Novel heterocyclic compound

Abstract

The present invention relates to a novel heterocyclic compound, which is a compound having FGFR2 protein activity. Specifically, the invention relates to a compound as shown in formula (I), or pharmaceutically acceptable salt, solvate, polymorphic substance or isomer thereof, and application of the compound in preparation of medicines for treating diseases related to FGFR (Factor Growth Factor Receptor). # imgabs0 #

Description

A new heterocyclic compound

[0001] Cross-references

[0002] This application claims the patent rights of Chinese Patent Application No. 202211270745.0 filed on October 18, 2022, entitled “A Novel Heterocyclic Compound”, Chinese Patent Application No. 202211409894.0 filed on November 11, 2022, entitled “A Novel Heterocyclic Compound”, and Chinese Patent Application No. 202211470946.5 filed on November 22, 2022, entitled “A Novel Heterocyclic Compound”. Application, Chinese Patent Application No. 202211704758.4 filed on December 29, 2022, entitled “A New Heterocyclic Compound”, Chinese Patent Application No. 202310050952.3 filed on January 19, 2023, Chinese Patent Application No. 202310193588.6 filed on March 2, 2022, entitled “A New Heterocyclic Compound”, and Chinese Patent Application No. 202310193588.6 filed on March 2, 2023. The Chinese patent application No. 202310231053.3, filed on March 10, with the patent name “A New Heterocyclic Compound”, the Chinese patent application No. 202310395422.2, filed on April 13, 2023, with the patent name “A New Heterocyclic Compound”, the Chinese patent application No. 202310500356.0, filed on May 5, 2023, and the Chinese patent application No. 202310500356.0, filed on June 9, 2023, with the patent name “A New Heterocyclic Compound” The present invention claims priority from Chinese Patent Application No. 202310684345.2, entitled “A Novel Heterocyclic Compound”, Chinese Patent Application No. 202310986341.X, filed on August 7, 2023, entitled “A Novel Heterocyclic Compound”, and Chinese Patent Application No. 202311166676.3, filed on September 11, 2023, entitled “A Novel Heterocyclic Compound”, all disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to compounds for inhibiting FGFR protein activity, and also relates to preparation methods of these compounds and uses of their pharmaceutical compositions. Background Art

[0004] Fibroblast growth factor receptors (FGFRs) are transmembrane polypeptide tyrosine kinases. Five types (FGFR1 to FGFR5) have been discovered. FGFR2 is primarily distributed in tissues of endodermal origin, such as the stomach, liver, pancreas, esophagus, and bile duct in the digestive system. FGFR2b is distributed in epithelial cells, while FGFR2c is distributed in mesenchymal cells. FGFR2 plays a significant role in promoting cell proliferation and differentiation, nerve fiber growth and development, wound healing, and apoptosis. FGFR2 activates the downstream p38 signaling pathway to trigger endochondral ossification. Activation of the downstream MAPK and PKC pathways regulates the proliferation of mesenchymal stem cells, playing a crucial role in promoting direct osteogenesis. FGFR2 also plays a crucial role in tooth development.

[0005] Previous studies have shown that FGFR2 is associated with a variety of tumors. FGFR2 gene amplification has been reported in triple-negative breast cancer and gastric cancer with a poor prognosis. FGFR2 gene mutations have been found in endometrial cancer, lung cancer, gastric cancer, and urothelial cancer. FGFR2 fusion proteins are present in lung adenocarcinoma, squamous cell carcinoma, thyroid cancer, prostate cancer, and bile duct cancer. In colorectal cancer, FGFR2 can upregulate programmed cell death ligand 1 (PD-L1) expression through the JAK / STAT3 pathway, regulating tumor immune evasion, and FGFR2 expression levels are closely correlated with prognosis. Studies have found that FGFR2 gene fusions are found in 10-20% of patients with intrahepatic bile duct cancer.

[0006] The development of drugs targeting FGFR2 isoforms is underway. In addition to the three marketed drugs, over ten FGFR inhibitors are in various stages of clinical development. Examples include bemarituzumab (currently in Phase II clinical trials), developed by Amgen and Zai Lab; alofanib (currently in Phase I clinical trials), developed by Russian Pharmaceutical Technologies; RLY-4008 (currently in Phase II clinical trials), developed by Relay Therapeutics; and TAS-120 (futibatinib), developed by Taiho Pharmaceuticals (currently in Phase II clinical trials). BRIEF DESCRIPTION OF THE DRAWINGS

[0007] Figure 1 shows the changes in tumor volume.

[0008] Figure 2 is a graph showing changes in body weight.

[0009] Summary of the Invention

[0010] The present invention provides an FGFR2 inhibitor, which is a compound represented by general formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof. The present invention also provides a series of compounds represented by general formula (I) and pharmaceutically acceptable salts, solvates, polymorphs, or isomers thereof, pharmaceutical compositions comprising these compounds, and methods for treating FGFR-related diseases using such compounds.

[0011] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof:

[0012] in,

[0013] X1 is CH or N,

[0014] One of X2 and X3 is C and the other is N.

[0015] R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0016] A is R0, -O-R0, -S-R0, -NR6-R0, -C≡C-R0, -O-(CH2)-R0, -S-(CH2)-R0, -NR6-(CH2)-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0017] R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2,

[0018] R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0019] L0 is -O-, -O-(CH2) 1-6 -、-S-、-S-(CH2) 1-6 -, -NH-, or -NH-(CH2) 1-6 -,

[0020] L1 and L2 are each independently selected from methylene, alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -O-R5, -OR 13 、-S-R5、-SR 13 、-NR5R6、-NH-R 13 , -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, and the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or

[0021] A does not exist, -(L0) p -(L1) m - is a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocyclic ring, or a 3-12 membered heterocyclic ring, and the C or N on the ring can be connected by -(L4) p1 -(L5) p2 -(L6) p3 -(L7) p4 - is linked to carbon 1 to form a carbocyclic or heterocyclic ring, or

[0022] R b Does not exist, -(L0) p -(L1) m - is a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocyclic ring, or a 3-12 membered heterocyclic ring, and the C or N on the ring can be connected by -(L4) p1 -(L5) p2 -(L6) p3 -(L7) p4 - is connected to carbon 2 to form a carbocyclic or heterocyclic ring,

[0023] L4 is a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocyclic ring, or a 3-12 membered heterocyclic ring,

[0024] L5, L6 and L7 are each independently selected from -O-(CH2) 1-8 -、-NH-(CH2) 1-8 -、-O-(CO)-(CH2) 1-8 -、-NH-(CO)-(CH2) 1-8 - and -(CH2) 1-8 -, wherein -O- and -O-, -NH- and -NH-, or -O- and -NH- are not directly connected,

[0025] P1, P2, P3 and P4 are each independently 0 or 1, and P2+P3+P4 is 1, 2, or 3,

[0026] R 13 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0027] L3 is the key, or The asterisk key is connected to R1.

[0028] Ring B is a 3-12 membered heterocyclic ring,

[0029] R1 is halogen, alkynyl, -CN, -(CO)-R3, or

[0030] R 10 、R 11 and R 12 are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 substituted with alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or

[0031] R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R 12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0032] R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, -O-R5, or -NR5R6,

[0033] R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2,

[0034] p is 0 or 1,

[0035] m and n are each independently 0, 1, or 2.

[0036] In some embodiments, X1 is CH or N,

[0037] One of X2 and X3 is C and the other is N.

[0038] R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0039] A is R0, -O-R0, -S-R0, -NR6-R0, -C≡C-R0, -O-(CH2)-R0, -S-(CH2)-R0, -NR6-(CH2)-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0040] R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2,

[0041] R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0042] L0 is -O-(CH2) 1-6 -,

[0043] L1 and L2 are each independently selected from methylene, alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0044] L3 is the key, or The asterisk key is connected to R1.

[0045] Ring B is a 3-12 membered heterocyclic ring,

[0046] R1 is halogen, alkynyl, -CN, -(CO)-R3, or

[0047] R 10 、R 11 and R 12 are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or

[0048] R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R 12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0049] R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, -O-R5, or -NR5R6,

[0050] R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2,

[0051] p is 0 or 1, and m and n are each independently 0, 1, or 2.

[0052] In some embodiments, X1 is CH or N,

[0053] One of X2 and X3 is C and the other is N.

[0054] R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0055] A is R0, -O-R0, -S-R0, -NR6-R0, -C≡C-R0, -O-(CH2)-R0, -S-(CH2)-R0, -NR6-(CH2)-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0056] R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2,

[0057] R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6-3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0058] L0 is -O-(CH2) 1-6 -,

[0059] L1 and L2 are each independently selected from alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0060] L3 is the key, or The asterisk key is connected to R1.

[0061] Ring B is a 3-12 membered heterocyclic ring,

[0062] R1 is halogen, alkynyl, -CN, -(CO)-R3, or

[0063] R 10 、R 11 and R 12are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or

[0064] R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R 12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0065] R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, -O-R5, or -NR5R6,

[0066] R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2,

[0067] p, m and n are each independently 0 or 1.

[0068] In some embodiments, X1 is CH or N,

[0069] One of X2 and X3 is C and the other is N.

[0070] R a and Rb Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0071] A is R0, -O-R0, -S-R0, -NR6-R0, -C≡C-R0, -O-(CH2)-R0, -S-(CH2)-R0, -NR6-(CH2)-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0072] R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2,

[0073] R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0074] L0 is -O-(CH2) 1-6 -,

[0075] L1 and L2 are each independently selected from alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0076] L3 is the key, or The asterisk carbon is connected to R1,

[0077] Ring B is a 3-12 membered heterocyclic ring,

[0078] R1 is halogen, alkynyl, -CN, -(CO)-R3, or

[0079] R 10 、R 11 and R 12 are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or

[0080] R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0081] R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted by halogen, -CN, -OH, -O-R5, or -NR5R6,

[0082] R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2,

[0083] p, m and n are each independently 0 or 1.

[0084] In some embodiments, X1 is CH or N,

[0085] One of X2 and X3 is C and the other is N.

[0086] R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0087] A is R0, -O-R0, -S-R0, -NR6-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0088] R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2,

[0089] R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclic group, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic group may be optionally replaced by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0090] L0 is -O-(CH2) 1-6 -,

[0091] L1 and L2 are each independently selected from alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0092] L3 is the key, or The asterisk carbon is connected to R1,

[0093] Ring B is a 3-12 membered heterocyclic ring,

[0094] R1 is halogen, alkynyl, -CN, -(CO)-R3, or

[0095] R 10 、R 11 and R 12 are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 substituted with alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or

[0096] R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R 12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6,

[0097] R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, -O-R5, or -NR5R6,

[0098] R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2,

[0099] p, m and n are each independently 0 or 1.

[0100] In some embodiments, X1 is CH, X2 is N, and X3 is C.

[0101] In some embodiments, R a H, R b It is -CN.

[0102] In some embodiments, R1 is R 10 、R 11 and R 12 As defined above.

[0103] In some embodiments, A is R0, -O-R0, -S-R0, or -NR6-R0, R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2, and R2 and R6 are as defined above.

[0104] In some embodiments, A is R0, -O-R0, -S-R0, or -NR6-R0, R0 is a 5-12 membered heteroaryl or a 3-12 membered heterocyclyl, and the heteroaryl and heterocyclyl may each be optionally substituted with 1-3 R2, and R2 and R6 are as defined above.

[0105] In some embodiments, A is R0, R0 is a 5-12 membered heteroaryl or a 3-12 membered heterocyclyl, and the heteroaryl and heterocyclyl may each be optionally substituted with 1-3 R2, and R2 is as defined above.

[0106] In some embodiments, A is R0, R0 is a 5-12 membered heteroaryl, each of which may be optionally substituted with 1-3 R2, and R2 is as defined above.

[0107] In some embodiments, A is R0, R0 is a 3-12 membered heterocyclyl, each of which may be optionally substituted with 1-3 R2, and R2 is as defined above.

[0108] In some embodiments, L1 and L2 are each independently selected from alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocyclic ring, or 3-12 membered heterocyclic ring, wherein the arylene, heteroarylene, carbocyclic ring and heterocyclic ring may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, preferably, the arylene, heteroarylene, carbocyclic and heterocyclic rings may be optionally substituted with halogen, -CN, -OH, C 1-6 The alkyl group is substituted with -O-R5, -S-R5, or -NR5R6, wherein R3, R5 and R6 are as defined above.

[0109] In some embodiments, R 10 、R 11 and R 12 Each independently selected from H or C 1-6 Alkyl, which may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6.

[0110] In some embodiments, L3 is wherein the asterisk bond is connected to R1 and the B ring is as defined above.

[0111] In some embodiments, for or

[0112] In some embodiments, R3 is independently selected from C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl may be optionally substituted by halogen, -CN, -OH or -NH2.

[0113] In some embodiments, p is 0.

[0114] In some embodiments, the present invention provides the following compounds or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof.

[0115] Another aspect of the present invention relates to a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

[0116] In another aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, or isomer thereof, or a composition thereof, in the preparation of a medicament for treating an FGFR-related disease. Preferably, the FGFR-related disease is a tumor. In some embodiments, the tumor has a mutation in FGFR2 N549, V561, V565, N550, N540, V555, E566, K660, or V550. In some embodiments, the FGFR-related cancer is bile duct cancer, urothelial cancer, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, leukemia, multiple myeloma, Hodgkin's lymphoma, melanoma, and the like.

[0117] The present invention also provides a use for treating diseases related to abnormal expression or mutation of FGFR receptors or abnormal expression and activity of corresponding ligands.

[0118] The present invention also relates to a method for treating tumors resistant to FGFR inhibitors, comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the above-mentioned composition; in some embodiments, the FGFR-related disease is bile duct cancer, urothelial carcinoma, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, leukemia, multiple myeloma, Hodgkin's lymphoma, melanoma, etc., preferably liver cancer and bile duct cancer.

[0119] In some embodiments of the present invention, the subject involved in the present invention is a mammal including humans.

[0120] Detailed Description of the Invention

[0121] Exemplary embodiments utilizing the principles of the present invention are set forth in the following detailed description of the invention. The features and advantages of the present invention may be better understood by reference to the following summary of the invention.

[0122] It should be understood that the scope of protection of various aspects of the present invention is determined by the claims, and methods and structures within the scope of these claims and their equivalents are all within the scope of the claims.

[0123] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by those skilled in the art to which the subject matter of the claims pertains. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

[0124] It should be understood that the foregoing brief description and the following detailed description are exemplary and explanatory, rather than limiting, of any subject matter of the present invention. Unless otherwise specifically stated, the use of the singular also includes the plural. Unless otherwise specified, the use of "or" and "alternatively" means "and / or." In addition, the use of the term "include," as well as other forms such as "comprises," "includes," and "comprising" are not limiting.

[0125] Some chemical terms

[0126] The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl." Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any hierarchy between monosubstituted and fully substituted (e.g., -CH2CHF2, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that would be sterically impossible and / or incomposable to synthesize will be introduced.

[0127] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet / visible spectroscopy and pharmacological methods, are adopted. Unless specifically defined, the relevant terms and experimental procedures and techniques of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry herein are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the test kit can be utilized, or reactions and purification can be carried out according to methods well known in the art or the description of the present invention. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description in the multiple summaries and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0128] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0129] As used herein, the terms "group" and "chemical group" refer to a specific part or functional group of a molecule. A chemical group is often considered to be a chemical entity embedded in or attached to a molecule.

[0130] Some chemical groups named herein may be abbreviated to indicate the total number of carbon atoms. For example, C1-C6 alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated in the abbreviated notation does not include carbon atoms in possible substituents.

[0131] The term "halogen," "halo," or "halide" refers to bromine, chlorine, fluorine, or iodine.

[0132] The compounds of the present invention may contain one or more (e.g., one, two, three, or four) isotopic substitutions. For example, in the compounds, H may be in any isotopic form, including 1 H. 2 H (D or deuterium) and 3 H (T or tritium); C can be any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16 O and 18 O etc.

[0133] As used herein, the terms "aromatic," "aromatic ring," "aromatic," "aromatic," and "aromatic ring" refer to a planar ring or ring moiety having a delocalized electron conjugate system containing 4n+2 electrons, where n is an integer. Aromatic rings can be formed by 5, 6, 7, 8, 9, or more atoms. Aromatic compounds can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term aromatic compound includes all carbon rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

[0134] As used herein, the term "heteroatom" or "hetero" refers to atoms other than carbon and hydrogen, either alone or as part of another component. Heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different from one another.

[0135]

[0046] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0136]

[00146] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0137] The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, connected to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

[0138] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight chain or optionally substituted branched monovalent hydrocarbon radical having one or more C=C double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The double bonds in these groups can be in cis or trans configurations and are understood to encompass both isomers. Examples include, but are not limited to, ethenyl (CH=CH2), 1-propenyl (CH2CH=CH2), isopropenyl (C(CH3)=CH2), butenyl, and 1,3-butadienyl, among others. Where alkenyl as defined herein appears in a numerical range, for example, "C2-C6 alkenyl" or "C 2-6 The term "alkenyl" refers to an alkenyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkenyl group herein also includes the case where no numerical range is specified.

[0139] The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted linear or branched monovalent hydrocarbon radical having one or more C≡C triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1,3-butadiynyl. When a numerical range appears for an alkynyl group as defined herein, for example, "C2-C6 alkynyl" or "C 2-6 The term "alkynyl" refers to an alkynyl group which may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms. The alkynyl group herein also encompasses the case where no numerical range is specified.

[0140] The term "alkynylene," as used herein, alone or in combination, refers to a divalent radical derived from a monovalent alkynyl radical as defined above.

[0141] The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated π electron system having 6-14 carbon atoms, preferably 6-12 carbon atoms, and most preferably 6 carbon atoms. Aryl can be unsubstituted or substituted with one or more substituents, examples of which include but are not limited to alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxyl, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic groups. Non-limiting examples of unsubstituted aryl include but are not limited to phenyl, naphthyl, and anthracenyl.

[0142] The term "arylene" as used herein, alone or in combination, refers to a divalent radical derived from a monovalent aryl radical as defined above.

[0143] The term "heteroaryl" refers to a monocyclic or fused ring of 5-12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, of which 1, 2, 3 or 4 are selected from N, O, S, with the remaining ring atoms being C, and having a completely conjugated π-electron system. Heteroaryl groups may be unsubstituted or substituted, with substituents including, but not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halogen, hydroxy, cyano, nitro, carbonyl and heteroalicyclic groups. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl and triazinyl.

[0144] The term "heteroarylene," as used herein, alone or in combination, refers to a divalent radical derived from a monovalent heteroaryl radical as defined above.

[0145] The term "cycloalkyl" as used herein, alone or as part of another component, refers to a stable, monovalent, non-aromatic, monocyclic or polycyclic hydrocarbon radical, containing only carbon and hydrogen atoms, which may include fused, spiro or bridged ring systems, containing 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, more preferably 3 to 8 ring carbon atoms, which may be saturated or unsaturated, and which is attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0146] The term "carbocycle" refers to a structure formed by a covalently closed ring of carbon, which may be saturated or partially unsaturated. The carbocycle may be formed by 3, 4, 5, 6, 7, 8, 9 or more atoms. The difference between the terms carbocycle and heterocycle is that the heterocycle's ring backbone contains at least one atom that is different from carbon. As used herein, "carbocycle" may be a monocyclic ring or a polycyclic ring, including spirocyclic, fused and bridged rings. The carbocycle may be arbitrarily substituted. As used herein, "carbocycle" preferably contains from about 5 to about 20, or from 5 to 10, or from 5 to 8, or from 5 to 6 backbone ring atoms.

[0147] The terms "heterocycloalkyl," "heterocyclyl," and "heterocycle," as used herein alone or as part of another component, refer to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur atoms of the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclyl group may be attached to the rest of the molecule via a single bond through a carbon atom or heteroatom in the ring. Heterocyclyl groups containing fused rings may contain one or more aromatic or heteroaromatic rings, as long as the atoms attached to the rest of the molecule are non-aromatic ring atoms. For the purposes of the present application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolane, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0148] The term "polymorph" or "polymorphism" as used herein refers to a compound of the present invention having multiple crystal lattice morphologies. Some compounds of the present invention may have more than one crystal form, and the present invention encompasses all polymorphic forms or mixtures thereof.

[0149] Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

[0150] Unless otherwise specified, compounds of the present invention containing olefinic double bonds include both E and Z isomers.

[0151] It should be understood that the compounds of the present invention may contain asymmetric centers. These asymmetric centers can independently be in the R or S configuration. Some compounds of the present invention may also exhibit cis-trans isomerism, which is apparent to those skilled in the art. It should be understood that the compounds of the present invention include their individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by implementing or modifying known methods, such as chromatography and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

[0152] As used herein, the term "pharmaceutically acceptable salt" includes both acid-addition salts and base-addition salts.

[0153] "Pharmaceutically acceptable salts" refer to salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, hexanoic acid, carbonic acid, cinnamic acid, and citric acid, which retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. "Pharmaceutically acceptable base-added salts" refer to salts that retain the biological efficacy and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by reacting the free acid with an inorganic or organic base. Salts formed by reaction with inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and manganese salts.

[0154] Organic bases for forming salts include, but are not limited to, primary amines, secondary amines, tertiary amines, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0155] Crystallization often produces solvates of the compounds of the invention. The term "solvate" as used herein refers to an association of one or more molecules of the compound of the invention with one or more solvent molecules.

[0156] The solvent may be water, in which case the solvate is a hydrate. Alternatively, it may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may simply accidentally retain water or a mixture of water and some other solvent. The compounds of the present invention may be reacted in a solvent or precipitated or crystallized in a solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention.

[0157] The term "pharmaceutical composition" as used herein refers to a preparation containing a compound of the present invention and a medium generally accepted in the art for delivering biologically active compounds to mammals (such as humans), including all pharmaceutically acceptable carriers.

[0158] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0159] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0160] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.

[0161] As used herein, the terms "subject," "patient," "subject," or "individual" refer to individuals suffering from a disease, disorder, or condition, and include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0162] The term "treatment" as used herein refers to the treatment of a disease or condition in a mammal, especially a human, including

[0163] (i) preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not yet been diagnosed with the disease or condition;

[0164] (ii) inhibiting the disease or condition, i.e., controlling its development;

[0165] (iii) alleviate the disease or condition, i.e., cause the disease or condition to regress;

[0166] (iv) Alleviate symptoms caused by a disease or condition.

[0167] As used herein, the terms "disease" and "disorder" are used interchangeably or may have different meanings because certain diseases or disorders do not yet have a known causative agent (and therefore the cause of the disease is unknown) and therefore cannot be considered diseases but rather are considered to be undesirable conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.

[0168] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to provide some relief to some degree from one or more symptoms of the disease or condition being treated. This can result in a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0169] As used herein, the terms "administer," "administer," "dosing," and the like refer to methods that enable a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0170] Preparation of the compounds of the present invention

[0171] The following reaction schemes show methods for preparing the compounds of the present invention.

[0172] It is understood that in the following description, combinations of substituent groups and / or variables of the described formulas are permissible only if such combinations result in stable compounds.

[0173] Those skilled in the art will also appreciate that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, sulfhydryl, and carboxyl. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butylmethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable amino, amidino, and guanidine protecting groups include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for sulfhydryl include -C(O)-R" (R" represents alkyl, aryl, or arylalkyl), p-methoxybenzyl, trityl, etc. Suitable carboxyl protecting groups include alkyl, aryl, or arylalkyl esters. Protecting groups can be added or removed by standard techniques known to those skilled in the art. Example

[0174] The following non-limiting examples are illustrative only and are not intended to limit the present invention in any way.

[0175] Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Sinopharm Chemical Reagent Beijing Co., Ltd., Alfa Aesar, or Beijing J&K Technology Co., Ltd. and were used directly without further purification unless otherwise stated.

[0176] Unless otherwise noted, the following reactions were performed at room temperature in anhydrous solvents under a positive pressure of nitrogen or argon or using a drying tube; the reaction flasks were fitted with rubber septa to facilitate the addition of substrates and reagents via syringe; and the glassware was oven-dried and / or heat-dried.

[0177] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography silica gel precast plates (HSGF254) produced by Yantai Institute of Chemical Industry were used; MS measurements were performed using a Thermo LCQ Fleet (ESI) liquid chromatography-mass spectrometer; and optical rotation was determined using an SGW-3 automatic polarimeter (Shanghai Shenguang Instrument Co., Ltd.).

[0178] NMR data ( 1 H NMR was performed using a Varian instrument at 400 MHz. Solvents used for NMR data included CDCl₃, CD₃OD, D₂O, and DMSO-d₆, with reference to tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃: 7.26 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; d₆-DMSO: 2.50 ppm). When peak shape multiplicity is indicated, the following abbreviations are used to denote the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), and dt (double of triplets). Coupling constants, if given, are in Hertz (Hz).

[0179] Abbreviations:

[0180] Intermediate 1: 3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-A]pyridin-4-yl trifluoromethanesulfonate (synthesized according to the method described in patent WO2017 / 11776)

[0181] Intermediate 2: 6-(1-methyl-1H-pyrazol-4-yl)-4-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile (synthesized according to the method described in patent WO2017 / 11776)

[0182] Intermediate 3: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (synthesized according to the method described in patent WO2017 / 11776)

[0183] Intermediate 4: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (synthesized according to the method described in patent WO2017 / 11776)

[0184] Intermediate 5: tert-Butyl 4-(5-(3-cyano-6-((trifluoromethanesulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate (synthesized according to the method described in patent WO2017 / 11776)

[0185] Intermediate 6: 2-amino-3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethylsulfonate (synthesized according to the method described in patent WO2020064009)

[0186] Intermediate 7: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]phenyl trifluoromethylsulfonate

[0187] Step 1: 4-(4-Hydroxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0188] Under nitrogen, intermediate 1 (371 mg), 4-hydroxyphenylboronic acid pinacol ester (220 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (275 mg).

[0189] Step 2: 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]phenyl trifluoromethylsulfonate

[0190] At room temperature, the product obtained in step 1 was dissolved in DMF (10 mL), and DIEA (260 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (360 mg). The mixture was stirred at room temperature overnight, water (50 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 (v:v)) to obtain intermediate 7 (289 mg).

[0191] Intermediate 8: 4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0192] Step 1: tert-Butyl 4-(4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate

[0193] Under nitrogen, 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethylsulfonate (369 mg), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)piperazine-1-carboxylate (389 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (395 mg).

[0194] Step 2: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0195] The above product was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (2 mL) was added, and the mixture was stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and cooled to 0°C. Dichloromethane (10 mL) was added to the residue, along with acryloyl chloride (100 mg) and triethylamine (200 mg), and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (271 mg).

[0196] Intermediate 9: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0197] Step 1: tert-Butyl 4-(4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)piperidine-1-carboxylate

[0198] At room temperature, tert-butyl 4-(4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate (482 mg) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added and the mixture was stirred for 2 hours. The mixture was then concentrated under reduced pressure and cooled to 0°C. Dichloromethane (20 mL) was added to the residue, followed by tert-butyl 4-oxopiperidine-1-carboxylate (300 mg) and sodium triacetoxyborohydride (500 mg). The mixture was then warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (348 mg).

[0199] Step 2: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0200] The above product was dissolved in dichloromethane (10 mL) at room temperature, trifluoroacetic acid (2 mL) was added, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and cooled to 0°C. Dichloromethane (20 mL) was added to the residue, followed by acryloyl chloride (90 mg) and triethylamine (200 mg). The mixture was then warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (247 mg).

[0201] Intermediate 10: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0202] Intermediate 10 was synthesized according to the synthesis method of intermediate 9.

[0203] Intermediate 11: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0204] Intermediate 11 was synthesized according to the synthetic method of intermediate 9.

[0205] Example 1: 4-(6-(4-cyanopiperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0206] Intermediate 3 (38 mg) was dissolved in dichloromethane (5 mL) at 0°C, and bromocyanurate (11 mg) and triethylamine (20 mg) were added. The mixture was then warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (25 mg).

[0207] MS m / z[LC-MS]:410.17[M+1]. 1 H NMR (400MHz, DMSO-d6) δ9.22(d,J=1.6Hz,1H),8.63(s,1H),8.39(d,J=2.4Hz,1H),8.37(s,1H),8.10(s,1H),7.85(dd, J=8.8Hz,2.4Hz,1H),7.77(d,J=1.6Hz,1H),7.02(d,J=8.8Hz,1H),3.86(s,3H),3.68-3.71(m,4H),3.30-3.33(m,4H).

[0208] Example 2: 4-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridyl]-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0209] Step 1: tert-Butyl 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0210] Under nitrogen, 4-(6-chloropyridin-3-yl)-6-(1-methyl-4,5-dihydro-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (340 mg) (synthesized according to patent CN111592538) and potassium carbonate (280 mg) were dissolved in a 4:1 mixture of dioxane and water (20 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (380 mg).

[0211] Step 2: 4-(1'-cyano-1',2',3',6'-tetrahydro-[2,4'-bipyridinyl]-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0212] At room temperature, tert-butyl 5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (48 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hours, then concentrated under reduced pressure. The mixture was cooled to 0°C, and dichloromethane (10 mL) was added to the residue. Bromocyanogen (20 mg) and triethylamine (50 mg) were then added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (27 mg).

[0213] MS m / z[LC-MS]:407.18[M+1]. 1 H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.81(d,J=2.4Hz,1H),8.66(s,1H),8.39(s,1H),8.12(s,1H),8.08(dd,J=8.8Hz,2.4Hz,1H ),7.91(s,1H),7.76(d,J=8.8Hz,1H),6.82(s,1H),4.03(q,J=2.8Hz,2H),3.86(s,3H),3.46(t,J=6.0Hz,2H),2.70-2.76(m,2H).

[0214] Example 3: 4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0215] Step 1: tert-Butyl 4-(5-(3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

[0216] Under nitrogen, intermediate 5 (55 mg), 3-methyl-3-acridinol hydrochloride (13 mg), tris(dibenzylideneacetone)dipalladium (5 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (7 mg), and cesium carbonate (66 mg) were added sequentially to toluene (10 mL). The mixture was heated to 110°C and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The combined filtrates were concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (27 mg).

[0217] Step 2: 4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0218] At room temperature, the product obtained in step 1 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, stirred for 2 hours, and concentrated under reduced pressure. Cooled to 0°C, the residue was dissolved in dichloromethane (10 mL), triethylamine (50 mg) and acryloyl chloride (10 mg) were added, and then the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (17 mg).

[0219] MS m / z[LC-MS]:444.21[M+1]. 1H NMR (400MHz, CDCl3) δ8.32(d,J=2.4Hz,1H),8.13(s,1H),7.74(dd,J=8.8Hz,2.4H z,1H),7.71(d,J=2.0Hz,1H),6.77(d,J=8.8Hz,1H),6.72(d,J=2.0Hz,1H),6.61(d d,J=16.8Hz,10.4Hz,1H),6.35(dd,J=16.8Hz,1.6Hz,1H),5.75(dd,J=10.4Hz,1.6 Hz, 1H), 3.91 (d, J = 7.6Hz, 2H), 3.80-3.88 (m, 4H), 3.60-3.78 (m, 6H), 1.66 (s, 3H).

[0220] Example 4: 4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0221] Step 1: tert-Butyl 4-(5-(2-amino-3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)piperazine-1-carboxylate

[0222] Intermediate 6 (39 mg), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2-yl-tert-butyl)piperazine-1-carboxylate (39 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (11 mg) was added under nitrogen, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (37 mg).

[0223] Step 2: 4-(6-(4-acryloylpiperazin-1-yl)pyridin-3-yl)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0224] At room temperature, the product obtained in step 1 was dissolved in dichloromethane (4 mL), trifluoroacetic acid (1 mL) was added, stirred for 2 hours, and concentrated under reduced pressure. The mixture was cooled to 0°C, and the residue was dissolved in dichloromethane (10 mL). Triethylamine (50 mg) and acryloyl chloride (9 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 10:1 (v:v)) to obtain the title compound (19 mg).

[0225] MS m / z[LC-MS]:454.17[M+1]. 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.33(d,J=2.4Hz,1H),8.26(s,1H),8.00(s,1H),7.78(dd,J=8.4Hz,2.4Hz,1H),7.53(s,1H),6.96(d,J=8.4Hz, 1H), 6.85 (dd, J = 16.8Hz, 10.4Hz, 1H), 6.27 (s, 2H), 6.14 (dd, J = 16.8Hz, 2.4Hz, 1H), 5.71 (dd, J = 10.4Hz, 2.0Hz, 1H), 3.84 (s, 3H), 3.57-3.73 (m, 8H).

[0226] Example 5: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0227] Intermediate 2 (38 mg) was dissolved in dichloromethane (5 mL) at 0°C, and triethylamine (30 mg) and acryloyl chloride (10 mg) were added. The mixture was then warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (37 mg).

[0228] MS m / z[LC-MS]:438.18[M+1]. 1H NMR(400MHz, CDCl3)δ8.61(s,1H),8.24(s,1H),7.78(s,1H),7.67(s,1H),7 .49(d,J=8.8Hz,2H),7.40(s,1H),7.03(d,J=8.8Hz,2H),6.61(dd,J=16.8H z,10.8Hz,1H),6.33(dd,J=16.8Hz,1.6Hz,1H),5.74(dd,J=10.8Hz,1.6Hz, 1H),3.97(s,3H),3.81-3.90(m,2H),3.68-3.79(m,2H),3.30-3.33(m,4H).

[0229] Example 6: 4-(6-(6-acryloyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0230] According to the synthesis method of Example 3, 3-(5-(3-cyano-6-(((trifluoromethyl)sulfonyl)oxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester (synthesized according to the method described in patent WO2017 / 11776) was used as the starting material to obtain the target compound.

