated and separated by preparative liquid chromatography, purified to obtain the target product 72 (26.20 mg, yield 30.77%). ESI-MS m / z: 575.44 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8 .91 (s, 1H), 8.66 - 8.58 (m, 1H), 8.56 (d, J = 8.5 Hz, 1H), 8.24 (s, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.76 (dd, J = 14.8, 8.5 Hz, 2H), 7.38 (t, J = 6.3 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.71 (s, 1H), 4.40 (dd, J = 33.7, 18.3 Hz, 2H), 4.25 - 3.47 (m, 11H), 2.66 (d, J = 23.5 Hz, 1H), 2.15 - 1.96 (m, 2H), 1.77 - 1.65 (m, 1H), 1.51 (d, J = 12.5 Hz, 1H), 1.38 (d, J = 12.6 Hz, 1H).

[0384] Example 85: 4-(7-Fluoroimidazo[1,2-a]pyridin-3-yl)-7-((7-(isopropyl(methyl)amino)-2’,3’,5’,6,6’,7-hexahydrospiro[cyclopenta[b]pyridin-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0385] Step 1: Synthesis of Compound 85-1 M8 (300 mg), N-methylisopropyl (255 mg), potassium carbonate (482 mg), and potassium iodide (39 mg) were weighed and added to ACN (10 mL), and reacted at 80 °C for 12 h. The reaction was stopped. The insoluble matter was filtered off, the residue was washed with DCM, the filtrate was concentrated, and separated by column chromatography (PE:EA = 2:1) to obtain the target product 85-1 (400 mg, yield 116.75%). ESI-MS m / z: 295.17 [M+H] + .

[0386] Step 2: Synthesis of Compound 85-2 85-1 (380 mg), M10 (437 mg), Pd2(dba)3 (118 mg), XantPhos (149 mg), and cesium carbonate (1.26 g) were weighed and added to dioxane (15 mL), and reacted under nitrogen gas protection at 120 °C for 4 h. The reaction was stopped. It was suction filtered through diatomaceous earth, the organic phase was collected and dried with a rotary evaporator, and separated by column chromatography (DCM:MeOH = 33:1) to obtain the target product 85-2 (729 mg, yield 104.53%). ESI-MS m / z: 541.28 [M+H] + .

[0387] Step 3: Synthesis of Compound 85-3 85-2 (719 mg), bis(pinacolato)diboron (675 mg), Pd2(dba)3 (365 mg), SPhos (327 mg), and KOAC (391 mg) were weighed and dioxane (15 mL) was added, and reacted under nitrogen gas protection at 120 °C for 8 h The reaction was stopped. It was suction filtered with diatomaceous earth, the organic phase was collected and dried with a rotary evaporator, separated by column chromatography (DCM:MeOH = 20:1), and the target product 85-3 (324 mg, 38.54%), ESI-MS m / z: 633.41 [M+H] + 。

[0388] Step 4: Synthesis of compound 85-4 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), and under N2 protection conditions, reacted at 90 °C for 2 h. The reaction was stopped. The insoluble matter was filtered off, the residue was washed with DCM, the filtrate was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 8:1) to obtain the target product 85-4 (300 mg, yield 91.41%). ESI-MS m / z: 641.36 [M+H] + 。

[0389] Step 5: Synthesis of compound 85 Compound 85-4 (300 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). Under ice bath conditions, a dioxane solution of hydrogen chloride (6 mL, 4 M dioxane solution) was slowly added dropwise, and the temperature was slowly raised to room temperature and reacted for 30 min. The reaction was stopped. It was concentrated and separated and purified by preparative liquid chromatography to obtain the target product 85 (133.60 mg, yield 52.78%). ESI-MS m / z: 541.50 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 10.23 (d, J = 5.9 Hz, 1H), 9.97 (d, J = 39.3 Hz, 1H), 8.95 (s, 1H), 8.69 - 8.56 (m, 1H), 8.44 (dd, J = 14.5, 8.5 Hz, 1H), 8.33 (s, 1H), 8.01 (dd, J = 8.4, 1.9 Hz, 1H), 7.88 - 7.77 (m, 2H), 7.47 (dd, J = 6.8, 4.3 Hz, 1H), 7.16 (t, J = 8.0 Hz, 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 = 4.4 Hz, 1H), 2.93 - 2.82 (m, 1H), 2.74 (d, J = 4.3 Hz, 2H), 2.24 - 2.03 (m, 2H), 1.64 (dd, J = 12.1, 8.4 Hz, 1H), 1.58 - 1.33 (m, 8H).

[0390] 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]naphthyridin]-2’-yl)amino)isoindol-1-one [Chemical Structure]

[0391] Step 1: Synthesis of Compound 87-1 At room temperature, compound M12 (250.00 mg) and DMAP (64.00 mg) were added to THF (6.00 mL), and di-t-butyl dicarbonate (457.00 mg) was slowly added dropwise. The reaction was carried out at room temperature for 3 h and then 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 separated by silica gel column chromatography (PE:EA = 3:1) to obtain the target product 87-1 (136.00 mg, yield 38.41%). ESI-MS m / z: 339.2 [M+H] + .

[0392] Step 2: Synthesis of Compound 87-2 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 100 °C for 3 h, and the reaction was stopped. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 1.5:1) to obtain the target product 87-2 (85.00 mg, yield 37.86%). ESI-MS m / z: 585.3 [M+H]+.

[0393] Step 3: Synthesis of compound 87-3 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 100 °C for 6 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 24:1) to obtain the target product 87-3 (80.00 mg, yield 81.37%). ESI-MS m / z: 677.4 [M+H]+.

[0394] Step 4: Synthesis of compound 87-4 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 85 °C for 40 min, and the reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 (DCM:MeOH = 24:1) to obtain the target product 87-4 (50.00 mg, yield 61.78%). ESI-MS m / z: 685.2 [M+H]+.

[0395] Step 5: Synthesis of compound 87 At room temperature, compound 87-4 (50.00 mg) was dissolved in dichloromethane (5.00 mL), TFA (396.22 mg) was added, and the reaction was carried out at room temperature for 0.5 h. The reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and the mixture was extracted 3 times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, slurried, and the target product 87 (30.40 mg, purity 99.40%, yield 85.94%) was obtained. ESI-MS m / z: 585.1 [M+H] + 。

[0396] 1 H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.83 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.45 (dd, J = 7.6, 5.7 Hz, 1H), 7.82 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.52 (dd, J = 10.1, 2.7 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.85 (d, J = 8.5 Hz, 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).

[0397] Example 89: 7 - ((7’-Cyclopropyl-2,3,5,6,7’,8’-hexahydro-6’H-spiro[pyran-4,5’-[1,7]naphthyridin]-2’-yl)amino)-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

Chemical Structure

[0398] Step 1: Synthesis of Compound 89-1 At room temperature, 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), and the reaction was carried out at 70 °C for 4 h, and then the reaction was stopped. A certain amount of aqueous ammonia was added, and the mixture was extracted 3 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 obtain the target product 89-1 (130.00 mg, yield 45.44%). ESI-MS m / z: 279.2 [M+H] + .

[0399] Step 2: Synthesis of compound 89-2 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 100 °C for 3 h, and then the reaction was stopped. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 4:1) to obtain the target product 89-2 (67.00 mg, yield 28.46%). ESI-MS m / z: 525.3 [M+H]+.

[0400] Step 3: Synthesis of compound 89-3 At room temperature, compound 89-2 (67.00 mg), B2Pin2 / bis(pinacolato)diboron (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). Then, under N2 protection, the reaction was carried out at 100 °C for 6 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 3:1) to obtain the target product 89-3 (70.00 mg, yield 91.71%). ESI-MS m / z: 617.4 [M+H]+.

[0401] Step 4: Synthesis of compound 89-4 At room temperature, 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). Then, under N2 protection, the reaction was carried out at 85 °C for 40 min, and the reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 (DCM:MeOH = 24:1) to obtain the target product 89-4 (50.00 mg, yield 70.52%). ESI-MS m / z: 625.2 [M+H]+.

[0402] Step 5: Synthesis of compound 89 At room temperature, compound 89-4 (50.00 mg) was dissolved in dichloromethane (5.00 mL), TFA (396.22 mg) was added, and the reaction was carried out at room temperature for 0.5 h, and the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and it was extracted 3 times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, slurried, to obtain the target product 89 (28.00 mg, purity 99.22%, yield 55.17%). ESI-MS m / z: 525.1 [M+H] + 。

[0403] 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]naphthyridin]-2’-yl)amino)isoindol-1-one

Chem.

[0404] Step 1: Synthesis of Compound 100-1 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 carried out at room temperature for 16 h and then stopped. A certain amount of water was added, and the mixture was extracted 3 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 (DCM:MeOH = 19:1) to obtain the target product 100-1 (207.00 mg, yield 78.86%). ESI-MS m / z: 256.2 [M+H] + .

[0405] Step 2: Synthesis of Compound 100-2 At room temperature, 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). Then, under N2 protection, the reaction was carried out at 100 °C for 3 h and then stopped. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the target product 100-2 (149.00 mg, yield 36.69%). ESI-MS m / z: 502.3 [M+H]+.

[0406] Step 3: Synthesis of Compound 100-3 At room temperature, compound 100-2 (149.00 mg), B2Pin2 / bis(pinacolato)diboron (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). Then, under N2 protection conditions, the reaction was carried out at 100 °C for 6 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the target product 100-3 (76.00 mg, yield 43.18%). ESI-MS m / z: 594.4 [M+H]+.

[0407] Step 4: Synthesis of compound 100-4 At room temperature, 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), and then, under N2 protection conditions, the reaction was carried out at 85 °C for 40 min, and the reaction was stopped. A certain amount of water was added to the reaction solution, and it was extracted 3 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 (DCM:MeOH = 19:1) to obtain the target product 100-4 (50.00 mg, yield 64.93%). ESI-MS m / z: 602.2 [M+H]+.

[0408] Step 5: Synthesis of compound 100 At room temperature, compound 100-4 (50.00 mg) was dissolved in dichloromethane (5.00 mL), and TFA (396.22 mg) was added. The reaction was carried out at room temperature for 0.5 h, and the reaction was stopped. The pH was adjusted to alkaline with saturated sodium bicarbonate solution, and it was extracted 3 times with DCM. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, slurried, and the target product 100 (30.700 mg, purity 96.46%, yield 59.21%) was obtained. ESI-MS m / z: 502.1 [M+H] + 。 11H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.84 (s, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.44 (dd, J = 7.5, 5.8 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.53 (dd, J = 10.0, 2.6 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.86 (d, J = 8.6 Hz, 1H), 4.39 (s, 2H), 3.75 - 3.71 (m, 2H), 3.63 - 3.57 (m, 2H), 3.52 (s, 2H), 2.73 (s, 2H), 1.95 - 1.88 (m, 2H), 1.58 - 1.54 (m, 2H).

[0409] 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]naphthyridin]-2’-yl)amino)isoindol-1-one

Chemical Structure

[0410] Step 1: Synthesis of Compound 123-1 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), and , under N2 protection conditions, the reaction was carried out at 80 °C for 18 h while maintaining the temperature, and the reaction was stopped. The reaction solution was concentrated directly to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~85:15) to obtain the target product 123-1 (2.2 g, yield 90.30%). ESI-MS m / z: 135.15 [M+H] + .

[0411] Step 2: Synthesis of Compound 123-2 At room temperature, compound 123-1 (1.00 g), sodium chlorodifluoroacetate (5.68 g), and potassium carbonate (2.06 g) were added to water (7.5 mL) and acetonitrile (37.50 mL), and then, under N2 protection conditions, the reaction was carried out at 110 °C for 24 h while maintaining the temperature, and the reaction was stopped. The solid in the reaction solution was directly filtered off, and the solid was washed with 10 mL of (DCM:MeOH = 10:1) three times in a row. The mother liquors were combined, concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 97:3~90:10) to obtain the target crude product 123-2 (1.4 g, yield 101.98%). ESI-MS m / z: 185.20 [M+H] + 。

[0412] Step 3: Synthesis of compound 123-3 At room temperature, the crude product of compound 123-2 (500.00 mg) was added to acetonitrile (10.00 mL), and under the condition of an ice-water bath, NIS (733.10 mg) was gradually added in several portions. The reaction was carried out at room temperature for 0.5 h and then stopped. The reaction solution was directly added to 50 mL of water for quenching, and then extracted three times with 10 mL of DCM, washed with saturated sodium chloride, and the organic phase was concentrated and dried to obtain a crude product. The crude product was separated by column chromatography (DCM:MeOH = 97:3~90:10) to obtain the target product 123-3 (75 mg, yield 8.91%). ESI-MS m / z: 311.10 [M+H] + 。

[0413] Step 4: Synthesis of compound 123-4 At room temperature, 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), and then reacted at 90 °C for 4 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~85:15) to obtain the target product 123-4 (30.00 mg, yield 55.40%). ESI-MS m / z: 733.71 [M+H] + 。

[0414] Step 5: Synthesis of compound 123 At room temperature, compound 123-4 (30.00 mg) was added to dichloromethane (4.00 mL), and then trifluoroacetic acid (1.00 mL) was added in an ice-water bath under N2 protection conditions, and reacted at room temperature for 1 h. The reaction was stopped. The reaction solvent was removed by a rotary evaporator and separated by preparative chromatography to obtain the target product 123 (2.20 mg, purity 99.42%, yield 10.04%). ESI-MS m / z: 533.53 [M+H] + 。 1 H NMR (500 MHz, DMSO) δ 10.27 (s, 1H), 9.31 (s, 2H), 8.98 (s, 1H), 8.77 (d, J = 8.6 Hz, 1H), 8.67 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.29 (dd, J = 7.4, 2.2 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 4.42 (s, 2H), 4.29 (s, 2H), 3.80 (dd, J = 11.4, 4.5 Hz, 2H), 3.65 (d, J = 11.7 Hz, 4H), 2.02 (td, J = 13.6, 4.9 Hz, 2H), 1.69 (d, J = 13.2 Hz, 2H).

[0415] Example 133: Compound 7-((7’,8’-dihydro-6’H-spiro[cyclopropa Synthesis of [[1,5'-[1,7]naphthyridin]-2'-yl)amino]-4-(7-fluoroimidazo[1,2-a]pyridin-3-yl)isoindol-1-one

Chemical formula

[0416] Step 1: Synthesis of Compound 133-1 At room temperature, NaH (2.18 g) was dissolved in DMF (40.00 mL). Then, under ice bath conditions and under nitrogen gas protection, 50-2 (5.00 g) dissolved in DMF (10.00 mL) was gradually added. After reacting while maintaining the temperature for 0.5 h, 1,2-dibromoethane (3.52 g) was gradually added dropwise, and the reaction was carried out at room temperature for 3 h, and then the reaction was stopped. Under ice bath conditions, it was quenched with saturated ammonium chloride solution and extracted 3 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 target product 133-1 (1.28 g, yield 22.78%). ESI-MS m / z: 236.78 [M+H] + 。

[0417] Step 2: Synthesis of Compound 133-2 At room temperature, Compound 133-1 (1.28 g) was dissolved in THF (20.00 mL). Then, under ice bath conditions, borane dimethyl sulfide solution (2.16 mL, 10 M) was gradually added dropwise. Under nitrogen gas protection, the reaction was carried out at 70 °C for 20 h, and then the reaction was stopped. The pH was adjusted to 1-2 with 1 M HCl solution and reacted at 70 °C for 1 h, and then the reaction was stopped. The pH was adjusted to 8-9 with 2 M NaOH solution and extracted 3 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 (DCM:MeOH = 19:1) to obtain the target product 133-2 (240.00 mg, yield 22.79%). ESI-MS m / z: 237.65 [M+H] + 。

[0418] Step 3: Synthesis of Compound 133-3 At room temperature, compound 133-2 (240.00 mg) and 4-DMAP (150.00 mg) were added to THF (8.00 mL), and di-t-butyl dicarbonate (670.00 mg) was gradually added dropwise. The reaction was carried out at room temperature for 5 h and then stopped. 8 ml of water was added and the mixture was extracted 3 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 target product 133-3 (310.00 mg, yield 85.31%). ESI-MS m / z: 295.80 [M+H]+ + 。

[0419] Step 4: Synthesis of compound 133-4 At room temperature, 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). Then, under N2 protection, the reaction was carried out at 100 °C for 8 h and then stopped. The reaction solution was concentrated and the concentrate was separated by silica gel column chromatography (PE:EA = 1.5:1) to obtain the target product 133-4 (330.00 mg, yield 37.86%). ESI-MS m / z: 542.08 [M+H]+.

[0420] Step 5: Synthesis of compound 133-5 At room temperature, compound 133-4 (330.00 mg), B2Pin2 / bis(pinacolato)diboron (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). Then, under N2 protection, the reaction was carried out at 100 °C for 8 h. The reaction solution was concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA:DCM = 10:1:1~5:1:1~3:1:1) to obtain the target product 133-5 (150.00 mg, yield 38.88%). ESI-MS m / z: 633.62 [M+H]+.

[0421] Step 6: Synthesis of compound 133-6 At room temperature, 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), and then, under N2 protection, the reaction was carried out at 85 °C for 30 min, and the reaction was stopped. The reaction solution was directly dried with a rotary evaporator to obtain a crude product. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 97:3~88:12) to obtain the target product 133-6 (70.00 mg, yield 76.78%). ESI-MS m / z: 641.63 [M+H]+.

[0422] Step 7: Synthesis of compound 133 At room temperature, compound 133-6 (70.00 mg) was dissolved in dichloromethane (4.00 mL), TFA (1.00 mL) was added, and the reaction was carried out at room temperature for 1.5 h, and the reaction was stopped. The reaction solution was concentrated to obtain a crude product, which was separated by preparative chromatography to obtain the target product 133 (34.10 mg, purity 99.80%, yield 70.69%). ESI-MS m / z: 441.16 [M+H] + . Trifluoroacetate 11H NMR (500 MHz, 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, 1H), 6.98 (d, J = 8.6, 1H), 4.41 (s, 4H), 1.19 (d, J = 48.0, 2H), 1.10 (s, 4H).

[0423] Example 146: Synthesis of 3-(7-((2,3,5,6,7’,8’-Hexahydro-6’-H-spiro[pyran-4,5’-[1,7]naphthyridin]-2’-yl)amino) -1-oxoisoindol-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile

Chemical Structure

[0424] Step 1: Synthesis of Intermediate 146-1 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), and the reaction was carried out at 80 °C for 8 h while maintaining the temperature under N2 protection conditions, and then the reaction was stopped. The reaction solution was concentrated directly to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 - 90:10) to obtain the target product 146-1 (1.64 g, yield 68.24%). ESI-MS m / z: 144.15 [M + H] + .

[0425] Step 2: Synthesis of Intermediate 146-2 At room temperature, compound 146-1 (1.64 g) was added to DMF (40.00 mL), and under the condition of an ice-water bath, NIS (3.09 g) was gradually added in several portions. The reaction was carried out at room temperature for 2 h and then stopped. The reaction solution was directly added to 50 mL of ice water to quench it, and a large amount of white solid was precipitated. It was filtered and dried to obtain the target product 146-2 (2.30 g, yield 74.62%). ESI-MS m / z: 270.12 [M+H] + 。

[0426] Step 3: Synthesis of intermediate 146-3 At room temperature, 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). Then, under N2 protection, the reaction was carried out at 90 °C for 1 h and stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~85:15) to obtain the target product 146-3 (80.00 mg, yield 78.24%). ESI-MS m / z: 692.73 [M+H] + 。

[0427] Step 4: Synthesis of compound 146 At room temperature, compound 146-3 (80.00 mg) was added to dichloromethane (4.00 mL), and under N2 protection, trifluoroacetic acid (1.00 mL) was added in an ice-water bath. The reaction was carried out at room temperature for 1.5 h and stopped. The reaction solvent was removed by a rotary evaporator and separated by preparative chromatography to obtain the target product 146 (55.50 mg, purity 99.67%, yield 97.67%). ESI-MS m / z: 491.53 [M+H] + 。Trifluoroacetate 11H NMR (500 MHz, DMSO) δ 10.27 (s, 1H), 9.27 (s, 2H), 8.95 (s, 1H), 8.75 (d, J = 8.6 Hz, 1H), 8.57 (d, J = 7.2 Hz, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 7.2, 1.3 Hz, 1H), 7.06 (d, J = 8.7 Hz, 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).

[0428] Example 147: Synthesis of 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 [Chemical Structure]

[0429] Step 1: Synthesis of Intermediate 147 - 1 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). Then, under N2 protection, the reaction was carried out at 80 °C for 4 h while maintaining the temperature, and the reaction was stopped. The reaction solution was concentrated directly to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 - 90:10) to obtain the target product 147 - 1 (1.00 g, yield 87.09%). ESI - MS m / z: 187.15 [M + H] + .