[0231] MS m / z[LC-MS]:456.22[M+1]. 1 H NMR (400MHz, CDCl3) δ8.31(d,J=2.0Hz,1H),8.12(s,1H),7.69-7.73(m,2H),6.69(d,J=2.0Hz,1H ),6.61(d,J=8.4Hz,1H),6.32(dd,J=17.2Hz,1.6Hz,1H),6.22(dd,J=17.2Hz,10.4Hz,1H),5.67( dd,J=10.4Hz,1.6Hz,1H),4.66(d,J=6.0Hz,2H),4.14(d,J=11.6Hz,1H),3.84-3.90(m,4H),3.80 (d, J=7.6Hz, 2H), 3.65 (d, J=11.2Hz, 1H), 2.79-2.84 (m, 1H), 1.74 (d, J=8.8Hz, 1H), 1.64 (s, 3H).

[0232] Example 7: 4-(4-(1-acryloylpiperidin-4-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0233] The target compound was obtained according to the synthesis method of Example 4 using Intermediate 1 and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate as starting materials.

[0234] MS m / z[LC-MS]:437.20[M+1]. 1 H NMR (400MHz, CDCl3) δ8.63(s,1H),8.22(s,1H),7.77(s,1H),7.68(s,1H),7.50(d,J=8.0Hz, 2H),7.43(s,1H),7.34(d,J=8.0Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H),6.28(d,J=16.8Hz, 1H),5.68(d,J=10.4Hz,1H),4.78-4.88(m,1H),4.08-4.18(m,1H),3.95(s,3H),3.18(t,J=1 2.8Hz,1H),2.80-2.90(m,1H),2.73(t,J=12.8Hz,1H),1.92-2.02(m,2H),1.60-1.68(m,2H).

[0235] Example 8: 4-(4-acryloylpiperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0236] Step 1: tert-Butyl 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate

[0237] Under nitrogen, Intermediate 1 (371 mg), tert-butyl piperazine-1-carboxylate (373 mg), tris(dibenzylideneacetone)dipalladium (90 mg), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (130 mg), and cesium carbonate (660 mg) were added sequentially to toluene (30 mL), heated to 110°C, and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (31 mg).

[0238] Step 2: 4-(4-Acryloylpiperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0239] The product obtained in step 1 was dissolved in dichloromethane (5 mL) at room temperature, trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and cooled to 0°C. The residue was dissolved in dichloromethane (10 mL), triethylamine (50 mg) and acryloyl chloride (10 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (18 mg).

[0240] MS m / z[LC-MS]:362.15[M+1]. 1 H NMR (400MHz, CDCl3) δ8.38(s,1H),8.20(s,1H),7.73(s,1H),7.64(s,1H),6.91(s,1H),6.60(dd,J=16.8Hz,10.8Hz,1H),6.32(d d, J=16.8Hz, 1.6Hz, 1H), 5.73 (dd, J=10.8Hz, 1.6Hz, 1H), 3.98-4.05 (m, 2H), 3.97 (s, 3H), 3.88-3.95 (m, 2H), 3.17-3.19 (m, 4H).

[0241] Example 9: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0242] According to the synthesis method of Example 4, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester was used as the starting material to obtain the target compound.

[0243] MS m / z[LC-MS]:453.22[M+1]. 1H NMR (400MHz, CDCl3) δ8.30(s,1H),7.72(s,1H),7.61(s,1H),7.48(d,J=8.8Hz,2H),7.30(s,1H),7.03(d,J=8.8Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1 H),6.34(dd,J=16.8Hz,1.6Hz,1H),5.75(d,J=10.4Hz,1.6Hz,1H),4.51(s, 2H),3.96(s,3H),3.82-3.92(m,2H),3.69-3.79(m,2H),3.30-3.33(m,4H).

[0244] Example 10: 5-(4-(4-acryloylpiperazin-1-yl)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile

[0245] Step 1: 5-Bromo-3-cyanoimidazolo[1,2-a]pyridin-7-yl trifluoromethanesulfonate

[0246] At room temperature, 5-bromo-7-hydroxyimidazo[1,2-a]pyridine-3-carbonitrile (238 mg) was dissolved in DMF (10 mL). DIEA (260 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (400 mg). The mixture was stirred at room temperature overnight, water (50 mL) was added, and extraction was performed with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (290 mg).

[0247] Step 2: 5-Bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile

[0248] Under nitrogen, 5-bromo-3-cyanoimidazolo[1,2-a]pyridin-7-yl trifluoromethylsulfonate (290 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole (208 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (137 mg).

[0249] Step 3: tert-Butyl 4-(4-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)phenyl)piperazine-1-carboxylate

[0250] Under nitrogen, 5-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile (137 mg), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)piperazine-1-carboxylate (200 mg), and potassium carbonate (140 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (50 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to obtain the title compound (157 mg).

[0251] Step 4: 5-(4-(4-acryloylpiperazin-1-yl)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile

[0252] At room temperature, the product tert-butyl 4-(4-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)phenyl)piperazine-1-carboxylate (48 mg) obtained in step 3 was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and stirred for 2 hours. The reaction was complete, concentrated under reduced pressure, and cooled to 0°C. (240 mg) 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.34(s,1H),8.15(s,1H),7.99(d,J=1 .6Hz,1H),7.49(d,J=8.8Hz,2H),7.29(d,J=1.6Hz,1H),7.08(d,J=8.8Hz,2H ),6.85(dd,J=16.8Hz,10.8Hz,1H),6.14(dd,J=16.8Hz,2.8Hz,1H),5.70(d d, J=10.8Hz, 2.4Hz, 1H), 3.85 (s, 3H), 3.65-3.77 (m, 4H), 3.24-3.32 (m, 4H).

[0253] Example 11: 1-(4-(4-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0254] According to the synthesis method of Example 4, 4-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine was used as the starting material to obtain the target compound

[0255] MS m / z[LC-MS]:413.21[M+1]. 1 H NMR (400MHz, DMSO-d6) δ8.29 (s, 1H), 8.02 (s, 1H), 7.98 (d, J = 2.4Hz, 1H), 7.65 (d,J=8.8Hz,2H),7.45(d,J=1.2Hz,1H),7.11(d,J=8.8Hz,2H),6.85(dd,J=16. 8Hz,10.4Hz,1H),6.65(d,J=2.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71 (dd, J=10.4Hz, 2.4Hz, 1H), 3.86 (s, 3H), 3.66-3.77 (m, 4H), 3.23-3.28 (m, 4H).

[0256] Example 12: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acrylamide

[0257] Under nitrogen, intermediate 1 (37 mg), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (27 mg), and potassium carbonate (28 mg) were dissolved in a mixed solvent (5 mL) of dioxane and water (4:1). Tetrakis(triphenylphosphine)palladium (11 mg) was added, and the temperature was raised to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (18 mg).

[0258] MS m / z[LC-MS]:369.15[M+1]. 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.24(d,J=1.2Hz,1H),8.63(s,1H),8.39(s,1H),8.11(s,1H),7.83(d,J=8.4Hz,2H),7.78(d,J=1.2Hz ,1H),7.59(d,J=8.4Hz,2H),6.46(dd,J=16.8Hz,10.4Hz,1H),6.29(dd,J=16.8Hz,2.0Hz,1H),5.78(dd,J=10.4Hz,2.0Hz,1H),3.86(s,3H).

[0259] Example 13: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0260] Step 1: 4-Bromo-6-((1-methyl-1H-pyrazol-4-yl)amino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0261] Under nitrogen, 5-bromo-3-cyanoimidazolo[1,2-a]pyridin-7-yl trifluoromethylsulfonate (37 mg), 1-methyl-1H-pyrazol-4-amine (10 mg), RuPhos Pd G3 (8 mg), and cesium carbonate (65 mg) were dissolved in dioxane (10 mL), heated to 100°C, and stirred for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (22 mg).

[0262] Steps 2 and 3: Obtain the target compound according to the synthesis method of Example 10

[0263] MS m / z[LC-MS]:453.21[M+1]. 1H NMR (400MHz, DMSO-d6) δ8.40 (s, 1H), 7.99 (d, J = 2.0Hz, 1H), 7.87 (s, 1H), 7.83 ( s,1H),7.42(d,J=8.8Hz,2H),7.39(s,1H),7.09(d,J=2.0Hz,1H),7.06(d,J=8. 8Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H),6.13(dd,J=16.8Hz,2.4Hz,1H),5.7 0(dd,J=10.4Hz,2.4Hz,1H),3.81(s,3H),3.65-3.76(m,4H),3.21-3.29(m,4H).

[0264] Example 14: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0265] Intermediate 2 (38 mg) was dissolved in dichloromethane (5 mL) at 0°C, and triethylamine (30 mg) was added. Cyanogen bromide (11 mg) was slowly added dropwise, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (31 mg).

[0266] MS m / z[LC-MS]:409.18[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.61(s,1H),8.36(s,1H),8.09(s,1H),7.70(s,1H),7.5 0(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),3.86(s,3H),3.34-3.39(m,4H),3.28-3.33(m,4H).

[0267] Example 15: 4-(4-(4-methacryloylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0268] Intermediate 2 (38 mg) was dissolved in dichloromethane (5 mL) at 0°C, triethylamine (30 mg) was added, and methacryloyl chloride (10 mg) was slowly added dropwise. The mixture was then warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (35 mg).

[0269] MS m / z[LC-MS]:452.21[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.61(s,1H),8.37(s,1H),8.09(s,1H),7.70(s,1H),7.50(d,J=8.4Hz,2H), 7.09(d,J=8.4Hz,2H),5.22(s,1H),5.03(s,1H),3.86(s,3H),3.60-3.66(m,4H),3.22-3.28(m,4H),1.87(s,3H).

[0270] Example 16: 4-(4-(4-but-2-ynyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0271] At 0°C, intermediate 2 (38 mg) and butynoic acid (9 mg) were dissolved in DMF (5 mL). Triethylamine (30 mg) was added, and the mixture was warmed to room temperature and stirred for 12 hours. The reaction solution was poured into water (20 mL), and the precipitate was filtered, washed with water, and dried to obtain the title compound (36 mg).

[0272] MS m / z[LC-MS]:450.22[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.61(s,1H),8.37(s,1H),8.09(s,1H),7.70(s,1H),7.50(d,J=8.0Hz,2 H),7.09(d,J=8.0Hz,2H),3.86(s,3H),3.80-3.85(m,2H),3.60-3.66(m,2H),3.21-3.34(m,4H),2.04(s,3H).

[0273] Example 17: 4-(1-(1-acryloylpiperidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0274] The target compound was obtained according to the synthesis method of Example 4 using Intermediate 1 and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate as starting materials.

[0275] MS m / z[LC-MS]:427.18[M+1]. 1 H NMR (400MHz, CDCl3) δ8.59(d,J=1.2Hz,1H),8.25(s,1H),7.92(s,1H),7.78(s,2H),7.69(s ,1H),7.47(d,J=1.2Hz,1H),6.60(dd,J=16.8Hz,10.4Hz,1H),6.29(dd,J=16.8Hz,2.0Hz,1 H),5.71(dd,J=10.4Hz,2.0Hz,1H),4.72-4.88(m,1H),4.43-4.52(m,1H),4.08-4.23(m,1H ),3.98(s,3H),3.20-3.34(m,1H),2.82-2.96(m,1H),2.26-2.38(m,2H),2.02-2.12(m,2H).

[0276] Example 18: N-(4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0277] Step 1: tert-Butyl (4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)carbamate

[0278] Under nitrogen, intermediate 1 (37 mg), tert-butyl (4-ethynylphenyl) carbamate (44 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (10 mL), heated to 100°C, and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (31 mg).

[0279] Step 2: N-(4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0280] The product obtained in step 1 was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and cooled to 0°C. The residue was dissolved in dichloromethane (10 mL), triethylamine (50 mg) and acryloyl chloride (9 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (16 mg).

[0281] MS m / z[LC-MS]:393.13[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.26(s,1H),8.68(s,1H),8.37(s,1H),8.10(s,2H),7.77(d,J=8.4Hz,2H),7.65(d,J =8.4Hz, 2H), 6.44 (dd, J = 16.8Hz, 10.0Hz, 1H), 6.28 (dd, J = 16.8Hz, 2.0Hz, 1H), 5.79 (d, J = 10.0Hz, 2.0Hz, 1H), 3.87 (s, 3H).

[0282] Example 19: 4-(6-(4-(4-(But-2-ynyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0283] At 0°C, intermediate 3 (38 mg) and butynoic acid (10 mg) were dissolved in DMF (5 mL). Triethylamine (30 mg) was added, and the mixture was warmed to room temperature and stirred for 12 hours. The reaction solution was poured into water (20 mL), and the precipitate was filtered, washed with water, and dried to obtain the title compound (39 mg).

[0284] MS m / z[LC-MS]:451.21[M+1].

[0285] Example 20: 4-(2-acryloyl-2,7-diazacyclo[3.5]non-7-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0286] The target compound was obtained according to the synthesis method of Example 8 using Intermediate 1 and 2-tert-butyloxycarbonyl-2,7-diazaspiro[3.5]nonane as starting materials.

[0287] MS m / z[LC-MS]:402.20[M+1]. 1 H NMR (400MHz, CDCl3) δ8.34(s,1H),8.18(s,1H),7.74(s,1H),7.64(s,1H),6.90(s,1H),6.35(dd,J=16.8Hz,2.0Hz,1H),6.21(dd,J= 16.8Hz, 10.4Hz, 1H), 5.68 (dd, J=10.4Hz, 2.0Hz, 1H), 3.98 (s, 2H), 3.97 (s, 3H), 3.88 (s, 2H), 2.90-3.30 (m, 4H), 2.04-2.23 (m, 4H).

[0288] Example 21: 4-((1-acryloylpiperidin-4-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0289] Step 1: tert-Butyl 4-(((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]oxy)methyl)piperidine-1-carboxylate

[0290] To a solution of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (240 mg), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (215 mg), and triphenylphosphine (526 mg) in toluene (20 mL) was slowly added dropwise DIAD (300 mg) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to afford a white solid (349 mg).

[0291] Step 2: 4-((1-acryloylpiperidin-4-yl)methoxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0292] The target compound was obtained by following the procedure of step 2 of Example 4.

[0293] MS m / z[LC-MS]:391.19[M+1]. 1H NMR (400MHz, CDCl3) δ8.27(s,1H),8.13(s,1H),7.73(s,1H),7.65(s,1H),6.70(s,1 H), 6.59 (dd, J=16.8Hz, 10.4Hz, 1H), 6.25 (dd, J=16.8Hz, 2.0Hz, 1H), 5.67 (dd, J=10. 4Hz,2.0Hz,1H),4.71-4.81(m,1H),4.05-4.14(m,2H),3.90-3.99(m,4H),3.10-3.21 (m,1H),2.67-2.78(m,1H),2.16-2.36(m,2H),1.91-2.01(m,1H),1.31-1.42(m,2H).

[0294] Example 22: 4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0295] According to the synthesis method of Example 4, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was used as the starting material to obtain the target compound.

[0296] MS m / z[LC-MS]:359.16[M+1]. 1 H NMR (400MHz, CDCl3) δ8.58(s,1H),8.22(s,1H),7.76(s,1H),7.67(s,1H),7.28(s,1H),6.56-6.70(m,1H),6.34( d,J=16.8Hz,1H),6.02(s,1H),5.73(d,J=10.8Hz,1H),4.30-4.46(m,2H),3.88-4.08(m,5H),2.57-2.66(m,2H).

[0297] Example 23: N-(4'-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-[1,1'-biphenyl]-4-yl)acrylamide

[0298] The target compound was obtained according to the synthesis method of Example 4 using intermediate 7 and N-Boc-4-aminophenylboronic acid pinacol ester as starting materials.

[0299] MS m / z[LC-MS]:445.14[M+1].1 H NMR (400MHz, CDCl3) δ8.67(s,1H),8.28(s,1H),7.81(s,1H),7.76(d,J=8.0Hz,2H),7.64-7.70(m, 7H),7.50(s,1H),7.32(s,1H),6.47(d,J=16.8Hz,1H),6.28(dd,J=16.8Hz,10.4Hz,1H),5.81(d,J =10.4Hz,1H),3.99(s,3H).

[0300] Example 24: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0301] Under nitrogen, intermediate 8 (44 mg), N-methylpiperazine (10 mg), Ruphos Pd G3 (8 mg), and cesium carbonate (66 mg) were added sequentially to dioxane (10 mL), heated to 100°C, and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The combined filtrates were concentrated under reduced pressure, and the residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (17 mg).

[0302] MS m / z[LC-MS]:456.24[M+1]. 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.99(d,J=1.6Hz,1H),7.46(d,J=8.4Hz,2H),7. 17(d,J=2.0Hz,1H),7.02(d,J=8.4Hz,2H),6.61(dd,J=16.8Hz,10.4Hz,1H),6.34(d d,J=16.8Hz,2.0Hz,1H),5.74(dd,J=10.4Hz,2.0Hz,1H),3.83-3.91(m,2H),3.70- 3.79(m,2H),3.30-3.32(m,4H),3.18-3.21(m,4H),2.60-2.62(m,4H),2.37(s,3H).

[0303] Example 25: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-morpholinopyrazolo[1,5-a]pyridine-3-carbonitrile

[0304] The target compound (16 mg) was synthesized by referring to the synthesis method of Example 24 using morpholine as a raw material.

[0305] MS m / z[LC-MS]:443.21[M+1]. 1 H NMR (400MHz, CDCl3) δ8.17 (s, 1H), 7.99 (d, J = 2.0Hz, 1H), 7.46 (d, J = 8.4Hz, 2H), 7.15 (d, J = 2.0Hz, 1H), 7.02 (d, J = 8.4Hz, 2H), 6.61 (dd, J = 16.8Hz, 10. 4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.74(dd,J=10.4Hz,2.0Hz,1H),3 .82-3.92(m,6H),3.70-3.78(m,2H),3.30-3.33(m,4H),3.14-3.16(m,4H).

[0306] Example 26: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(3-(dimethylamino)azacyclyl-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0307] The target compound (16 mg) was synthesized by referring to the synthesis method of Example 24 using 3-dimethylaminoazetidine as a raw material.

[0308] MS m / z[LC-MS]:456.25[M+1]. 1 H NMR (400MHz, CDCl3) δ8.12 (s, 1H), 7.68 (d, J = 2.0Hz, 1H), 7.45 (d, J = 9.2Hz, 2H) ,7.02(d,J=9.2Hz,2H),6.73(d,J=2.0Hz,1H),6.61(dd,J=16.8Hz,10.4Hz,1H) ,6.34(dd,J=16.8Hz,2.0Hz,1H),5.74(dd,J=10.4Hz,2.0Hz,1H),4.01(t,J=6. 8Hz,2H),3.82-3.90(m,2H),3.68-3.78(m,4H),3.26-3.32(m,5H),2.22(s,6H).

[0309] Example 27: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0310] The target compound (28 mg) was synthesized by referring to the synthesis method of step 1 of Example 4 using 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as the raw material.

[0311] MS m / z[LC-MS]:474.17[M+1]. 1 H NMR (400MHz, CDCl3) δ8.69 (d, J = 1.2Hz, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H) ,7.51(d,J=8.4Hz,2H),7.42(d,J=1.2Hz,1H),7.24(t,J=60.8Hz,1H),7.05(d,J=8 .4Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.75( dd,J=10.4Hz,2.0Hz,1H),3.83-3.92(m,2H),3.70-3.80(m,2H),3.32-3.35(m,4H).

[0312] Example 28: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(2-oxa-6-azaspiro[3.3]heptane-6-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0313] The target compound (14 mg) was synthesized by referring to the synthesis method of step 1 of Example 4 using 2-oxa-6-azaspiro[3.3]heptane hydrochloride as a raw material.

[0314] MS m / z[LC-MS]:455.20[M+1]. 1 H NMR (400MHz, CDCl3) δ8.13(s,1H),7.68(d,J=2.0Hz,1H),7.44(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.70(d,J=2.0Hz,1H),6.61(dd,J=16.8Hz,10.4Hz ,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.74(dd,J=10.4Hz,2.0Hz,1H),4.86( s,4H),4.08(s,4H),3.82-3.91(m,2H),3.70-3.78(m,2H),3.30-3.33(m,4H).

[0315] Example 29: N-(4-((3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0316] Step 1: tert-Butyl (4-((3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)formate

[0317] Under nitrogen, 3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethylsulfonate (38 mg), tert-butyl(4-ethynylphenyl)carbamate (43 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (10 mL). The mixture was heated to 100°C and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (26 mg).

[0318] Step 2: N-(4-((3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0319] The target compound (16 mg) was obtained by following the procedure of step 2 of Example 4.

[0320] MS m / z[LC-MS]:398.16[M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.38(s, 1H),8.51(s,1H),8.11(d,J=2.0Hz,1H),7.76(d,J=8.8Hz,2H),7.64(d,J=8.8Hz,2H),7.29(d,J=2.0Hz,1H),6.44(dd,J=16.8Hz,10.0Hz,1 H), 6.28 (dd, J = 16.8Hz, 2.0Hz, 1H), 5.78 (dd, J = 10.0Hz, 2.0Hz, 1H), 3.82 (d, J = 8.0Hz, 2H), 3.68 (d, J = 8.0Hz, 2H), 1.44 (s, 3H), 1.21 (s, 1H).

[0321] Example 30: N-(3-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0322] The target compound (44 mg) was synthesized by referring to the synthesis method of Example 18 using tert-butyl (3-ethynylphenyl) carbamate as the raw material.

[0323] MS m / z[LC-MS]:393.14[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.30(d,J=1.2Hz,1H),8.70(s,1H),8.40(s,1H),8.19(d,J=1.2Hz,1H),8.13(s,1H),8.08-8.11(m,1H),7.6 2-7.66(m,1H),7.43-7.45(m,2H),6.44(dd,J=16.8Hz,10.4Hz,1H),6.28(dd,J=16.8Hz,2.0Hz,1H),5.78(dd,J=10.4Hz,2.0Hz,1H),3.87(s,3H).

[0324] Example 31: N-(3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)prop-2-yn-1-yl)acrylamide

[0325] The target compound (12 mg) was synthesized by referring to the synthesis method of Example 18 using N-Boc-aminopropyne as the raw material.

[0326] MS m / z[LC-MS]:331.11[M+1]. 1 H NMR (400MHz, DMSO-d6) δ9.26(d,J=1.2Hz,1H),8.69(t,J=5.6Hz,1H),8.65(s,1H),8.36(s,1H),8.09(s,1H),8.00(d,J=1.2Hz,1H),6 .24(dd,J=17.2Hz,10.0Hz,1H),6.13(dd,J=17.2Hz,2.4Hz,1H),5.64(dd,J=10.0Hz,2.4Hz,1H),4.30(d,J=5.6Hz,2H),3.85(s,3H).

[0327] Example 32: 4-(4-(6-acryloyl-3,6-diazabicyclo[3.1.1]heptane-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0328] The target compound was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate as starting materials. (11 mg)

[0329] MS m / z[LC-MS]:450.18[M+1]. 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),8.23(s,1H),7.77(s,1H),7.67(s,1H),7.49(d,J=8.8Hz,2 H),7.37(s,1H),6.81(d,J=8.8Hz,2H),6.33(dd,J=17.2Hz,2.0Hz,1H),6.22(dd,J=17.2Hz,10 .4Hz,1H),5.67(dd,J=10.4Hz,2.0Hz,1H),4.67(d,J=6.4Hz,2H),4.07(d,J=10.4Hz,1H),3.9 7(s,3H),3.63-3.70(m,2H),3.53(d,J=10.4Hz,1H),2.78-2.83(m,1H),1.75(d,J=8.4Hz,1H).

[0330] Example 33: 4-(4-(4-cyanopiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0331] Intermediate 2 (38 mg) was dissolved in dichloromethane (5 mL) at 0°C, and bromocyanurate (11 mg) and triethylamine (20 mg) were added. The mixture was then warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (29 mg).

[0332] MS m / z[LC-MS]:409.19[M+1]. 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.25(s,1H),7.79(s,1H),7.68(s,1H),7.48(d,J=8.8Hz,2H),7.41(s,1H),7 .05(d,J=8.8Hz,2H),3.98(s,3H),3.51-3.57(m,2H),3.20-3.26(m,2H),2.80-2.86(m,1H),1.97-2.13(m,4H).

[0333] Example 34: N-(4-((3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0334] Step 1: N-(4-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0335] Under nitrogen, 6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (37 mg), N-(4-ethylphenyl)acrylamide (20 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (10 mL), heated to 100°C, and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (31 mg).

[0336] Step 2: N-(4-((3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0337] Under nitrogen, N-(4-((6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide (31 mg), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (24 mg), and potassium carbonate (28 mg) were dissolved in a 4:1 mixture of dioxane and water (5 mL). Tetrakis(triphenylphosphine)palladium (11 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (28 mg).

[0338] MS m / z[LC-MS]:429.13[M+1]. 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),9.45(d,J=1.2Hz,1H),8.99(s,1H),8.73(s,1H),8.50(s,1H),8.24(d,J=1.2Hz,1H),7.87(t,J=59.2Hz,1H ), 7.78 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.4Hz, 2H), 6.44 (dd, J = 16.8Hz, 10.0Hz, 1H), 6.28 (dd, J = 16.8Hz, 1.6Hz, 1H), 5.79 (dd, J = 10.0Hz, 1.6Hz, 1H).

[0339] Example 35: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0340] According to the synthesis method of Example 4, 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used to obtain the target compound.

[0341] MS m / z[LC-MS]:452.20[M+1]. 1 H NMR(400MHz, CDCl3)δ8.62(s,1H),8.25(s,1H),7.80(s,1H),7.71(s,1H),7.51(d, J=8.4Hz,2H),7.42(s,1H),7.05(d,J=8.4Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H), 6.34(dd,J=16.8Hz,1.6Hz,1H),5.75(dd,J=10.4Hz,1.6Hz,1H),4.25(q,J=7.2Hz,2 H), 3.84-3.92 (m, 2H), 3.71-3.80 (m, 2H), 3.32-3.34 (m, 4H), 1.55 (t, J = 7.2Hz, 3H).

[0342] Example 36: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0343] The target compound was obtained by the synthesis method of Example 4.

[0344] MS m / z[LC-MS]:464.22[M+1].

[0345] 1 H NMR (400MHz, CDCl3) δ8.61(d,J=1.6Hz,1H),8.24(s,1H),7.76(s,2H),7.50(d,J=8.4Hz ,2H),7.40(d,J=1.6Hz,1H),7.04(d,J=8.4Hz,2H),6.61(dd,J=16.8Hz,10.4Hz,1H),6.3 4(dd,J=16.8Hz,2.0Hz,1H),5.74(dd,J=10.4Hz,2.0Hz,1H),3.82-3.92(m,2H),3.71-3 .79(m,2H),3.63-3.69(m,1H),3.31-3.34(m,4H),1.17-1.21(m,2H),1.06-1.11(m,2H).

[0346] Example 37: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0347] The target compound was obtained by the synthesis method of Example 4.

[0348] MS m / z[LC-MS]:466.24[M+1]. 1 H NMR (400MHz, CDCl3) δ8.63 (d, J = 1.2Hz, 1H), 8.25 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.5 1(d,J=8.4Hz,2H),7.42(d,J=1.2Hz,1H),7.05(d,J=8.4Hz,2H),6.62(dd,J=16.8Hz,10 .4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),4.53-4.59( m,1H),3.82-3.92(m,2H),3.70-3.80(m,2H),3.32-3.34(m,4H),1.57(d,J=6.8Hz,6H).

[0349] Example 38: N-(4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)-2-fluorophenyl)acrylamide

[0350] The target compound (14 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl (4-ethynyl-2-fluorophenyl)carbamate as the raw material.

[0351] MS m / z[LC-MS]:411.14[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),9.31(s,1H),8.71(s,1H),8.38(s,1H),8.24(t,J=8.4Hz,1H),8.14(s,1H),8.11(s,1H),7 .49-7.62(m,2H),6.66(dd,J=17.2Hz,10.0Hz,1H),6.30(dd,J=17.2Hz,2.0Hz,1H),5.80(dd,J=10.0Hz,2.0Hz,1H),3.87(s,3H).

[0352] Example 39: N-(4-((3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)ethynyl)phenyl)acrylamide

[0353] The target compound (44 mg) was synthesized by referring to the synthesis method of Example 18 using 5-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile as the raw material.

[0354] MS m / z[LC-MS]:393.13[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.50(s,1H),8.48(s,1H),8.19(s,1H),8.10(d,J=1.6Hz,1H),7.84(d,J=1.6Hz,1H),7.81(d,J=8.4Hz ,2H),7.70(d,J=8.4Hz,2H),6.45(dd,J=17.2Hz,10.0Hz,1H),6.29(dd,J=17.2Hz,2.0Hz,1H),5.80(dd,J=10.0Hz,2.0Hz,1H),3.88(s,3H).

[0355] Example 40: 4-(2-(4-acryloylpiperazin-1-yl)pyrimidin-5-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0356] The target compound (34 mg) was obtained by the synthesis method of Example 4 using Intermediate 1 and tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylpiperazine-1-carboxylate as starting materials.

[0357] MS m / z[LC-MS]:440.18[M+1]. 1 H NMR (400MHz, DMSO-d6) δ9.25(d,J=1.6Hz,1H),8.69(s,2H),8.64(s,1H),8.36(s,1H),8.10(s,1H),7.85(d,J=1.6Hz,1H),6.85(dd,J=16.8 Hz, 10.4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.71 (dd, J=10.4Hz, 2.4Hz, 1H), 3.82-3.89 (m, 5H), 3.61-3.72 (m, 4H), 3.23-3.29 (m, 2H).

[0358] Example 41: N-(3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acrylamide

[0359] The target compound (16 mg) was obtained by the synthesis method of Example 4 using Intermediate 1 and tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate as starting materials.

[0360] MS m / z[LC-MS]:369.17[M+1].

[0361] Example 42: N-(4-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)phenyl)acrylamide

[0362] The target compound (44 mg) was synthesized by referring to the synthesis method of Example 4 using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate as a raw material.

[0363] MS m / z[LC-MS]:369.13[M+1]. 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.46(s,1H),8.38(s,1H),8.17(s,1H),8.04(s,1H),7.84(d,J=8.8Hz,2H),7.61(d,J=8.8Hz ,2H),7.36(s,1H),6.47(dd,J=16.8Hz,10.0Hz,1H),6.30(dd,J=16.8Hz,2.0Hz,1H),5.80(dd,J=10.0Hz,2.0Hz,1H),3.86(s,3H).

[0364] Example 43: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0365] The target compound (22 mg) was synthesized by referring to the synthesis method of Example 8 using tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate as a raw material.

[0366] MS m / z[LC-MS]:445.26[M+1]. 1 H NMR (400MHz, CDCl3) δ8.33(s,1H),8.18(s,1H),7.73(s,1H),7.64(s,1H),6.88(s,1H),6.55(dd,J=16.8Hz,10.4Hz,1H),6.28(dd,J=16.8 Hz, 2.0Hz, 1H), 5.70 (dd, J = 10.4Hz, 2.0Hz, 1H), 3.97 (s, 3H), 3.72-3.83 (m, 2H), 3.54-3.70 (m, 4H), 2.58-2.82 (m, 7H), 1.96-2.12 (m, 4H).

[0367] Example 44: 4-(4-(4-acetylpiperazin-1-yl)piperidin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0368] The target compound (12 mg) was synthesized by referring to the synthesis method of Example 8 using tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate and acetyl chloride as raw materials.

[0369] MS m / z[LC-MS]:433.26[M+1]. 1H NMR (400MHz, CDCl3) δ8.36(s,1H),8.18(s,1H),7.73(s,1H),7.67(s,1H),6.92(s,1H),3.97(s ,3H),3.80-3.95(m,2H),3.56-3.72(m,3H),2.72-3.35(m,8H),2.14-2.34(m,4H),2.12(s,3H).

[0370] Example 45: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-2-fluoroacrylamide

[0371] The target compound (10 mg) was synthesized by referring to the synthesis method of Example 4 using tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate and 2-fluoroacryloyl chloride as raw materials.

[0372] MS m / z[LC-MS]:387.17[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),9.25(d,J=1.6Hz,1H),8.63(s,1H),8.39(s,1H),8.11(s,1H),7.90(d,J=8.4 Hz, 2H), 7.79 (d, J = 1.6Hz, 1H), 7.61 (d, J = 8.4Hz, 2H), 5.75 (dd, J = 48.0Hz, 3.6Hz, 1H), 5.46 (dd, J = 15.6Hz, 3.6Hz, 1H), 3.86 (s, 3H).

[0373] Example 46: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methacrylamide

[0374] The target compound (13 mg) was synthesized by referring to the synthesis method of Example 4 using methacryloyl chloride as a raw material.

[0375] MS m / z[LC-MS]:383.15[M+1]. 1H NMR (400MHz, DMSO-d6) δ9.97(s,1H),9.23(s,1H),8.63(s,1H),8.39(s,1H),8.11(s,1H),7.86(d,J= 8.4Hz,2H),7.77(s,1H),7.58(d,J=8.4Hz,2H),5.84(s,1H),5.54(s,1H),3.86(s,3H),1.97(s,3H).

[0376] Example 47: N-(4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)phenyl)acrylamide

[0377] The target compound (17 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (4-bromophenyl)carbamate as raw materials.

[0378] MS m / z[LC-MS]:452.22[M+1]. 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),8.22(s,1H),7.76(s,1H),7.68(s,1H),7.48(d,J=8. 8Hz,2H),7.43(s,1H),7.35(s,1H),6.95(d,J=8.8Hz,2H),6.40(d,J=16.8Hz,1H),6.24 (dd,J=16.8Hz,10.0Hz,1H),5.72(d,J=10.0Hz,1H),3.97(s,3H),3.80(d,J=12.4Hz,2H ),3.46-3.55(m,1H),3.03(t,J=12.0Hz,2H),2.17(d,J=12.4Hz,2H),1.90-2.00(m,2H).