[0430] Step 2: Synthesis of Intermediate 147 - 2 At room temperature, compound 147-1 (1.00 g) was added to DMF (15.00 mL), and under the condition of an ice-water bath, NIS (1.05 g) was gradually added in several portions. The reaction was carried out at room temperature for 1 h and then stopped. The reaction solution was directly added to 50 mL of ice water to quench it, and a large amount of pale yellow solid was precipitated. It was filtered and dried to obtain the target product 147-2 (0.70 g, yield 41.76%). ESI-MS m / z: 313.12 [M+H] + 。

[0431] Step 3: Synthesis of intermediate 147-3 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 90 °C for 1 h and then stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (PE:EA = 95:5~50:50) to obtain the target product 147-3 (70.00 mg, yield 80.60%). ESI-MS m / z: 735.73 [M+H] + 。

[0432] Step 4: Synthesis of compound 147 At room temperature, compound 147-3 (70.00 mg) was added to dichloromethane (4.00 mL), and under N2 protection conditions, trifluoroacetic acid (1.00 mL) was added in an ice-water bath. The reaction was carried out at room temperature for 1.5 h and then stopped. The reaction solvent was removed by a rotary evaporator and separated by preparative chromatography to obtain the target product 147 (50.80 mg, purity 99.77%, yield 99.49%). ESI-MS m / z: 534.53 [M+H] + 。Trifluoroacetate 11H NMR (500 MHz, DMSO) δ 10.26 (s, 1H), 9.20 (s, 2H), 8.94 (s, 1H), 8.75 (d, J = 8.5 Hz, 1H), 8.61 (d, J = 7.3 Hz, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.23 (dd, J = 7.3, 1.8 Hz, 1H), 7.06 (d, J = 8.7 Hz, 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).

[0433] Example 149: Synthesis of 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]naphthyridin]-2’-yl)amino)isoindol-1-one [Chemical formula]

[0434] Step 1: Synthesis of Compound 149-1 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 110 °C for 20 h and the reaction was stopped. The reaction solution was filtered to remove salts, and the filter cake was washed 3 times with EA, 30 mL each time. The filtrates were combined and concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 90:10 - 75:25) to obtain the target product 149-1 (4.20 g, yield 91.63%). ESI-MS m / z: 291.41 [M + H] + .

[0435] Step 2: Synthesis of Compound 149-2 At room temperature, compound 149-1 (4.20 mg) was added to dichloromethane (15.00 mL), and then HCl (10.00 mL, 4M dioxane solution) was added in an ice-water bath. The reaction was carried out at room temperature for 1 h and then stopped. The reaction solvent was removed by a rotary evaporator to obtain a crude product. Then, 30 mL of H2O and 30 mL of EA were added, and extraction was performed with EA to remove impurities. The remaining aqueous phase was added to saturated sodium bicarbonate to adjust the alkalinity to pH = 8-9, and then extracted 3 times with DCM, 50 mL each time. It was washed with saturated sodium chloride and separated by column chromatography (PE:EA = 90:10 - 50:50) to obtain the target product 149-2 (1.20 g, yield 65.77%) as a pale yellow solid. ESI-MS m / z: 127.13 [M+H] + 。

[0436] Step 3: Synthesis of intermediate 149-3 At room temperature, compound 149-2 (1.24 g) and 2-bromo-1,1-diethoxyethane (3.75 g) were added to ethanol (8.00 mL). Then, under N2 protection and in an ice-water bath, HBr (1.5 mL, 40% H2O) was gradually added. The reaction was carried out for 36 h while maintaining the temperature at 80 °C and then stopped. An aqueous NaOH solution was added to the reaction solution to adjust the alkalinity to pH > 10, and then extracted 4 times with DCM, 50 mL each time. It was washed with saturated sodium chloride and separated by column chromatography (PE:EA = 90:10 - 50:50) to obtain the target product 149-3 (0.62 g, yield 43.40%) as a pale yellow solid. ESI-MS m / z: 151.13 [M+H] + 。

[0437] Step 4: Synthesis of intermediate 149-4 At room temperature, compound 149-3 (0.62 g) was added to DMF (10.00 mL). Then, under an ice-water bath, NIS (1.11 g) was gradually added in several portions. The reaction was carried out at room temperature for 2 h and then stopped. The reaction solution was directly added to 50 mL of ice water to quench it, and a large amount of pale yellow solid precipitated. It was filtered and dried to obtain the target product 149-4 (0.90 g, yield 78.96%) as a pale yellow solid. ESI-MS m / z: 277.10 [M+H]+ .

[0438] Step 5: Synthesis of Intermediate 149-5 At room temperature, 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), and then reacted at 90 °C for 1 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:EA = 95:5~50:50) to obtain the target product 149-5 (70.00 mg, yield 84.75%) as a pale yellow solid. ESI-MS m / z: 699.80 [M+H] + .

[0439] Step 6: Synthesis of Compound 149 At room temperature, compound 149-5 (70.00 mg) was added to dichloromethane (4.00 mL), and then trifluoroacetic acid (1.00 mL) was added in an ice-water bath under N2 protection conditions, and reacted at room temperature for 1.5 h. The reaction was stopped. The reaction solvent was removed by a rotary evaporator and separated by preparative chromatography to obtain the target product 149 (4.50 mg, purity 99.86%, yield 9.00%) as a white solid. ESI-MS m / z: 499.81 [M+H] + . Trifluoroacetate 1 1H NMR (500 MHz, DMSO) δ 10.24 (s, 1H), 9.22 (s, 2H), 8.93 (s, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 6.9 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 8.7 Hz, 1H), 6.95 (s, 1H), 4.41 (s, 2H), 4.28 (s, 2H), 3.84 - 3.77 (m, 2H), 3.64 (d, J = 11.5 Hz, 4H), 2.37 (s, 3H), 2.04 - 1.98 (m, 2H), 1.70 - 1.65 (m, 2H).

[0440] 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]naphthyridin]-2’-yl)amino)isoindol-1-one [Chemical formula]

[0441] Step 1: Synthesis of Intermediate 152-1 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), and then, under N2 protection conditions, the reaction was carried out at 90 °C for 0.5 h and the reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~85:15) to obtain the target product 152-1 (40.00 mg, yield 85.60%) in the form of a white solid. ESI-MS m / z: 657.22 [M+H] + .

[0442] Step 2: Synthesis of Compound 152 At room temperature, Compound 152-1 (40.00 mg) was added to dichloromethane (4.00 mL), and then, under N2 protection conditions, trifluoroacetic acid (1.00 mL) was added in an ice-water bath and the reaction was carried out at room temperature for 1.5 h and the reaction was stopped. The reaction solvent was removed by a rotary evaporator and separated by preparative chromatography to obtain the target product 152 (31.60 mg, purity 99.57%, yield 90.49%) in the form of a white solid. ESI-MS m / z: 457.23 [M+H] + . Trifluoroacetate 11H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 9.45 (s, 2H), 8.91 (s, 1H), 8.72 (d, J = 8.5 Hz, 1H), 8.48 (d, J = 7.4 Hz, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 4.41 (s, 4H), 1.10 (s, 4H).

[0443] Example 157: Synthesis of 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

Chemical Structure

[0444] Step 1: Synthesis of Intermediate 157-1 At room temperature, 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), and then reacted at 90 °C for 0.5 h under N2 protection conditions to stop the reaction. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5 - 85:15) to obtain the target product 157-1 (90.00 mg, yield 87.80%). ESI-MS m / z: 620.71 [M+H] + 。

[0445] Step 2: Synthesis of Compound 157 At room temperature, compound 157-1 (90.00 mg) was added to dichloromethane (4.00 mL), and under N2 protection conditions, trifluoroacetic acid (1.00 mL) was added in an ice-water bath. The reaction was carried out at room temperature for 1.5 h and then stopped. The reaction solvent was removed by a rotary evaporator, the crude product was added to 10 mL of H2O, and saturated sodium bicarbonate was further added to adjust the pH to 8-9. After a pale yellow solid precipitated, it was filtered, the filter cake was added to 10 mL of methanol to form a slurry, filtered and dried to obtain the target product 157 (46.80 mg, purity 99.28%, yield 61.58%). ESI-MS m / z: 520.23 [M+H] + 。

[0446] 1 H NMR (500 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.87 (s, 1H), 8.77 (d, J = 8.5 Hz, 1H), 8.56 (d, J = 7.1 Hz, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 7.2, 1.8 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.42 (s, 2H), 4.22 (t, J = 7.8 Hz, 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 - 1.32 m, 1H).

[0447] Example 158: Synthesis of 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 mino)isoindol-1-one

Chemical Structure

[0448] Step 1: Synthesis of Intermediate 158-1 At room temperature, 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), and then reacted at 80 °C for 3 h under N2 protection conditions. The reaction was stopped. The reaction solution was concentrated to obtain a crude product, and the crude product was separated by column chromatography (DCM:MeOH = 95:5~85:15) to obtain the target product 158-1 (80.00 mg, yield 73.21%). ESI-MS m / z: 661.75 [M+H] + 。

[0449] Step 2: Synthesis of Compound 158 At room temperature, compound 158-1 (80.00 mg) was added to dichloromethane (4.00 mL), and then trifluoroacetic acid (1.00 mL) was added in an ice-water bath under N2 protection conditions, and reacted at room temperature for 1 h. The reaction was stopped. The reaction solvent was removed by a rotary evaporator and separated by preparative chromatography to obtain the target product 158 (43.70 mg, purity 99.59%, yield 64.11%). ESI-MS m / z: 561.56 [M+H] + 。Trifluoroacetate 1 H NMR (500 MHz, DMSO) δ 10.34 (d, J = 19.9 Hz, 2H), 8.98 (s, 1H), 8.68 (d, J = 8.6 Hz, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.28 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.81 (s, 1H), 7.79 - 7.72 (m, 2H), 7.66 (s, 1H), 7.52 (s, 1H), 7.27 (d, J = 5.6 Hz, 1H), 7.13 (d, J = 8.5 Hz, 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 = 4.7 Hz, 3H), 2.81 (d, J = 4.8 Hz, 3H), 2.77 - 2.71 (m, 1H), 2.17 - 2.06 (m, 2H), 1.73 - 1.64 (m, 1H), 1.52 (d, J = 12.1 Hz, 1H), 1.41 (d, J = 11.9 Hz, 1H).

[0450] Chiral resolution of Example 158: [Chemical formula]

[0451] The racemic mixture of Compound 158-1 (2800 mg) was dissolved in a mixed solution of DCM (22 ml) and ethanol (10 ml), and separated by a preparative chiral column [CHIRAL ART Cellulose IC (YMC) 30×250 mm 5um, model: GX-271 (GILSON); mobile phase A: n-hexane (AR, Shuanglin Chemical, add 0.1% diethylamine.), mobile phase B: ethanol (AR, Shuanglin Chemical, add 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, recovery amount 1200 mg; Compound 158B-1 (peak 2): retention time = 28.70 min, recovery amount 1020 mg.

[0452] Step 2: Synthesis of Compound 158A At room temperature, Compound 158A-1 (1200.00 mg) was added to dichloromethane (40.00 mL), and under N2 protection conditions, trifluoroacetic acid (5.00 mL) was added in an ice-water bath, and the reaction was carried out at room temperature for 0.5 h, and then the reaction was stopped. The reaction solvent was removed by a rotary evaporator, the concentrate was dissolved in 5 ml of DCM, and then saturated sodium bicarbonate was gradually added to adjust the pH to 8-9, and a pale yellow solid was precipitated. Ammonia water was added to adjust the pH = 11-12, the aqueous phase was taken out, and then 40 ml of water was added to form a slurry, and the mixture was allowed to stand and the aqueous phase was taken out. 20 ml of methanol was added to the remaining solid to form a slurry, and the solid was filtered, washed with methanol, and dried to obtain the target product 158A (872.2 mg, purity 99.24%, yield 85.01%). ESI-MS m / z: 561.56 [M+H] + .

[0453] Step 3: Synthesis of Compound 158B At room temperature, compound 158B-1 (1040.00 mg) was added to dichloromethane (40.00 mL), and under N2 protection conditions, trifluoroacetic acid (5.00 mL) was added in an ice-water bath, and the reaction was carried out at room temperature for 0.5 h, and then the reaction was stopped. The reaction solvent was removed by a rotary evaporator, and the concentrate was dissolved in 5 ml of DCM. Then, saturated sodium bicarbonate was gradually added to adjust the pH to 8-9, and a pale yellow solid was precipitated. Ammonia water was added to adjust the pH to 11-12, the aqueous phase was separated, and 40 ml of water was added to form a slurry, and the mixture was allowed to stand and the aqueous phase was separated. The remaining solid was added to 20 ml of methanol to form a slurry, filtered, and the solid was washed with methanol and dried to obtain the target product 158B (797.50 mg, purity 99.12%, yield 89.69%). ESI-MS m / z: 561.56 [M+H] + 。

[0454] 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[cyclopenta[b]pyridine-5,4’-pyran]-2- yl)amino)isoindolin-1-one

Chemical Structure

[0455] Step 1: Synthesis of compound 158A-1 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), replaced with nitrogen gas, heated to 100 °C, and reacted for 4 hours. After cooling, suction filtration was carried out, and the residue was washed with DCM. 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, yield 67%). ESI-MS m / z: 431.2 [M+H] + 。

[0456] Step 2: Synthesis of Compound 158A-2 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 gas, heated to 90 °C, and reacted for 4 hours. After cooling, suction filtration was performed, washed with EA, the filtrate was concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 93:7 - 90:10) to obtain Compound 158A-2 (5.05 g, yield 88%). ESI-MS m / z: 661.3 [M+H] + .

[0457] Step 3: Synthesis of Compound 158A Compound 158A-2 (4.30 g) was dissolved in DCM (60 mL), trifluoroacetic acid (10.00 ml) was added dropwise at room temperature under N2 protection, and then reacted at room temperature for 1 hour. The reaction solution was concentrated to dryness, the crude product was added to DCM (8 ml) and dissolved, then saturated sodium bicarbonate was gradually added to adjust the pH to 8 - 9, a pale yellow solid was precipitated, ammonia water was added to adjust the pH = 11 - 12, the aqueous phase was removed, and then 50 ml of water was added to form a slurry, and the aqueous phase was removed after standing. 100 ml of methanol was added to the remaining solid to form a slurry, filtered, and the solid was washed 3 times with methanol (5 ml / time), dried, and the target product 158A (3.158 g, purity 99.20%, yield 85.88%, retention time was the same as that of 158A in Example 158.) was obtained. ESI-MS m / z: 561.56 [M+H] + .

[0458] 11H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.83 (s, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.43 (t, J = 73.5 Hz, 1H), 7.41 (d, J = 2.5 Hz, 1H), 6.88 - 6.81 (m, 2H), 4.39 (s, 2H), 4.22 (t, J = 7.8 Hz, 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).

[0459] Example 160: Synthesis of 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

Chemical Structure

[0460] Step 1: Synthesis of Compound 160-1 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 the reaction was completed, the mixture was concentrated, and the sample was separated by silica gel column chromatography (DCM:MeOH = 24:1) to obtain the target product 160-1 (110.00 mg, yield 94.28%). ESI-MS m / z: 169.03 [M + H] + 。

[0461] Step 2: Synthesis of Compound 160-2 160-1 (110.00 mg) was dissolved in DMF (5.00 mL). Under an ice bath, NIS (162.00 mg) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, EA / THF and water were added for extraction. After separation, the organic phase was washed with saturated brine, concentrated, the samples were mixed, and separated by silica gel column chromatography (DCM:MeOH = 25:1) to obtain the target product 160-2 (150.00 mg, yield 77.98%). ESI-MS m / z: 295.05 [M+H] + 。

[0462] Step 3: Synthesis of Compound 160-3 160-2 (58.00 mg), 2-2 (100.00 mg), Pd(dppf)Cl2·CH2Cl2 (13.00 mg), and sodium carbonate (52.00 mg) were dissolved in DMF (2.00 mL) and water (0.30 mL), and the reaction was carried out at 90 °C for 1 h. After the reaction was completed, it was concentrated, the samples were mixed, and separated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the target product 160-3 (49.00 mg, yield 45.95%). ESI-MS m / z: 645.45 [M+H] + 。

[0463] Step 4: Synthesis of Compound 160 At room temperature, compound 160-3 (49.00 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 to stop the reaction. It was concentrated and purified by preparative RP-HPLC to obtain the trifluoroacetate salt of the product 160 (32.60 mg, purity 99.9%, yield 78.69%). ESI-MS m / z: 545.20 [M+H] + 。

[0464] 11H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.32 (s, 1H), 8.96 (s, 1H), 8.68 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 8.11 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 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 = 4.6 Hz, 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).

[0465] Example 163: Synthesis of 7 - ((7 - (dimethylamino) - 2’,3’,5’,6,6’,7 - hexahydrospiro[cyclopenta[b]pyridine - 5,4’ - pyran] - 2 - yl)amino) - 4 - (7 - isopropylimidazo[1,2 - a]pyridin - 3 - yl)isoindol - 1 - one

Chemical Structure

[0466] Step 1: Synthesis of Compound 163 - 1 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 the reaction was completed, it was filtered, washed with dichloromethane, concentrated, the samples were mixed, and separated by silica gel column chromatography (DCM:MeOH = 30: 1) to obtain the target product 163 - 1 (510.00 mg, yield 65.76%). ESI - MS m / z: 135.11 [M + H] + .

[0467] Step 2: Synthesis of Compound 163-2 163-1 (510.00 mg) and Pd / C (161.00 mg) were dissolved in methanol (10.00 mL), replaced with H2, and reacted overnight at room temperature. After the reaction was completed, it was filtered, the filtrates were mixed, separated by silica gel column chromatography (DCM:MeOH = 15:1), and the target product 163-2 (252.00 mg, yield 48.68%) was obtained. ESI-MS m / z: 137.10 [M+H] + .

[0468] Step 3: Synthesis of Compound 163-3 2-Chloroacetaldehyde (252.00 mg), 40% aqueous solution of chloroacetaldehyde (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 the reaction was completed, it was concentrated, the samples were mixed, separated by silica gel column chromatography (DCM:MeOH = 19:1), and the target product 163-3 (290.00 mg, yield 97.83%) was obtained. ESI-MS m / z: 161.19 [M+H] + .

[0469] Step 4: Synthesis of Compound 163-4 163-3 (290.00 mg) was dissolved in DMF (5.00 mL), NIS (448.00 mg) was added under an ice bath, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, EA / THF and water were added for extraction, separated, the organic phase was washed with saturated brine, concentrated, the samples were mixed, separated by silica gel column chromatography (DCM:MeOH = 15:1), and the target product 163-4 (298.00 mg, yield 57.54%) was obtained. ESI-MS m / z: 287.07 [M+H] + .

[0470] Step 5: Synthesis of Compound 163-5 163-4 (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 was completed, it was concentrated, the samples were mixed, separated by silica gel column chromatography (DCM:MeOH = 15:1), and the target product 163-5 (65.00 mg, yield 61.71%) was obtained. ESI-MS m / z: 637.30 [M+H] + .

[0471] Step 6: Synthesis of Compound 163 At room temperature, compound 163-5 (65.00 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, and the reaction was stopped. It was concentrated, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted 3 times with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and purified on a preparative plate (DCM:MeOH = 18:1) to separate the product 163 (11.50 mg, purity 98.73%, yield 20.72%). ESI-MS m / z: 537.20 [M+H] + .

[0472] 1 H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.32 (s, 1H), 8.97 (s, 1H), 8.68 (d, J = 8.5 Hz, 1H), 8.54 (d, J = 7.1 Hz, 1H), 8.38 (s, 1H), 7.89 - 7.83 (m, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 7.2, 1.7 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 5.15 - 5.12 (m, 1H), 4.42 (s, 2H), 3.92 - 3.88 (m, 2H), 3.66 - 3.49 (m, 2H), 3.24 - 3.17 (m, 1H), 2.98 (d, J = 4.6 Hz, 3H), 2.82 (d, J = 4.7 Hz, 3H), 2.75 (dd, J = 13.7, 8.5 Hz, 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 = 6.8 Hz, 6H).

[0473] 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]pyridin-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0474] Step 1: Synthesis of Compound 164-1 At room temperature, 7-Bromoimidazo[1,2-a]pyridine (1.00 g), Cyclopropylboronic acid (566.70 mg), Palladium(II) acetate (113.90 mg), Tricyclohexylphosphine (284.70 mg) and Potassium phosphate (3.23 g) were dissolved in Toluene (10 mL) and Water (1 mL), heated to 100 °C and reacted for 15 hours. The reaction mixture was cooled, filtered through Celite under suction, the filtrate was concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 97:3) to obtain Compound 164-1 (707.00 mg, yield 88%). ESI-MS m / z: 159.2 [M+H] + .

[0475] Step 2: Synthesis of Compound 164-2 At room temperature, 164-1 (707.00 mg) was dissolved in DMF (8 mL), NIS (1.21 g) was added, reacted at room temperature for 3 hours, diluted with water, extracted with DCM, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH = 97:3) to obtain Compound 164-2 (1.15 g, yield 91%). ESI-MS m / z: 285.0 [M+H] + .