[0379] Example 48: 4-(4-((1S,4S)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0380] The target compound (9 mg) was synthesized by referring to the synthesis method of Example 8 using (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester as a raw material.

[0381] MS m / z[LC-MS]:450.21[M+1]. 1 H NMR(400MHz,CDOD)δ8.86(s,1H),8.35(s,1H),8.10(s,1H),7.94(s,1H),7.57(s,1H),7.4 3-7.46(m,2H),6.71-6.77(m,2.5H),6.42(dd,J=16.8Hz,10.4Hz,0.5H),6.23-6.29(m,1H ),5.76(dd,J=10.4Hz,2.0Hz,0.5H),5.71(dd,J=10.4Hz,2.0Hz,0.5H),4.96(d,J=19.2Hz ,1H),4.68(d,J=17.2Hz,1H),3.94(s,3H),3.68-3.75(m,2H),3.54-3.63(m,1H),3.21(t, J=9.6Hz,1H),2.00-2.18(m,2H).

[0382] Example 49: 4-(4-(2-fluoroacryloyl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0383] The target compound (14 mg) was synthesized by referring to the synthesis method of Example 8.

[0384] MS m / z[LC-MS]:456.18[M+1]. 1 H NMR (400MHz, CDCl3) δ8.62(s,1H),8.25(s,1H),7.79(s,1H),7.68(s,1H),7.50(d,J=8.4Hz,2H),7.41(s,1H),7.05(d,J=8.4 Hz, 2H), 5.32 (dd, J = 47.6Hz, 3.6Hz, 1H), 5.18 (dd, J = 16.8Hz, 3.6Hz, 1H), 3.99 (s, 3H), 3.76-3.84 (m, 4H), 3.33-3.36 (m, 4H).

[0385] Example 50: N-(4-((3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)ethynyl)phenyl)methacrylamide

[0386] The target compound (24 mg) was synthesized by referring to the synthesis method of Example 18.

[0387] MS m / z[LC-MS]:407.13[M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.28(s,1H),8.70(s,1H),8.38(s,1H),8.11(s,2H),7.8 1(d,J=8.8Hz,2H),7.64(d,J=8.8Hz,2H),5.81(s,1H),5.55(s,1H),3.87(s,3H),1.94(s,3H).

[0388] Example 51: N-(1-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ylphenyl)piperidin-4-yl]acrylamide

[0389] The target compound (10 mg) was synthesized by referring to the synthesis method of Example 8 using tert-butyl piperidin-4-ylcarbamate as a raw material.

[0390] MS m / z[LC-MS]:452.21[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.14(d,J=1.2Hz,1H),8.59(s,1H),8.33(s,1H),8.13(d,J=7.6Hz,1H),8 .07(s,1H),7.66(d,J=1.2Hz,1H),7.46(d,J=8.8Hz,2H),7.06(d,J=8.8Hz,2H),6.20(dd,J=17.2 Hz,10.0Hz,1H),6.07(dd,J=17.2Hz,2.4Hz,1H),5.57(dd,J=10.0Hz,2.4Hz,1H),3.85(s,3H),3. 74-3.81(m,2H),3.67-3.72(m,1H),2.89(t,J=11.2Hz,2H),1.82-1.89(m,2H),1.45-1.56(m,2H).

[0391] Example 52: N-(1-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0392] The target compound (12 mg) was synthesized by referring to the synthesis method of Example 8 using tert-butyl azetidin-3-ylcarbamate as a raw material.

[0393] MS m / z[LC-MS]:424.18[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.81(d,J=7.6Hz,1H),8.61(s,1H),8.37(s,1 H),8.09(s,1H),7.67(s,1H),7.46(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),6.21(d d,J=16.8Hz,10.0Hz,1H),6.11(dd,J=16.8Hz,2.4Hz,1H),5.63(dd,J=10.0Hz,2.4 Hz, 1H), 4.67-4.76 (m, 1H), 4.20 (t, J = 7.6Hz, 2H), 3.86 (s, 3H), 3.68-3.71 (m, 2H).

[0394] Example 53: N-(4-((3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0395] Step 1: 3-Cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate

[0396] Under nitrogen, 6-bromo-4-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (237 mg), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg), and potassium carbonate (278 mg) were dissolved in a 4:1 mixture of dioxane and water (50 mL). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, saturated aqueous ammonium chloride (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was dissolved in DMF (5 mL), and DIEA (260 mg) was added, followed by N-phenylbis(trifluoromethanesulfonyl)imide (360 mg). The mixture was stirred at room temperature overnight, and water (50 mL) was added, followed by extraction with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to give the title compound (293 mg).

[0397] Step 2: N-(4-((3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0398] Under nitrogen, 3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (39 mg), N-(4-ethynylphenyl)acrylamide (20 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (5 mL). The mixture was heated to 100°C and stirred for 2 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (27 mg).

[0399] MS m / z[LC-MS]:407.16[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),9.28(s,1H),8.70(s,1H),8.47(s,1H),8.11-8.14(m,2H),7.78(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H), 6.44(dd,J=16.8Hz,10.0Hz,1H), 6.28(dd,J=16.8Hz,2.0Hz,1H), 5.79(dd,J=10.0Hz,2.0Hz,1H), 4.15(q,J=7.2Hz,2H), 1.41(t,J=7.2Hz,3H).

[0400] Example 54: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-3-methylbut-2-enamide

[0401] The target compound (16 mg) was synthesized by referring to the synthesis method of Example 4 using 3-methylbut-2-enoyl chloride as a raw material.

[0402] MS m / z[LC-MS]:397.19[M+1].

[0403] Example 55: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)butyne-2-amide

[0404] The target compound (16 mg) was synthesized by referring to the synthesis method of Example 4 using 3-methylbut-2-enoyl chloride as a raw material.

[0405] MS m / z[LC-MS]:381.14[M+1]. 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),9.23(s,1H),8.62(s,1H),8.37(s,1H),8 .10(s,1H),7.73-7.76(m,3H),7.57(d,J=8.8Hz,2H),3.86(s,3H),2.05(s,3H).

[0406] Example 56: 4-(1-acryloylpiperidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0407] The target compound (17 mg) was synthesized by referring to the synthesis method of Example 7.

[0408] MS m / z[LC-MS]:361.18[M+1]. 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),8.20(s,1H),7.73(s,1H),7.69(s,1H),7.28(s,1H), 6.59(dd,J=16.8Hz,10.4Hz,1H),6.25(dd,J=16.8Hz,2.0Hz,1H),5.70(dd,J=10.4Hz,2. 0Hz,1H),4.82-4.90(m,1H),4.12-4.20(m,1H),3.94(s,3H),3.55-3.65(m,1H),3.32-3 .42(m,1H),2.83-2.92(m,1H),2.05-2.14(m,1H),1.68-1.85(m,2H),1.53-1.67(m,1H).

[0409] Example 57: N-(4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)phenyl)acrylamide

[0410] The target compound (9 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl (4-bromophenyl)carbamate as the raw material.

[0411] MS m / z [LC-MS]: 453.22M+1]. 1H NMR (400MHz, CDCl3) δ8.37(s,1H),8.21(s,1H),7.76(s,1H),7.66(s,1H),7.50(d,J=8.8Hz,2H),7.18(s,1H),6.98(d,J=8.8Hz,2H),6.96( s,1H),6.41(d,J=17.2Hz,1H),6.23(dd,J=17.2Hz,10.0Hz,1H),5.74(d,J=10.0Hz,1H),3.99(s,3H),3.47-3.52(m,4H),3.32-3.38(m,4H).

[0412] Example 58: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)cyclopropanecarboxamide

[0413] The target compound (22 mg) was synthesized by referring to the synthesis method of Example 18.

[0414] MS m / z[LC-MS]:407.16[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),9.21(s,1H),8.65(s,1H),8.32(s,1H),8.07(s,1H),8.06(s,1H),7.68(d,J=8.8 Hz, 2H), 7.61 (d, J = 8.8Hz, 2H), 3.86 (s, 3H), 1.73-1.82 (m, 1H), 0.78-0.83 (m, 4H).

[0415] Example 59: 4-(1-acryloyl-1,2,3,4-tetrahydroquinolin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0416] The target compound (14 mg) was synthesized by referring to the synthesis method of Example 4 using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline.

[0417] MS m / z[LC-MS]:409.19[M+1]. 1H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.63(s,1H),8.40(s,1H),8.12(s,1H),7.84(s, 1H),7.49(d,J=2.0Hz,1H),7.45(dd,J=8.4Hz,2.0Hz,1H),7.28(d,J=8.4Hz,1H),6.6 1(dd,J=16.8Hz,10.0Hz,1H),6.25(d,J=16.8Hz,2.0Hz,1H),5.72(dd,J=10.0Hz,2.0 Hz, 1H), 3.86 (s, 3H), 3.78 (t, J = 6.4Hz, 2H), 2.79 (t, J = 6.4Hz, 2H), 1.89-1.96 (m, 2H).

[0418] Example 60: N-(4-((2-amino-3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0419] The target compound (14 mg) was synthesized by referring to the synthesis method of Example 18.

[0420] MS m / z[LC-MS]:408.16[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.83(s,1H),8.27(s,1H),8.00(s,1H),7.85(s,1H),7.76(d,J=8.8Hz,2H),7. 62(d,J=8.8Hz,2H),6.41-6.47(m,3H),6.27(dd,J=17.2Hz,2.4Hz,1H),5.78(dd,J=10.0Hz,2.4Hz,1H),3.85(s,3H).

[0421] Example 61: 4-((1-acryloylpiperidin-4-yl)ethynyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0422] The target compound (34 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl 4-ethynylpiperidine-1-carboxylate as the raw material.

[0423] MS m / z[LC-MS]:385.17[M+1]. 1H NMR(400MHz,DMSO-d6)δ9.23(d,J=1.2Hz,1H),8.63(s,1H),8.35(s,1H),8.08(s,1H) ,7.97(d,J=1.2Hz,1H),6.80(dd,J=16.8Hz,10.8Hz,1H),6.08(dd,J=16.8Hz,2.4Hz, 1H),5.65(dd,J=10.8Hz,2.4Hz,1H),3.94-4.03(m,1H),3.84-3.93(m,4H),3.37-3.4 4(m,1H),3.18-3.27(m,1H),3.04-3.11(m,1H),1.87-2.00(m,2H),1.60-1.74(m,2H).

[0424] Example 62: N-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0425] The target compound (34 mg) was synthesized by referring to the synthesis method of Example 18 using (6-aminopyridin-3-yl)boronic acid as the raw material.

[0426] MS m / z[LC-MS]:370.15[M+1]. 1 H NMR (400MHz, DMSO-d6) δ10.97 (s, 1H), 9.29 (d, J = 1.2Hz, 1H), 8.65 (s, 1H), 8.6 1(d,J=2.8Hz,1H),8.39(s,1H),8.34(d,J=8.8Hz,1H),8.12(s,1H),8.09(dd, J=8.8Hz,2.8Hz,1H),7.89(d,J=1.2Hz,1H),6.64(dd,J=16.8Hz,10.4Hz,1H), 6.33 (dd, J=16.8Hz, 2.0Hz, 1H), 5.81 (dd, J=10.4Hz, 2.0Hz, 1H), 3.87 (s, 3H).

[0427] Example 63: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0428] The target compound (24 mg) was obtained using 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the synthesis method of Example 4.

[0429] MS m / z[LC-MS]:508.27[M+1]. 1 H NMR (400MHz, CDCl3) δ8.63 (d, J=1.2Hz, 1H), 8.25 (s, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.51 (d, J= 8.4Hz,2H),7.42(d,J=1.2Hz,1H),7.05(d,J=8.4Hz,2H),6.62(dd,J=17.2Hz,10.4Hz,1H),6.3 4(dd,J=17.2Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),4.37-4.45(m,1H),4.10-4.18(m, 2H), 3.71-3.91 (m, 4H), 3.57 (td, J = 11.2Hz, 2.4Hz, 2H), 3.32-3.34 (m, 4H), 2.06-2.20 (m, 4H).

[0430] Example 64: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0431] The target compound (24 mg) was obtained using 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine according to the synthesis method of Example 4.

[0432] MS m / z[LC-MS]:537.27[M+1]. 1H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 8.25 (s, 1H), 7.78-7.89 (m, 2H), 7.51 (d, J = 8 .4Hz,2H),7.41(s,1H),7.05(d,J=8.4Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H), 6.34(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),4.20-4.53(m,2 H),3.62-3.96(m,8H),3.32-3.34(m,4H),2.80-3.06(m,2H),2.40-2.74(m,4H).

[0433] Example 65: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0434] The target compound (14 mg) was obtained using N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-amine according to the synthesis method of Example 4.

[0435] MS m / z[LC-MS]:495.25[M+1]. 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 8.25(s,1H),7.83(s,1H),7.80(s,1H),7.50(d,J=8.4Hz,2H),7.42(s,1H),7.05(d,J=8.4Hz,2H),6.62(dd,J=16.8Hz,10.8Hz,1H),6.34(dd,J =16.8Hz, 2.0Hz, 1H), 5.75 (dd, J = 10.8Hz, 2.0Hz, 1H), 4.27-4.36 (m, 2H), 3.70-3.93 (m, 4H), 3.32-3.34 (m, 4H), 2.79-2.92 (m, 2H), 2.33 (s, 6H).

[0436] Example 66: 4-((1-((6-methoxypyridin-3-yl)methyl)azetidin-3-yl(ethynyl))-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0437] Step 1: Tert-butyl 3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]ethynyl)azetidine-1-carboxylate

[0438] Under nitrogen, intermediate 1 (37 mg), tert-butyl 3-ethynylazetidine-1-carboxylate (19 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (10 mL), heated to 70°C, and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (28 mg).

[0439] Step 2: 4-((1-((6-methoxypyridin-3-yl)methyl)azetidin-3-yl(ethynyl))-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0440] The product obtained in step 1 was dissolved in dichloromethane (4 mL) at room temperature, trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and cooled to 0°C. The residue was dissolved in dichloromethane (10 mL), followed by 6-methoxynicotinaldehyde (15 mg) and sodium cyanoborohydride (50 mg). The mixture was then warmed to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (18 mg).

[0441] MS m / z[LC-MS]:424.17[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.23(s,1H),8.64(s,1H),8.33(s,1H),8.05-8.10(m,2H),7.97(s,1H),7.63(dd,J =8.0Hz, 2.0Hz, 1H), 6.77 (d, J = 8.0Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H), 3.58-3.73 (m, 5H), 3.38-3.50 (m, 2H).

[0442] Example 67: 4-((1-acryloylaziridin-3-yl)ethynyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0443] The target compound (24 mg) was obtained according to the synthesis method of Example 18.

[0444] MS m / z[LC-MS]:357.16[M+1]. 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),8.64(s,1H),8.33(s,1H),8.07(s,1H),8. 02(s,1H),6.29(dd,J=16.8Hz,10.4Hz,1H),6.10(dd,J=16.8Hz,2.4Hz,1H),5. 68(dd,J=10.4Hz,2.4Hz,1H),4.58(t,J=8.8Hz,1H),4.37-4.40(m,1H),4.28(t ,J=9.2Hz,1H),4.09(dd,J=8.8Hz,6.4Hz,1H),3.86-3.92(m,1H),3.85(s,3H).

[0445] Example 68: N-(5-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0446] Step 1: tert-Butyl (5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)carbamate

[0447] Under nitrogen, 5-bromo-3-cyanoimidazolo[1,2-a]pyridin-7-yl trifluoromethylsulfonate (290 mg), tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate (32 mg), and potassium carbonate (278 mg) were dissolved in a mixed solvent (50 mL) of dioxane and water (4:1). Tetrakis(triphenylphosphine)palladium (110 mg) was added, and the temperature was raised to 90°C and stirred for 4 hours. The mixture was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to give the title compound (237 mg).

[0448] Step 2: Tert-butyl (5-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)carbamate

[0449] Under nitrogen protection, tert-butyl (5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)carbamate (207 mg), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (140 mg) and potassium carbonate (140 mg) were dissolved in a mixed solvent (50 mL) of dioxane and water (4:1), tetrakis(triphenylphosphine)palladium (50 mg) was added, and the temperature was raised to 90°C and stirred for 4 hours. The mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to give the title compound (147 mg).

[0450] Step 3: N-(5-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0451] At room temperature, the product obtained in step 2 was dissolved in dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and cooled to 0°C. The residue was dissolved in dichloromethane (10 mL), triethylamine (100 mg) and acryloyl chloride (50 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (92 mg).

[0452] MS m / z[LC-MS]:440.20[M+1]. 1H NMR (400MHz, DMSO-d6) δ10.97(s,1H),9.30(s,1H),8.65(s,1H),8.61(d,J=2.0Hz,1H),8.55(s,1 H),8.35(d,J=8.8Hz,1H),8.16(s,1H),8.09(dd,J=8.8Hz,2.4Hz,1H),7.93(s,1H),6.64(dd,J=1 6.8Hz,10.4Hz,1H),6.34(dd,J=16.8Hz,1.6Hz,1H),5.81(dd,J=10.4Hz,1.6Hz,1H),4.36-4.44( m,1H),3.92-3.99(m,2H),3.47(td,J=12.0Hz,1.6Hz,2H),1.99-2.07(m,2H),1.87-1.97(m,2H).

[0453] Example 69: N-(4-((3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0454] Step 1: tert-Butyl (4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)carbamate

[0455] Under nitrogen, 5-bromo-3-cyanoimidazolo[1,2-a]pyridin-7-yl trifluoromethylsulfonate (37 mg), tert-butyl(4-ethynylphenyl)carbamate (22 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (10 mL). The mixture was heated to 70°C and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (28 mg).

[0456] Step 2: tert-Butyl (4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl(ethynyl)phenyl)carbamate

[0457] Under nitrogen, tert-butyl (4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)carbamate (22 mg), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14 mg), and potassium carbonate (14 mg) were dissolved in a 4:1 mixture of dioxane and water (10 mL). Tetrakis(triphenylphosphine)palladium (5 mg) was added, and the mixture was heated to 90°C and stirred for 4 hours. After cooling to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (15 mg).

[0458] Step 3: N-(4-((3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0459] At room temperature, the product obtained in step 2 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.1 mL) was added, and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and cooled to 0°C. The residue was dissolved in dichloromethane (5 mL), triethylamine (50 mg) and acryloyl chloride (10 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (7 mg).

[0460] MS m / z[LC-MS]:463.19[M+1]. 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.30(d,J=1.2Hz,1H),8.69(s,1H),8.56(s,1H), 8.16(s,2H),7.78(d,J=8.8Hz,2H),7.66(d,J=8.8Hz,2H),6.44(dd,J=16.8Hz,10.0Hz,1 H),6.28(dd,J=16.8Hz,2.0Hz,1H),5.79(dd,J=10.0Hz,2.0Hz,1H),4.37-4.44(m,1H),3 .92-4.00(m,2H),3.48(td,J=11.6Hz,2.0Hz,2H),2.00-2.08(m,2H),1.88-1.98(m,2H).

[0461] Example 70: N-(3-chloro-4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)-2-methylphenyl)acrylamide

[0462] The target compound (24 mg) was obtained according to the synthesis method of Example 18.

[0463] MS m / z[LC-MS]:441.12[M+1].

[0464] Example 71: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0465] The target compound (44 mg) was obtained using pyrimidine-2-boronic acid as a starting material according to the synthesis method of Example 4.

[0466] MS m / z[LC-MS]:436.18[M+1]. 1 H NMR (400MHz, DMSO-d6)9.55(s,1H),8.96(d,J=5.2Hz,2H),8.78(s,1H),8.25(s,1H),7.52-7.55(m,3H),7.11(d,J=8.4Hz,2H),6.86 (dd,J=16.8Hz,10.4Hz,1H),6.15(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),3.66-3.77(m,4H),3.25-3.32(m,4H).

[0467] Example 72: (E)-N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-4-methoxybutyl-2-enamide

[0468] The target compound (24 mg) was obtained using the synthetic method of Example 4 using ethyl fumarate chloride as a starting material.

[0469] MS m / z[LC-MS]:413.16[M+1]. 1H NMR(400MHz,DMSO-d6)10.05(s,1H),9.22(s,1H),8.62(s,1H),8.38(s,1H),8.10(s,1H),7.73-7.75(m,3H),7.55(d, J=8.4Hz,2H),6.13(d,J=6.0Hz,1H),4.57(q,J=7.2Hz,1H),3.86(s,3H),3.58(s,3H),3.11(dd,J=6.8Hz,1.2Hz,2H).

[0470] Example 73: N-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acrylamide

[0471] The target compound (24 mg) was obtained using 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole according to the synthesis method of Example 4.

[0472] MS m / z[LC-MS]:439.20[M+1]. 1 H NMR(400MHz,DMSO-d6)10.34(s,1H),9.26(s,1H),8.63(s,1H),8.56(s,1H),8.15(s,1 H),7.82-7.84(m,3H),7.59(d,J=8.0Hz,2H),6.46(dd,J=17.2Hz,10.0Hz,1H),6.29(dd J=17.2Hz,1.6Hz,1H),5.78(dd,J=10.0Hz,1.6Hz,1H),4.36-4.44(m,1H),3.92-3 .98(m,2H),3.47(td,J=11.2Hz,1.6Hz,2H),1.99-2.06(m,2H),1.88-1.98(m,2H).

[0473] Example 74: 4-(4-(8-acryloyl-3,8-diazabicyclo[3.2.1]oct-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0474] The target compound (8 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate as starting materials.

[0475] MS m / z[LC-MS]:464.26[M+1]. 1 H NMR (400MHz, CDCl3) δ8.60(s,1H),8.25(s,1H),7.79(s,1H),7.68(s,1H),7.48(d,J=8. 8Hz,2H),7.41(d,J=1.2Hz,1H),6.95(d,=8.8Hz,2H),6.51(dd,J=16.8Hz,10.4Hz,1H),6 .30(dd,J=16.8Hz,2.0Hz,1H),5.69(dd,J=10.4Hz,2.0Hz,1H),4.31-4.40(m,3H),3.98( s,3H),3.58-3.68(m,2H),3.20(d,J=13.2Hz,1H),2.03-2.16(m,2H),1.76-1.92(m,2H).

[0476] Example 75: 4-(4-((1R,4R)-5-acryloyl-2,5-diazabicyclo[2.2.1]heptane-2-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0477] The target compound (6 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate as starting materials.

[0478] MS m / z[LC-MS]:450.19[M+1]. 1H NMR (400MHz, CDCl3) δ8.59 (d, J = 1.6Hz, 1H), 8.25 (s, 0.7H), 8.24 (s, 0.3H), 7.79 (s, 0.3H), 7.78 (s, 0.7H), 7.68 (s, 0.3H), 7.66 (s, 0.7H) ,7.43-7.47(m,2H),7.39(d,J=1.6Hz,0.7H),7.37(d,J=1.6Hz,0.3H),6.68-6.71(m,2H),6.50(dd,J=16.8Hz,10.4Hz,0.3H),6.35-6.41( m,1H),6.25(dd,J=16.8Hz,10.4Hz,0.7H),5.72(dd,=10.4Hz,2.0Hz,0.3H),5.67(dd,J=10.4Hz,2.0Hz,0.7H),5.11(s,0.7H),4.71(s,0. 3H), 4.60 (s, 0.7H), 4.55 (s, 0.3H), 3.98 (s, 3H), 3.60-3.76 (m, 3H), 3.34 (d, J = 8.8Hz, 0.7H), 3.24 (d, J = 8.8Hz, 0.3H), 1.95-2.18 (m, 2H).

[0479] Example 76: N-(4-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-4-yl)phenyl)acrylamide

[0480] The target compound (11 mg) was obtained according to the synthetic method of Example 8 using intermediate 7 and tert-butyl (4-(piperidin-4-yl)phenyl)carbamate as starting materials.

[0481] MS m / z[LC-MS]:452.23[M+1]. 1 H NMR(400MHz, CDCl3)δ8.35(s,1H),8.20(s,1H),7.77(s,1H),7.66(s,1H),7.50-7. 56(m,2H),7.29(d,J=8.4Hz,2H),7.20(s,1H),6.94(s,1H),6.43(d,J=16.8Hz,1H) ,6.24(dd,=16.8Hz,10.4Hz,1H),5.77(d,J=10.4Hz,1H),3.99(s,3H),3.64-3.71( m,2H),2.86-2.94(m,2H),2.67-2.77(m,1H),2.18-2.29(m,2H),1.96-2.04(m,2H).

[0482] Example 77: N-(4-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-1,2,3,6-tetrahydropyridine-4-)phenyl)acrylamide

[0483] The target compound (14 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine as starting materials.

[0484] MS m / z[LC-MS]:450.22[M+1]. 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),8.13(s,1H),7.67(s,1H),7.66(s,1H),7.51(d,J=8.4H z,2H),7.34(d,J=8.4Hz,2H),6.92(s,1H),6.25-6.28(m,2H),6.11-6.14(m,1H),5.63(dd J=8.8Hz, 2.8Hz, 1H), 3.87 (s, 3H), 3.79-3.83 (m, 2H), 3.42 (t, J=5.2Hz, 2H), 2.76-2.82 (m, 2H).

[0485] Example 78: N-(6-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)pyridin-3-yl)acrylamide

[0486] The target compound (18 mg) was obtained according to the synthesis method of Example 18 using tert-butyl (6-ethynylpyridin-3-yl)carbamate as a starting material.

[0487] MS m / z[LC-MS]:394.13[M+1]. 1 H NMR (400MHz, CDCl3) δ8.75(s,1H),8.61(d,J=1.2Hz,1H),8.23(s,1H),8.20(dd,J=8.0Hz,2.8Hz,1H),7.79-7.83(m,2H),7.73 -7.76(m,2H),6.41(dd,J=16.8Hz,1.6Hz,1H),6.30(dd,J=16.8Hz,10.4Hz,1H),5.74(dd,J=10.4Hz,1.6Hz,1H),3.93(s,3H).

[0488] Example 79: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0489] The target compound (24 mg) was obtained according to the synthesis method of Example 4 using 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0490] MS m / z[LC-MS]:482.20[M+1]. 1 H NMR(400MHz, CDCl3)8.64(d,J=1.6Hz,1H),8.25(s,1H),7.81(s,1H),7.79(s,1H),7. 50(d,J=8.8Hz,2H),7.43(d,J=1.6Hz,1H),7.05(d,J=8.8Hz,2H),6.62(dd,J=16.8Hz ,10.4Hz,1H),6.34(d,J=16.8Hz,1.6Hz,1H),5.75(dd,J=10.4Hz,1.6Hz,1H),4.35(t ,J=5.2Hz,2H),3.83-3.92(m,2H),3.71-3.81(m,4H),3.36(s,3H),3.31-3.35(m,4H).

[0491] Example 80: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(3-cyanoazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0492] The target compound (5 mg) was synthesized by referring to the synthesis method of Example 24 using azetidine-3-carbonitrile as the raw material.

[0493] MS m / z[LC-MS]:438.21[M+1]. 1H NMR (400MHz, CDCl3)8.16(s,1H),7.72(d,J=2.0Hz,1H),7.45(d,J=8.8Hz,2H),7.03(d ,J=8.8Hz,2H),6.69(d,J=2.0Hz,1H),6.61(dd,J=16.8Hz,10.4Hz,1H),6.34(dd,J=16 .8Hz, 2.0Hz, 1H), 5.75 (dd, J=10.4Hz, 2.0Hz, 1H), 4.25 (t, J=7.6Hz, 2H), 4.14 (t, J=6. 8Hz,2H),3.82-3.91(m,2H),3.71-3.79(m,2H),3.63-3.70(m,1H),3.31-3.33(m,4H).

[0494] Example 81: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0495] The target compound (26 mg) was obtained according to the synthesis method of Example 4 using 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole as a starting material.

[0496] MS m / z[LC-MS]:455.18[M+1]. 1 H NMR (400MHz, CDCl3)8.67(d,J=1.6Hz,1H),8.29(s,1H),7.86(s,1H),7.51(d,J=8.8Hz,2H),7.45(d,J=1.6Hz,1H),7.05(d,J=8.8Hz,2H),6.61( dd,J=16.8Hz,10.4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),3.71-3.93(m,4H),3.33-3.35(m,4H),2.77(s,3H).

[0497] Example 82: 4-(4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0498] The target compound (7 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl (2R,6S)-2,6-dimethylpiperazine-1-carboxylate as starting materials.

[0499] MS m / z[LC-MS]:466.25[M+1]. 1 H NMR (400MHz, CDCl3)8.62(s,1H),8.26(s,1H),7.78(s,1H),7.67(s,1H),7.51(d,J=8 .8Hz,2H),7.41(s,1H),7.07(d,J=8.8Hz,2H),6.63(dd,J=16.8Hz,10.4Hz,1H),6.38 (dd,J=16.8Hz,2.0Hz,1H),5.73(dd,J=10.4Hz,2.0Hz,1H),4.26-4.84(m,2H),3.99( s, 3H), 3.59 (d, J = 12.0Hz, 2H), 3.04 (dd, J = 12.0Hz, 4.0Hz, 2H), 1.46 (d, J = 6.8Hz, 6H).

[0500] Example 83: N-(2-(4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)ethyl)acrylamide

[0501] The target compound (7 mg) was obtained according to the synthetic method of Example 8 using intermediate 7 and tert-butyl (2-(piperazin-1-yl)ethyl)carbamate as starting materials.

[0502] MS m / z[LC-MS]:481.25[M+1]. 1 H NMR(400MHz, DMSO-d6)9.17(s,1H),8.61(s,1H),8.37(s,1H),8.09(s,1H),8.05(t,J=5.6Hz,1H),7.69(s,1H),7.47(d,J=8.8Hz,2H), 7.05(d,J=8.8Hz,2H),6.23(dd,J=17.2Hz,10.4Hz,1H),6.06(dd,J=17.2Hz,2.0Hz,1H),5.56(dd,J=10.4Hz,2.0Hz,1H),3.86(s,3H), 3.21-3.26(m,6H),2.54-2.59(m,4H),2.44(t,J=7.2Hz,2H).

[0503] Example 84: 4-(4-Acryloylpiperazin-1-yl)phenyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0504] The target compound (20 mg) was obtained according to the synthesis method of Example 4 using 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0505] MS m / z[LC-MS]:452.20[M+1]. 1 H NMR (400MHz, DMSO-d6)8.84(d,J=1.6Hz,1H),8.63(s,1H),8.13(s,1H),7.49-7.51(m,3H),7.08(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10. 8Hz, 1H), 6.13 (dd, J = 16.8Hz, 2.4Hz, 1H), 5.70 (dd, J = 10.8Hz, 2.4Hz, 1H), 3.78 (s, 3H), 3.65-3.76 (m, 4H), 3.23-3.29 (m, 4H), 2.35 (s, 3H).

[0506] Example 85: 4-((4-(((6-methoxypyridin-3-yl)methyl)amino)phenyl)ethynyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0507] The target compound (15 mg) was synthesized by referring to the synthesis method of Example 66.

[0508] MS m / z[LC-MS]:460.20[M+1]. 1 H NMR (400MHz, DMSO-d6)9.19(s,1H),8.65(s,1H),8.36(s,1H),8.15(d,J=2.0Hz,1H),8.09(s,1H),7.96(s,1H),7.67(dd,J=8.8Hz,2.4Hz,1H) ,7.41(d,J=8.8Hz,2H),6.83(t,J=6.0Hz,1H),6.78(d,J=8.8Hz,1H),6.65(d,J=8.8Hz,2H),4.25(d,J=5.6Hz,2H),3.86(s,3H),3.80(s,3H).

[0509] Example 86: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0510] Step 1: tert-Butyl 4-(4-(3-cyano-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate

[0511] To a solution of tert-butyl 4-(4-(3-cyano-6-hydroxypyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate (42 mg), tetrahydro-2H-pyran-4-ol (15 mg), and triphenylphosphine (53 mg) in toluene (10 mL) was slowly added dropwise DIAD (40 mg) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to afford a white solid (35 mg).

[0512] Step 2: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-((tetrahydro-2H-pyran-4-yl)oxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0513] The target compound (15 mg) was obtained by following the procedure of step 2 of Example 4.

[0514] MS m / z[LC-MS]:458.22[M+1]. 1 H NMR (400MHz, CDCl3)8.32(s,1H),8.17(s,1H),7.46(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.85(s,1H),6.61(dd,J= 16.8Hz, 10.4Hz, 1H), 6.35 (dd, J=16.8Hz, 2.0Hz, 1H), 5.75 (dd, J=10.4Hz, 2.0Hz, 1H), 4.82-4.87 (m, 1H),4.06-4.12(m,2H),3.68-3.93(m,6H),3.27-3.30(m,4H),2.09-2.17(m,2H),1.97-2.05(m,2H).

[0515] Example 87: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0516] The target compound (5 mg) was synthesized by following the procedure of Example 86 using (tetrahydro-2H-pyran-4-yl)methanol as the starting material.

[0517] MS m / z[LC-MS]:472.22[M+1]. 1H NMR (400MHz, CDCl3)8.32(s,1H),8.16(s,1H),7.49(d,J=8.8Hz,2H),7.02(d,J=8. 8Hz,2H),6.84(s,1H),6.61(dd,J=16.8Hz,10.4Hz,1H),6.35(d,J=16.8Hz,1H),5. 75(d,J=10.4Hz,1H),4.01-4.10(m,4H),3.70-3.94(m,4H),3.50(t,J=11.2Hz,2H) ,3.27-3.30(m,4H),2.24-2.38(m,1H),1.93(d,J=12.0Hz,2H),1.45-1.57(m,2H).

[0518] Example 88: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0519] The target compound (25 mg) was synthesized by following the method of Example 4 using tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate as a raw material.