[0476] Step 3: Synthesis of Compound 164-3 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), replaced with nitrogen gas, heated to 90 °C, and reacted for 2 hours. After cooling, suction filtration was performed through diatomaceous earth. Water was added to the filtrate for dilution, and extraction was carried out with EA. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure and purified by column chromatography (DCM:MeOH = 95:5) to obtain Compound 164-3 (86.00 mg, yield 82%). ESI-MS m / z: 635.4 [M+H] + .

[0477] Step 4: Synthesis of Compound 164 At room temperature, 164-3 (86.00 mg) was dissolved in DCM (4 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated, a small amount of methanol was added for dissolution, the pH was adjusted to alkaline with saturated sodium bicarbonate, extraction was carried out with DCM, the organic layers were combined, washed with saturated brine, dried, and concentrated under reduced pressure. Purification was performed by column chromatography (DCM:MeOH = 92:8) to obtain Compound 164 (16.20 mg, yield 21%). ESI-MS m / z: 535.3 [M+H] + .

[0478] 11H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.84 (s, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.37 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.65 (dd, J = 7.3, 1.9 Hz, 1H), 4.39 (s, 2H), 4.23 (s, 1H), 3.83 (t, J = 13.2 Hz, 2H), 3.56 (dt, J = 24.2, 12.0 Hz, 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)

[0479] Example 165: Synthesis of 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]pyridin-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0480] Step 1: Synthesis of Compound 165-1 At room temperature, 3-morpholinone (1.00 g), aminoacetaldehyde dimethyl acetal (2.08 g) was added to the reaction flask, and SnCl4 (0.35 mL) was slowly added dropwise. Then, under N2 protection conditions, the reaction was carried out at 150 °C for 3 h, and the reaction was stopped. 50 mL of water was added to the reaction solution to quench it, and it was filtered through diatomaceous earth. After the filter cake was washed with water, the pH was adjusted to 8 - 9 with saturated sodium bicarbonate solution, extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated by silica gel column chromatography (DCM:MeOH = 9:1) to obtain the target product 165-1 (840.00 mg, yield 68.41%). ESI-MS m / z: 125.2 [M+H] + 。

[0481] Step 2: Synthesis of Compound 165-2 At room temperature, 165-1 (840.00 mg) was dissolved in ACN (15.00 mL). Under the condition of an ice-water bath, NBS (1.20 g) was added in several portions, reacted at room temperature for 1 h, and the reaction was stopped. The reaction solution was poured into 50 mL of water, extracted with EA, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the concentrate was separated by silica gel column chromatography (PE:EA = 20:80) to obtain the target product 165-2 (840.00 mg, yield 61.14%). ESI-MS m / z: 203.2 [M+H] + 。

[0482] Step 3: Synthesis of Compound 165-3 At room temperature, 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). Then, under N2 protection conditions, the reaction was carried out at 95 °C for 6 h, and the reaction was stopped. The reaction solution was concentrated directly. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the target product 165-3 (60.00 mg, yield 75.47%). ESI-MS m / z: 601.2 [M+H] + 。

[0483] Step 4: Synthesis of Compound 165 At room temperature, compound 165-3 (60.00 mg) was dissolved in dichloromethane (5.00 mL), TFA (396.22 mg) was added, and the mixture was reacted at room temperature for 0.5 h, then the reaction was stopped. The reaction solution was concentrated directly. The concentrate was separated by preparative liquid chromatography to obtain the target product 165 (31.50 mg, yield 63.00%). ESI-MS m / z: 501.2 [M+H] + 。 1 H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.98 (s, 1H), 8.60 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.4 Hz, 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, 10.6 Hz, 2H), 2.98 (d, J = 4.4 Hz, 3H), 2.81 (d, J = 4.5 Hz, 3H), 2.74 (dd, J = 13.8, 8.6 Hz, 1H), 2.22 - 2.05 (m, 2H), 1.69 (td, J = 12.8, 4.7 Hz, 1H), 1.56 - 1.47 (m, 1H), 1.44 - 1.35 (m, 1H).

[0484] Example 166: Synthesis of compound 7 - ((7 - (dimethylamino)-2’,3’,5’,6,6’,7 - hexahydrospiro[cyclopenta[b]pyridine - 5,4’ - pyran]-2 - yl)amino)-4-(5,6,7,8 - tetrahydroimidazo[1,2 - a]pyridin - 3 - yl)isoindol - 1 - one

Chemical formula

[0485] Step 1: Synthesis of compound 166 - 1 At room temperature, 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (300.00 mg) was dissolved in ACN (8.00 mL), and NBS (480.76 mg) was added in several portions. The reaction was carried out at room temperature for 1 h and then stopped. The reaction solution was concentrated as it was. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 19:1) to obtain the target product 166-1 (200.00 mg, yield 40.51%). ESI-MS m / z: 201.2 [M+H] + 。

[0486] Step 2: Synthesis of Compound 166-2 At room temperature, 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), and the reaction was carried out at 95 °C for 6 h under N2 protection conditions and then stopped. The reaction solution was concentrated as it was. The concentrate was separated by silica gel column chromatography (DCM:MeOH = 10:1) to obtain the target product 166-2 (60.00 mg, yield 75.59%). ESI-MS m / z: 599.2 [M+H] + 。

[0487] Step 3: Synthesis of Compound 166 At room temperature, Compound 166-2 (60.00 mg) was dissolved in dichloromethane (5.00 mL), TFA (396.22 mg) was added, and the reaction was carried out at room temperature for 0.5 h and then stopped. The reaction solution was concentrated as it was. The concentrate was separated by preparative liquid chromatography to obtain the target product 166 (22.40 mg, yield 44.80%). ESI-MS m / z: 499.2 [M+H] + 。

[0488] 11H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.96 (s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.63 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 5.12 (t, J = 7.4 Hz, 1H), 4.42 (s, 2H), 3.96 (s, 2H), 3.89 (t, J = 13.2 Hz, 2H), 3.65 - 3.50 (m, 2H), 3.07 (d, J = 5.4 Hz, 2H), 2.98 (d, J = 4.5 Hz, 3H), 2.81 (d, J = 4.7 Hz, 3H), 2.74 (dd, J = 13.8, 8.5 Hz, 1H), 2.12 (dt, J = 13.0, 6.8 Hz, 2H), 1.95 (s, 4H), 1.69 (td, J = 12.9, 4.7 Hz, 1H), 1.51 (d, J = 12.9 Hz, 1H), 1.43 - 1.37 (m, 1H).

[0489] 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 [Chemical Structure Diagram]

[0490] Step 1: Synthesis of Compound 168-1 Compound 40-5 (300.00 mg), 146-2 (128.01 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (38.87 mg), sodium carbonate (151.29 mg), and water (1.00 mL) were added to 1,4-dioxane (6.00 mL), purged with nitrogen gas, and reacted at 90 °C for 2 h. The reaction mixture was concentrated and separated by column chromatography (DCM:MeOH = 90%:10%) to obtain the target product 168-1 (200.00 mg, yield 65.09%). ESI-MS m / z: 646.5 [M+H] + .

[0491] Step 2: Synthesis of Compound 168 Compound 168-1 (200.00 mg) was added to DCM (5.00 mL), and further TFA (1.00 mL) was added. The reaction was carried out at room temperature for 0.5 h. The reaction solution was concentrated and separated by preparative chromatography to obtain the target product 168 (81.30 mg, yield 46.77%). ESI-MS m / z: 546.3 [M+H] + . Trifluoroacetate 1 H NMR (500 MHz, DMSO) δ 10.50 (d, J = 5.5 Hz, 1 H), 10.26 (s, 1H), 8.94 (s, 1H), 8.58 - 8.46 (m, 3H), 8.19 (s, 1H), 7.82 (t, J = 8.6 Hz, 2H), 7.27 (d, J = 7.1 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.12 (dd, J = 14.5, 7.8 Hz, 1H), 4.44 (d, J = 12.2 Hz, 2H), 3.92 - 3.84 (m, 2H), 3.70 - 3.32 (m, 6H), 2.91 (dd, J = 13.2, 8.1 Hz, 1H), 2.10 (dtd, J = 21.8, 13.2, 6.6 Hz, 4H), 1.99 - 1.80 (m, 2H), 1.68 (dd, J = 12.3, 8.6 Hz, 1H), 1.52 (d, J = 12.7 Hz, 1H), 1.41 (d, J = 12.1 Hz, 1H).

[0492] Example 169: Synthesis of 4-(7-(Difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-(Pyrrolidin-1-yl)-2’,3’,5’,6,6’,7-hexahydrospiro[cyclopenta[b]pyridin-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical Structure

[0493] Step 1: Synthesis of Compound 169-1 Compound 40-5 (150 mg), 123-3 (82 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (17.4 mg), and an aqueous sodium carbonate solution (0.357 mL, 2 M) were added to DMF (10 mL), replaced with nitrogen gas, and reacted at 95 °C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM / MeOH = 90 / 10) to obtain the target product 169-1 (110 mg, yield 67.3%). ESI-MS m / z: 687.3 [M+H]+.

[0494] Step 2: Synthesis of Compound 169 Compound 169-1 (110 mg) was added to DCM (3 mL) and MeOH (3 mL), and a dioxane solution of hydrogen chloride (6 mL) was further added, followed by reaction at room temperature for 2 h. The reaction solution was concentrated and separated by preparative chromatography to obtain the target product 169 (17.8 mg, yield 20.8%). ESI-MS m / z: 587.4 [M+H] + . Hydrochloride 1 H NMR (500 MHz, DMSO) δ 11.26 (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, 4.4 Hz, 2H), 7.70 (d, J = 17.2 Hz, 2H), 7.29 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.10 (d, J = 6.6 Hz, 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).

[0495] 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

Chemical Structure

[0496] Step 1: Synthesis of Compound 172-1 Compound 58-14 (260 mg), 123-3 (164 mg), [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (36 mg), and sodium carbonate (140 mg) were added to DMF (10 mL) and water (2 mL), purged with nitrogen gas, and 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 product 172-1 (221 mg, yield 77.6%). ESI-MS m / z: 647.30 [M+H] + 。

[0497] Step 2: Synthesis of the Hydrochloride Salt of Compound 172 Compound 172-1 (221 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). Under ice bath conditions, a dioxane solution of hydrogen chloride (6 mL, 4 M dioxane solution) was slowly added dropwise, and the temperature was gradually raised to room temperature and reacted for 30 min to stop the reaction. The reaction solution was concentrated and separated and purified by preparative liquid chromatography to obtain the hydrochloride salt of the target product 172 (87.50 mg, purity 99.27%, yield 46.85%). ESI-MS m / z: 547.38 [M+H] 。 + 。 1 H NMR (500 MHz, DMSO) δ 11.58 (s, 1H), 10.32 (s, 1H), 8.95 (d, J = 41.9 Hz, 2H), 8.68 (s, 1H), 8.46 (s, 1H), 7.94 - 7.58 (m, 4H), 7.39 (s, 1H), 7.11 (s, 1H), 5.13 (s, 1H), 4.42 (s, 2H), 4.15 - 3.33 (m, 4H), 2.85 (d, J = 17.5 Hz, 6H), 2.45 - 2.25 (m, 2H), 2.20 - 2.05 (m, 1H), 2.05 - 1.85 (m, 1H).