[0520] MS m / z[LC-MS]:446.23[M+1]. 1 H NMR(400MHz, CDCl3)8.34(s,1H),8.17(s,1H),7.49(d,J=8.8Hz,2H),7.03(d,J=8.8Hz,2H),6.86(s,1H),6.61(dd,J=16.8Hz,10.4Hz,1H),6.35( dd,J=16.8Hz,1.6Hz,1H),5.76(dd,J=10.4Hz,1.6Hz,1H),4.04(s,2H),3.71-3.94(m,4H),3.28-3.31(m,4H),2.34-2.54(brs,1H),1.47(s,6H).

[0521] Example 89: 4-(4-(4-acryloylpiperazin-1-yl)-3-nitrophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0522] The target compound (16 mg) was obtained by the synthesis method of Example 4 using Intermediate 1 and tert-butyl 4-(2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate as starting materials.

[0523] MS m / z[LC-MS]:483.17[M+1].

[0524] Example 90: N-(4-((3-cyano-6-(1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0525] The target compound (39 mg) was obtained according to the synthesis method of Example 69 using 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0526] MS m / z[LC-MS]:421.17[M+1]. 1 H NMR (400MHz, DMSO-d6)10.39(s,1H),9.29(s,1H),8.69(s,1H),8.53(s,1H),8.15(s,1H),8.12(s,1H),7.78(d,J=8.4Hz,2H),7.66(d,J=8.4Hz, 2H), 6.44 (dd, J = 17.2Hz, 10.0Hz, 1H), 6.28 (dd, J = 17.2Hz, 1.6Hz, 1H), 5.79 (dd, J = 10.0Hz, 2.0Hz, 1H), 4.46-4.52 (m, 1H), 1.45 (d, J = 6.4Hz, 6H).

[0527] Example 91: N-(4-((3-cyano-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0528] The target compound (18 mg) was obtained according to the synthesis method of Example 69 using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0529] MS m / z[LC-MS]:419.16[M+1]. 1H NMR (400MHz, DMSO-d6)10.39(s,1H),9.28(s,1H),8.69(s,1H),8.50(s,1H),8.13(s,1H),8.11(s,1H),7.78(d,J=8.4Hz,2H),7.65(d,J=8.4Hz ,2H),6.44(dd,J=17.2Hz,10.0Hz,1H),6.28(dd,J=17.2Hz,1.6Hz,1H),5.79(dd,J=10.0Hz,1.6Hz,1H),3.71-3.77(m,1H),0.97-1.09(m,4H).

[0530] Example 92: N-(5-(3-cyano-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0531] The target compound (6 mg) was obtained according to the synthesis method of Example 68 using 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0532] MS m / z[LC-MS]:396.16[M+1]. 1 H NMR (400MHz, DMSO-d6)10.97(s,1H),9.30(s,1H),8.65(s,1H),8.61(d,J=2.4H z,1H),8.51(s,1H),8.35(d,J=8.8Hz,1H),8.13(s,1H),8.09(dd,J=8.8Hz,2.4 Hz,1H),7.92(s,1H),6.64(dd,J=17.2Hz,10.4Hz,1H),6.34(dd,J=17.2Hz,1.6 Hz, 1H), 5.81 (dd, J = 10.4Hz, 2.0Hz, 1H), 3.71-3.77 (m, 1H), 0.96-1.08 (m, 4H).

[0533] Example 93: N-(5-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0534] The target compound (22 mg) was obtained according to the synthesis method of Example 68 using 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0535] MS m / z[LC-MS]:384.16[M+1]. 1 H NMR (400MHz, DMSO-d6)10.98(s,1H),9.30(s,1H),8.65(s,1H),8.61(d,J=2.4Hz ,1H),8.46(s,1H),8.35(d,J=8.8Hz,1H),8.14(s,1H),8.09(dd,J=8.8Hz,2.4Hz, 1H),7.91(s,1H),6.64(dd,J=17.2Hz,10.4Hz,1H),6.34(dd,J=17.2Hz,2.0Hz,1 H), 5.81 (dd, J = 10.4Hz, 2.0Hz, 1H), 4.15 (q, J = 7.2Hz, 2H), 1.40 (t, J = 7.2Hz, 3H).

[0536] Example 94: N-(5-(3-cyano-6-(1-difluoromethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0537] The target compound (20 mg) was obtained according to the synthesis method of Example 68 using 1-difluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0538] MS m / z[LC-MS]:406.11[M+1]. 1 H NMR(400MHz, DMSO-d6)10.99(s,1H),9.48(d,J=1.2Hz,1H),9.00(s,1H),8.70(s ,1H),8.63(d,J=2.0Hz,1H),8.53(s,1H),8.35(d,J=8.8Hz,1H),8.11(dd,J=8.8 Hz,2.4Hz,1H),8.05(d,J=1.2Hz,1H),7.87(t,J=49.2Hz,1H),6.64(dd,J=16.8H z, 10.0Hz, 1H), 6.34 (dd, J = 16.8Hz, 1.6Hz, 1H), 5.81 (dd, J = 10.0Hz, 1.6Hz, 1H).

[0539] Example 95: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0540] The target compound (14 mg) was obtained according to the synthesis method of Example 4 using 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol as a starting material.

[0541] MS m / z[LC-MS]:496.23[M+1]. 1 H NMR(400MHz,DMSO-d6)9.22(s,1H),8.61(s,1H),8.36(s,1H),8.11(s,1H),7 .73(s,1H),7.50(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.85(dd,J=16.8Hz, 10.4Hz, 1H), 6.13 (dd, J=16.8Hz, 2.0Hz, 1H), 5.70 (dd, J=10.4Hz, 2.0Hz, 1H), 4.72(s,1H),4.01(s,2H),3.68-3.78(m,4H),3.22-3.32(m,4H),1.08(s,6H).

[0542] Example 96: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-((3,5-dimethoxyphenyl)ethynyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0543] The target compound (33 mg) was obtained according to the synthesis method of Example 18 using 1-ethynyl-3,5-dimethoxybenzene as a starting material.

[0544] MS m / z[LC-MS]:518.23[M+1]. 1 H NMR(400MHz, DMSO-d6)9.24(s,1H),8.74(s,1H),7.52(s,1H),7.49(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),6.85(dd,J=16.8Hz,10.8Hz,1H),6.7 5(d,J=2.4Hz,2H),6.58(t,J=2.4Hz,1H),6.13(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H),3.65-3.78(m,10H),3.24-3.31(m,4H).

[0545] Example 97: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-cyclobutyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0546] The target compound (15 mg) was obtained according to the synthesis method of Example 4 using 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0547] MS m / z[LC-MS]:478.23[M+1]. 1 H NMR(400MHz,DMSO-d6)9.21(d,J=1.6Hz,1H),8.62(s,1H),8.57(s,1H),8.14(s,1H),7 .76(d,J=1.6Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz, 10.4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.71 (dd, J=10.4Hz, 2.4Hz, 1H), 4.77-4. 85(m,1H),3.66-3.77(m,4H),3.21-3.30(m,6H),2.35-2.44(m,3H),1.76-1.83(m,1H).

[0548] Example 98: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-tert-butyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0549] The target compound (15 mg) was obtained according to the synthesis method of Example 4 using 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0550] MS m / z[LC-MS]:480.26[M+1]. 1 H NMR(400MHz, DMSO-d6)9.22(d,J=1.2Hz,1H),8.61(s,1H),8.58(s,1H),8.1 3(s,1H),7.80(d,J=1.2Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H ),6.85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(d d, J=10.4Hz, 2.4Hz, 1H), 3.66-3.77 (m, 4H), 3.22-3.30 (m, 4H), 1.53 (s, 9H).

[0551] Example 99: N-(6-((3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)pyridin-3-yl)acrylamide

[0552] The target compound (8 mg) was obtained according to the synthesis method of Example 18 using 3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as a starting material.

[0553] MS m / z[LC-MS]:408.16[M+1]. 1 H NMR (400MHz, DMSO-d6)8.95(s,1H),8.88(d,J=2.4Hz,1H),8.39(s,1H),8.20(dd,J=8.8Hz,2.4Hz,1H),8.15(s,1H), 8.04(s,1H),7.95(s,1H),7.86(d,J=8.8Hz,1H),6.40-6.46(m,2H),5.81-5.84(m,1H),4.24(q,J=6.8Hz,2H),1.51(t,J=6.8Hz,3H).

[0554] Example 100: N-(4-((3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0555] The target compound (28 mg) was obtained according to the synthesis method of Example 69 using 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0556] MS m / z[LC-MS]:437.16[M+1]. 1H NMR(400MHz,DMSO-d6)10.40(s,1H),9.30(s,1H),8.70(s,1H),8.43(s,1H ),8.13-8.16(m,2H),7.78(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),6.45(d d, J=16.8Hz, 10.0Hz, 1H), 6.28 (dd, J=16.8Hz, 1.6Hz, 1H), 5.79 (dd, J=10.0Hz, 1.6Hz, 1H), 4.27 (t, J=5.2Hz, 2H), 3.71 (t, J=5.2Hz, 2H), 3.24 (s, 3H).

[0557] Example 101: N-(5-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0558] The target compound (12 mg) was obtained according to the synthesis method of Example 68 using 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0559] MS m / z[LC-MS]:414.18[M+1]. 1 H NMR (400MHz, DMSO-d6)10.97(s,1H),9.31(s,1H),8.65(s,1H),8.62(d,J=2.4Hz,1H ),8.43(s,1H),8.35(d,J=8.8Hz,1H),8.16(s,1H),8.10(dd,J=8.8Hz,2.4Hz,1H),7 .92(s,1H),6.64(dd,J=17.2Hz,10.4Hz,1H),6.34(dd,J=17.2Hz,1.6Hz,1H),5.81( dd,J=10.4Hz,1.6Hz,1H),4.27(t,J=5.2Hz,2H),3.70(t,J=5.2Hz,2H),3.23(s,3H).

[0560] Example 102: N-(5-(3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0561] The target compound (14 mg) was obtained according to the synthesis method of Example 8 using 3-methylazetidin-3-ol as a starting material.

[0562] MS m / z[LC-MS]:375.17[M+1]. 1 H NMR (400MHz, DMSO-d6)10.95(s,1H),8.54(d,J=2.4Hz,1H),8.67(s,1H),8.31(d,J=8 .4Hz,1H),8.11(d,J=2.0Hz,1H),8.02(dd,J=8.4Hz,2.4Hz,1H),7.08(d,J=1.6Hz,1H ),6.63(dd,J=17.2Hz,10.0Hz,1H),6.33(d,J=17.2Hz,2.0Hz,1H),5.80(dd,J=10.0H z, 2.0Hz, 1H), 5.56 (s, 1H), 3.83 (d, J = 8.0Hz, 2H), 3.70 (d, J = 8.0Hz, 2H), 1.45 (s, 3H).

[0563] Example 103: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-morpholinylphenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0564] The target compound (16 mg) was obtained according to the synthesis method of Example 4 using 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine as a starting material.

[0565] MS m / z[LC-MS]:519.25[M+1]. 1 H NMR(400MHz, DMSO-d6)9.13(d,J=1.6Hz,1H),8.64(s,1H),7.74(d,J=8.8Hz,2H), 7.70(d,J=1.6Hz,1H),7.54(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),7.03(d,J=8.8 Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(d d, J=10.4Hz, 2.4Hz, 1H), 3.66-3.77 (m, 8H), 3.23-3.30 (m, 4H), 3.14-3.19 (m, 4H).

[0566] Example 104: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(oxacyclyl-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0567] The target compound (25 mg) was obtained according to the synthesis method of Example 4 using 1-(oxolan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-1H-pyrazole as a starting material.

[0568] MS m / z[LC-MS]:480.22[M+1]. 1 H NMR(400MHz,DMSO-d6)9.24(s,1H),8.67(s,1H),8.62(s,1H),8.27(s,1H),7.77(s ,1H),7.51(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H) ,6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,=10.4Hz,2.4Hz,1H),5.53-5.59(m,1H), 4.95(t,J=7.2Hz,2H), 4.89(t,J=6.4Hz,2H), 3.66-3.77(m,4H), 3.22-3.30(m,4H).

[0569] Example 105: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0570] The target compound (20 mg) was obtained according to the synthesis method of Example 4 using 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0571] MS m / z[LC-MS]:478.22[M+1]. 1H NMR (400MHz, DMSO-d6)9.21(d,J=1.2Hz,1H),8.61(s,1H),8.47(s,1H),8.11(s,1H),7.73(d ,J=1.2Hz,1H),7.50(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H ),6.13(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H),3.97(d,J=7.2Hz,2H),3. 66-3.77(m,4H),3.22-3.30(m,4H),1.18-1.28(m,1H),0.52-0.56(m,2H),0.35-0.40(m,2H).

[0572] Example 106: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0573] The target compound (9 mg) was obtained according to the synthesis method of Example 4 using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine as a starting material.

[0574] MS m / z[LC-MS]:521.28[M+1]. 1 H NMR(400MHz,DMSO-d6)8.62(s,1H),8.25(s,1H),7.80(s,1H),7.74(s,1H),7.50(d,J =8.8Hz,2H),7.41(s,1H),7.05(d,J=8.8Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H),6. 34(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),4.15-4.24(m,1H),3.7 0-3.93(m,4H),3.32-3.34(m,4H),3.00-3.08(m,2H),2.37(s,3H),1.98-2.27(m,6H).

[0575] Example 107: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0576] The target compound (23 mg) was obtained according to the synthesis method of Example 4 using 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0577] MS m / z[LC-MS]:500.22[M+1]. 1 H NMR(400MHz,DMSO-d6)9.35(s,1H),9.26(s,1H),8.65(s,1H),8.47(s,1H),7. 89(s,1H),7.86(d,J=7.6Hz,2H),7.51-7.54(m,4H),7.33(t,J=7.6Hz,1H),7. 11(d,J=8.4Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4 Hz, 1H), 5.71 (dd, J = 10.4Hz, 2.4Hz, 1H), 3.67-3.78 (m, 4H), 3.22-3.32 (m, 4H).

[0578] Example 108: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-cyclohexyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0579] The target compound (13 mg) was obtained according to the synthesis method of Example 4 using 1-cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0580] MS m / z[LC-MS]:506.27[M+1]. 1H NMR(400MHz,DMSO-d6)9.19(s,1H),8.61(s,1H),8.50(s,1H),8.10(s,1H),7.75(s,1H),7.50(d ,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4H z,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.06-4.16(m,1H),3.66-3.78(m,4H),3.22-3.30(m,4H) ,2.02-2.09(m,2H),1.76-1.84(m,2H),1.62-1.74(m,3H),1.33-1.46(m,2H),1.16-1.26(m,1H).

[0581] Example 109: 1-(4-(4-(3-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0582] Step 1: tert-Butyl 4-(4-(3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate

[0583] Example 11 (92 mg) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (0.01 mL) was added. The mixture was cooled to 0°C, and NIS (50 mg) was added. The mixture was then warmed to room temperature and stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (66 mg).

[0584] Step 2: tert-Butyl 4-(4-(3-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate

[0585] Under nitrogen, tert-butyl 4-(4-(3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazine-1-carboxylate (59 mg), trimethylsilyl acetylene (100 mg), bis(triphenylphosphine)palladium(II) dichloride (7 mg), cuprous iodide (4 mg), and triethylamine (100 mg) were added sequentially to dioxane (10 mL), heated to 60°C, and stirred overnight. The mixture was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrates were combined and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and tetrabutylammonium fluoride (4 mg) was added, followed by stirring for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to give the title compound (17 mg).

[0586] Step 3: 1-(4-(4-(3-ethynyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0587] The product obtained in step 2 was dissolved in dichloromethane (5 mL) at room temperature, trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and cooled to 0°C. The residue was dissolved in dichloromethane (10 mL), triethylamine (50 mg) and acryloyl chloride (9 mg) were added, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (30 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (6 mg).

[0588] MS m / z[LC-MS]:437.22[M+1]. 1H NMR(400MHz, CH3OD+CDCl3)8.46(d,J=1.6Hz,1H),7.97(s,1H),7.68(s,1H),7.65(s, 1H),7.42(d,J=8.8Hz,2H),7.15(d,J=1.6Hz,1H),6.91(d,J=8.8Hz,2H),6.55(dd,J= 16.8Hz,10.4Hz,1H),6.21(dd,J=16.8Hz,1.6Hz,1H),5.69(dd,J=10.4Hz,1.6Hz,1H) ,3.87(s,3H),3.74-3.81(m,2H),3.65-3.73(m,2H),3.20-3.22(m,4H),2.89(s,1H).

[0589] Example 110: 1-(4-(4-(6-(1-methyl-1H-pyrazol-4-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0590] The target compound (7 mg) was obtained according to the synthetic methods of Example 4 and Example 109 using pyridine-4-boronic acid as a starting material.

[0591] MS m / z[LC-MS]:490.25[M+1]. 1 H NMR(400MHz, CH3OD+CDCl3)9.06(d,J=1.2Hz,1H),8.34(s,1H),8.24(s,1H),8.13(d, J=6.0Hz,2H),8.07(s,1H),7.49(s,1H),7.05(d,J=8.4Hz,2H),6.85(dd,J=16.8Hz,10 .8Hz,1H),6.79(d,J=6.0Hz,2H),6.76(d,J=8.4Hz,2H),6.14(dd,J=16.8Hz,2.4Hz,1H ), 5.70 (dd, J = 10.8Hz, 2.4Hz, 1H), 3.86 (s, 3H), 3.62-3.72 (m, 4H), 3.07-3.14 (m, 4H).

[0592] Example 111: 1-(4-(4-(6-(1-methyl-1H-pyrazol-4-yl)-3-phenylpyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0593] The target compound (17 mg) was obtained using phenylboronic acid as a starting material according to the synthetic methods of Example 4 and Example 109.

[0594] MS m / z[LC-MS]:489.24[M+1]. 1 H NMR(400MHz, CH3OD+CDCl3)8.56(s,1H),7.91(s,1H),7.74(s,1H),7.70(s,1H),7.15(s,1H),6.92-7.03(m,5H),6.80-6.83(m,2H),6.53-6.60 (m,3H),6.25(dd,J=16.8Hz,1.6Hz,1H),5.72(dd,J=10.8Hz,1.6Hz,1H),3.91(s,3H),3.73-3.80(m,2H),3.64-3.71(m,2H),3.05-3.08(m,4H).

[0595] Example 112: 1-(4-(4-(3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0596] The target compound (3 mg) was obtained according to the synthetic methods of Examples 4 and 109 using 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine as a starting material.

[0597] MS m / z[LC-MS]:615.26[M+1]. 1 H NMR(400MHz, CH3OD+CDCl3)8.57(s,1H),8.27(d,J=4.8Hz,1H),7.94(s,1H),7.75 (s,1H),7.68(s,1H),7.19(s,1H),7.01(d,J=8.4Hz,2H),6.85-6.89(m,2H),6.66 -6.71(m,3H),6.52-6.61(m,2H),6.24(dd,J=16.8Hz,1.2Hz,1H),5.70(dd,J=10. 4Hz,1.2Hz,1H),3.92(s,3H),3.62-3.77(m,4H),3.05-3.13(m,4H),2.44(s,3H).

[0598] Example 113: N-(4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridin-1(2H)-yl)phenyl)acrylamide

[0599] The target compound (5 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (4-bromophenyl)carbamate as raw materials.

[0600] MS m / z[LC-MS]:450.22[M+1]. 1 H NMR (400MHz, CH3OD+CDCl3)8.53(s,1H),8.16(s,1H),7.68-7.70(m,2H),7.44(d,J=8.8Hz,2H),7.30(s,1H),6.89(d,J=8.8H z,2H),6.22-6.25(m,2H),6.04-6.08(m,1H),5.59-5.62(m,1H),3.82-3.90(m,5H),3.50(t,J=5.2Hz,2H),2.57-2.63(m,2H).

[0601] Example 114: N-(5-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)pyridin-2-yl)acrylamide

[0602] The target compound (25 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl (5-ethynylpyridin-2-yl)carbamate as the raw material.

[0603] MS m / z[LC-MS]:394.12[M+1]. 1H NMR(400MHz, DMSO-d6)11.00(s,1H),9.31(d,J=1.6Hz,1H),8.71(s,1H),8.6 5(d,J=2.4Hz,1H),8.38(s,1H),8.30(d,J=8.8Hz,1H),8.15(d,J=1.2Hz,1H), 8.11(s,1H),8.05(dd,J=8.8Hz,2.4Hz,1H),6.62(dd,J=17.2Hz,10.4Hz,1H) ,6.34(dd,J=17.2Hz,1.6Hz,1H),5.82(d,J=10.4Hz,1.6Hz,1H),3.87(s,3H).

[0604] Example 115: N-(5-((3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)pyridin-2-yl)acrylamide

[0605] Referring to the synthesis method of Example 18, the target compound (20 mg) was synthesized using 3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate and tert-butyl (5-ethynylpyridin-2-yl)carbamate as raw materials.

[0606] MS m / z[LC-MS]:408.15[M+1]. 1 H NMR (400MHz, DMSO-d6)11.00(s,1H),9.30(s,1H),8.70(s,1H),8.65(d,J=2.4Hz ,1H),8.45(s,1H),8.30(d,J=8.8Hz,1H),8.17(s,1H),8.12(s,1H),8.05(dd,8. 8Hz, 2.4Hz, 1H), 6.61 (dd, J=17.2Hz, 10.4Hz, 1H), 6.33 (dd, J=17.2Hz, 1.6Hz, 1H ), 5.82 (dd, J = 10.4Hz, 1.6Hz, 1H), 4.15 (q, J = 7.2Hz, 2H), 1.41 (t, J = 7.2Hz, 3H).

[0607] Example 116: N-(5-((3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)pyridin-2-yl)acrylamide

[0608] Referring to the synthesis method of Example 18, the target compound (16 mg) was synthesized using 3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate and tert-butyl (5-ethynylpyridin-2-yl)carbamate as raw materials.

[0609] MS m / z[LC-MS]:399.15[M+1]. 1 H NMR (400MHz, DMSO-d6)10.99(s,1H),8.64(d,J=2.4Hz,1H),8.53(s,1H),8.28(d,J=8.4Hz,1H), 8.14(d,J=1.6Hz,1H),8.04(dd,J=8.4Hz,2.4Hz,1H),7.33(d,J=1.6Hz,1H),6.61(dd,J=17.2Hz, 10.4Hz, 1H), 6.33 (dd, J = 17.2Hz, 1.6Hz, 1H), 5.81 (dd, J = 10.4Hz, 1.6Hz, 1H), 5.58 (s, 1H), 3.82 (d, J = 7.6Hz, 2H), 3.69 (d, J = 7.6Hz, 2H), 1.44 (s, 3H).

[0610] Example 117: N-(5-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)pyridin-2-yl)acrylamide

[0611] The target compound (36 mg) was obtained according to the synthesis method of Example 4 using 5-bromo-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile as the starting material.

[0612] MS m / z[LC-MS]:370.41[M+1].

[0613] Example 118: N-(4-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)phenyl)acrylamide

[0614] The target compound (7 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8 using 3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and (4-bromophenyl)carbamate as raw materials.

[0615] MS m / z[LC-MS]:466.24[M+1]. 1 H NMR(400MHz,DMSO-d6)9.93(s,1H),9.12(s,1H),8.61(s,1H),8.46(s,1H),8.10(s,1H ),7.71(s,1H),7.53(d,J=9.2Hz,2H),6.97(d,J=9.2Hz,2H),6.38(dd,J=17.2Hz,9.6Hz ,1H),6.19(d,J=17.2Hz,1H),5.68(d,J=9.6Hz,1H),4.14(q,J=7.2Hz,2H),3.80-3.86( m,2H),3.16-3.26(m,1H),2.76-2.84(m,2H),1.92-2.10(m,4H),1.40(t,J=7.2Hz,3H).

[0616] Example 119: 3-(4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide

[0617] The target compound (27 mg) was obtained according to the synthetic methods of Examples 4 and 109 using (3-(methylcarbamoyl)phenyl)boronic acid as a starting material.

[0618] MS m / z[LC-MS]:546.28[M+1]. 1 H NMR (400MHz, CDCl3)8.64(d,J=1.6Hz,1H),8.05(s,1H),7.80(s,1H),7.67(s,1H),7.56(d,J=8.0Hz ,1H),7.20-7.28(m,3H),7.09(d,J=8.8Hz,2H),6.97(s,1H),6.65(d,J=8.8Hz,2H),6.60(dd,J=16. 8Hz,10.4Hz,1H),6.35(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),5.46(q,J=4.4Hz ,1H),3.99(s,3H),3.78-3.87(m,2H),3.66-3.75(m,2H),3.07-3.17(m,4H),2.88(d,J=4.8Hz,3H).

[0619] Example 120: 1-(4-(4-(6-(1-methyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[0620] The target compound (20 mg) was obtained according to the synthetic methods of Example 4 and Example 109 using pyridine-3-boronic acid as a starting material.

[0621] MS m / z[LC-MS]:490.25[M+1]. 1 H NMR(400MHz, CDCl3)8.64(d,J=1.2Hz,1H),8.22-8.31(m,2H),8.01(s,1H),7.80(s,1H),7.67( s,1H),7.22(d,J=1.2Hz,1H),7.08(d,J=8.4Hz,1H),7.02(d,J=8.8Hz,2H),6.89-6.92(m,1H),6 .65(d,J=8.8Hz,2H),6.61(dd,J=16.8Hz,10.8Hz,1H),6.35(dd,J=16.8Hz,1.6Hz,1H),5.75(d d, J=10.8Hz, 1.6Hz, 1H), 3.98 (s, 3H), 3.80-3.87 (m, 2H), 3.68-3.75 (m, 2H), 3.13-3.16 (m, 4H).

[0622] Example 121: 4'-(4-(4-acryloylpiperazin-1-yl)phenyl)-4,5,6,7-tetrahydro-[3,6'-bispyrazolo[1,5-a]pyridine]-3'-carbonitrile

[0623] The target compound (18 mg) was obtained according to the synthesis method of Example 4 using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine as a starting material.

[0624] MS m / z[LC-MS]:478.26[M+1].

[0625] Example 122: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(1-cyanopiperidin-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0626] The target compound (15 mg) was obtained according to the synthesis method of Example 4 using 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carbonitrile as a raw material.

[0627] MS m / z[LC-MS]:532.26[M+1]. 1 H NMR(400MHz,DMSO-d6)9.22(s,1H),8.62(s,1H),8.57(s,1H),8.16(s,1H),7.76( s,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10.4Hz,1 H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.30-4.40(m ,1H),3.65-3.78(m,4H),3.47-3.53(m,2H),3.20-3.30(m,6H),1.93-2.12(m,4H).

[0628] Example 123: N-(5-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)acrylamide

[0629] The target compound (23 mg) was obtained according to the synthesis method of Example 4 using tert-butyl (5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)carbamate as a starting material.

[0630] MS m / z[LC-MS]:469.20[M+1]. 1H NMR (400MHz, DMSO-d6)10.97(s,1H),9.30(s,1H),8.65(s,1H),8.61(d,J=2.4Hz,1H),8.4 5(s,1H),8.35(d,J=8.8Hz,1H),8.14(s,1H),8.09(dd,J=8.8Hz,2.4Hz,1H),7.90(s,1H),6 .64(dd,J=16.8Hz,10.4Hz,1H),6.34(dd,J=16.8Hz,1.6Hz,1H),5.81(dd,J=10.4Hz,1.6H z,1H),4.24(t,J=6.8Hz,2H),3.52-3.54(m,4H),2.73(t,J=6.8Hz,2H),2.37-2.43(m,4H).

[0631] Example 124: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0632] The target compound (35 mg) was obtained according to the synthesis method of Example 4 using 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as a starting material.

[0633] MS m / z[LC-MS]:466.22[M+1]. 1 H NMR(400MHz, DMSO-d6)9.19(d,J=1.2Hz,1H),8.61(s,1H),8.43(s,1H),8.11(s,1H),7.7 2(d,J=1.2Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10. 4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.70 (dd, J=10.4Hz, 2.4Hz, 1H), 4.06 (t, J=6.8 Hz, 2H), 3.66-3.77 (m, 4H), 3.22-3.31 (m, 4H), 1.76-1.85 (m, 2H), 0.84 (t, J = 7.6Hz, 3H).

[0634] Example 125: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0635] The target compound (32 mg) was obtained according to the synthesis method of Example 4 using 1-trifluoroethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as a starting material.

[0636] MS m / z[LC-MS]:506.19[M+1]. 1 H NMR(400MHz, DMSO-d6)9.28(d,J=1.6Hz,1H),8.64(s,1H),8.55(s,1H),8.28( s,1H),7.76(d,J=1.6Hz,1H),7.52(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6. 85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10 .4Hz, 2.4Hz, 1H), 5.16 (q, J = 9.2Hz, 2H), 3.66-3.78 (m, 4H), 3.23-3.32 (m, 4H).

[0637] Example 126: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-isobutyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0638] The target compound (22 mg) was obtained according to the synthesis method of Example 4 using 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as a starting material.

[0639] MS m / z[LC-MS]:480.26[M+1]. 1 H NMR(400MHz,DMSO-d6)9.20(s,1H),8.61(s,1H),8.42(s,1H),8.12(s,1H),7.73(s ,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H) ,6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(d,J=10.4Hz,2.4Hz,1H),3.91(d,J=7.2Hz,2 H), 3.66-3.77 (m, 4H), 3.20-3.31 (m, 4H), 2.07-2.17 (m, 1H), 0.85 (d, J = 6.8Hz, 6H).

[0640] Example 127: N-(4-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)acrylamide

[0641] The target compound (21 mg) was obtained according to the synthesis method of Example 4 using tert-butyl (4-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)phenyl)carbamate as a starting material.

[0642] MS m / z[LC-MS]:413.17[M+1]. 1 H NMR (400MHz, DMSO-d6)10.37(s,1H),9.25(s,1H),8.63(s,1H),8.43(s,1H),8.14(s,1H),7.83(d,J=8.4Hz,2H),7.80(s,1H),7.59(d,J=8. 4Hz,2H),6.47(dd,J=17.2,10.0Hz,1H),6.29(d,J=17.2Hz,1H),5.78(d,J=10.0Hz,1H),4.23-4.30(m,2H),3.67-3.74(m,2H),3.23(s,3H).

[0643] Example 128: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-(-4-methylpiperazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0644] The target compound (6 mg) was obtained according to the synthesis method of Example 4 using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)piperazine as a starting material.

[0645] MS m / z[LC-MS]:532.27[M+1]. 1H NMR (400MHz, DMSO-d6)9.12(s,1H),8.64(s,1H),7.72(d,J=8.8Hz,2H),7.70(d,J=1.2H z,1H),7.54(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),7.02(d,J=8.8Hz,2H),6.85(dd,=1 6.8Hz, 10.4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.70 (dd, J=10.4Hz, 2.4Hz, 1H), 3. 66-3.76(m,4H),3.23-3.30(m,4H),3.19-3.21(m,4H),2.42-2.45(m,4H),2.21(s,3H).

[0646] Example 129: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-((4-methylpiperazin-1-)methyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0647] The target compound (9 mg) was obtained according to the synthesis method of Example 4 using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzyl)piperazine as a starting material.

[0648] MS m / z[LC-MS]:546.29[M+1]. 1 H NMR(400MHz, DMSO-d6)9.22(s,1H),8.69(s,1H),7.82(d,J=8.0Hz,2H),7.74(s,1H) ,7.55(d,J=8.4Hz,2H),7.40(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.85(dd,J=16 .8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H), 3.65-3.77(m,4H),3.49(s,2H),3.23-3.31(m,4H),2.21-2.54(m,8H),2.14(s,3H).

[0649] Example 130: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-(morpholinomethyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0650] The target compound (19 mg) was obtained according to the synthesis method of Example 4 using 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine as a starting material.

[0651] MS m / z[LC-MS]:533.25[M+1]. 1 H NMR(400MHz, DMSO-d6)9.23(d,J=1.2Hz,1H),8.69(s,1H),7.83(d,J=8.4Hz,2H),7.75(d, J=1.2Hz,1H),7.55(d,J=8.8Hz,2H),7.42(d,J=8.4Hz,2H),7.09(d,J=8.8Hz,2H),6.85(d d,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H) ,3.66-3.77(m,4H),3.55-3.58(m,4H),3.50(s,2H),3.22-3.32(m,4H),2.32-2.40(m,4H).

[0652] Example 131: N-(4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)benzyl)acrylamide

[0653] The target compound (14 mg) was synthesized by referring to the synthesis method of Example 18 using tert-butyl (4-ethynylbenzyl) carbamate as the raw material.

[0654] MS m / z[LC-MS]:407.15[M+1].

[0655] Example 132: N-(4-(4-(3-cyano-6-(3-hydroxy-3-methylazepin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)phenyl)acrylamide

[0656] The target compound (13 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8 using 3-cyano-6-(3-hydroxy-3-methyl-zetidine-1-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester and (4-bromophenyl)carbamic acid tert-butyl ester as raw materials.

[0657] MS m / z[LC-MS]:457.25[M+1].

[0658] Example 133: N-(4-(3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl)phenyl)acrylamide

[0659] The target compound (8 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8 using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate and tert-butyl (4-bromophenyl)carbamate as raw materials.

[0660] MS m / z[LC-MS]:476.22[M+1]. 1 H NMR(400MHz, CDCl3)8.50(d,J=1.2Hz,1H),8.22(s,1H),7.67(s,1H),7.63(s,1H),7.44 (d,J=8.8Hz,2H),7.11-7.22(brs,1H),6.91-7.01(m,2H),6.89(s,1H),6.52-6.60(m,1 H),6.39(d,J=16.8Hz,1H),6.23(dd,J=16.8Hz,10.4Hz,1H),5.74(d,J=10.4Hz,1H),4. 32-4.56(m,2H),3.96(s,3H),2.88-2.98(m,1H),2.36-2.56(m,2H),2.15-2.30(m,3H).

[0661] Example 134: N-(4-((3-cyano-6-(1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)-N-methylacrylamide

[0662] Example 90 (42 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (26 mg).

[0663] MS m / z[LC-MS]:435.18[M+1].

[0664] Example 135: N-(4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)phenyl)-N-methylacrylamide

[0665] Example 47 (45 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (20 mg).

[0666] MS m / z[LC-MS]:466.23[M+1].

[0667] Example 136: N-(4-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)phenyl)-N-methylacrylamide

[0668] Example 52 (42 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (23 mg).

[0669] MS m / z[LC-MS]:438.19[M+1].

[0670] Example 137: N-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-N-methylacrylamide

[0671] Example 62 (38 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (18 mg).

[0672] MS m / z[LC-MS]:384.17[M+1].

[0673] Example 138: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0674] The target compound (19 mg) was obtained according to the synthesis method of Example 4 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol as a starting material.

[0675] MS m / z[LC-MS]:468.21[M+1]. 1 H NMR(400MHz,DMSO-d6)9.20(d,J=1.2Hz,1H),8.61(s,1H),8.41(s,1H),8.12(s,1H) ,7.73(d,J=1.2Hz,1H),7.51(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16 .8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H), 4.91(t,J=5.2Hz,1H), 4.14(t,J=6.0Hz,2H), 3.66-3.79(m,6H), 3.23-3.30(m,4H).

[0676] Example 139: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-cyclopentyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0677] The target compound (28 mg) was obtained according to the synthesis method of Example 4 using 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0678] MS m / z[LC-MS]:492.22[M+1]. 1 H NMR(400MHz, DMSO-d6)9.20(d,J=1.6Hz,1H),8.60(s,1H),8.49(s,1H),8.11(s,1H),7.76(d,J= 1.6Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H),6.14( dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H),4.64-4.71(m,1H),3.66-3.78(m,4H) ,3.22-3.32(m,4H),2.05-2.13(m,2H),1.89-1.98(m,2H),1.73-1.83(m,2H),1.59-1.69(m,2H).

[0679] Example 140: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0680] The target compound (24 mg) was obtained according to the synthesis method of Example 4 using 1-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0681] MS m / z[LC-MS]:496.26[M+1]. 1 H NMR(400MHz, DMSO-d6)9.20(d,J=1.6Hz,1H),8.61(s,1H),8.43(s,1H),8.12(s,1H),7.72( d,J=1.6Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1 H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H),4.15(t,J=7.2Hz,2H),3 .66-3.78(m,4H),3.30(t,J=6.0Hz,2H),3.23-3.29(m,4H),3.22(s,3H),1.99-2.05(m,2H).

[0682] Example 141: 4-(4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0683] The target compound (17 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester as starting materials.

[0684] MS m / z[LC-MS]:480.25[M+1]. 1 H NMR(400MHz,DMSO-d6)9.19(s,1H),8.62(s,1H),8.44(s,1H),8.11(s,1H),7.73(s,1H ),7.51(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),6.82(dd,J=16.8Hz,10.4Hz,1H),6.15 (d,J=16.8Hz,1H),5.70(d,J=10.4Hz,1H),4.36-4.56(m,2H),4.14(q,J=6.8Hz,2H),3 .72(d,J=12.4Hz,2H),2.89-2.98(m,2H),1.40(t,J=6.8Hz,3H),1.30(d,J=6.8Hz,6H).

[0685] Example 142: 4-(4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0686] The target compound (18 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester as starting materials.

[0687] MS m / z[LC-MS]:510.26[M+1]. 1H NMR(400MHz,DMSO-d6)9.21(s,1H), 8.62(s,1H),8.41(s,1H),8.13(s,1H),7.73(s,1H),7.51(d,J=8.4Hz,2H),7. 11(d,J=8.4Hz,2H),6.82(dd,J=16.8Hz,10.4Hz,1H),6.15(dd,J=16.8Hz,2.0 Hz,1H),5.70(dd,J=10.4Hz,2.0Hz,1H),4.36-4.58(m,2H),4.26(t,J=5.6Hz, 2H), 3.69-3.73 (m, 4H), 3.23 (s, 3H), 2.89-2.98 (m, 2H), 1.30 (d, J = 7.2Hz, 6H).

[0688] Example 143: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl]pyrazolo[1,5-a]pyridine-3-carbonitrile

[0689] The target compound (26 mg) was obtained according to the synthesis method of Example 4 using (6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)boronic acid as a starting material.

[0690] MS m / z[LC-MS]:652.30[M+1]. 1H NMR(400MHz, DMSO-d6)9.20(d,J=1.6Hz,1H),8.67(d,J=2.4Hz,1H),8.66(s,1H),8.09(dd,J=8.8Hz,2.4Hz,1H),8.0 5(d,J=2.4Hz,1H),7.74(d,J=1.6Hz,1H),7.65(dd,J=8.4Hz,2.4Hz,1H),7.55(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H ),6.85(dd,J=16.8Hz,10.4Hz,1H),6.73-6.78(m,2H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1 H), 3.80 (s, 3H), 3.62-3.77 (m, 8H), 3.45-3.56 (m, 4H), 3.23-3.31 (m, 4H), 2.45-2.50 (m, 1H), 1.54 (d, J = 8.4Hz, 1H).

[0691] Example 144: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0692] The target compound (14 mg) was obtained according to the synthesis method of Example 4 using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridin-2(1H)-one as a starting material.

[0693] MS m / z[LC-MS]:465.22[M+1]. 1 H NMR(400MHz, DMSO-d6)9.36(d,J=1.6Hz,1H),8.73(s,1H),7.81(d,J=6.8Hz,1H),7.75( d,J=1.6Hz,1H),7.56(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.96(d,J=2.0Hz,1H),6.8 5(dd,J=16.8Hz,10.4Hz,1H),6.80(dd,J=6.8Hz,2.4Hz,1H),6.13(dd,J=16.8Hz,2.4Hz, 1H), 5.70 (dd, J = 10.4Hz, 2.4Hz, 1H), 3.66-3.76 (m, 4H), 3.45 (s, 3H), 3.24-3.31 (m, 4H).

[0694] Example 145: N-(1-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0695] Referring to the synthesis method of Example 8, the target compound (11 mg) was synthesized using 4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0696] MS m / z[LC-MS]:494.20[M+1]. 1 H NMR (400MHz, DMSO-d6)8.60(s,1H),8.24(s,1H),7.81(s,1H),7.75(s,1H),7.43(d,J=8.4H z,2H),7.40(s,1H),6.57(d,J=8.4Hz,2H),6.34(d,J=16.8Hz,1H),6.30(d,J=7.6Hz,1H),6. 13(dd,J=16.8Hz,10.4Hz,1H),5.71(d,J=10.4Hz,1H),4.93-5.01(m,1H),4.32-4.46(m,3H ),4.10-4.18(m,2H),3.73-3.76(m,2H),3.57(td,J=11.2Hz,2.4Hz,2H),2.06-2.22(m,4H).

[0697] Example 146: N-(1-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0698] Referring to the synthesis method of Example 8, the target compound (12 mg) was synthesized using 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0699] MS m / z[LC-MS]:438.21[M+1]. 1H NMR(400MHz, DMSO-d6)9.17(s,1H),8.81(d,J=7.2Hz,1H),8.60(s,1H),8.44(s,1H),8.10 (s,1H),7.69(s,1H),7.46(d,J=8.0Hz,2H),6.58(d,J=8.0Hz,2H),6.21(dd,J=16.8Hz,10. 0Hz,1H),6.11(dd,J=16.8Hz,2.0Hz,1H),5.63(dd,J=10.0Hz,2.0Hz,1H),4.67-4.76(m,1 H), 4.20 (t, J = 7.6Hz, 2H), 4.14 (q, J = 7.2Hz, 2H), 3.68-3.71 (m, 2H), 1.40 (t, J = 7.6Hz, 3H).

[0700] Example 147: 4-(4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0701] The target compound (17 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester as starting materials.

[0702] MS m / z[LC-MS]:480.25[M+1]. 1 H NMR (400MHz, CDCl3)8.63(s,1H),8.27(s,1H),7.82(s,1H),7.74(s,1H),7.52(d,J=8.8Hz ,2H),7.42(s,1H),7.07(d,J=8.8Hz,2H),6.64(dd,J=16.8Hz,10.4Hz,1H),6.38(dd,J=16. 8Hz, 1.6Hz, 1H), 5.73 (dd, J=10.4Hz, 1.6Hz, 1H), 4.24-4.79 (m, 3H), 4.11-4.18 (m, 2H), 3. 53-3.62(m,4H),3.04(dd,J=12.0Hz,3.6Hz,2H),2.06-2.23(m,4H),1.46(d,J=7.2Hz,6H).

[0703] Example 148: N-(6-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)pyridin-3-yl)acrylamide

[0704] The target compound (14 mg) was synthesized by referring to the synthesis methods of Examples 4 and 8 using tert-butyl 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-1-carboxylate and tert-butyl (6-bromopyridin-3-yl)carbamate as raw materials.

[0705] MS m / z[LC-MS]:453.23[M+1]. 1 H NMR (400MHz, CDCl3+CD3OD)8.50(s,1H),8.18(s,1H),8.11(d,J=2.4Hz,1H),7.99(dd ,J=9.2Hz,2.4Hz,1H),7.68-7.70(m,2H),7.26-7.29(m,1H),6.69(d,J=9.2Hz,1H),6. 21-6.34(m,2H),5.66(dd,J=10.0Hz,1.6Hz,1H),4.32(d,J=12.4Hz,2H),3.89(s,3H), 3.48-3.58(m,1H),3.07(t,J=12.4Hz,2H),2.10(d,J=13.6Hz,2H),1.72-1.82(m,2H).

[0706] Example 149: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro-2H-[1,2'-bipyridyl]-5'-yl)acrylamide

[0707] The target compound (16 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8, using tert-butyl 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (6-bromopyridin-3-yl)carbamate as raw materials.

[0708] MS m / z[LC-MS]:451.18[M+1]. 1H NMR (400MHz, CDCl3) 8.56 (s, 1H), 8.21 (s, 1H), 8.13 (d, J = 2.4Hz, 1H), 8.04 (dd, J = 8. 8Hz,2.4Hz,1H),7.74(s,1H),7.69(s,1H),7.31(s,1H),6.69(d,J=8.8Hz,1H),6.36( dd,J=16.8Hz,2.0Hz,1H),6.26(dd,J=16.8Hz,10.4Hz,1H),6.10-6.13(m,1H),5.69 (dd,J=10.4Hz,2.0Hz,1H),4.14-4.19(m,2H),3.88-3.97(m,5H),2.59-2.68(m,2H).

[0709] Example 150: N-(4-(3-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-8-azabicyclo[3.2.1]oct-8-yl)phenyl)acrylamide

[0710] The intermediate of Example 133 was used as a starting material and the target compound (5 mg) was synthesized by hydrogenation reduction according to the method of Example 4.

[0711] MS m / z[LC-MS]:478.23[M+1]. 1 H NMR(400MHz, CDCl3)8.51(s,1H),8.19(s,1H),7.77(s,1H),7.67(s,1H),7.39-7.52(m,3H),6.70-7.18(m,3H),6.32-6.46(m,1H),6.18-6. 25(m,1H),5.63-5.78(m,1H),4.22-4.52(m,2H),4.00(s,3H),3.44-3 .57(m,1H),2.74-2.84(m,2H),2.04-2.20(m,2H),1.66-1.90(m,4H).

[0712] Example 151: N-(1-(4-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0713] Referring to the synthesis method of Example 8, the target compound (10 mg) was synthesized using 4-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0714] MS m / z[LC-MS]:468.21[M+1]. 1 H NMR(400MHz,DMSO-d6)9.19(d,J= 1.2Hz,1H),8.81(d,J=7.2Hz,1H),8.61(s,1H),8.41(s,1H),8.12(s,1H),7.69(d,J =1.2Hz,1H),7.46(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),6.21(dd,J=17.2Hz,9.6H z,1H),6.11(dd,J=17.2Hz,2.4Hz,1H),5.63(dd,J=9.6Hz,2.4Hz,1H),4.68-4.76(m ,1H),4.26(t,J=5.2Hz,2H),4.20(t,J=7.6Hz,2H),3.67-3.72(m,4H),3.22(s,3H).

[0715] Example 152: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-(1-methylpiperidin-4-yl)phenylphenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0716] The target compound (23 mg) was obtained according to the synthesis method of Example 4 using 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine as a starting material.

[0717] MS m / z[LC-MS]:531.27[M+1]. 1H NMR (400MHz, DMSO-d6)9.22(s,1H),8.70(s,1H),7.82(d,J=8.0Hz,2H),7.74(d,J=1 .2Hz,1H),7.55(d,J=8.4Hz,2H),7.36(d,J=8.4Hz,2H),7.09(d,J=8.8Hz,2H),6.86( dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4 Hz,1H),3.64-3.78(m,4H),3.12-3.34(m,6H),2.38-2.77(m,6H),1.74-1.96(m,4H).

[0718] Example 153: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylphenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0719] The target compound (20 mg) was obtained according to the synthesis method of Example 4 using 4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,3,2-dioxaborolane as a starting material.

[0720] MS m / z[LC-MS]:518.27[M+1]. 1 H NMR(400MHz, DMSO-d6)9.20(d,J=1.2Hz,1H),8.68(s,1H),7.80(d,J=8.4Hz,2H),7.74(d,J=1.2 Hz,1H),7.55(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.86(dd,J=16.8Hz, 10.4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.70 (dd, J=10.4Hz, 2.4Hz, 1H), 3.91-3.98 (m, 2H) ,3.66-3.77(m,4H),3.40-3.48(m,2H),3.23-3.32(m,4H),2.78-2.86(m,1H),1.63-1.74(m,4H).

[0721] Example 154: 2-(4-(4-(4-(4-acryloylpiperazin-1-yl)phenyl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)acetamide

[0722] The target compound (14 mg) was obtained according to the synthesis method of Example 4 using 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide as a starting material.

[0723] MS m / z[LC-MS]:481.20[M+1]. 1 H NMR (400MHz, DMSO-d6)9.23(s,1H),8.63(s,1H),8.39(s,1H),8.14(s,1H),7.74(s,1H),7.55(s,1H),7.51(d,J=8.8Hz,2H),7.31(s,1H ),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.76(s,2H), 3.66-3.77(m,4H),3.22-3.28(m,4H).

[0724] Example 155: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-(piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0725] The target compound (17 mg) was obtained according to the synthesis method of Example 4 using 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenyl)piperidine as a raw material.

[0726] MS m / z[LC-MS]:517.27[M+1]. 1 H NMR(400MHz, DMSO-d6)9.12(d,J=1.2Hz,1H),8.65(s,1H),7.69-7.71(m,3H ),7.54(d,J=8.4Hz,2H),7.09(d,J=8.8Hz,2H),7.00(d,J=8.8Hz,2H),6.86 (dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,10.4Hz,1H),5.71(dd,J=1 0.4Hz,2.4Hz,1H),3.66-3.76(m,4H),3.19-3.29(m,8H),1.50-1.63(m,6H).

[0727] Example 156: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0728] The target compound (18 mg) was obtained according to the synthesis method of Example 4 using 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile as a raw material.

[0729] MS m / z[LC-MS]:477.20[M+1]. 1 H NMR(400MHz,DMSO-d6)9.24(s,1H),8.63(s,1H),8.52(s,1H),8.22(s,1H),7.7 3(s,1H),7.51(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10. 4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.70 (dd, J=10.4Hz, 2.4Hz, 1H), 4.39 (t,J=6.0Hz,2H),3.66-3.77(m,4H),3.22-3.31(m,4H),3.09(t,J=6.0Hz,2H).

[0730] Example 157: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(cyclopropylsulfonyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0731] The target compound (22 mg) was obtained according to the synthesis method of Example 4 using 1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0732] MS m / z[LC-MS]:528.19[M+1]. 1H NMR(400MHz,DMSO-d6)9.45(s,1H),9.12(s,1H),8.69(s,1H),8.68(s,1H),7 .96(s,1H),7.53(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz, 10.4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.71 (dd, J=10.4Hz, 2.4Hz, 1H) ,3.66-3.76(m,4H),3.23-3.31(m,4H),3.12-3.18(m,1H),1.18-1.32(m,4H).

[0733] Example 158: N-(4-((4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)methyl)phenyl)acrylamide

[0734] Using tert-butyl 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidine-1-carboxylate and tert-butyl (4-formylphenyl)carbamate as raw materials, reductive amination was performed and the target compound (5 mg) was synthesized according to the method of Example 4.

[0735] MS m / z[LC-MS]:466.24[M+1]. 1 H NMR(400MHz, CDCl3)8.53(d,J=1.2Hz,1H),8.21(s,1H),7.76-7.90(brs,1H),7.74(s,1H), 7.68(s,1H),7.63(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),7.37(s,1H),6.43(dd,J=16.8Hz ,1.6Hz,1H),6.32(dd,J=16.8Hz,10.0Hz,1H),5.75(dd,J=10.0Hz,1.6Hz,1H),3.98(s,3H) ,3.75(s,2H),3.39-3.48(m,1H),3.20-3.31(m,2H),2.42-2.58(m,2H),2.01-2.19(m,4H).

[0736] Example 159: 4-(4-((1-acryloylazetidin-3-yl)ethynyl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0737] The target compound (15 mg) was obtained by the synthetic method of Example 18 using intermediate 7 and tert-butyl 3-ethynylazetidine-1-carboxylate as raw materials.

[0738] MS m / z[LC-MS]:433.16[M+1]. 1 H NMR (400MHz, CDCl3)8.67(d,J=1.2Hz,1H),8.26(s,1H),7.80(s,1H),7.70(s,1H),7.59(d,J=8.4 Hz,2H),7.53(d,J=8.4Hz,2H),7.45(d,J=1.2Hz,1H),6.37(dd,J=16.8Hz,1.6Hz,1H),6.20(dd,J =16.8Hz,10.4Hz,1H),5.71(dd,J=10.4Hz,1.6Hz,1H),4.53(t,J=8.4Hz,1H),4.41(t,J=9.2Hz,1 H), 4.33 (dd, J = 7.6Hz, 6.4Hz, 1H), 4.19 (dd, J = 9.2Hz, 6.4Hz, 1H), 3.99 (s, 3H), 3.65-3.73 (m, 1H).

[0739] Example 160: 5-(4-((1-acryloylazetidin-3-yl)ethynyl)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile

[0740] The target compound (10 mg) was obtained according to the synthesis method of Example 18 using 4-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)phenyl trifluoromethanesulfonate and tert-butyl 3-ethynylazetidine-1-carboxylate as raw materials.

[0741] MS m / z[LC-MS]:433.17[M+1]. 1H NMR(400MHz, CDCl3)8.16(s,1H),7.87(s,1H),7.84(s,1H),7.79(s,1H),7.61(d,J=8.0Hz,2 H),7.50(d,J=8.0Hz,2H),7.06(s,1H),6.37(dd,J=16.8Hz,1.2Hz,1H),6.20(dd,J=16.8Hz, 10.0Hz,1H),5.71(dd,J=10.0Hz,1.2Hz,1H),4.54(t,J=8.4Hz,1H),4.42(t,J=9.6Hz,1H),4 .34(dd,J=8.4Hz,6.4Hz,1H),4.20(dd,J=9.6Hz,6.4Hz,1H),3.99(s,3H),3.66-3.73(m,1H).

[0742] Example 161: 4-((4-(4-acryloylpiperazin-1-yl)phenyl)ethynyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0743] The target compound (35 mg) was obtained by the synthesis method of Example 18 using Intermediate 1 and tert-butyl 4-(4-ethynylphenyl)piperazine-1-carboxylate as raw materials.

[0744] MS m / z[LC-MS]:462.20[M+1]. 1 H NMR (400MHz, DMSO-d6)9.24(s,1H),8.68(s,1H),8.38(s,1H),8.11(s,1H),8.04(s,1H),7.56(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),6.84(d d, J=16.8Hz, 10.4Hz, 1H), 6.13 (dd, J=16.8Hz, 2.0Hz, 1H), 5.70 (dd, J=10.4Hz, 2.0Hz, 1H), 3.86 (s, 3H), 3.63-3.74 (m, 4H), 3.26-3.36 (m, 4H).

[0745] Example 162: N-(4-(4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridin-1(2H)-yl)phenyl)acrylamide

[0746] The target compound (18 mg) was synthesized by referring to the synthesis method of Example 4 and Example 8 using 3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester and (4-bromophenyl)carbamate as raw materials.

[0747] MS m / z[LC-MS]:486.18[M+1].

[0748] Example 163: 4-(4-(1-acryloylpiperidin-4-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0749] The target compound (8 mg) was obtained by the synthesis method of Example 4 using intermediate 7 and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate as starting materials.

[0750] MS m / z[LC-MS]:421.15[M+1].

[0751] Example 164: N-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro-2H-[1,3'-bipyridyl]-6'-yl)acrylamide

[0752] According to the synthesis method of Example 3, the target compound (24 mg) was obtained using tert-butyl 4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (5-bromopyridin-2-yl)carbamate as raw materials.

[0753] MS m / z[LC-MS]:451.19[M+1]. 1H NMR (400MHz, CDCl3+CD3OD)8.56(d,J=1.2Hz,1H),8.19(s,1H),8.13(d,J=9.2Hz,1H),7.92 (d,J=2.8Hz,1H),7.72(s,1H),7.69(s,1H),7.34(dd,J=9.2Hz,2.8Hz,1H),7.31(d,J=1.2H z,1H),6.37(dd,J=16.8Hz,2.0Hz,1H),6.28(dd,J=16.8Hz,9.6Hz,1H),6.07-6.11(m,1H), 5.72(dd,J=9.6Hz,2.0Hz,1H),3.86-3.94(m,5H),3.58(t,J=5.6Hz,2H),2.62-2.68(m,2H).

[0754] Example 165: (R)-3-(4-((1-acryloylpyrrolidin-3-yl)oxy)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)-N-methylbenzamide

[0755] Step 1: tert-Butyl (R)-3-((3-iodo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)pyrrolidine-1-carboxylate

[0756] To a toluene (5 mL) solution of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (21 mg), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (19 mg), and triphenylphosphine (53 mg) was slowly added dropwise DIAD (40 mg) at 0°C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 1:1 (v:v)) to yield a white solid (35 mg). At room temperature, the residue was dissolved in dichloromethane (5 mL), and NIS (40 mg) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was washed with saturated sodium carbonate solution, and the organic phase was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: petroleum ether:ethyl acetate = 1:1 (v:v)) to yield a white solid (30 mg).

[0757] Steps 2 and 3 were carried out according to the procedure of Example 4 to obtain the target compound (4 mg).

[0758] MS m / z[LC-MS]:471.22[M+1]. 1H NMR(400MHz, CDCl3)8.31(s,0.4H),8.29(s,0.6H),7.85-7.91(m,2H),7.74(s,0.4H) ,7.73(s,0.6H),7.62(s,0.4H),7.61(s,0.6H),7.46-7.55(m,2H),7.34(t,J=7.6Hz, 1H),6.42-6.56(m,2H),6.19-6.35(m,2H),5.63-5.67(m,1H),5.01-5.11(m,1H),3.9 8(s,3H),3.49-3.80(m,3H),3.02-3.16(m,4H),2.19-2.32(m,1H),1.98-2.12(m,1H).

[0759] Example 166: N-(5-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)pyridin-2-yl)acrylamide

[0760] The intermediate of Example 164 was used as a raw material and then subjected to hydrogenation reduction according to the synthesis method of Example 4 to obtain the target compound (14 mg).

[0761] MS m / z[LC-MS]:453.22[M+1]. 1 H NMR (400MHz, DMSO-d6)10.48(s,1H),9.12(d,J=1.2Hz,1H),8.62(s,1H),8.39(s,1H),8.09-8. 10(m,2H),8.06(d,J=9.2Hz,1H),7.70(s,1H),7.49(dd,J=9.2Hz,2.8Hz,1H),6.56(dd,J=17.2 Hz,10.0Hz,1H),6.24(dd,J=17.2Hz,1.6Hz,1H),5.70(dd,J=10.0Hz,1.6Hz,1H),3.90(d,J=12 .0Hz, 2H), 3.86 (s, 3H), 3.22-3.40 (m, 1H), 3.85 (td, J = 12.0Hz, 2.0Hz, 2H), 1.94-2.09 (m, 4H).

[0762] Example 167: 4-(4-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0763] The target compound (10 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as starting materials.

[0764] MS m / z[LC-MS]:478.25[M+1]. 1 H NMR(400MHz, CDCl3)8.61(s,1H),8.25(s,1H),7.78(s,1H),7.67(s,1H),7.4 7(d,J=8.8Hz,2H),7.40(s,1H),7.05(d,J=8.8Hz,2H),6.36(dd,J=17.2Hz,1 .2Hz,1H),6.22(dd,J=17.2Hz,10.4Hz,1H),5.68(dd,J=10.4Hz,1.2Hz,1H), 3.98(s,3H),3.96(s,2H),3.85(s,2H),3.26-3.28(m,4H),1.92-1.94(m,4H).

[0765] Example 168: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0766] The target compound (3 mg) was synthesized by using the intermediate tert-butyl 2,4-oxopiperidine-1-carboxylate as a raw material through reductive amination and referring to the method of Example 4.

[0767] MS m / z[LC-MS]:521.30[M+1]. 1 H NMR (400MHz, CDCl3)8.60(s,1H),8.24(s,1H),7.78(s,1H),7.67(s,1H),7.47(d,J=8.4Hz ,2H),7.40(s,1H),7.03(d,J=8.4Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.27(d,J=16. 8Hz,1H),5.68(d,J=10.4Hz,1H),4.64-4.76(m,1H),4.01-4.12(m,1H),3.97(s,3H),3.26 -3.37(m,4H),3.04-3.14(m,1H),2.52-2.80(m,6H),1.90-2.02(m,2H),1.44-1.58(m,2H).

[0768] Example 169: 4-(4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0769] The target compound (7 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate as starting materials.

[0770] MS m / z[LC-MS]:466.25[M+1]. 1 H NMR(400MHz, CDCl3)8.61(d,J=1.2Hz,1H),8.26(s,1H),7.79(s,1H),7.68(s,1H),7.49(d,J=8.8Hz,2H),7.4 1(d,J=1.2Hz,1H),6.99(d,J=8.8Hz,2H),6.67(dd,J=16.8Hz,10.4Hz,0.4H),6.56(dd,J=16.8Hz,10.4Hz,0.6 H),6.31-6.39(m,1H),5.72-5.77(m,1H),4.98-507(m,0.6H),4.42-4.45(m,0.4H),4.27-4.38(m,0.4H),4.09 -4.23(m,1H),3.99(s,3H),3.64-3.82(m,1H),3.28-3.43(m,2.6H),1.34-1.42(m,3H),1.10(d,J=6.8Hz,3H).

[0771] Example 170: 4-(4-((2R,5S)-4-acryloyl-2,5-dimethylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0772] The target compound (8 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate as starting materials.

[0773] MS m / z[LC-MS]:466.25[M+1]. 1H NMR(400MHz, CDCl3)8.61(d,J=1.2Hz,1H),8.26(s,1H),7.79(s,1H),7.68(s,1H),7.49(d,J=8.8Hz,2H),7.4 1(d,J=1.2Hz,1H),6.99(d,J=8.8Hz,2H),6.67(dd,J=16.8Hz,10.4Hz,0.4H),6.56(dd,J=16.8Hz,10.4Hz,0.6 H),6.31-6.39(m,1H),5.72-5.77(m,1H),4.98-507(m,0.6H),4.42-4.45(m,0.4H),4.27-4.38(m,0.4H),4.09 -4.23(m,1H),3.99(s,3H),3.64-3.82(m,1H),3.28-3.43(m,2.6H),1.34-1.42(m,3H),1.10(d,J=6.8Hz,3H).

[0774] Example 171: N-(1-(4-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0775] Referring to the synthesis method of Example 8, the target compound (12 mg) was synthesized using 4-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0776] MS m / z[LC-MS]:523.30[M+1]. 1H NMR(400MHz, CDCl3)8.60(s,1H),8.24(s,1H),7.79(s,1H),7.78(s,1H),7.43(d,J=8.4Hz,2H),7. 39(s,1H),6.58(d,J=8.4Hz,2H),6.34(d,J=16.8Hz,1H),6.20(d,J=8.0Hz,1H),6.13(dd,J=16.8H z,10.4Hz,1H),5.71(d,J=10.4Hz,1H),4.93-5.01(m,1H),4.34(t,J=7.6Hz,2H),4.29(t,J=6.8Hz ,2H),3.75(dd,J=8.0Hz,5.6Hz,2H),3.68-3.71(m,4H),2.85(t,J=6.8Hz,2H),2.49-2.51(m,4H).

[0777] Example 172: 4-(4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)phenyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0778] Referring to the synthesis method of Example 8, the target compound (8 mg) was synthesized using 4-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester as raw materials.

[0779] MS m / z[LC-MS]:565.30[M+1]. 1 H NMR(400MHz, CDCl3)8.63(d,J=1.2Hz,1H),8.27(s,1H),7.79(s,1H),7.78(s,1H),7.52(d,J=8.8Hz, 2H),7.42(d,J=1.2Hz,1H),7.07(d,J=8.8Hz,2H),6.64(dd,J=16.8Hz,10.4Hz,1H),6.38(dd,J=16.8H z,2.0Hz,1H),5.73(dd,J=10.4Hz,2.0Hz,1H),4.16-4.84(m,4H),3.69-3.71(m,4H),3.59(d,J=12.0H z, 2H), 3.04 (dd, J = 12.0, 4.0Hz, 2H), 2.86 (t, J = 6.4Hz, 2H), 2.49-2.51 (m, 4H), 1.46 (d, J = 7.2Hz, 6H).

[0780] Example 173: (S)-4-(4-(4-acryloyl-2-methylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0781] The target compound (18 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and (S)-tert-butyl 3-methylpiperazine-1-carboxylate as starting materials.

[0782] MS m / z[LC-MS]:452.24[M+1]. 1 H NMR(400MHz, CDCl3)8.62(d,J=1.2Hz,1H),8.25(s,1H),7.79(s,1H),7.68(s,1H),7.49(d,J=8.8Hz,2H), 7.41(d,J=1.2Hz,1H),7.01(d,J=8.8Hz,2H),6.56-6.69(m,1H),6.37(dd,J=16.8Hz,1.6Hz,1H),5.72-5.7 9(m,1H),4.56-4.64(m,0.5H),4.34-4.41(m,1H),4.05-4.14(m,1H),3.98(s,3H),3.78-3.86(m,0.5H),3. 60-3.68(m,0.5H),3.40-3.54(m,1.5H),3.31-3.38(m,0.5H),3.10-3.26(m,1.5H),1.10(d,J=6.4Hz,3H).

[0783] Example 174: 4-(4-(7-acryloyl-2,7-diazaspiro[3.5]non-2-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0784] The target compound (18 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate as starting materials.

[0785] MS m / z[LC-MS]:478.28[M+1]. 1H NMR(400MHz, CDCl3)8.59(s,1H),8.23(s,1H),7.77(s,1H),7.67(s,1H),7.42 (d,J=8.4Hz,2H),7.37(s,1H),6.59(dd,J=16.8Hz,10.8Hz,1H),6.55(d,J=8.4 Hz,2H),6.37(dd,J=16.8Hz,1.2Hz,1H),5.69(dd,J=10.8Hz,1.2Hz,1H),3.97 (s,3H),3.72(s,4H),3.61-3.69(m,2H),3.48-3.58(m,2H),1.80-1.91(m,4H).

[0786] Example 175: (R)-4-(4-(4-acryloyl-3-methylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0787] The target compound (14 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and (R)-tert-butyl 2-methylpiperazine-1-carboxylate as starting materials.

[0788] MS m / z[LC-MS]:452.23[M+1]. 1 H NMR (400MHz, CDCl3)8.62(s,1H),8.25(s,1H),7.79(s,1H),7.68(s,1H),7.50(d,J=8.8Hz,2H),7. 40(s,1H),7.02(d,J=8.8Hz,2H),6.61(dd,J=16.8Hz,10.8Hz,1H),6.34(d,J=16.8Hz,1H),5.74(d ,J=10.8Hz,1H),4.80-5.08(m,0.5H),4.17-4.65(m,1H),3.80-4.06(m,3.5H),3.46-3.75(m,2.5H ), 3.19-3.42 (m, 0.5H), 3.04-3.17 (m, 1H), 2.92 (td, J = 12.0Hz, 3.2Hz, 1H), 1.40 (d, J = 4.4Hz, 3H).

[0789] Example 176: (S)-4-(4-(4-acryloyl-3-methylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0790] The target compound (4 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and (S)-tert-butyl 2-methylpiperazine-1-carboxylate as starting materials.

[0791] MS m / z[LC-MS]:452.22[M+1]. 1 H NMR (400MHz, CDCl3)8.61(s,1H),8.24(s,1H),7.78(s,1H),7.67(s,1H),7.48(d,J=8.8Hz,2H),7 .39(s,1H),7.00(d,J=8.8Hz,2H),6.60(dd,J=16.8Hz,10.8Hz,1H),6.33(d,J=16.8Hz,1H),5.73 (d,J=10.8Hz,1H),4.79-5.08(m,0.5H),4.17-4.65(m,1H),3.78-4.04(m,3.5H),3.44-3.76(m,2 .5H), 3.19-3.40 (m, 0.5H), 3.01-3.16 (m, 1H), 2.90 (td, J = 11.6Hz, 3.2Hz, 1H), 1.33-1.46 (m, 3H).

[0792] Example 177: (R)-4-(4-(4-acryloyl-2-methylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0793] The target compound (8 mg) was obtained by the synthetic method of Example 8 using intermediate 7 and (R)-tert-butyl 3-methylpiperazine-1-carboxylate as starting materials.