[0498] 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[cyclopenta[b]pyridine-5,4’-pyran]-2-yl)amino)isoindol-1-one

Chemical formula

[0499] Step 1: Synthesis of Compound 174-1 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), purged with N2, and reacted at 100 °C for 8 h. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and separated by silica gel column chromatography (DCM:MeOH = 32:1) to obtain the target product 174-1 (980.00 mg, yield 82.78%).

[0500] Step 2: Synthesis of Compound 174-2 174-1 (960.00 mg) was dissolved in DMF (10.00 mL), and NIS (1.11 g) was added under an ice bath and reacted at room temperature for 5 h. After the reaction was completed, the reaction system was poured into ice water to precipitate the product, which was collected by suction filtration and dried to obtain the target product 174-2 (1.32 g, yield 89.30%).

[0501] Step 3: Synthesis of Compound 174-3 174-2 (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 the reaction was completed, water was added, and the mixture was extracted with EA / THF (1:1). The organic phase was washed with saturated brine, separated, concentrated, and the samples were mixed. They were separated by silica gel column chromatography (DCM:MeOH = 13:1) to obtain the target product 174-3 (160.00 mg, yield 45.43%). ESI-MS m / z: 710.49 [M+H] + 。

[0502] Step 4: Synthesis of Compound 174 At room temperature, compound 174-3 (160.00 mg) was dissolved in dichloromethane (4.00 mL), and TFA (1.00 mL) was added. The mixture was reacted at room temperature for 0.5 h. The reaction was stopped, and the reaction solution was concentrated and purified by preparative RP-HPLC to obtain the trifluoroacetate salt of compound 174 (86.90 mg, purity 99.32%, yield 75.14%). ESI-MS m / z: 510.40 [M+H] + 。

[0503] 1 H NMR (500 MHz, DMSO-d6) δ 13.50 (s, 1H), 10.82 (s, 1H), 10.31 (s, 1H), 8.97 (s, 1H), 8.69 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.95 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 6.81 (dd, J = 7.5, 2.2 Hz, 1H), 6.68 (d, J = 2.1 Hz, 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).

[0504] Example 177: Synthesis of Compound 177 4-(7-(Difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)-7-((7-morpholine-2’,3’,5’,6,6’,7-hexahydropyrrolo[b]pyridin-54’-pyran]-2-yl)amino)isoindol-1-one:

Chemical Structure

[0505] Step 1: Synthesis of Compound 177-1 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 the reaction was completed, it was filtered to remove insoluble substances, water was added, and extraction was performed with EA / THF (1:1). The organic phase was washed with saturated brine, separated, concentrated, the samples were mixed, and separated by silica gel column chromatography (PE:EA = 1:99) to obtain the target compound 177-1 (176.00 mg, yield 28.80%). ESI-MS m / z: 632.23 [M+H] + .

[0506] Step 2: Synthesis of Compound 177-2 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. Further, NaBH3CN (60.00 mg) was added and reacted at 40 °C for 2 h. After the reaction was completed, water was added to quench it, the reaction solution was concentrated, and separated by silica gel column chromatography (DCM:MeOH = 13:1) to obtain the target compound 177-2 (35.00 mg, yield 17.88%). ESI-MS m / z: 703.24 [M+H] + .

[0507] Step 3: Synthesis of Compound 177 At room temperature, compound 177-2 (35.00 mg) was dissolved in dichloromethane (4.00 mL), trifluoroacetic acid (1.00 mL) was added, and the mixture was reacted at room temperature for 0.5 h, then the reaction was stopped. The reaction solution was concentrated, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, extracted three times with DCM, the organic phases were combined, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to separate, and compound 177 (24.10 mg, purity 95.23%, yield 76.47%) was obtained. ESI-MS m / z: 603.43 [M+H] + 。

[0508] 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.92 (s, 1H), 8.50 - 8.45 (m, 2H), 7.99 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.66 - 7.3 7 (m 3H), 7.01 (d, J = 7.5 Hz, 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).

[0509] Example 178: Synthesis of compound 178 7-((7-(Cyclopropylamino)-2’,3’,5’,6,6’,7-hexahydrospiro[cyclopenta[b]pyridine-5,4’-pyran]-2-yl)amino)-4-(7-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)isoindolin-1-one

Chemical formula

[0510] Step 1: Synthesis of compound 178-1 Compound 62-2 (700 mg), 123-3 (245 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (99 mg), and sodium carbonate (387 mg) were added to DMF (20 mL) and water (4 mL), purged with nitrogen gas, and reacted at 95 °C for 2 h. The reaction solution was concentrated and separated by column chromatography (DCM / MeOH = 95 / 5) to obtain the target product 178-1 (615 mg, yield 80.1%). ESI-MS m / z: 632.29 [M+H] + 。

[0511] Step 2: Synthesis of Compound 178-2 Compound 178-1 (615 mg), cyclopropylamine (405 mL), and tetraethyl titanate (222 mg) were weighed, DCE (5 mL) and MeOH (2 mL) were added, and the mixture was reacted at 40 °C for 4 h. Sodium cyanoborohydride (184 mg) was gradually added, the temperature was raised to 80 °C and the mixture was reacted for 1 h to stop the reaction. The reaction solution was extracted with DCM, the organic phase was washed with saturated brine, the organic phase was collected and dried on a rotary evaporator, and separated by column chromatography (DCM:MeOH = 90:10) to obtain the target compound 178-2 (655 mg, yield 99.8%). ESI-MS m / z: 673.35 [M+H] + 。

[0512] Step 3: Synthesis of the hydrochloride salt of Compound 178 Compound 178-2 (655 mg) was weighed and dissolved in dichloromethane (5 mL) and methanol (5 mL). Under ice bath conditions, a dioxane solution of hydrogen chloride (10 mL, 4 M dioxane solution) was gradually added dropwise, the temperature was gradually raised to room temperature and the mixture was reacted for 30 min to stop the reaction. The mixture was concentrated and separated by preparative liquid chromatography and purified to obtain the hydrochloride salt of the target product 178 (83.40 mg, purity 96.37%, yield 14.96%). ESI-MS m / z: 573.40 [M+H] + 。

[0513] 1 1H NMR (500 MHz, DMSO) δ 10.29 (s, 1H), 9.69 (s, 1H), 9.21 (s, 1H), 8.96 (s, 1H), 8.71 (t, J = 12.0 Hz, 1H), 8.56 (d, J = 7.5 Hz, 1H), 8.23 (s, 1H), 7.83 (t, J = 11.9 Hz, 1H), 7.79 - 7.75 (m, 1H), 7.72 (s, 1H), 7.57 (d, J = 72.4 Hz, 1H), 7.23 (d, J = 5.5 Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 5.02 (s, 1H), 4.49 - 4.35 (m, 2H), 3.95 - 3.81 (m, 2H), 3.57 (dt, J = 39.2, 11.5 Hz, 2H), 3.09 (s, 1H), 2.89 (dd, J = 13.3, 8.2 Hz, 1H), 2.15 (dd, J = 12.1, 8.5 Hz, 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, 7.1 Hz, 2H), 0.64 - 0.49 (m, 1H).

[0514] Example 180: Synthesis of 7 - ((7 - (dimethylamino) - 4’,5’,6,7 - tetrahydro - 2’H - spiro[cyclopenta[b]pyridine - 5,3’ - furan] - 2 - yl)amino) - 4 - (7 - methoxyimidazo[1,2 - a]pyridin - 3 - yl)isoindolin - 1 - one

Chemical Structure

[0515] Step 1: Synthesis of Compound 180 - 1 Compound 58-14 (347 mg), 7-methoxy-H-imidazo[1,2-a]pyridine (193 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (48 mg), and sodium carbonate (187 mg) were added to DMF (10 mL) and water (2 mL), purged with nitrogen gas, and 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, yield 23.7%). ESI-MS m / z: 611.32 [M+H] + 。

[0516] Step 2: Synthesis of Compound 180 Hydrochloride Compound 180-1 (85 mg) was weighed and dissolved in dichloromethane (3 mL) and methanol (3 mL). Under ice bath conditions, a dioxane solution of hydrogen chloride (6 mL, 4 M dioxane solution) was slowly added dropwise, and the temperature was gradually raised to room temperature and reacted for 30 min, then the reaction was stopped. It was concentrated and separated by preparative liquid chromatography and purified to obtain the hydrochloride salt of the target product 180 (4.50 mg, purity 95.01%, yield 5.38%). ESI-MS m / z: 511.42 [M+H] + 。

[0517] The following compounds are synthesized by the above method or by a similar method of the corresponding intermediates.

Chemical Structure

[0518]

Chemical Structure

[0519]

Chemical Structure

[0520]

Chemical Structure

[0521]

Chem.

[0522]

Chem.

[0523]

Chem.

[0524] 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,1H),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).

[0525] Compound 14: 11H NMR (500 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.33 (d, J = 5.0 Hz, 1H), 7.54 (d, J = 3.4 Hz, 1H), 7.35 (d, J = 5.0 Hz, 1H), 7.02 (d, J = 2.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 3.4 Hz, 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 = 13.8 Hz, 2H).

[0526] Compound 15: 1 1H 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).

[0527] Compound 16: 11H 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).

[0528] 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).

[0529] 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).

[0530] 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).

[0531] Compound 33: 1 1H 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).

[0532] 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).

[0533] 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).

[0534] 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).

[0535] 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), 1.4 3 - 1.38 (m, 1H).

[0536] 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).

[0537] 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).

[0538] 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).

[0539] Compound 45: 11H NMR (500 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.36 (s, 1H), 9.21 (d, J = 7.0 Hz, 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).

[0540] Compound 47: 1 1H 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).