[0794] MS m / z[LC-MS]:452.21[M+1]. 1H NMR (400MHz, CDCl3)8.61(s,1H),8.24(s,1H),7.79(s,1H),7.68(s,1H),7.48(d,J=8.8Hz.2H),7. 41(s,1H),7.00(d,J=8.8Hz,2H),6.55-6.69(m,1H),6.36(dd,J=16.8Hz,1.6Hz,1H),5.71-5.79(m ,1H),4.55-4.64(m,0.5H),4.33-4.41(m,0.5H),4.05-4.14(m,1H),3.92-4.04(m,3.5H),3.77-3. 86(m,0.5H),3.59-3.68(m,0.5H),3.30-3.54(m,2H),3.08-3.26(m,1.5H),1.09(d,J=6.4Hz,3H).

[0795] Example 178: 4-(4-(9-acryloyl-3,9-diazaspiro[5.5]undec-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0796] The target compound (13 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate as starting materials.

[0797] MS m / z[LC-MS]:506.28[M+1]. 1 H NMR(400MHz, CDCl3)8.60(s,1H),8.24(s,1H),7.78(s,1H),7.68(s,1H),7.47(d,J= 8.4Hz,2H),7.40(s,1H),7.04(d,J=8.4Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.2 8(dd,J=16.8Hz,1.6Hz,1H),5.68(dd,=10.4Hz,1.6Hz,1H),3.98(s,3H),3.63-3.71 (m,2H),3.51-3.58(m,2H),3.28-3.31(m,4H),1.68-1.71(m,4H),1.53-1.60(m,4H).

[0798] Example 179: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0799] The target compound (23 mg) was obtained using intermediate 8 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0800] MS m / z[LC-MS]:424.23[M+1]. 1 H NMR(400MHz, DMSO-d6)13.08(s,1H),9.23(d,J=1.2Hz,1H),8.61(s,1H),8. 45(s,1H),8.17(s,1H),7.77(d,J=1.2Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d ,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz ,1H),5.70(dd,J=10.4Hz,2.4Hz,1H),3.65-3.77(m,4H),3.22-3.30(m,4H).

[0801] Example 180: N-(4-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)phenyl)acrylamide

[0802] The target compound (5 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl (4-bromophenyl)carbamate as the raw material.

[0803] MS m / z [LC-MS]: 467.24M+1]. 1 H NMR(400MHz, CDCl3)8.39(s,1H),8.21(s,1H),7.78(s,1H),7.70(s,1H),7.51(d,J=8.4Hz,2H),6.97-7.00(m,3H),6.42(d,J=17.2Hz,1H),6 .23(dd,J=17.2Hz,10.0Hz,1H),5.74(d,J=10.0Hz,1H),4.25(q,J=7.2Hz,2H),3.46-3.53(m,4H),3.32-3.38(m,4H),1.56(t,J=7.2Hz,3H).

[0804] Example 181: N-(4-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)phenyl)acrylamide

[0805] The target compound (7 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl (4-bromophenyl)carbamate as the raw material.

[0806] MS m / z [LC-MS]: 523.28M+1]. 1 H NMR(400MHz, CDCl3)8.39(s,1H),8.21(s,1H),7.79(s,1H),7.73(s,1H),7.50(d,J= 8.8Hz,2H),7.23(s,1H),6.96-6.99(m,3H),6.42(d,J=16.8Hz,1H),6.23(dd,J=16.8 Hz,10.0Hz,1H),5.74(d,J=10.0Hz,1H),4.38-4.46(m,1H),4.12-4.18(m,2H),3.57 (td,J=11.2Hz,2.8Hz,2H),3.45-3.53(m,4H),3.31-3.38(m,4H),2.08-2.20(m,4H).

[0807] Example 182: N-(4-(4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)phenyl)acrylamide

[0808] The target compound (4 mg) was obtained according to the synthetic method of Example 166.

[0809] MS m / z[LC-MS]:488.20[M+1].

[0810] Example 183: N-(1-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)-3-methylazetidin-3-yl)acrylamide

[0811] The target compound (15 mg) was obtained by the synthetic method of Example 8 using intermediate 7 and tert-butyl (3-methylazetidin-3-yl) carbamate as starting materials.

[0812] MS m / z[LC-MS]:438.22[M+1]. 1H NMR (400MHz, CDCl3)8.58(s,1H),8.22(s,1H),7.77(s,1H),7.67(s,1H),7.40(d,J=8.4Hz,2H),7.36(s,1H),6.52(d,J=8.4Hz,2H ), 6.49 (s, 1H), 6.28 (d, J = 17.2Hz, 1H), 6.10 (dd, J = 17.2Hz, 10.4Hz, 1H), 5.64 (d, J = 10.4Hz, 1H), 3.92-3.98 (m, 7H), 1.72 (s, 3H).

[0813] Example 184: N-(4-(1-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)azetidin-3-yl)phenyl)acrylamide

[0814] The target compound (5 mg) was obtained according to the synthetic method of Example 8 using intermediate 7 and tert-butyl (4-(azetidin-3-yl)phenyl)carbamate as starting materials.

[0815] MS m / z[LC-MS]:424.19[M+1]. 1 H NMR (400MHz, CDCl3)8.25(s,1H),8.19(s,1H),7.75(s,1H),7.65(s,1H),7.54-7.61(m,2H),7.36(d,J=8.4Hz,2H),7.22(s,1H),6.42-6.46(m,2 H), 6.24 (dd, J = 17.2Hz, 10.4Hz, 1H), 5.78 (dd, J = 10.4Hz, 1.2Hz, 1H), 4.70 (t, J = 8.0Hz, 2H), 4.19-4.22 (m, 2H), 3.99-4.07 (m, 1H), 3.98 (s, 3H).

[0816] Example 185: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0817] The target compound (13 mg) was obtained using Intermediate 8 and 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[0818] MS m / z[LC-MS]:488.22[M+1]. 1H NMR(400MHz, DMSO-d6)9.25(d,J=1.6Hz,1H),8.63(s,1H),8.49(s,1H),8.23(s,1H),7.7 4(d,J=1.6Hz,1H),7.51(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz,10. 4Hz, 1H), 6.38 (tt, J=55.2Hz, 3.6Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.70 (dd, J=10 .4Hz, 2.4Hz, 1H), 4.64 (td, J = 15.2Hz, 4.0Hz, 2H), 3.65-3.77 (m, 4H), 3.22-3.29 (m, 4H).

[0819] Example 186: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(1-hydroxy-2-methylpropane-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0820] The target compound (20 mg) was obtained using Intermediate 8 and 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol as starting materials.

[0821] MS m / z[LC-MS]:496.25[M+1]. 1 H NMR(400MHz, DMSO-d6)9.22(d,J=1.2Hz,1H),8.61(s,1H),8.53(s,1H),8.13(s,1H),7 .80(d,J=1.2Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.85(dd,J=16.8Hz, 10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.96(t,J =5.6Hz,1H),3.66-3.77(m,4H),3.58(d,J=5.6Hz,2H),3.22-3.29(m,4H),1.48(s,6H).

[0822] Example 187: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0823] The target compound (10 mg) was obtained using intermediate 8 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1-(trifluoromethyl)-1H-pyrazole as starting materials.

[0824] MS m / z[LC-MS]:492.20[M+1]. 1 H NMR(400MHz, DMSO-d6)9.43(d,J=1.6Hz,1H),9.24(s,1H),8.70(s,1H),8.69(s,1H),7.91(d,J=1.6Hz,1H),7.52(d,J=8.8Hz,2H),7.10(d,J=8.8 Hz,2H),6.86(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),3.66-3.67(m,4H),3.22-3.30(m,4H).

[0825] Example 188: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0826] The target compound (8 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[0827] MS m / z[LC-MS]:450.20[M+1]. 1 H NMR(400MHz,DMSO-d6)9.17(d,J=1.6Hz,1H),8.61(s,1H),8.37(s,1H),8.0 9(s,1H),7.66(d,J=1.6Hz,1H),7.45(d,J=8.8Hz,2H),6.55(d,J=8.8Hz,2H ),6.29(dd,=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,1H),5.66(dd ,J=10.4Hz,2.4Hz,1H),4.43(s,2H),4.13(s,2H),4.03(s,4H),3.85(s,3H).

[0828] Example 189: 4-(4-((3S,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0829] The target compound (18 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate as starting materials.

[0830] MS m / z[LC-MS]:466.23[M+1]. 1 H NMR(400MHz,DMSO-d6)9.17(d,J=1.2Hz,1H),8.62(s,1H),8.37(s,1H),8.10(s,1H),7 .69(d,J=1.2Hz,1H),7.50(d,J=8.8Hz,2H),6.82(d,J=8.8Hz,2H),6.78(dd,J=16.8Hz ,10.4Hz,1H),6.21(dd,J=16.8Hz,2.4Hz,1H),5.72(dd,J=10.4Hz,2.4Hz,1H),4.40-4 .51(m,2H),3.86(s,3H),3.69-3.78(m,2H),3.46-3.52(m,2H),1.21(d,J=7.2Hz,6H).

[0831] Example 190: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0832] The target compound (12 mg) was obtained using Intermediate 8 and 2-(1-(ethylsulfonyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile as starting materials.

[0833] MS m / z[LC-MS]:610.23[M+1].

[0834] Example 191: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0835] The target compound (16 mg) was obtained using Intermediate 8 and 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[0836] MS m / z[LC-MS]:494.22[M+1]. 1 H NMR(400MHz,DMSO-d6)9.21(s,1H),8.62(s,1H),8.44(s,1H),8.13(s,1H),7.72( s,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.4Hz,10.4Hz,1 H),6.14(dd,J=16.4Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.63-4.66(m ,2H),4.40-4.43(m,4H),3.66-3.76(m,4H),3.36-3.46(m,1H),3.21-3.30(m,4H).

[0837] Example 192: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(fluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0838] The target compound (4 mg) was obtained using intermediate 8 and 1-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0839] MS m / z[LC-MS]:456.20[M+1]. 1 H NMR (400MHz, DMSO-d6)9.31(s,1H),8.74(s,1H),8.65(s,1H),8.38(s,1H),7.77(s,1H),7.52(d,J=8.8Hz,2H),7.10(d,J=8.8Hz,2H),6.86(dd,J=1 6.8Hz, 10.4Hz, 1H), 6.16 (d, J = 53.2Hz, 2H), 6.14 (dd, J = 16.8Hz, 2.4Hz, 1H), 5.71 (dd, J = 10.4Hz, 2.4Hz, 1H), 3.65-3.78 (m, 4H), 3.20-3.32 (m, 4H).

[0840] Example 193: 4-(4-((4-acryloylpiperazin-1-yl)methyl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0841] The target compound (22 mg) was obtained according to the synthetic method of Example 8 using intermediate 2 and (4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)boronic acid as starting materials.

[0842] MS m / z[LC-MS]:452.22[M+1]. 1 H NMR(400MHz, CDCl3)8.66(s,1H),8.25(s,1H),7.80(s,1H),7.69(s,1H),7.48-7.54(m,4H),7.46(s,1H),6.56(dd,J=16.8Hz,10.4Hz,1H),6.2 8(d,J=16.8Hz,2.0Hz,1H),5.68(dd,J=10.4Hz,2.0Hz,1H),3.99(s,3H),3.68-3.76(m,2H),3.62(s,2H),3.54-3.61(m,2H),2.44-2.56(m,4H).

[0843] Example 194: (S)-4-((1-acryloylpyrrolidin-3-yl)oxy)-N-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

[0844] The target compound (11 mg) was obtained by following the procedure of Example 165.

[0845] MS m / z[LC-MS]:395.17[M+1].

[0846] Example 195: N-(1-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0847] Example 145 (20 mg) was dissolved in DMF (1 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (10 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (10 mg).

[0848] MS m / z[LC-MS]:508.24[M+1]. 1 H NMR(400MHz,DMSO-d6)9.19(s,1H),8.61(s,1H),8.54(s,1H),8.14(s,1H),7.72(s,1H) ,7.46(d,J=8.0Hz,2H),6.72-6.84(m,1H),6.58(d,J=8.8Hz,2H),6.04-6.18(m,1H),5. 65-5.74(m,1H),5.12-5.30(m,1H),4.35-4.44(m,1H),4.10-4.20(m,2H),3.84-4.02(m ,4H),3.47(td,J=12.0Hz,1.6Hz,2H),3.14(s,1.7H),3.02(s,1.3H),1.87-2.06(m,4H).

[0849] Example 196: N-(6-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[0850] The target compound (19 mg) was synthesized by referring to the synthesis method of Example 18 using tert-butyl (6-bromopyridin-3-yl)carbamate as a raw material.

[0851] MS m / z [LC-MS]: 454.25M+1]. 1H NMR(400MHz, CDCl3)8.38(s,1H),8.27(s,1H),8.21(s,1H),8.07(d,J=9.6 Hz,1H),7.75(s,1H),7.66(s,1H),7.32-7.52(brs,1H),6.95(s,1H),6.76( d,J=9.6Hz,1H),6.44(d,J=17.2Hz,1H),6.28(dd,J=17.2Hz,10.0Hz,1H), 5.78(d,J=10.0Hz,1H),3.98(s,3H),3.84-3.92(m,4H),3.27-3.33(m,4H).

[0852] Example 197: 4-(4-(5-acryloylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0853] The target compound (5 mg) was obtained by the synthesis method of Example 8 using intermediate 7 and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate as starting materials.

[0854] MS m / z[LC-MS]:464.27[M+1]. 1 H NMR(400MHz, CDCl3)8.59(d,J=1.2Hz,1H),8.24(s,1H),7.78(s,1H),7.67(s ,1H),7.47(d,J=8.4Hz,2H),7.38(d,J=1.2Hz,1H),6.69(d,J=8.4Hz,2H),6.4 0-6.43(m,2H),5.70(dd,J=8.8Hz,3.2Hz,1H),3.98(s,3H),3.84-3.93(m,2H) ,3.63-3.70(m,3H),3.51-3.55(m,1H),3.28-3.36(m,2H),3.04-3.21(m,2H).

[0855] Example 198: N-(1-(4-(3-cyano-7-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)phenyl)azetidin-3-yl)acrylamide

[0856] The target compound (6 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-7-(1-ethyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as starting materials.

[0857] MS m / z[LC-MS]:438.22[M+1]. 1 H NMR (400MHz, CDCl3)8.11(s,1H),7.87(s,1H),7.85(s,1H),7.78(s,1H),7.31(d,J=8. 4Hz,2H),7.06(s,1H),6.54(d,J=8.4Hz,2H),6.31(dd,J=17.2Hz,1.2Hz,1H),6.11(dd, J=17.2Hz,10.4Hz,1H),5.67(dd,J=10.4Hz,1.2Hz,1H),4.98-5.04(m,1H),4.35(t,J=8 .0Hz, 2H), 4.22 (q, J = 7.2Hz, 2H), 3.72 (dd, J = 8.0Hz, 5.2Hz, 2H), 1.52 (t, J = 7.2Hz, 3H).

[0858] Example 199: N-(1-(4-(3-cyano-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0859] Example 171 (54 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (6 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (33 mg).

[0860] MS m / z[LC-MS]:537.28[M+1]. 1H NMR(400MHz,DMSO-d6)9.18(s,1H),8.61(s,1H),8.43(s,1H),8.11(s,1H),7.67(s,1H),7 .47(d,J=8.0Hz,2H),6.70-6.85(m,1H),6.58(d,J=8.0Hz,2H),6.04-6.18(m,1H),5.66-5 .75(m,1H),5.12-5.28(m,1H),4.23(t,J=6.4Hz,2H),4.10-4.20(m,2H),3.84-4.03(m,2H ),3.49-3.56(m,4H),3.14(s,2H),3.02(s,1H),2.72(t,J=6.4Hz,2H),2.35-2.43(m,4H).

[0861] Example 200: N-(1-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0862] Example 146 (44 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (6 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (26 mg).

[0863] MS m / z[LC-MS]:452.22[M+1]. 1 H NMR(400MHz,DMSO-d6)9.18(s,1H),8.61(s,1H),8.43(s,1H),8.11(s,1H),7.67(s,1H),7 .47(d,J=8.0Hz,2H),6.70-6.85(m,1H),6.58(d,J=8.0Hz,2H),6.04-6.18(m,1H),5.66-5 .75(m,1H),5.12-5.28(m,1H),4.23(t,J=6.4Hz,2H),4.10-4.20(m,2H),3.84-4.03(m,2H ),3.49-3.56(m,4H),3.14(s,2H),3.02(s,1H),2.72(t,J=6.4Hz,2H),2.35-2.43(m,4H).

[0864] Example 201: N-(1-(4-(3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0865] Referring to the synthesis method of Example 8, the target compound (22 mg) was synthesized using 4-(3-cyano-6-(3-hydroxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0866] MS m / z[LC-MS]:429.23[M+1]. 1 H NMR(400MHz,DMSO-d6)8.81(d,J= 7.6Hz,1H),8.43(s,1H),8.00(d,J=2.0Hz,1H),7.28(d,J=8.4Hz,2H),6.84(d,J =2.0Hz,1H),6.55(d,J=8.4Hz,2H),6.20(dd,J=17.2Hz,10.0Hz,1H),6.11(dd,J= 17.2Hz,2.8Hz,1H),5.62(dd,J=10.0Hz,2.8Hz,1H),5.56(s,1H),4.66-4.74(m,1 H), 4.19 (t, J = 7.6Hz, 2H), 3.81 (d, J = 7.6Hz, 2H), 3.66-3.69 (m, 4H), 1.44 (s, 3H).

[0867] Example 202: N-(1-(4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0868] Referring to the synthesis method of Example 8, the target compound (12 mg) was synthesized using 4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0869] MS m / z[LC-MS]:460.23[M+1]. 1H NMR (400MHz, DMSO-d6)9.36(d,J=1.6Hz,1H),9.00(s,1H),8.82(d,J=6.8Hz,1H),8.66(s,1H ),8.51(s,1H),7.85(t,J=59.6Hz,1H),7.83(d,J=1.6Hz,1H),7.48(d,J=8.8Hz,2H),6.59(d ,J=8.8Hz,2H),6.21(dd,J=17.2Hz,9.6Hz,1H),6.11(dd,J=17.2Hz,2.8Hz,1H),5.63(dd,J= 9.6Hz, 2.8Hz, 1H), 4.68-4.76 (m, 1H), 4.21 (t, J = 7.6Hz, 2H), 3.69 (dd, J = 7.6Hz, 5.6Hz, 2H).

[0870] Example 203: N-(1-(4-(3-cyano-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)acrylamide

[0871] Referring to the synthesis method of Example 8, the target compound (9 mg) was synthesized using 4-(3-cyano-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0872] MS m / z[LC-MS]:450.23[M+1]. 1 H NMR(400MHz, CDCl3)8.59(d,J=1.2Hz,1H),8.24(s,1H),7.76(s,2H),7.43(d,J=8.4Hz, 2H),7.38(d,J=1.2Hz,1H),6.58(d,J=8.4Hz,2H),6.34(dd,J=16.8Hz,1.2Hz,1H),6.09- 6.16(m,2H),5.72(dd,J=10.0Hz,1.2Hz,1H),4.92-5.02(m,1H),4.32(t,J=7.6Hz,2H), 3.75(dd,J=7.6Hz,5.2Hz,2H),3.63-3.69(m,1H),1.17-1.21(m,2H),1.06-1.11(m,2H).

[0873] Example 204: N-(1-(4-(3-cyano-6-(3-methoxy-3-methylazetidin-1-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0874] Example 201 (43 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (10 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (30 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (21 mg).

[0875] MS m / z[LC-MS]:457.24[M+1]. 1 H NMR (400MHz, CDCl3)8.12(s,1H),7.68(d,J=1.6Hz,1H),7.41(d,J=8.4Hz,2H),6.72(d,J= 1.6Hz,1H),6.52-6.64(m,3H),6.24-6.39(m,1H),5.70-5.79(m,1H),5.42-5.52(m,0.7H) ,4.96-5.08(m,0.3H),4.23(t,J=7.6Hz,2H),3.99-4.10(m,0.6H),3.88-3.96(m,1.4H),3 .84(d,J=7.2Hz,2H),3.76(d,J=7.2Hz,2H),3.28(s,3H),3.13-3.25(m,3H),1.59(s,3H).

[0876] Example 205: N-(1-(4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0877] Example 202 (46 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (6 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (13 mg).

[0878] MS m / z[LC-MS]:474.20[M+1]. 1 H NMR(400MHz, CDCl3)8.67(s,1H),8.27(s,1H),8.13(s,1H),7.96(s,1H),7 .45(d,J=8.4Hz,2H),7.39(s,1H),7.24(t,J=60.4Hz,1H),6.48-6.64(m,3H ),6.20-6.41(m,1H),5.74(d,J=10.0Hz,1H),5.38-5.53(m,0.7H),4.96-5 .12(m,0.3H),4.23(t,J=7.6Hz,2H),3.86-4.12(m,2H),3.10-3.26(m,3H).

[0879] Example 206: N-(1-(4-(3-cyano-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0880] Example 203 (45 mg) was dissolved in DMF (2 mL), cooled to 0°C, and NaH (6 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (15 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (13 mg).

[0881] MS m / z[LC-MS]:464.22[M+1]. 1 H NMR(400MHz, CDCl3)8.60(s,1H),8.25(s,1H),7.77(s,2H),7.45(d,J=8.4Hz, 2H),7.38(s,1H),6.52-6.64(m,3H),6.34-6.42(m,1H),5.71-5.79(m,1H),5.4 2-5.53(m,0.7H),5.15-5.26(m,0.3H),4.24(t,J=8.0Hz,2H),3.89-4.11(m,2H ),3.62-3.69(m,1H),3.14-3.26(m,3H),1.16-1.22(m,2H),1.06-1.11(m,2H).

[0882] Example 207: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0883] The target compound (5 mg) was synthesized by referring to the synthesis method of Example 8 using tert-butyl 4-(piperazin-1-yl)piperidine-1-carboxylate as a raw material.

[0884] MS m / z[LC-MS]:445.26[M+1]. 1 H NMR(400MHz, CDCl3)8.36(s,1H),8.19(s,1H),7.74(s,1H),7.65(s,1H),6.92 (s,1H),6.58(dd,J=16.8Hz,10.4Hz,1H),6.27(d,J=16.8Hz,1H),5.69(d,J=10 .4Hz,1H),4.66-4.78(m,1H),4.02-4.13(m,1H),3.98(s,3H),3.17-3.35(m,4H ),2.88-3.14(m,5H),2.62-2.77(m,2H),1.96-2.08(m,2H),1.48-1.64(m,2H).

[0885] Example 208: N-(5-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperidin-1-yl)pyridin-2-yl)acrylamide

[0886] The target compound (14 mg) was obtained by following the synthetic method of Example 166.

[0887] MS m / z[LC-MS]:467.24[M+1]. 1H NMR(400MHz, CDCl3)8.56(d,J=1.2Hz,1H),8.21-8.24(m,2H),8.10-8.16(brs,1H),8.01(d,J=3.2Hz,1H),7.78(s,1H),7.70( s,1H),7.39(dd,J=8.8Hz,3.2Hz,1H),7.36(s,1H),6.45(dd,J=16.8Hz,1.2Hz,1H),6.26(dd,J=16.8Hz,10.4Hz,1H),5.79(d,d J=10.4Hz,1.2Hz,1H),4.25(q,J=7.2Hz,2H),3.78-3.84(m,2H),3.49-3.58(m,1H),3.09 (td,J=12.0Hz,1.6Hz,2H),2.20-2.27(m,2H),1.92-2.03(m,2H),1.56(t,J=7.6Hz,3H).

[0888] Example 209: N-(4-(3-cyano-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro-2H-[1,3'-bipyridyl]-6'-yl)acrylamide

[0889] The target compound (24 mg) was obtained by following the synthetic method of Example 164.

[0890] MS m / z[LC-MS]:491.23[M+1] 1 H NMR(400MHz, CDCl3)8.61(d,J=1.2Hz,1H),8.22-8.25(m,2H),7.98-8.05(m,2H),7.81(s,1H),7.79(s,1 H),7.38(dd,J=8.8Hz,2.8Hz,1H),7.37(d,J=2.8Hz,1H),6.45(dd,J=17.2Hz,1.2Hz,1H),6.26(dd,J=17. 2Hz,10.8Hz,1H),6.15-6.18(m,1H),5.78(dd,J=10.8Hz,1.2Hz,1H),4.05(d,J=7.2Hz,2H),3.98-4.02(m ,2H),3.66(t,J=5.2Hz,2H),2.70-2.76(m,2H),1.30-1.38(m,1H),0.69-0.74(m,2H),0.42-0.45(m,2H).

[0891] Example 210: N-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro-2H-[1,3'-bipyridyl]-6'-yl)acrylamide

[0892] The target compound (14 mg) was obtained by following the synthetic method of Example 164.

[0893] MS m / z[LC-MS]:465.25[M+1]. 1 H NMR(400MHz, CDCl3)8.60(s,1H),8.20-8.25(m,2H),8.03(s,1H),7.94(s,1H),7.79(s,1H),7.70(s, 1H),7.35-7.38(m,2H),6.44(d,J=16.8Hz,1H),6.25(dd,J=16.8Hz,10.4Hz,1H),6.12-6.19(m,1H), 5.78(d,J=10.4Hz,1H),4.25(q,J=7.2Hz,2H),3.99(s,2H),3.63-3.67(m,2H),2.67-2.76(m,2H),1.56(t,J=7.2Hz,3H).

[0894] Example 211: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(cyanomethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0895] The target compound (13 mg) was obtained using intermediate 8 and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetonitrile as starting materials.

[0896] MS m / z[LC-MS]:463.20[M+1]. 1H NMR (400MHz, CDCl3)8.65(d J=1.6Hz,1H),8.28(s,1H),7.89(s,1H),7.87(s,1H),7.51(d,J=8.8Hz,2H),7.39(d,J=1.6Hz,1H),7.06(d J=8.8Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J =10.4Hz, 2.0Hz, 1H), 5.16 (s, 2H), 3.83-3.92 (m, 2H), 3.71-3.80 (m, 2H), 3.32-3.35 (m, 4H).

[0897] Example 212: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-cyanopropan-2-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0898] The target compound (10 mg) was obtained using intermediate 8 and 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile as starting materials.

[0899] MS m / z[LC-MS]:491.23[M+1]. 1 H NMR(400MHz, CDCl3)8.66(d,J=1.6Hz,1H),8.27(s,1H),7.98(s,1H),7.90(s,1 H),7.52(d,J=8.8Hz,2H),7.42(d,J=1.6Hz,1H),7.10(d,J=8.8Hz,2H),6.62(dd ,J=16.8Hz,10.4Hz,1H),6.35(dd,J=16.8Hz,2.0Hz,1H),5.76(dd,J=10.4Hz,2. 0Hz,1H),3.86-3.95(m,2H),3.74-3.83(m,2H),3.33-3.36(m,4H),2.06(s,6H).

[0900] Example 213: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0901] The target compound (15 mg) was synthesized by referring to the synthesis method of Example 8 using intermediate 7 and tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate as raw materials.

[0902] MS m / z[LC-MS]:521.29[M+1]. 1 H NMR (400MHz, CDCl3)8.60(s,1H),8.25(s,1H),7.78(s,1H),7.67(s,1H),7.47(d,J=8. 4Hz,2H),7.40(s,1H),7.04(d,J=8.4Hz,2H),6.56(dd,J=16.8Hz,10.4Hz,1H),6.31(d ,J=16.8Hz,1H),5.71(d,J=10.4Hz,1H),3.98(s,3H),3.84-3.94(m,2H),3.49-3.80(m ,4H),2.84(t,J=11.6Hz,2H),2.36-2.76(m,5H),1.86-2.05(m,2H),1.48-1.74(m,2H).

[0903] Example 214: N-(1-(4-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0904] Example 151 (47 mg) was dissolved in DMF (1 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (10 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (30 mg).

[0905] MS m / z[LC-MS]:482.23[M+1]. 1H NMR(400MHz,DMSO-d6)9.20(s,1H),8.62(s,1H),8.42(s,1H),8.13(s,1H),7.69(s, 1H),7.47(d,J=8.4Hz,2H),6.72-6.85(m,1H),6.58(d,J=8.4Hz,2H),6.05-6.18(m,1 H),5.66-5.75(m,1H),5.13-5.31(m,1H),4.26(t,J=5.2Hz,2H),4.09-4.20(m,2H),3 .84-4.04(m,2H),3.70(t,J=5.2Hz,2H),3.22(s,3H),3.14(s,1.8H),3.02(s,1.2H).

[0906] Example 215: N-(1-(4-(3-cyano-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidine-3-)acrylamide

[0907] Referring to the synthesis method of Example 8, the target compound (12 mg) was synthesized using 4-(3-cyano-6-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl azetidin-3-ylcarbamate as raw materials.

[0908] MS m / z[LC-MS]:466.25[M+1]. 1 H NMR(400MHz, DMSO-d6)9.23(s,1H),8.83(d,J=6.8Hz,1H),8.68(s,1H),8.62(s,1H),8.27(s,1H), 7.74(s,1H),7.46(d,J=8.4Hz,2H),6.58(d,J=8.4Hz,2H),6.21(dd,J=16.8Hz,10.0Hz,1H),6.11( dd,J=16.8Hz,2.4Hz,1H),5.63(dd,J=10.0Hz,2.4Hz,1H),5.53-5.60(m,1H),4.95(t,J=6.8Hz,2H ), 4.89 (t, J = 6.8Hz, 2H), 4.68-4.76 (m, 1H), 4.20 (t, J = 7.6Hz, 2H), 3.69 (dd, J = 7.6Hz, 6.0Hz, 2H).

[0909] Example 216: N-(1-(4-(3-cyano-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)azetidin-3-yl)-N-methylacrylamide

[0910] Example 215 (47 mg) was dissolved in DMF (1 mL), cooled to 0°C, and NaH (5 mg) was added. The mixture was stirred for 0.5 hours, and iodomethane (10 mg) was slowly added. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 20:1 (v:v)) to obtain the title compound (16 mg).

[0911] MS m / z[LC-MS]:480.23[M+1]. 1 H NMR(400MHz,DMSO-d6)9.24(s,1H),8.67(s,1H),8.63(s,1H),8.27(s,1H),7.74(s,1H),7.47(d ,J=8.0Hz,2H),6.72-6.85(m,1H),6.58(d,J=8.0Hz,2H),6.05-6.18(m,1H),5.66-5.75(m,1H), 5.53-5.60(m,1H),5.14-5.30(m,1H),4.95(t,J=7.2Hz,2H),4.89(t,J=6.4H z,2H),4.10-4.20(m,2H),3.85-4.04(m,2H),3.14(s,1.7H),3.02(s,1.3H).

[0912] Example 217: N-(5-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-2-yl)acrylamide

[0913] The target compound (11 mg) was synthesized by referring to the synthesis method of Example 18 using tert-butyl (5-bromopyridin-2-yl)carbamate as a raw material.

[0914] MS m / z [LC-MS]: 454.24M+1]. 1H NMR(400MHz, CDCl3)8.39(s,1H),8.18-8.27(m,3H),8.03(d,J=2.0Hz,1H),7.76(s,1H),7.67(s,1H),7.38(dd,J=8.8Hz,2.8Hz,1H),6.97( s,1H),6.45(d,J=16.8Hz,1H),6.26(dd,J=16.8Hz,10.4Hz,1H),5.78(d,J=10.4Hz,1H),3.99(s,3H),3.48-3.54(m,4H),3.33-3.39(m,4H).

[0915] Example 218: N-(4-(3-cyano-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-5-yl)-3,6-dihydro-2H-[1,3'-bipyridyl]-6'-yl)acrylamide

[0916] The target compound (4 mg) was obtained by following the synthetic method of Example 164.

[0917] MS m / z[LC-MS]:451.19[M+1].

[0918] Example 219: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0919] The target compound (19 mg) was obtained by following the synthetic method of Example 168.

[0920] MS m / z[LC-MS]:577.33[M+1]. 1H NMR (400MHz, CDCl3)8.60(d,J=1.2Hz,1H),8.25(s,1H),7.79(s,1H),7.67(s,1H),7.48(d,J=8.8Hz,2H),7.39(d,J=1 .2Hz,1H),7.04(d,J=8.8Hz,2H),6.60(dd,J=16.8Hz,10.4Hz,1H),6.28(dd,=16.8Hz,2.0Hz,1H),5.69(dd,J=10.4Hz ,2.0Hz,1H),4.87(t,J=7.2Hz,2H),4.66-4.76(m,1H),4.54(t,J=6.4Hz,2H),4.50(d,J=7.6Hz,2H),4.03-4.12(m,1H ),3.53-3.60(m,1H),3.24-3.38(m,4H),3.04-3.15(m,1H),2.49-2.82(m,6H),1.88-2.02(m,2H),1.46-1.60(m,2H).

[0921] Example 220: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0922] The target compound (14 mg) was obtained using intermediate 8 and 1-(fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0923] MS m / z[LC-MS]:470.22[M+1]. 1 H NMR (400MHz, DMSO-d6)9.23(d,J=1.2Hz,1H),8.63(s,1H),8.49(s,1H),8.19(s,1H),7. 74(d,J=1.2Hz,1H),7.51(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10 .4Hz, 1H), 6.14 (dd, J=16.8Hz, 2.4Hz, 1H), 5.71 (dd, J=10.4Hz, 2.4Hz, 1H), 4.79 (dt, J= 47.6Hz, 4.8Hz, 2H), 4.44 (dt, J = 28Hz, 4.8Hz, 2H), 3.65-3.77 (m, 4H), 3.23-3.30 (m, 4H).

[0924] Example 221: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0925] The target compound (10 mg) was obtained using Intermediate 8 and 1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0926] MS m / z[LC-MS]:530.22[M+1]. 1 H NMR(400MHz, DMSO-d6)9.22(d,J=1.2Hz,1H),8.63(s,1H),8.52(s,1H),8.21(s, 1H),7.72(d,J=1.2Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd ,J=16.4Hz,10.4Hz,1H),6.14(dd,J=16.4Hz,2.4Hz,1H),5.71(d,J=10.4Hz,2.4H z, 1H), 4.55 (t, J = 6.8Hz, 2H), 3.66-3.78 (m, 6H), 3.20-3.32 (m, 4H), 2.88 (s, 3H).

[0927] Example 222: 4-(4-((3R,5S)-4-acryloyl-3,5-dimethylpiperazin-1-yl)piperidin-1-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0928] Using 6-(1-methyl-1H-pyrazol-4-yl)-4-(4-oxopiperidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile and (2R,6S)-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester as raw materials, reductive amination was performed and the target compound (6 mg) was synthesized according to the method of Example 4.

[0929] MS m / z[LC-MS]:473.29[M+1].

[0930] Example 223: 4-(4-((4-acryloylpiperazin-1-yl)methyl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0931] The title compound (12 mg) was obtained according to the synthesis method of Example 8 using 3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate and (4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)boronic acid as starting materials.

[0932] MS m / z[LC-MS]:522.27[M+1]. 1 H NMR (400MHz, DMSO-d6)8.67(d,J=1.6Hz,1H),8.25(s,1H),7.83(s,1H),7.76(s,1H),7. 49-7.54(m,4H),7.47(d,J=1.6Hz,1H),6.55(dd,J=16.8Hz,10.4Hz,1H),6.28(dd,J=16. 8Hz, 2.0Hz, 1H), 5.68 (dd, J=10.4Hz, 2.0Hz, 1H), 4.37-4.45 (m, 1H), 4.10-4.18 (m, 2H), 3 .69-3.78(m,2H),3.63(s,2H),3.54-3.61(m,4H),2.45-2.56(m,4H),2.06-2.20(m,4H).

[0933] Example 224: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0934] The target compound (20 mg) was obtained using Intermediate 8 and 1-(4-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0935] MS m / z[LC-MS]:544.25[M+1].

[0936] Example 225: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0937] The target compound (8 mg) was obtained using Intermediate 8 and 1-(2-(pyrrolidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0938] MS m / z[LC-MS]:521.29[M+1]. 1 H NMR(400MHz, DMSO-d6)9.20(d,J=1.6Hz,1H),8.62(s,1H),8.45(s,1H),8.11(s,1H),7.72(d, J=1.6Hz,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10.4Hz,1H), 6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.20(t,J=6.8Hz,2H),3.66- 3.77(m,4H),3.21-3.32(m,4H),2.83(t,J=6.8Hz,2H),2.42-2.48(m,4H),1.60-1.67(m,4H).

[0939] Example 226: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(methoxymethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0940] The target compound (15 mg) was obtained using intermediate 8 and 1-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[0941] MS m / z[LC-MS]:468.23[M+1]. 1 H NMR (400MHz, DMSO-d6)9.27(s,1H),8.64(s,1H),8.62(s,1H),8.25(s,1H),7.78(s,1H),7.52(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86 (dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd,J=10.4Hz,2.4Hz,1H),5.38(s,2H),3.64-3.77(m,4H),3.23-3.31(m, 7H).

[0942] Example 227: (S)-4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0943] The target compound (14 mg) was obtained using intermediate 8 and (S)-1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[0944] MS m / z[LC-MS]:494.22[M+1]. 1 H NMR (400MHz, DMSO-d6)9.24(d,J=1.6Hz,1H),8.62(s,1H),8.53(s,1H),8.16(s,1H),7.77(d,J=1.6Hz,1H) ,7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz, 1H),5.71(dd,J=10.4Hz,2.4Hz,1H),4.97-5.03(m,1H),3.96-4.02(m,2H),3.92(dd,J=9.6Hz,3.2Hz,1H), 3.82(td,J=8.0Hz,5.2Hz,1H),3.64-3.78(m,4H),3.20-3.30(m,4H),2.35-2.41(m,1H),2.28-2.33(m,1H).

[0945] Example 228: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0946] The target compound (12 mg) was obtained using intermediate 8 and 1-((tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole as starting materials.

[0947] MS m / z[LC-MS]:522.27[M+1]. 1H NMR (400MHz, DMSO-d6)9.21(d,J=1.2Hz,1H),8.62(s,1H),8.42(s,1H),8.13(s,1H),7.72(d,J=1.2H z,1H),7.50(d,J=8.8Hz,2H),7.09(d,J=8.8Hz,2H),6.86(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16 .8Hz, 2.4Hz, 1H), 5.71 (dd, J=10.4Hz, 2.4Hz, 1H), 4.00 (d, J=6.8Hz, 2H), 3.81 (dd, J=11.6Hz, 3.2Hz, 2H),3.66-3.77(m,4H),3.18-3.32(m,6H),1.99-2.12(m,1H),1.37-1.46(m,2H),1.18-1.28(m,2H).

[0948] Example 229: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-2-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0949] The target compound (7 mg) was synthesized by using the intermediate of Example 9, tert-butyl 4-oxopiperidine-1-carboxylate, as a raw material through reductive amination and referring to the method of Example 4.

[0950] MS m / z[LC-MS]:536.29[M+1]. 1 H NMR (400MHz, DMSO-d6)8.73(s,1H),8.25(s,1H),7.98(s,1H),7.46(s,1H),7.41(d,J=8.8Hz,2H) ,7.01(d,J=8.8Hz,2H),6.80(dd,J=16.8Hz,10.4Hz,1H),6.21(s,2H),6.06(dd,J=16.8Hz,2.4Hz, 1H),5.64(dd,J=10.4Hz,2.4Hz,1H),4.37-4.46(m,1H),4.02-4.11(m,1H),3.83(s,3H),3.15-3.25(m ,5H),2.98-3.08(m,1H),2.59-2.70(m,4H),2.36-2.48(m,1H),1.78-1.88(m,2H),1.24-1.38(m,2H).

[0951] Example 230: Methyl 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-3-cyanopyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazole-1-carboxylate

[0952] The target compound (19 mg) was obtained using intermediate 8 and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate as starting materials.

[0953] MS m / z[LC-MS]:482.23[M+1].

[0954] Example 231: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0955] The target compound (4 mg) was synthesized by using the intermediate of Example 5, tert-butyl 3-oxoazetidine-1-carboxylate, as a starting material, through reductive amination and referring to the method of Example 4.

[0956] MS m / z[LC-MS]:493.25[M+1]. 1 H NMR(400MHz,DMSO-d6)9.19(s,1H),8.62(s,1H),8.38(s,1H),8.10(s,1H),7.70(s,1H),7.48( d,J=8.8Hz,2H),7.07(d,J=8.8Hz,2H),6.30(dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2 .0Hz,1H),5.66(dd,J=10.4Hz,2.0Hz,1H),4.24-4.28(m,1H),4.05-4.09(m,1H),3.94-3.98(m ,1H),3.86(s,3H),3.76-3.80(m,1H),3.23-3.29(m,4H),3.15-3.20(m,1H),2.6-2.50(m,4H).

[0957] Example 232: 4-(4-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0958] Referring to the synthesis method of Example 8, the target compound (11 mg) was synthesized using 4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as raw materials.

[0959] MS m / z[LC-MS]:548.28[M+1]. 1 H NMR (400MHz, DMSO-d6)9.20(d,J=1.2Hz,1H),8.61(s,1H),8.55(s,1H),8.14(s,1H),7.75(d,=1. 2Hz,1H),7.47(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,2H),6.31(dd,J=16.8Hz,10.4Hz,1H),6.09(dd, J=16.8Hz,2.0Hz,1H),5.65(dd,J=10.4Hz,2.0Hz,1H),4.35-4.44(m,1H),3.91-4.00(m,4H),3.68 (s,2H),3.47(td,J=12.0Hz,2.0Hz,2H),3.21-3.29(m,4H),1.87-2.06(m,4H),1.77-1.85(m,4H).

[0960] Example 233: N-(4-(3-cyano-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro-2H-[1,3'-bipyridyl]-6'-yl)acrylamide

[0961] The target compound (6 mg) was obtained by following the synthetic method of Example 164.

[0962] MS m / z[LC-MS]:507.22[M+1]. 1H NMR (400MHz, CDCl3)8.59(d,J=1.2Hz,1H),8.25(s,1H),8.23(d,J=9.2Hz,1H),8.03(d,J=2.8Hz,1H),7.97(s ,1H),7.78(s,1H),7.68(s,1H),7.37(dd,J=9.2Hz,2.8Hz,1H),7.32(d,J=1.2Hz,1H),6.44(d,J=16.8Hz,1H) ,6.25(dd,J=16.8Hz,10.4Hz,1H),6.14-6.18(m,1H),5.78(d,J=10.4Hz,1H),4.82-4.90(m,2H),4.49-4.56( m,2H),4.43(d,J=7.2Hz,2H),3.97-4.01(m,2H),3.66(t,J=5.6Hz,2H),3.50-3.61(m,1H),2.69-2.75(m,2H).

[0963] Example 234: N-(4-(3-cyano-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)-3,6-dihydro-2H-[1,3'-bipyridyl]-6'-yl)acrylamide

[0964] The target compound (14 mg) was obtained by following the synthetic method of Example 164.

[0965] MS m / z[LC-MS]:495.23[M+1]. 1 H NMR(400MHz, CDCl3)8.61(d,J=1.6Hz,1H),8.22-8.24(m,2H),7.99-8.06(m,2H),7.80(s,1 H),7.79(s,1H),7.36-7.39(m,2H),6.44(dd,J=17.2Hz,1.2Hz,1H),6.26(dd,J=17.2Hz,10 .4Hz,1H),6.14-6.18(m,1H),5.78(dd,J=10.4Hz,1.2Hz,1H),4.35(t,J=4.8Hz,2H),3.97- 4.01(m,2H),3.78(t,J=5.2Hz,2H),3.65(t,J=5.2Hz,2H),3.37(s,3H),2.70-2.76(m,2H).

[0966] Example 235: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0967] The target compound (23 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as raw materials.

[0968] MS m / z[LC-MS]:535.30[M+1]. 1 H NMR(400MHz, CDCl3)8.60(s,1H),8.23(s,1H),7.78(s,1H),7.70(s,1H),7.47(d,J=8.4Hz,2H),7.40 (s,1H),7.02(d,J=8.4Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.26(dd,J=16.8Hz,1.6Hz,1H),5.67 (dd,J=10.4Hz,2.0Hz,1H),4.64-4.75(m,1H),4.23(q,J=7.2Hz,2H),3.99-4.11(m,1H),3.24-3.36(m ,4H),3.02-3.14(m,1H),2.63-2.78(m,5H),2.50-2.60(m,1H),1.88-2.00(m,2H),1.44-1.58(m,5H).

[0969] Example 236: 4-(4-(2-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(4-(1-methylpiperidin-4-)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0970] The target compound (25 mg) was obtained by the synthesis method of step 1 of reference example 4 using intermediate 9 and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine as raw materials.

[0971] MS m / z[LC-MS]:614.37[M+1]. 1H NMR (400MHz, CDCl3)8.68(d,J=1.6Hz,1H),8.27(s,1H),7.53-7.55(m,3H),7.49(d,J=8.8Hz,2H),7.35(d, J=8.0Hz,2H),7.03(d,J=8.8Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.25(dd,J=16.8Hz,2.0Hz,1H),5.6 7(dd,J=10.4Hz,2.0Hz,1H),4.62-4.73(m,1H),4.00-4.10(m,1H),3.28-3.31(m,4H),2.95-3.13(m,3H),2 .63-2.75(m,5H),2.50-2.58(m,2H),2.33(s,3H),2.04-2.10(m,2H),1.78-1.97(m,6H),1.42-1.56(m,2H).

[0972] Example 237: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0973] The target compound (10 mg) was obtained by the synthesis method of step 1 of reference example 4 using intermediate 9 and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine as raw materials.

[0974] MS m / z[LC-MS]:620.36[M+1]. 1H NMR (400MHz, CDCl3)8.60(d,J=1.2Hz,1H),8.23(s,1H),7.78(s,2H),7.47(d,J=8.8Hz,2H),7.39(d,J=1.6Hz,1H),7.02 (d,J=8.8Hz,2H),6.58(dd,J=16.8Hz,10.4Hz,1H),6.25(dd,J=16.8Hz,2.0Hz,1H),5.67(dd,J=10.4Hz,2.0Hz,1H),4.63 -4.76(m,1H),4.28(t,J=6.4Hz,2H),3.99-4.11(m,1H),3.67-3.69(m,4H),3.29-3.32(m,4H),3.08(t,J=12.4Hz,1H),2. 84(t,J=6.4Hz,2H),2.72-2.74(m,4H),2.68(t,J=12.4Hz,1H),2.44-2.60(m,5H),1.90-1.99(m,2H),1.44-1.56(m,2H).

[0975] Example 238: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0976] The target compound (15 mg) was obtained by the synthesis method of step 1 of reference example 4 using intermediate 9 and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole as raw materials.

[0977] MS m / z[LC-MS]:591.31[M+1].

[0978] Example 239: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0979] The target compound (15 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[0980] MS m / z[LC-MS]:565.31[M+1]. 1H NMR(400MHz, CDCl3)8.63(s,1H),8.25(s,1H),7.81(s,1H),7.80(s,1H),7.49(d,J=8.8Hz,2H),7 .42(s,1H),7.04(d,J=8.8Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.28(d,J=16.8Hz,1H),5.70( d,J=10.4Hz,1H),4.64-4.79(m,1H),4.35(t,J=4.8Hz,2H),4.04-4.14(m,1H),3.78(t,=4.8Hz,2H ),3.22-3.40(m,7H),3.04-3.15(m,1H),2.48-2.86(m,6H),1.88-2.05(m,2H),1.44-1.64(m,2H).

[0981] Example 240: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0982] The target compound (12 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile as raw materials.

[0983] MS m / z[LC-MS]:560.31[M+1]. 1 H NMR (400MHz, CDCl3)8.63(d,J=1.2Hz,1H),8.26(s,1H),7.87(s,1H),7.82(s,1H),7.49(d,J=8.8Hz,2H) ,7.40(d,J=1.2Hz,1H),7.04(d,J=8.8Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.28(dd,J=16.8Hz,1.2H z,1H),5.70(d,J=10.4Hz,1H),4.62-4.82(m,1H),4.46(t,J=6.4Hz,2H),4.02-4.16(m,1H),3.22-3.50(m ,4H),3.05-3.15(m,1H),3.01(t,J=6.4Hz,2H),2.48-2.92(m,6H),1.87-2.08(m,2H),1.42-1.68(m,2H).

[0984] Example 241: N-(4-((3-cyano-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[0985] The target compound (18 mg) was obtained according to the synthesis method of Example 69 using 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0986] MS m / z[LC-MS]:449.16[M+1]. 1 H NMR (400MHz, DMSO-d6)10.40(s,1H),9.29(d,J=1.2Hz,1H),8.70(s,1H),8.45(s ,1H),8.14(s,1H),8.12(d,J=1.2Hz,1H),7.78(d,J=8.8Hz,2H),7.66(d,J=8.8Hz ,2H),6.44(dd,J=16.8Hz,10.0Hz,1H),6.28(dd,J=16.8Hz,2.0Hz,1H),5.79(dd ,J=10.0Hz,2.0Hz,1H),4.64-4.68(m,2H),4.41-4.44(m,4H),3.37-3.46(m,1H).

[0987] Example 242: N-(4-((3-cyano-6-(4-(1-methylpiperidin-4-yl)phenyl)pyrazolo[1,5-a]pyridin-4-yl)ethynylphenyl)acrylamide

[0988] The target compound (18 mg) was obtained according to the synthesis method of Example 69 using 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[0989] MS m / z[LC-MS]:486.24[M+1]. 1H NMR (400MHz, DMSO-d6)10.49(s,1H),9.30(s,1H),8.76(s,1H),8.15(s,1H),7. 78-7.83(m,4H),7.66(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),6.47(dd,J=16.8 Hz,10.0Hz,1H),6.28(dd,J=16.8Hz,1.6Hz,1H),5.78(dd,J=10.0Hz,1.6Hz,1H ),3.10-3.20(m,2H),2.63-2.74(m,1H),2.38-2.60(m,5H),1.77-1.91(m,4H).

[0990] Example 243: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0991] The target compound (14 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)-1H-pyrazole as raw materials.

[0992] MS m / z[LC-MS]:563.30[M+1]. 1 H NMR (400MHz, DMSO-d6)9.21(d,J=1.2Hz,1H),8.62(s,1H),8.55(s,1H),8.14(s,1H),7.76(d,J=1.2Hz,1H),7.48(d,J=8. 8Hz,2H),7.07(d,J=8.8Hz,2H),6.30(dd,J=17.2Hz,10.4Hz,1H),6.09(dd,J=17.2Hz,2.0Hz,1H),5.66(d,J=10.4Hz,2.0 Hz,1H),4.35-4.43(m,1H),4.26(t,J=8.0Hz,1H),4.07(dd,J=8.8Hz,4.4Hz,1H),3.91-3.99(m,3H),3.78(dd,J=10.0Hz, 5.2Hz,1H),3.47(td,J=12.0Hz,2.0Hz,2H),3.25-3.27(m,4H),3.15-3.21(m,1H),2.46-2.54(m,4H),1.87-2.06(m,4H).

[0993] Example 244: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-((3-methyloxetan-3-yl)methyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0994] The target compound (11 mg) was obtained using intermediate 8 and 1-((3-methyloxetan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[0995] MS m / z[LC-MS]:508.26[M+1]. 1 H NMR (400MHz, DMSO-d6)8.63(d,J=1.6Hz,1H),8.26(s,1H),7.81(s,1H),7.68(s,1H),7.51(d,J =8.4Hz,2H),7.40(d,J=1.2Hz,1H),7.08(d,J=8.4Hz,2H),6.62(d,J=16.8Hz,10.4Hz,1H),6.3 5(dd,J=16.8Hz,2.0Hz,1H),5.75(dd,J=10.4Hz,2.0Hz,1H),4.73(d,J=6.4Hz,2H),4.44(d,J= 6.4Hz,2H),4.39(s,2H),3.85-3.93(m,2H),3.73-3.81(m,2H),3.32-3.35(m,4H),1.29(s,3H).

[0996] Example 245: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0997] The target compound (17 mg) was obtained using intermediate 11 and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[0998] MS m / z[LC-MS]:489.30[M+1]. 1H NMR(400MHz,DMSO-d6)8.88(s,1H),8.55(s,1H),8.37(s,1H),8.07(s,1H),7.22( s,1H),6.79(dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,1H),5.66(dd ,J=10.4Hz,2.0Hz,1H),4.25(t,J=5.2Hz,2H),3.70(t,J=5.2Hz,2H),3.44-3.59( m, 6H), 3.22 (s, 3H), 2.77 (t, J = 10.8Hz, 2H), 2.38-2.56 (m, 5H), 1.73-1.92 (m, 4H).

[0999] Example 246: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1000] The target compound (13 mg) was obtained using intermediate 11 and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[1001] MS m / z[LC-MS]:459.28[M+1]. 1 H NMR(400MHz, DMSO-d6)8.87(d,J=1.2Hz,1H),8.55(s,1H),8.40(s,1H),8.05(s,1H), 7.23(d,J=1.2Hz,1H),6.79(dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,2 .0Hz,1H),5.66(dd,J=10.4Hz,2.0Hz,1H),4.14(q,J=7.2Hz,2H),3.47-3.58(m,6H), 2.77(t,J=11.2Hz,2H),2.38-2.54(m,5H),1.74-1.92(m,4H),1.40(t,J=7.2Hz,3H).

[1002] Example 247: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1003] The target compound (12 mg) was obtained using intermediate 11 and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[1004] MS m / z[LC-MS]:515.29[M+1]. 1 H NMR(400MHz,DMSO-d6)8.89(s,1H),8.55(s,1H),8.50(s,1H),8.08(s,1H),7.2 6(s,1H),6.79(dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,1H),5.66 (dd,J=10.4Hz,2.0Hz,1H),4.35-4.43(m,1H),3.96(dd,J=11.2Hz,3.2Hz,2H),3 .43-3.60(m,8H),2.77(t,J=11.2Hz,2H),2.38-2.55(m,5H),1.74-2.05(m,8H).

[1005] Example 248: 4-(4-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1006] Referring to the synthesis method of Example 8, the target compound (19 mg) was synthesized using 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as raw materials.

[1007] MS m / z[LC-MS]:492.27[M+1]. 1H NMR(400MHz, DMSO-d6)9.18(d,J=1.2Hz,1H),8.61(s,1H),8.44(s,1H),8.11(s,1H),7.71 (d,J=1.2Hz,1H),7.47(d,J=8.8Hz,2H),7.07(d,J=8.8Hz,2H),6.31(dd,J=17.2Hz,10.0Hz ,1H),6.09(dd,J=17.2Hz,2.0Hz,1H),5.65(dd,J=10.0Hz,2.0Hz,1H),4.14(q,J=7.2Hz,2 H), 3.97 (s, 2H), 3.68 (s, 2H), 3.21-3.28 (m, 4H), 1.80-1.83 (m, 4H), 1.40 (t, J = 7.2Hz, 3H).

[1008] Example 249: N-(1-(4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)azetidin-3-yl)acrylamide

[1009] The target compound (5 mg) was synthesized by referring to the synthesis method of Example 18 and using tert-butyl (1-(4-ethynylphenyl)azetidin-3-yl)carbamate as the raw material.

[1010] MS m / z[LC-MS]:448.20[M+1]. 1 H NMR(400MHz, DMSO-d6)9.22(s,1H),8.82(d,J=7.2Hz,1H),8.67(s,1H),8.37(s,1H), 8.10(s,1H),8.01(s,1H),7.52(d,J=8.8Hz,2H),6.51(d,J=8.8Hz,2H),6.21(dd,J=1 7.2Hz, 10.0Hz, 1H), 6.10 (dd, J=17.2Hz, 2.4Hz, 1H), 5.62 (dd, J=10.0Hz, 2.4Hz, 1H), 4.64-4.71(m,1H),4.20(t,J=8.0Hz,2H),3.87(s,3H),3.72(dd,J=8.0Hz,5.2Hz,2H).

[1011] Example 250: 4-(4-(1-acryloylpiperidin-4-yl)phenyl)piperazin-1-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1012] Referring to the synthesis method of Example 8, the target compound (9 mg) was synthesized using 4-(piperazin-1-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile and tert-butyl 4-(4-bromophenyl)piperidine-1-carboxylate as raw materials.

[1013] MS m / z[LC-MS]:591.32[M+1].

[1014] Example 251: 4-(4-(4-acryloylpiperazinyl)phenyl)piperazin-1-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1015] Referring to the synthesis method of Example 8, the target compound (7 mg) was synthesized using 4-(piperazin-1-yl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile and tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate as raw materials.

[1016] MS m / z[LC-MS]:592.33[M+1].

[1017] Example 252: N-(6-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[1018] The target compound (17 mg) was synthesized by referring to the synthesis method of Example 196 and using tert-butyl (6-bromopyridin-3-yl) carbamate as the raw material.

[1019] MS m / z [LC-MS]: 524.25M+1]. 1H NMR (400MHz, CDCl3)8.39(s,1H),8.24(d,J=2.4Hz,1H),8.21(s,1H),8.00(dd,J=8.8Hz,2.4Hz,1H ),7.78(s,1H),7.72(s,1H),7.19-7.25(brs,1H),6.95(s,1H),6.74(d,J=8.8Hz,1H),6.44(d,J=1 6.8Hz,1H),6.25(dd,J=16.8Hz,10.4Hz,1H),5.78(d,J=10.4Hz,1H),4.37-4.45(m,1H),4.12-4.1 8(m,2H),3.83-3.92(m,4H),3.57(td,J=11.2Hz,3.2Hz,2H),3.26-3.34(m,4H),2.07-2.20(m,4H).

[1020] Example 253: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1021] The target compound (10 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as raw materials.

[1022] MS m / z[LC-MS]:524.31[M+1]. 1 H NMR (400MHz, CDCl3)8.61(d,J=1.2Hz,1H),8.25(s,1H),7.78(s,1H),7.67(s,1H),7.48(d,J=8. 8Hz,2H),7.40(d,J=1.2Hz,1H),7.04(d,J=8.8Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.28(d d,J=16.8Hz,2.0Hz,1H),5.69(dd,J=10.4Hz,2.0Hz,1H),4.66-4.80(m,1H),4.01-4.14(m,1H), 3.22-3.46(m,4H),3.05-3.16(m,1H),2.48-2.88(m,6H),1.87-2.06(m,2H),1.45-1.64(m,2H).

[1023] Example 254: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1024] The target compound (7 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1025] MS m / z[LC-MS]:563.30[M+1]. 1 H NMR (400MHz, CDCl3)8.63(d,J=1.2Hz,1H),8.26(s,1H),7.89(s,2H),7.49(d,J=8.8Hz,2H),7.41(s,1H),7.04(d,J=8.8Hz,2H),6.59(d d,J=16.8Hz,10.4Hz,1H),6.28(dd,J=16.8Hz,1.2Hz,1H),5.69(dd,J=10.4Hz,1.2Hz,1H),5.47-5.54(m,1H),5.11(s,2H),5.09(s,2H), 4.65-4.78(m,1H),4.01-4.14(m,1H),3.20-3.46(m,4H),3.02-3.16(m,1H),2.48-2.88(m,6H),1.89-2.06(m,2H),1.45-1.66(m,2H).

[1026] Example 255: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1027] The target compound (7 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1028] MS m / z[LC-MS]:571.27[M+1]. 1H NMR (400MHz, CDCl3)8.63(d,J=1.2Hz,1H),8.26(s,1H),7.86(s,1H),7.78(s,1H),7.48(d,J=8.8Hz,2H),7.40( d,J=1.6Hz,1H),7.04(d,J=8.8Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.28(dd,J=16.8Hz,2.0Hz,1H),6.13(t t,J=55.2Hz,4.0Hz,1H),5.69(dd,J=10.4Hz,2.0Hz,1H),4.65-4.79(m,1H),4.53(td,J=13.6Hz,4.0Hz,2H),4. 01-4.15(m,1H),3.20-3.46(m,4H),3.03-3.15(m,1H),2.46-2.88(m,6H),1.88-2.05(m,2H),1.43-1.65(m,2H).

[1029] Example 256: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1030] The target compound (14 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1031] MS m / z[LC-MS]:549.31[M+1]. 1 H NMR(400MHz, CDCl3)8.62(d,J=1.2Hz,1H),8.24(s,1H),7.80(s,1H),7.72(s,1H),7.49(d,J=8.8Hz, 2H),7.42(d,J=1.6Hz,1H),7.04(d,J=8.8Hz,2H),6.59(dd,J=17.2Hz,10.8Hz,1H),6.28(dd,J=17.2 Hz,2.0Hz,1H),5.69(dd,J=10.8Hz,2.0Hz,1H),4.64-4.77(m,1H),4.51-4.61(m,1H),4.02-4.12(m, 1H),3.24-3.41(m,4H),3.04-3.15(m,1H),2.48-2.83(m,6H),1.89-2.04(m,2H),1.45-1.60(m,8H).

[1032] Example 257: 4-(4-(2-acryloyl-2,7-diazaspiro[3.5]non-7-yl)phenyl)-6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1033] Referring to the synthesis method of Example 8, the target compound (6 mg) was synthesized using 4-(3-cyano-6-(1-(oxetane-3-ylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate as raw materials.

[1034] MS m / z[LC-MS]:534.27[M+1].

[1035] Example 258: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1036] The target compound (8 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[1037] MS m / z[LC-MS]:520.24[M+1].

[1038] Example 259: 4-(4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1039] The target compound (12 mg) was obtained by the synthetic method of step 1 of reference example 4 using intermediate 9 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as raw materials.

[1040] MS m / z[LC-MS]:507.27[M+1]. 1H NMR(400MHz, CDCl3)8.70-9.36(brs,1H),8.66(d,J=1.6Hz,1H),8.25(s,1H),7.90(s,1H),7.48(d ,J=8.8Hz,2H),7.44(d,J=1.6Hz,1H),7.03(d,J=8.8Hz,2H),6.59(dd,J=16.8Hz,10.4Hz,1H),6.28 (dd,J=16.8Hz,2.0Hz,1H),5.70(dd,J=10.4Hz,2.0Hz,1H),4.68-4.78(m,1H),4.02-4.13(m,1H),3 .31-3.41(m,4H),3.10(t,J=12.4Hz,2H),2.61-2.87(m,6H),1.92-2.06(m,2H),1.49-1.59(m,2H).

[1041] Example 260: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1042] The target compound (15 mg) was obtained using intermediate 11 and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[1043] MS m / z[LC-MS]:487.27[M+1]. 1 H NMR(400MHz,DMSO-d6)8.92(s,1H),8.64(s,1H),8.56(s,1H),8.20(s,1H),7.27(s ,1H),6.79(dd,J=16.8Hz,10.4Hz,1H),6.098(dd,J=16.8Hz,2.4Hz,1H),5.66(dd,J =10.4Hz,2.4Hz,1H),5.53-5.60(m,1H),4.95(t,J=7.2Hz,2H),4.89(t,J=7.2Hz,2H ),3.45-3.60(m,6H),2.77(t,J=11.2Hz,2H),2.38-2.55(m,5H),1.74-1.93(m,4H).

[1044] Example 261: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1045] The target compound (18 mg) was obtained using Intermediate 11 and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[1046] MS m / z[LC-MS]:481.23[M+1].

[1047] Example 262: N-(4-(2-((3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)phenyl)acrylamide

[1048] The target compound (14 mg) was obtained by following the procedure of Example 165.

[1049] MS m / z[LC-MS]:427.20[M+1].

[1050] Example 263: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1051] The target compound (10 mg) was obtained using intermediate 11 and 1-(difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[1052] MS m / z[LC-MS]:495.25[M+1]. 1 H NMR(400MHz,DMSO-d6)8.92(s,1H),8.56(s,1H),8.44(s,1H),8.17(s,1H),7.23(s ,1H),6.78(dd,J=16.8Hz,10.4Hz,1H),6.38(tt,J=55.2Hz,3.6Hz,1H),6.09(dd,J= 16.8Hz, 2.0Hz, 1H), 5.66 (dd, J=10.4Hz, 2.0Hz, 1H), 4.63 (td, J=15.2Hz, 3.6Hz, 2H ),3.47-3.60(m,6H),2.77(t,J=11.2Hz,2H),2.38-2.56(m,5H),1.73-1.93(m,4H).

[1053] Example 264: N-(4-((3-cyano-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)ethynyl)phenyl)acrylamide

[1054] The target compound (5 mg) was obtained according to the synthesis method of Example 69 using 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a starting material.

[1055] MS m / z[LC-MS]:443.16[M+1]. 1 H NMR(400MHz,DMSO-d6)10.42(s,1H),9.35(s,1H),8.71(s,1H),8.50(s,1H) ,8.24(s,1H),8.16(s,1H),7.78(d,J=8.4Hz,2H),7.66(d,J=8.4Hz,2H),6. 45(dd,J=16.8Hz,10.0Hz,1H),6.39(tt,J=54.8Hz,3.2Hz,1H),6.28(d,J=1 6.8Hz, 1H), 5.79 (dd, J = 10.0Hz, 1.6Hz, 1H), 4.66 (td, J = 15.2Hz, 3.2Hz, 2H).

[1056] Example 265: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1057] The target compound (24 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as raw materials.

[1058] MS m / z[LC-MS]:507.27[M+1]. 1H NMR (400MHz, DMSO-d6)8.62(d,J=1.6Hz,1H),8.25(s,1H),7.79(s,1H),7.70(s,1H),7.49(d,J=8.8H z,2H),7.41(d,J=1.6Hz,1H),7.05(d,J=8.8Hz,2H),6.34(dd,J=17.2Hz,2.0Hz,1H),6.21(dd,J=17. 2Hz, 10.0Hz, 1H), 5.68 (dd, J=10.0Hz, 2.0Hz, 1H), 4.22-4.28 (m, 3H), 4.10-4.17 (m, 2H), 4.00 (dd, J= 10.4Hz, 5.2Hz, 1H), 3.33-3.36 (m, 4H), 3.24-3.31 (m, 1H), 2.51-2.63 (m, 4H), 1.55 (t, J = 7.2Hz, 3H).

[1059] Example 266: 4-(4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1060] The target compound (22 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-difluoroethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as raw materials.

[1061] MS m / z[LC-MS]:543.25[M+1]. 1 H NMR (400MHz, DMSO-d6)8.63(d,J=1.2Hz,1H),8.26(s,1H),7.86(s,1H),7.78(s,1H),7.49(d,J=8.8Hz, 2H),7.40(d,J=1.2Hz,1H),7.05(d,J=8.8Hz,2H),6.34(dd,J=17.2Hz,2.0Hz,1H),6.21(dd,J=17.2Hz,1 0.0Hz, 1H), 6.13 (tt, J=55.2Hz, 4.4Hz, 1H), 5.68 (dd, J=10.0Hz, 2.0Hz, 1H), 4.53 (td, J=13.6Hz, 4.4Hz, 2H), 4.27 (t, J = 8.0Hz, 1H), 4.10-4.17 (m, 2H), 3.98-4.02 (m, 1H), 3.24-3.40 (m, 5H), 2.51-2.63 (m, 4H).