[0541] Compound 48: 11H NMR (500 MHz, DMSO) δ 10.14 (s, 1H), 10.08 (s, 1H), 8.88 (s, 1H), 8.77 (d, J = 7.0 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.36 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.36 - 7.29 (m, 1H), 6.99 (t, J = 6.8 Hz, 1H), 6.87 (s, 1H), 5.04 (t, J = 8.6 Hz, 1H), 4.51 (d, J = 18.9 Hz, 2H), 3.89 (t, J = 8.2 Hz, 2H), 3.65 (t, J = 11.4 Hz, 1H), 3.54 (t, J = 11.6 Hz, 1H), 2.98 (d, J = 4.3 Hz, 3H), 2.80 (dd, J = 14.4, 6.8 Hz, 4H), 2.46 (s, 3H), 2.03 (ddd, J = 23.6, 14.8, 7.3 Hz, 3H), 1.54 (d, J = 12.8 Hz, 1H), 1.34 (d, J = 13.1 Hz, 1H).

[0542] Trifluoroacetate salt of compound 54: δ 10.12 (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 = 5.4 Hz, 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 = 13.0 Hz, 2H).

[0543] 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).

[0544] 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).

[0545] 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).

[0546] 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).

[0547] 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).

[0548] 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).

[0549] 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).

[0550] 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...

Claims

1. Compounds represented by general formula (I), their stereoisomers, tautomers, deuterides, or pharmaceutically acceptable salts, 【Chemistry 1】 Ring A is C ５－１４ Bicyclic carbocyclyl group, 5-14 member bicyclic heterocyclyl group, C １０－１８ Selected from a bicyclic aryl group or a 10-18 membered bicyclic heteroaryl group, L is selected from bond, NH, O, or S. R １ is selected from H, halogen, C １－６ alkyl group, C １－６ alkoxy group, haloalkyl group, hydroxyalkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C ３－１４ cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ aryl group, or 6- to 18-membered heteroaryl group, and the C １－６ alkyl group, C １－６ alkoxy group, haloalkyl group, hydroxyalkyl group, C ３－１４ cycloalkyl group, 3- to 14-membered heterocyclyl group, C ６－１８ aryl group, or 6- to 18-membered heteroaryl group may be further substituted with one or more R ａ s, R ａ These are independently H, hydroxyl group, cyano group, halogen, and C １－６ Alkyl alkyl group, C １－６ Haloalkyl group, -C ０－３ Alkylene-OR ｂ -OC(=O)C １－６ Alkyl alkyl group, -C ０－３ Alkilen-SR ｂ , -C ０－３ Alkylene-N(R) ｂ ) ２ , -C ０－３ Alkylene-S(=O)R ｂ , -C ０－３ Alkylene-S (=O) ２ R ｂ , -C ０－３ Alkylene-S (R ｂ ) ５ , -C ０－３ Alkylene-C(=O)R ｂ , -C ０－３ Alchile N-C (=O) OR ｂ , -C ０－３ Alkylene-C(=O)N(R) ｂ ) ２ , C ２－６ Alkenyl group, C ２－６ Alkynyl group, -C ０－３ Alkylene-C ３－１４ Cycloalkyl group, -C ０－３ Alkilen-(3-14 member heterocyclyl),-C ０－３ Alkylene-C ６－１８ Aryl group, or -C ０－３ Selected from alkylene (a 5-18 membered heteroaryl group), the C １－６ Alkyl alkyl group, C １－６ Haloalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -C ０－３ Alkylene-C ３－１４ Cycloalkyl group, -C ０－３ Alkilen-(3-14 member heterocyclyl),-C ０－３ Alkylene-C ６－１８ Aryl group, or -C ０－３ Alkylene-(5-18 member heteroaryl group) optionally contains one or more R ｂ It is further replaced by, Each R ｂ These are independently H, halogen, hydroxyl group, cyano group, and C １－６ Alkyl alkyl group, -(CH ２ ) ０－３ C １－６ Alkoxy group, C ３－６ Cycloalkyl groups or C １－６ It is a haloalkyl group, R ２ H, C １－６ Selected from alkyl groups or haloalkyl groups, R ３ is selected from H, halogen, cyano group, C １－６ alkyl group, C １－６ alkoxy group, haloalkyl group, hydroxy group, hydroxyalkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, -(CH ２ ) ０－３ N(R ｂ ) ２ -(CH ２ ) ０－３ -C ３－１４ cycloalkyl group, -(CH ２ ) ０－３ -3- to 14-membered heterocyclyl group, -(CH ２ ) ０－３ -C ６－１８ aryl group, or -(CH ２ ) ０－３ -5- to 18-membered heteroaryl group, and the C １－６ alkyl group, C １－６ alkoxy group, haloalkyl group, hydroxyalkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, -(CH ２ ) ０－３ -C ３－１４ cycloalkyl group, -(CH ２ ) ０－３ -3- to 14-membered heterocyclyl group, -(CH ２ ) ０－３ -C ６－１８ aryl group or -(CH ２ ) ０－３ -5- to 18-membered heteroaryl group may be further substituted with one or more R ｃ s, R ｃ These are halogens and C １－６ Alkyl alkyl group, C １－６ Alkoxy group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, haloalkyl group, cyano group, amino group, nitro group, hydroxyl group, hydroxyalkyl group, -C ０－３ Alkylene-C(=O)R ｂ , -C ０－３ Alkylene-C(=O)N(R) ｂ ) ２ ,-(CH ２ ) ０－３ N(R) ｂ ) ２ , -O(CH ２ ) ０－３ C ３－１４ Cycloalkyl groups, -O(CH ２ ) ０－３ -3-14 member heterocyclyl group, C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Selected from aryl groups and 5-18 membered heteroaryl groups, R ４ or R ５ Each of them is independently C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH ２ ) １－３ N(R) ｂ ) ２ , C ２－６ Alkenyl group, C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Selected from an aryl group or a 6-18 member heteroaryl group, the C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH ２ ) １－３ N(R) ｂ ) ２ , C ２－６ Alkenyl group, C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ The aryl group, or a 6-18 membered heteroaryl group, is optionally further substituted with one or more Rd groups. R ４ or R ５ These are atoms that are independently directly bonded to the A ring, and C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Forming an aryl group or a 6-18 member heteroaryl group, the C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ The aryl group or the 6-18 membered heteroaryl group may be further substituted with one or more Rd, or R ４ and R ５ This consists of an atom bonded to the A ring and C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Forming an aryl group or a 6-18 member heteroaryl group, the C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ The aryl group or the 6-18 membered heteroaryl group may be further substituted with one or more Rd groups. R ｄ H, halogen, C １－６ Alkyl alkyl group, C ３－６ Cycloalkyl groups, C １－６ Haloalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, or hydroxyalkyl groups Selected from the group, X is CR ６ Or selected from N, R ６ H, halogen, C １－６ Alkyl alkyl group, C ３－６ Cycloalkyl groups, or C １－６ Selected from haloalkyl groups, m is selected from 0, 1, 2, 3, or 4. n is selected from 0, 1, or 2. Compounds, their stereoisomers, tautomers, deuterides, or pharmaceutically acceptable salts.

2. Each of the aforementioned R ｂ These are independently H, halogen, hydroxyl group, cyano group, and C １－６ Alkyl alkyl group, C ３－６ Cycloalkyl groups or C １－６ It is a haloalkyl group, The aforementioned R ３ H, halogen, cyano group, C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, -(CH ２ ) ０－３ N(R) ｂ ) ２ ,-(CH ２ ) ０－３ -C ３－１４ Cycloalkyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group, -(CH ２ ) ０－３ -C ６－１８ Aryl group, or -(CH ２ ) ０－３ - Selected from 5-18 member heteroaryl groups, the C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH ２ ) ０－３ -C ３－１４ Cycloalkyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group, -(CH ２ ) ０－３ -C ６－１８ Aryl group or -(CH ２ ) ０－３ -5-18 member heteroaryl group optionally contains one or more R ｃ It is further replaced by, The aforementioned R ｃ These are halogens and C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C ０－３ Alkylene-C(=O)R ｂ , -C ０－３ Alkylene-C(=O)N(R) ｂ ) ２ ,-(CH ２ ) ０－３ N(R) ｂ ) ２ , -O(CH ２ ) ０－３ C ３－１４ Cycloalkyl groups, -O(CH ２ ) ０－３ -3-14 member heterocyclyl group, C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Selected from aryl groups and 5-18 membered heteroaryl groups, n is selected from 1 or 2. The R4 or R5 each independently forms a C3-14 cycloalkyl group, a 3-14 membered heterocyclyl group, a C6-18 aryl group, or a 6-18 membered heteroaryl group with an atom directly bonded to the A ring, and the C3-14 cycloalkyl group, a 3-14 membered heterocyclyl group, a C6-18 aryl group, or a 6-18 membered heteroaryl group is optionally further substituted with one or more Rd, where Rd is selected from H, halogen, C1-6 alkyl group, C3-6 cycloalkyl group, C1-6 haloalkyl group, cyano group, amino group, nitro group, hydroxyl group, or hydroxyalkyl group. The L is selected from a bond or NH, The R1 is selected from a C6-18 aryl group or a 6-18 membered heteroaryl group, and the C6-18 aryl group or 6-18 membered heteroaryl group is optionally further substituted with one or more Ra. Ra is independently selected from H, hydroxyl group, cyano group, halogen, C1-6 alkyl group, C1-6 haloalkyl group, -C0-3 alkylene-OR b, -OC(=O)C1-6 alkyl group, -C0-3 alkylene-N(R b)2, -C0-3 alkylene-C(=O)R b, -C0-3 alkylene-C(=O)OR b, -C0-3 alkylene-C(=O)N(R b)2, C2-6 alkenyl group or C2-6 alkynyl group. Each R b is independently H, halogen, hydroxyl group, cyano group, C1-6 alkyl group, -(CH2)0-3 C1-6 alkoxy group, C3-6 cycloalkyl group, or C1-6 haloalkyl group. The R2 is H, and / or The ring A is selected from a C8-10 bicyclic carbocyl group, an 8-10 membered bicyclic heterocycloalkyl group, a C10-12 bicyclic aryl group, or a 10-12 membered bicyclic heteroaryl group. A compound according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 1.

3. Each of the aforementioned R ｂ These are independently H, halogen, hydroxyl group, cyano group, and C １－６ Alkyl alkyl group, C ３－６ Cycloalkyl groups, or C １－６ It is a haloalkyl group, The aforementioned R ３ H, halogen, C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, -(CH ２ ) ０－３ N(R) ｂ ) ２ ,-(CH ２ ) ０－３ -C ３－１４ Cycloalkyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group, -(CH ２ ) ０－３ -C ６－１８ Aryl group, or -(CH ２ ) ０－３ - Selected from 5-18 member heteroaryl groups, the C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyalkyl group, -(CH ２ ) ０－３ -C ３－１４ Cycloalkyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group, -(CH ２ ) ０－３ -C ６－１８ Aryl group, or -(CH ２ ) ０－３ -5-18 member heteroaryl group optionally contains one or more R ｃ It is further replaced by, The aforementioned R ｃ These are halogens and C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, -C ０－３ Alkylene-C(=O)R ｂ , -C ０－３ Alkylene-C(=O)N(R) ｂ ) ２ ,-(CH ２ ) ０－３ N(R) ｂ ) ２ , -O(CH ２ ) ０－３ C ３－１４ Cycloalkyl groups, -O(CH ２ ) ０－３ -3-14 member heterocyclyl group, C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Selected from aryl groups and 5-18 membered heteroaryl groups, The n is selected from 1 or 2, and / or The aforementioned R1 is, 【Chemistry 2】 Selected from, 【Transformation 3】 This is further replaced by one or more Ra a, Ra is independently H, hydroxyl group, cyano group, halogen, C1-6 alkyl group, C1-6 haloalkyl group, -C0-3 alkylene-ORb, -OC(=O)C1-6 alkyl Selected from the following groups: -C0-3 alkylene-N(R b)2, -C0-3 alkylene-C(=O)R b, -C0-3 alkylene-C(=O)OR b, -C0-3 alkylene-C(=O)N(R b)2, C2-6 alkenyl group, or C2-6 alkynyl group, Each R b is independently H, halogen, hydroxyl group, cyano group, C1-6 alkyl group, -(CH2)0-3 C1-6 alkoxy group, C3-6 cycloalkyl group, or C1-6 haloalkyl group, and / or The aforementioned ring A is 【Chemistry 4】 Selected from, and / or, The aforementioned R4 forms a C3-14 cycloalkyl group, a 3-14 membered heterocyclyl group, a C6-18 aryl group, or a 6-18 membered heteroaryl group with an atom directly bonded to the A ring. A compound according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 1.

4. The aforementioned R １ teeth, 【Transformation 5】 Selected from, and / or, The aforementioned ring A is 【Transformation 6】 Selected from A compound according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 1.

5. The aforementioned R １ teeth, 【Transformation 7】 A compound according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

6. The aforementioned R ３ H, halogen, cyano group, C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, hydroxyl group, hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -(CH ２ ) ０－３ -C ３－１４ Cycloalkyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group, or -(CH ２ ) ０－３ N(R) ｂ ) ２ Selected from, the C １－６ Alkyl alkyl group, C １－６ Alkoxy group, -(CH ２ ) ０－３ -C ３－１４ Cycloalkyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group, haloalkyl group, hydroxyalkyl group, C ２－６ Alkenyl group or C ２－６ The alkynyl group can be any one or more R ｃ It is further replaced by, The aforementioned R ｃ These are halogens and C １－６ Alkyl alkyl group, C １－６ Alkoxy group, haloalkyl group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -C ０－３ Alkylene-C(=O)R ｂ , -C ０－３ Alkylene-C(=O)N(R) ｂ ) ２ ,-(CH ２ ) ０－３ N(R) ｂ ) ２ , -O(CH ２ ) ０－３ C ３－１４ Cycloalkyl groups, -O(CH ２ ) ０－３ -3-14 member heterocyclyl group, C ３－１４ Cycloalkyl group, 3-14 member heterocyclyl group, C ６－１８ Selected from aryl groups and 5-18 membered heteroaryl groups, Each R ｂ These are independently H, halogen, hydroxyl group, cyano group, and C １－６ Alkyl alkyl group, -(CH ２ ) ０－３ C １－６ Alkoxy group, C ３－６ Cycloalkyl groups or C １－６ The compound according to claim 1, characterized by being a haloalkyl group, its stereoisomer, tautomer, deuteride, or pharmaceutically acceptable salt.

7. The aforementioned R ３ H, -(CH ２ ) ０－３ N(R) ｂ ) ２ cyano group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, -(CH ２ ) ０－３ -3-14 member heterocyclyl group or C １－６ It is an alkyl group, Each of the R ｂ These are independently H, halogen, hydroxyl group, cyano group, and C １－６ Alkyl alkyl group, C ３－６ Cycloalkyl group, -(CH ２ ) ０－３ C １－６ Alkoxy group or C １－６ The compound according to claim 1, characterized by being a haloalkyl group, its stereoisomer, tautomer, deuteride, or pharmaceutically acceptable salt.

8. Equation (I) is Equation (IA): 【Transformation 8】 Selected from, The aforementioned ring B is C ３－１４ Cycloalkyl groups, 3-14 member heterocycloalkyl groups, C ６－１８ Selected from aryl groups or 6-18 membered heteroaryl groups, The aforementioned R １ , R ２ , R ３ , R ５ , X, L, A ring, R ｄ The compound according to claim 1, its stereoisomer, tautomer, deuteride, or pharmaceutically acceptable salt thereof, characterized in that the definitions of m and n are the same as those described in claim 1.

9. The aforementioned ring A is C ８－１０ Bicyclic carbocyrillyl group, 8-10 membered bicyclic heterocycloalkyl group, C １０－１２ Selected from a bicyclic aryl group or a 10-12 membered bicyclic heteroaryl group, The R3 is selected from H, halogen, C1-6 alkyl group, C1-6 alkoxy group, haloalkyl group, C2-6 alkenyl group, C2-6 alkynyl group, -(CH2)0-3-C3-14 cycloalkyl group, -(CH2)0-3-3-14 membered heterocyclyl group, or -(CH2)0-3N(Rb)2, and the C1-6 alkyl group, C1-6 alkoxy group, -(CH2)0-3-C3-14 cycloalkyl group, -(CH2)0-3-3-14 membered heterocyclyl group, haloalkyl group, or hydroxyl group is optionally further substituted with one or more Rc. R c is independently selected from halogens, C1-6 alkyl groups, C1-6 alkoxy groups, haloalkyl groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, -C0-3 alkylene-C(=O)R b, -C0-3 alkylene-C(=O)N(R b) 2, -(CH2)0-3N(R b) 2, O(CH2)0-3 C3-14 cycloalkyl groups, -O(CH2)0-3 -3-14 membered heterocyclyl groups, C3-14 cycloalkyl groups, 3-14 membered heterocyclyl groups, C6-18 aryl groups, and 5-18 membered heteroaryl groups. Each R b is independently H, halogen, hydroxyl group, cyano group, C1-6 alkyl group, -(CH2)0-3 C1-6 alkoxy group, C3-6 cycloalkyl group, or C1-6 haloalkyl group. m is selected from 0, 1, 2, or 3. The aforementioned R5 is selected from C1-6 alkyl groups, The aforementioned n is selected from 0 or 1. The aforementioned L is NH, The aforementioned R1 is, 【Chemistry 9】 Selected from, 【Chemistry 10】 This is further replaced by one or more Ra a, Ra is independently selected from H, a hydroxyl group, a cyano group, a halogen, a C1-6 alkyl group, a C1-6 haloalkyl group, -C0-3 alkylene-OR b, -OC(=O)C1-6 alkyl group, -C0-3 alkylene-N(R b)2, -C0-3 alkylene-C(=O)R b, -C0-3 alkylene-C(=O)OR b, -C0-3 alkylene-C(=O)N(R b)2, a C2-6 alkenyl group, or a C2-6 alkynyl group. A compound according to claim 8, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 8.

10. The aforementioned ring A is 【Chemistry 11】 Selected from, The aforementioned D, E, and G are each independently selected from C, N, or O. The aforementioned R3 is H, -(CH2)0-3N(Rb)2, a cyano group, a C2-6 alkenyl group, a C2-6 alkynyl group, a -(CH2)0-3-3-14 member heterocyclyl group, or a C1-6 alkyl group. Each of the R b is independently H, halogen, hydroxyl group, cyano group, C1-6 alkyl group, C3-6 cycloalkyl group, -(CH2)0-3 C1-6 alkoxy group or C1-6 haloalkyl group, and / or The aforementioned R1 is, 【Chemistry 12】 Selected from A compound according to claim 8, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is a compound according to claim 8.

11. The aforementioned ring A is 【Chemistry 13】 A compound according to claim 10, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

12. The aforementioned 【Chemistry 14】 teeth, 【Chemistry 15】 Selected from, The compound according to claim 8, its stereoisomers, tautomers, deuterides, or pharmaceutically acceptable salts, characterized in that D, E, G, and Z are each independently selected from C, N, or O.

13. The aforementioned 【Chemistry 16】 teeth, 【Chemistry 17】 Selected from, The aforementioned R1 is, [Chemistry 18] Selected from, 【Chemistry 19】 This is further replaced by one or more Ra a, Ra is independently selected from H, a hydroxyl group, a cyano group, a halogen, a C1-6 alkyl group, a C1-6 haloalkyl group, -C0-3 alkylene-OR b, -OC(=O)C1-6 alkyl group, -C0-3 alkylene-N(R b)2, -C0-3 alkylene-C(=O)R b, -C0-3 alkylene-C(=O)OR b, -C0-3 alkylene-C(=O)N(R b)2, a C2-6 alkenyl group, or a C2-6 alkynyl group. The compound according to claim 12, its stereoisomers, tautomers, deuterides or pharmaceutically acceptable salts, characterized in that each Rb is independently H, halogen, hydroxyl group, cyano group, C1-6 alkyl group, -(CH2)0-3 C1-6 alkoxy group, C3-6 cycloalkyl group, or C1-6 haloalkyl group. 【Request Item 14】 【Chemistry 20】 teeth, 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 A compound according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

15. Equation (I) is, 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 A compound according to claim 1, a stereoisomer thereof, a tautomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, characterized by being selected from among.

16. An intermediate compound used in the synthesis of the compound or its stereoisomer, tautomer, deuteride, or pharmaceutically acceptable salt, 【Chemistry 29】 Selected from, A compound according to claim 1, characterized by the stereoisomer, tautomer, deuteride, or pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition, The pharmaceutical composition is characterized by containing a therapeutically effective amount of the compound described in claim 1 or its stereoisomer, tautomer, deuteride, or pharmaceutically acceptable salt.

18. Use of the compound according to claim 1 or its stereoisomer, tautomer, or pharmaceutically acceptable salt in the preparation of an agent for treating and / or preventing HPK1-mediated diseases.

19. Use of the pharmaceutical composition according to claim 17 in the preparation of a drug for treating and / or preventing HPK1-mediated diseases.

20. The use according to claim 18, characterized in that the disease is cancer.

21. The use according to claim 19, characterized in that the disease is cancer.

22. The use according to claim 20 or 21, characterized in that the cancer is selected from breast cancer, multiple osteomyeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumor, intrahepatic cholangiocarcinoma, osteomyelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Schwann cell tumor, pulmonary squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.

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