[1062] Example 267: 4-(4-(2-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(oxolan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1063] The target compound (19 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1064] MS m / z[LC-MS]:535.25[M+1]. 1 H NMR (400MHz, DMSO-d6)8.64(d,J=1.6Hz,1H),8.26(s,1H),7.89(s,2H),7.50(d,J=8.8Hz,2H),7 .42(d,J=1.6Hz,1H),7.05(d,J=8.8Hz,2H),6.35(dd,J=17.2Hz,2.0Hz,1H),6.21(dd,J=17.2Hz ,10.0Hz,1H),5.68(dd,J=10.0Hz,2.0Hz,1H),5.48-5.54(m,1H),5.11(s,2H),5.09(s,2H),4.2 7(t,J=7.2Hz,1H),4.10-4.20(m,2H),3.97-4.05(m,1H),3.23-3.42(m,5H),2.50-2.65(m,4H).

[1065] Example 268: 1-(4-(4-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl)piperazin-1-yl)prop-2-en-1-one

[1066] The target compound (5 mg) was synthesized by following the method of Example 4 using 6-chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine as a raw material.

[1067] MS m / z[LC-MS]:414.22[M+1].

[1068] Example 269: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1069] The target compound (16 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[1070] MS m / z[LC-MS]:464.24[M+1]. 1 H NMR(400MHz,DMSO-d6)9.17(d,J=1.2Hz,1H),8.60(s,1H),8.44(s,1H),8.10(s ,1H),7.68(d,J=1.2Hz,1H),7.45(d,J=8.8Hz,2H),6.55(d,J=8.8Hz,2H),6.29( dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,1H),5.66(dd,J=10.4Hz, 2.0Hz, 1H), 4.43 (s, 2H), 4.11-4.17 (m, 4H), 4.03 (s, 4H), 1.40 (t, J = 7.2Hz, 3H).

[1071] Example 270: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1072] The target compound (16 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[1073] MS m / z[LC-MS]:486.20[M+1]. 1H NMR(400MHz, DMSO-d6)9.36(d,J=1.6Hz,1H),8.99(s,1H),8.65(s,1H),8.50( s,1H),7.85(t,J=59.2Hz,1H),7.82(d,J=1.6Hz,1H),7.47(d,J=8.8Hz,2H),6. 56(d,J=8.8Hz,2H),6.29(dd,J=17.2Hz,10.8Hz,1H),6.09(dd,J=17.2Hz,2.4H z, 1H), 5.66 (dd, J = 10.8Hz, 2.4Hz, 1H), 4.43 (s, 2H), 4.13 (s, 2H), 4.04 (s, 4H).

[1074] Example 271: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(3-hydroxy-3-methylazepin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1075] The target compound (23 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(3-hydroxy-3-methylcyclobutyl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[1076] MS m / z[LC-MS]:455.22[M+1].

[1077] Example 272: 4-(4-(4-acryloylpiperazin-1-yl)-3-methoxyphenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1078] The target compound (16 mg) was synthesized by referring to the synthesis method of Example 18 using tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate as a raw material.

[1079] MS m / z[LC-MS]:482.24[M+1]. 1H NMR (400MHz, DMSO-d6)9.22(d,J=1.2Hz,1H),8.63(s,1H),8.45(s,1H),8.12(s,1H),7.79(d,J =1.2Hz,1H),7.24(d,J=2.0Hz,1H),7.14(dd,J=8.4Hz,2.0Hz,1H),7.01(d,J=8.4Hz,1H),6.84 (dd,J=16.8Hz,10.4Hz,1H),6.13(dd,J=16.8Hz,2.4Hz,1H),5.70(dd,J=10.4Hz,2.4Hz,1H),4 .14(q,J=7.2Hz,2H),3.90(s,3H),3.65-3.76(m,4H),2.98-3.07(m,4H),1.40(t,J=7.2Hz,3H).

[1080] Example 273: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1081] The target compound (13 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[1082] MS m / z[LC-MS]:500.22[M+1]. 1 H NMR(400MHz,DMSO-d6)9.22(d,J=1.2Hz,1H),8.62(s,1H),8.48(s,1H),8.22(s,1H),7.6 9(d,J=1.2Hz,1H),7.46(d,J=8.8Hz,2H),6.55(d,J=8.8Hz,2H),6.38(tt,J=55.2Hz,3.6 Hz, 1H), 6.29 (dd, J=16.8Hz, 10.4Hz, 1H), 6.09 (dd, J=16.8Hz, 2.0Hz, 1H), 5.66 (dd, J=10 .4Hz, 2.0Hz, 1H), 4.64 (td, J = 15.2Hz, 3.6Hz, 2H), 4.43 (s, 2H), 4.13 (s, 2H), 4.03 (s, 4H).

[1083] Example 274: 6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-4-(4-(6-methacryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1084] The target compound (8 mg) was obtained according to the synthetic method of Example 273 using methacryloyl chloride as a starting material.

[1085] MS m / z[LC-MS]:514.22[M+1].

[1086] Example 275: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1087] The target compound (23 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate as starting materials.

[1088] MS m / z[LC-MS]:492.24[M+1].

[1089] Example 276: 4-(4-(6-(2-fluoroacryloyl)-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1090] The target compound (4 mg) was obtained according to the synthetic method of Example 275 using 2-fluoroacryloyl chloride as a starting material.

[1091] MS m / z[LC-MS]:510.21[M+1].

[1092] Example 277: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile

[1093] The target compound (22 mg) was obtained according to the synthesis method of Example 4 using 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate as starting materials.

[1094] MS m / z[LC-MS]:439.20[M+1]. 1 H NMR (400MHz, DMSO-d6)8.51(s,1H),8.33(s,1H),7.99(s,1H),7.96(s,1H),7.89(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,2H),6.62(dd,J=17.2Hz,10. 4Hz, 1H), 6.35 (dd, J = 17.2Hz, 2.0Hz, 1H), 5.76 (dd, J = 10.4Hz, 2.0Hz, 1H), 3.98 (s, 3H), 3.83-3.93 (m, 2H), 3.71-3.81 (m, 2H), 3.38-3.41 (m, 4H).

[1095] Example 278: N-(4-((3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)ethynyl)phenyl)acrylamide

[1096] The target compound (5 mg) was synthesized by referring to the synthesis method of Example 18 using 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile and tert-butyl (4-ethynylphenyl)carbamate as raw materials.

[1097] MS m / z[LC-MS]:394.15[M+1]. 1 H NMR (400MHz, DMSO-d6)10.50(s,1H),9.40(s,1H),8.84(s,1H),8.38(s,1H),8.11(s,1H),7.82(d,J=8.8Hz,2H),7.77(d, J=8.8Hz, 2H), 6.46 (dd, J=16.8Hz, 10.0Hz, 1H), 6.29 (dd, J=16.8Hz, 2.0Hz, 1H), 5.80 (dd, J=10.0Hz, 2.0Hz, 1H), 3.89 (s, 3H).

[1098] Example 279: 4-(4-(1-(1'-acryloyl-[1,4'-bipiperidinyl]-4-yl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1099] The target compound (13 mg) was synthesized using the intermediate of Example 168, tert-butyl 4-oxopiperidine-1-carboxylate, as a starting material, through reductive amination and the method of Example 4.

[1100] MS m / z[LC-MS]:604.35[M+1]. 1 H NMR (400MHz, CDCl3)8.61(d,J=1.2Hz,1H),8.25(s,1H),7.78(s,1H),7.67(s,1H),7.48(d,J=8.8H z,2H),7.40(d,J=1.2Hz,1H),7.03(d,J=8.8Hz,2H),6.57(dd,J=17.2Hz,11.2Hz,1H),6.27(dd,J=1 7.2Hz,1.6Hz,1H),5.69(dd,J=11.2Hz,1.6Hz,1H),4.68-4.81(m,1H),4.02-4.12(m,1H),3.98(s,3 H),3.28-3.42(m,4H),2.99-3.19(m,3H),2.56-2.86(m,6H),2.16-2.52(m,2H),1.44-2.10(m,9H).

[1101] Example 280: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(4-(-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-ylphenyl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1102] The target compound (12 mg) was obtained using intermediate 8 and 1-(tetrahydro-2H-pyran-4-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine as starting materials.

[1103] MS m / z[LC-MS]:602.34[M+1].

[1104] Example 281: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(cyclobutylmethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1105] The target compound (17 mg) was obtained using Intermediate 8 and 2-(4-(cyclobutylmethyl)phenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane as starting materials.

[1106] MS m / z[LC-MS]:492.26[M+1].

[1107] Example 282: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1108] The target compound (9 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1109] MS m / z[LC-MS]:537.30[M+1]. 1 H NMR(400MHz, CDCl3)8.63(d,J=1.6Hz,1H),8.25(s,1H),7.81(s,1H),7.80(s,1H),7.49(d,J=8.8 Hz,2H),7.43(d,J=1.6Hz,1H),7.05(d,J=8.8Hz,2H),6.35(dd,J=17.2Hz,2.0Hz,1H),6.20(dd,J= 17.2Hz, 10.4Hz, 1H), 5.69 (dd, J=10.4Hz, 2.0Hz, 1H), 4.35 (t, J=5.2Hz, 2H), 4.24-4.31 (m, 1H), 4 .10-4.20(m,2H),3.97-4.09(m,1H),3.78(t,J=5.2Hz,2H),3.20-3.52(m,8H),2.42-2.72(m,4H).

[1110] Example 283: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1111] The target compound (6 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine as raw materials.

[1112] MS m / z[LC-MS]:592.34[M+1]. 1 H NMR(400MHz, CDCl3)8.62(d,J=1.2Hz,1H),8.25(s,1H),7.79(s,2H),7.49(d,J=8.8Hz,2H),7.41 (d,J=1.2Hz,1H),7.05(d,J=8.8Hz,2H),6.34(dd,J=17.2Hz,2.0Hz,1H),6.20(dd,J=17.2Hz,10. 0Hz,1H),5.68(dd,J=10.0Hz,2.0Hz,1H),4.23-4.37(m,3H),4.11-4.17(m,2H),3.98-4.02(m,1H ),3.67-3.74(m,4H),3.33-3.36(m,4H),3.24-3.30(m,1H),2.80-2.94(m,2H),2.44-2.63(m,8H).

[1113] Example 284: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1114] The target compound (15 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1115] MS m / z[LC-MS]:519.28[M+1]. 1 H NMR(400MHz, CDCl3)8.60(d,J=1.2Hz,1H),8.25(s,1H),7.76(s,2H),7.49(d,J=8.8Hz,2H),7.40 (d, J=1.2Hz, 1H), 7.05 (d, J=8.8Hz, 2H), 6.34 (dd, J=17.2Hz, 2.0Hz, 1H), 6.21 (dd, J=17.2Hz, 10. 0Hz,1H),5.68(dd,J=10.0Hz,2.0Hz,1H),4.25-4.29(m,1H),4.10-4.18(m,2H),3.98-4.04(m,1H ),3.63-3.69(m,1H),3.22-3.42(m,5H),2.50-2.65(m,4H),1.17-1.21(m,2H),1.06-1.11(m,2H).

[1116] Example 285: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1117] The target compound (11 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1118] MS m / z[LC-MS]:521.30[M+1]. 1 H NMR (400MHz, CDCl3)8.62(d,J=1.6Hz,1H),8.25(s,1H),7.80(s,1H),7.68(s,1H),7.50(d,J=8. 8Hz,2H),7.42(d,J=1.6Hz,1H),7.05(d,J=8.8Hz,2H),6.34(dd,J=17.2Hz,2.0Hz,1H),6.21(dd, J=17.2Hz,10.4Hz,1H),5.68(dd,J=10.4Hz,2.0Hz,1H),4.25-4.28(m,1H),4.12-4.16(m,4H),3. 98-4.02(m,1H),3.23-3.38(m,5H),2.50-2.64(m,4H),1.90-1.99(m,2H),0.96(t,J=7.2Hz,3H).

[1119] Example 286: N-(5-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-2-yl)acrylamide

[1120] Referring to the synthesis method of Example 217, the target compound (5 mg) was synthesized using tert-butyl 4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the raw material.

[1121] MS m / z [LC-MS]: 424.27M+1]. 1H NMR (400MHz, CDCl3)8.98(s,1H),8.40(s,1H),8.30(d,J=9.2Hz,1H),8.22(s,1H),7.97(d,J =2.8Hz,1H),7.79(s,1H),7.73(s,1H),7.42(dd,J=9.2Hz,2.8Hz,1H),6.97(s,1H),6.47(dd ,J=16.8Hz,1.6Hz,1H),6.33(dd,J=16.8Hz,10.0Hz,1H),5.79(dd,J=10.0Hz,1.6Hz,1H),4. 38-4.46(m,1H),4.12-4.18(m,2H),3.51-3.61(m,6H),3.35-3.38(m,4H),2.08-2.20(m,4H).

[1122] Example 287: N-(5-(4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-2-yl)acrylamide

[1123] The target compound (9 mg) was synthesized by referring to the method of Example 217 using tert-butyl 4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the starting material. MS m / z [LC-MS]: 490.20 M+1. 1 H NMR(400MHz, CDCl3)9.82(s,1H),8.46(s,1H),8.34(d,J=9.2Hz,1H),8.24(s ,1H),8.13(s,1H),7.94(s,1H),7.91(s,1H),7.43(dd,J=9.2Hz,2.0Hz,1H),7 .26(t,J=60.4Hz,1H),6.96(s,1H),6.47(d,J=16.8Hz,1H),6.37(dd,J=16.8H z,10.0Hz,1H),5.77(d,J=10.0Hz,1H),3.46-3.56(m,4H),3.31-3.41(m,4H).

[1124] Example 288: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1125] The target compound (10 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-difluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1126] MS m / z[LC-MS]:529.24[M+1]. 1 H NMR(400MHz, CDCl3)8.61(s,1H),8.25(s,1H),7.78(s,1H),7.61(s,1H),7.49(d, J=8.4Hz,2H),7.41(s,1H),7.05(d,J=8.4Hz,2H),6.34(dd,J=16.8Hz,2.0Hz,1H) ,6.21(dd,J=16.8Hz,10.4Hz,1H),5.68(dd,J=10.4Hz,2.0Hz,1H),4.25-4.29(m, 1H),4.11-4.17(m,2H),3.97-4.03(m,1H),3.23-3.38(m,5H),2.50-2.64(m,4H).

[1127] Example 289: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1128] The target compound (18 mg) was synthesized by referring to the method of Example 4 using intermediate 10 and 1-(methyl-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as raw materials.

[1129] MS m / z[LC-MS]:496.30[M+1]. 1 H NMR(400MHz, CDCl3)8.68(s,1H),8.29(s,1H),8.12(s,1H),7.96(s,1H),7.50(d,J =8.8Hz,2H),7.42(s,1H),7.25(t,J=60.8Hz,1H),7.05(d,J=8.8Hz,2H),6.34(d,J= 17.2Hz,1H),6.21(dd,J=17.2Hz,10.0Hz,1H),5.68(d,J=10.0Hz,1H),4.25-4.29( m,1H),4.13-4.17(m,2H),3.98-4.02(m,1H),3.23-3.39(m,5H),2.50-2.64(m,4H).

[1130] Example 290: 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-(3-methoxypropoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1131] The title compound (3 mg) was obtained using Intermediate 8 and 4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(2-(3-methoxypropoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile as starting materials. MS m / z [LC-MS]: 540.27 [M+1]. 1 H NMR(400MHz, CDCl3)8.63(s,1H),8.25(s,1H),7.81(s,1H),7.80(s,1H),7.50(d,J=8.8Hz,2H),7.43( s,1H),7.05(d,J=8.8Hz,2H),6.62(dd,J=16.8Hz,10.4Hz,1H),6.34(dd,J=16.8Hz,2.0Hz,1H),5.75(d d,J=10.4Hz,2.0Hz,1H),4.35(t,J=5.2Hz,2H),3.84-3.92(m,2H),3.82(t,J=5.2Hz,2H),3.72-3.79(m ,2H),3.52(t,J=6.4Hz,2H),3.39(t,J=6.4Hz,2H),3.32-3.34(m,4H),3.26(s,3H),1.78-1.84(m,2H).

[1132] Example 291: 4-(4-(4-acryloylpiperazin-1-yl)piperidin-1-yl)-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1133] The target compound (16 mg) was obtained using intermediate 11 and 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrazole as starting materials.

[1134] MS m / z[LC-MS]:473.30[M+1]. 1H NMR (400MHz, DMSO-d6)8.87(s,1H),8.54(s,1H),8.38(s,1H),8.05(s,1H),7. 22(s,1H),6.78(dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,1H),5. 66(dd,J=10.4Hz,2.0Hz,1H),4.06(t,J=6.8Hz,2H),3.44-3.62(m,6H),2.77( t,J=11.2Hz,2H),2.36-2.59(m,5H),1.73-1.94(m,6H),0.84(t,J=7.2Hz,3H).

[1135] Example 292: N-(5-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-2-yl)acrylamide

[1136] Referring to the synthesis method of Example 217, the target compound (19 mg) was synthesized using tert-butyl 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the raw material.

[1137] MS m / z [LC-MS]: 468.24M+1]. 1 H NMR(400MHz, CDCl3)8.67(s,1H),8.39(s,1H),8.22(d,J=9.2Hz,1H),8.20(s,1H), 8.01(s,1H),7.77(s,1H),7.70(s,1H),7.36(dd,J=9.2Hz,2.0Hz,1H),6.97(s,1H) ,6.44(d,J=16.8Hz,1H),6.27(dd,J=16.8Hz,10.4Hz,1H),5.76(d,J=10.4Hz,1H), 4.24(q,J=7.2Hz,2H),3.44-3.53(m,4H),3.26-3.40(m,4H),1.54(t,J=7.2Hz,3H).

[1138] Example 293: N-(6-(4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[1139] The target compound (10 mg) was synthesized by referring to the synthesis method of Example 196 using tert-butyl 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the raw material.

[1140] MS m / z [LC-MS]: 468.25M+1]. 1 H NMR(400MHz, CDCl3)8.38(s,1H),8.24(d,J=2.0Hz,1H),8.21(s,1H),7.99(dd,J= 8.8Hz,2.0Hz,1H),7.76(s,1H),7.69(s,1H),6.96(s,1H),6.73(d,J=8.8Hz,1H),6 .43(d,J=16.8Hz,1H),6.25(dd,J=16.8Hz,10.4Hz,1H),5.77(d,J=10.4Hz,1H),4 .24(q,J=7.2Hz,2H),3.82-3.90(m,4H),3.26-3.34(m,4H),1.55(t,J=7.2Hz,3H).

[1141] Example 294: 4-(4-(-4-(1-acryloylazetidin-3-yl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile

[1142] The intermediate of step 1 in Example 277 was used as the starting material to undergo reductive amination and then synthesize the target compound (13 mg) according to the method of Example 4.

[1143] MS m / z[LC-MS]:494.26[M+1]. 1 H NMR (400MHz, DMSO-d6)9.25(s,1H),8.79(s,1H),8.33(s,1H),8.10(s,1H),7.78(d,J=8.8H z,2H),7.12(d,J=8.8Hz,2H),6.31(dd,J=16.8Hz,10.4Hz,1H),6.09(dd,J=16.8Hz,2.0Hz,1 H),5.66(dd,J=10.4Hz,2.0Hz,1H),4.24-4.28(m,1H),4.06-4.10(m,1H),3.94-3.98(m,1H ),3.89(s,3H),3.77-3.80(m,1H),3.32-3.34(m,4H),3.14-3.24(m,1H),2.45-2.55(m,4H).

[1144] Example 295: 4-(4-(-4-(1-acryloylpiperidin-4-yl)piperazin-1-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile

[1145] The intermediate of step 1 in Example 277 was used as the starting material to undergo reductive amination and then synthesize the target compound (19 mg) according to the method of Example 4.

[1146] MS m / z[LC-MS]:522.29[M+1].

[1147] Example 296: (S)-4-(4-(4-acryloylpiperazin-1-yl)phenyl)-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1148] The target compound (13 mg) was obtained using intermediate 8 and (S)-1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as starting materials.

[1149] MS m / z[LC-MS]:494.27[M+1].

[1150] Example 297: N-(5-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)pyridin-2-yl)acrylamide

[1151] The target compound (21 mg) was obtained by the synthesis method of Example 4 using intermediate 7 and tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate as starting materials.

[1152] MS m / z[LC-MS]:446.18[M+1]. 1H NMR(400MHz,DMSO-d6)10.89(s,1H),9.29 (s,1H),8.78(d,J=2.0Hz,1H),8.67(s,1H),8.41(s,1H),8.32(d,J=8.4Hz,1H),8.24(dd,J=8.4Hz,2.0Hz,1H),8.14(s,1H),7.92(d,J=8.0Hz, 2H), 7.86 (s, 1H), 7.75 (d, J = 8.0Hz, 2H), 6.63 (dd, J = 16.8Hz, 10.0Hz, 1H), 6.33 (d, J = 16.8Hz, 1H), 5.80 (dd, J = 10.0Hz, 1.6Hz, 1H), 3.87 (s, 3H).

[1153] Example 298: N-(6-(4-(3-cyano-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[1154] The target compound (11 mg) was synthesized by referring to the synthesis method of Example 196 using tert-butyl 4-(3-cyano-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the raw material.

[1155] MS m / z [LC-MS]: 490.19M+1]. 1 H NMR (400MHz, CDCl3)8.44(d,J=1.2Hz,1H),8.25(s,1H),8.23(d,J=2.8Hz,1H),8.10(s,1 H),8.00(dd,J=8.4Hz,2.8Hz,1H),7.93(s,1H),7.24(t,J=60.4Hz,1H),7.08(s,1H),6.9 4(d,J=1.2Hz,1H),6.75(d,J=8.4Hz,1H),6.44(dd,J=16.8Hz,1.2Hz,1H),6.24(dd,J=16 .8Hz, 10.0Hz, 1H), 5.78 (dd, J=10.0Hz, 1.2Hz, 1H), 3.85-3.90 (m, 4H), 3.30-3.32 (m, 4H).

[1156] Example 299: 4-(4-(6-acryloyl-2,6-diazaspiro[3.3]heptane-2-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile

[1157] The target compound (15 mg) was obtained according to the synthesis method of Example 4 using 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile and 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester as starting materials.

[1158] MS m / z[LC-MS]:451.20[M+1]. 1 H NMR (400MHz, CDCl3)8.49(s,1H),8.32(s,1H),7.98(s,1H),7.95(s,1H),7.84(d,J=8.4Hz,2H),6.60(d,J=8.4Hz,2H),6.36(dd,J=16.8Hz ,2.0Hz,1H),6.20(dd,J=16.8Hz,10.4Hz,1H),5.71(dd,J=10.4Hz,2.0Hz,1H),4.42(s,2H),4.28(s,2H),4.11-4.18(m,4H),3.98(s,3H).

[1159] Example 300: N-(1-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)azetidin-3-yl)acrylamide

[1160] The target compound (5 mg) was obtained according to the synthesis method of Example 4 using 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile and tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-yl)carbamate as starting materials.

[1161] MS m / z[LC-MS]:425.18[M+1]. 1H NMR(400MHz, CDCl3)8.49(s,1H),8.32(s,1H),7.99(s,1H),7.95(s,1H),7.83(d,J=8.8Hz,2H),6 .60(d,J=8.8Hz,2H),6.35(d,J=16.8Hz,1H),6.13(dd,J=16.8Hz,10.0Hz,1H),6.07(d,J=8.0Hz, 1H), 5.73 (d, J = 10.0Hz, 1H), 4.93-5.04 (m, 1H), 4.39 (t, J = 7.6Hz, 2H), 3.98 (s, 3H), 3.80 (dd, J = 7.6Hz, 4.8Hz, 2H).

[1162] Example 301: N-(5-(4-(3-cyano-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-2-yl)acrylamide

[1163] Referring to the synthesis method of Example 217, the target compound (9 mg) was synthesized using tert-butyl 4-(3-cyano-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the raw material.

[1164] MS m / z[LC-MS]:482.24[M+1]. 1 H NMR(400MHz, CDCl3)8.40(s,1H),8.21-8.24(m,2H),8.13(s,1H),8.02(s,1H),7.7 8(s,1H),7.68(s,1H),7.39(dd,J=8.8Hz,2.0Hz,1H),6.98(s,1H),6.45(d,J=16.8H z,1H),6.26(dd,J=16.8Hz,10.4Hz,1H),5.79(d,J=10.4Hz,1H),4.15(t,J=7.2Hz,2 H), 3.49-3.55 (m, 4H), 3.33-3.40 (m, 4H), 1.91-2.00 (m, 2H), 0.97 (t, J = 7.2Hz, 3H).

[1165] Example 302: N-(6-(4-(3-cyano-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[1166] The target compound (12 mg) was synthesized by referring to the synthesis method of Example 196 using tert-butyl 4-(3-cyano-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazine-1-carboxylate as the raw material.

[1167] MS m / z [LC-MS]: 482.25M+1].

[1168] Example 303: N-(6-(4-(3-cyano-6-(1-propyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)-N-methylacrylamide

[1169] The target compound (3 mg) was synthesized by referring to the synthesis method of Example 134 and using the final product of Example 133 as a raw material.

[1170] MS m / z [LC-MS]: 496.28M+1]. 1 H NMR(400MHz, CDCl3)8.37(s,1H),8.25(d,J=2.4Hz,1H),8.19(s,1H),7.96(dd,J=8.8Hz,2 .4Hz,1H),7.76(s,1H),7.75(s,1H),7.68(s,1H),6.95(s,1H),6.68(d,J=8.8Hz,1H),6.41 (d,J=16.8Hz,1H),6.27(dd,J=16.8Hz,10.4Hz,1H),5.7.3(d,J=10.4Hz,1H),4.13(t,J=7 .2Hz,2H),3.78-3.86(m,4H),3.22-3.32(m,4H),1.89-1.98(m,2H),0.95(t,J=7.2Hz,3H).

[1171] Example 304: N-(5-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)acrylamide

[1172] The target compound (22 mg) was obtained by the synthesis method of Example 4 using intermediate 7 and tert-butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate as starting materials.

[1173] MS m / z[LC-MS]:371.19[M+1].

[1174] Example 305: 4-(4-(2-acryloyl-2-azaspiro[3.3]heptane-6-yl)piperazin-1-yl)phenyl)-6-(1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1175] The target compound (17 mg) was synthesized by referring to the method of Example 168.

[1176] MS m / z[LC-MS]:547.29[M+1].

[1177] Example 306: N-(2-(4-(3-cyano-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenoxy)ethyl)acrylamide

[1178] The target compound (5 mg) was obtained by following the procedure of Example 165.

[1179] MS m / z[LC-MS]:413.17[M+1].

[1180] Example 307: (R)-N-(1-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)pyrrolidin-3-yl)acrylamide

[1181] The target compound (3 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and (R)-tert-butyl pyrrolidin-3-ylcarbamate as starting materials.

[1182] MS m / z[LC-MS]:508.25[M+1].

[1183] Example 308: (S)-N-(1-(4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)pyrrolidin-3-yl)acrylamide

[1184] The target compound (6 mg) was obtained according to the synthesis method of Example 8 using 4-(3-cyano-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl trifluoromethanesulfonate and (S)-tert-butyl pyrrolidin-3-ylcarbamate as starting materials.

[1185] MS m / z[LC-MS]:508.25[M+1].

[1186] Example 309: 4-(4-(4-acryloylpiperazin-1-yl)-2-methoxyphenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1187] The target compound (13 mg) was synthesized by referring to the synthesis method of Example 4 using tert-butyl 4-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate.

[1188] MS m / z[LC-MS]:468.23[M+1]. 1 H NMR(400MHz, DMSO-d6)9.14(d,J=1.2Hz,1H),8.52(s,1H),8.33(s,1H),8.06(s,1H ),7.62(d,J=1.2Hz,1H),7.21(d,J=8.4Hz,1H),6.85(dd,J=16.8Hz,10.8Hz,1H),6. 65(d,J=1.6Hz,1H), 6.62(dd,J=8.4Hz,1.6Hz,1H), 6.14(dd,J=16.8Hz,2.4Hz,1H), 5.71(dd,J=10.4Hz,2.4Hz,1H),3.85(s,3H),3.66-3.76(m,7H),3.24-3.32(m,4H).

[1189] Example 310: 4-(4-(4-acryloylpiperazin-1-yl)-2-fluorophenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[1190] The target compound (12 mg) was synthesized by referring to the synthesis method of Example 4 using tert-butyl 4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate.

[1191] MS m / z[LC-MS]:456.23[M+1]. 1H NMR(400MHz, DMSO-d6)9.24(d,J=1.2Hz,1H),8.60(s,1H),8.36(s,1H),8. 09(s,1H),7.76(d,J=1.2Hz,1H),7.40(t,J=8.8Hz,1H),6.91-6.95(m,2H), 6.85(dd,J=16.8Hz,10.4Hz,1H),6.14(dd,J=16.8Hz,2.4Hz,1H),5.71(dd ,J=10.4Hz,2.4Hz,1H),3.85(s,3H),3.64-3.76(m,4H),3.26-3.33(m,4H).

[1192] Example 311: N-(6-(4-(3-cyano-6-(1-isopropyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)piperazin-1-yl)pyridin-3-yl)acrylamide

[1193] Referring to the synthesis method of Example 196, the target compound (16 mg) was synthesized using t...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof: in, X1 is CH or N, One of X2 and X3 is C and the other is N. R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, A is R0, -O-R0, -S-R0, -NR6-R0, -C≡C-R0, -O-(CH2)-R0, -S-(CH2)-R0, -NR6-(CH2)-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2, R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, L0 is -O-, -O-(CH2) 1-6 -、-S-、-S-(CH2) 1-6 -, -NH-, or -NH-(CH2) 1-6 -, L1 and L2 are each independently selected from methylene, alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -O-R5, -OR 13 、-S-R5、-SR 13 、-NR5R6、-NH-R 13 、-(CO)-R3、-(CO)OR5、 -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or A does not exist, -(L0) p -(L1) m - is a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocyclic ring, or a 3-12 membered heterocyclic ring, and the C or N on the ring can be connected by -(L4) p1 -(L5) p2 -(L6) p3 -(L7) p4 - is linked to carbon 1 to form a carbocyclic or heterocyclic ring, or R b Does not exist, -(L0) p -(L1) m - is a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocyclic ring, or a 3-12 membered heterocyclic ring, and the C or N on the ring can be connected by -(L4) p1 -(L5) p2 -(L6) p3 -(L7) p4 - is connected to carbon 2 to form a carbocyclic or heterocyclic ring, L4 is a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocyclic ring, or a 3-12 membered heterocyclic ring, L5, L6 and L7 are each independently selected from -O-(CH2) 1-8 -、-NH-(CH2) 1-8 -、-O-(CO)-(CH2) 1-8 -、-NH-(CO)-(CH2) 1-8 - and -(CH2) 1-8 -, wherein -O- and -O-, -NH- and -NH-, or -O- and -NH- are not directly connected, P1, P2, P3 and P4 are each independently 0 or 1, and P2+P3+P4 is 1, 2, or 3, R 13 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, L3 is the key, or The asterisk key is connected to R1. Ring B is a 3-12 membered heterocyclic ring, R1 is halogen, alkynyl, -CN, -(CO)-R3, or R 10 、R 11 and R 12 are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R 12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, -O-R5, or -NR5R6, R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2, p is 0 or 1, and m and n are each independently 0, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein X1 is CH or N, One of X2 and X3 is C and the other is N. R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, A is R0, -O-R0, -S-R0, -NR6-R0, -C≡C-R0, -O-(CH2)-R0, -S-(CH2)-R0, -NR6-(CH2)-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R0 is selected from 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclyl may each be optionally substituted with 1-3 R2, R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, L0 is -O-(CH2) 1-6 -, L1 and L2 are each independently selected from methylene, alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, L3 is the key, or The asterisk key is connected to R1. Ring B is a 3-12 membered heterocyclic ring, R1 is halogen, alkynyl, -CN, -(CO)-R3, or R 10 、R 11 and R 12 are each independently selected from H, halogen, C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, or R 10 and R 11 Can be linked together to form a bond, or R 10 and R 11 Can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, or R 11 and R 12 They can be connected together to form a 5-12 membered carbocyclic ring or a 5-12 membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring can be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R3 are each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, -O-R5, or -NR5R6, R5 and R6 are each independently selected from H and C 1-6 Alkyl, or R5 and R6 may be linked together to form a 3-8 membered heterocyclic group, which may be optionally substituted with halogen, -CN, -OH, or -NH2, p is 0 or 1, and m and n are each independently 0, 1, or 2.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L1 and L2 are each independently selected from alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted with halogen, -CN, -OH, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, p, m and n are each independently 0 or 1, R3, R5, and R6 are as defined in claim 2.

4. The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R a and R b Each independently selected from H, halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R3, R5, and R6 are as defined in claim 2.

5. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein A is R0, -O-R0, -S-R0, -NR6-R0, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R2 is selected from halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, -(CH2) 1-6 -3-12 membered cycloalkyl, -(CH2) 1-6 -3-12 membered heterocyclic group, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclic group may be optionally replaced by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, L1 and L2 are each independently selected from alkynylene, 6-10 membered arylene, 5-12 membered heteroarylene, 3-12 membered carbocycle, or 3-12 membered heterocycle, wherein the arylene, heteroarylene, carbocycle and heterocycle may be optionally substituted by halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl groups may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, R0, R3, R5, and R6 are as defined in claim 2.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein X1 is CH, X2 is N, X3 is C, R a H, R b For -CN, A is R0, R0 is a 5-12 membered heteroaryl or a 3-12 membered heterocyclic group, and the heteroaryl and heterocyclic groups may each be optionally substituted by 1-3 R2, R1 is R2, R 10 、R 11 and R 12 As defined in claim 1.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein for or 8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein A is R0, -O-R0, -S-R0, or -NR6-R0, R0 is a 5-12 membered heteroaryl or a 3-12 membered heterocyclyl, each of which may be optionally substituted with 1-3 R2, and R2 and R6 are as defined in claim 1.

9. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein L1 and L2 are each independently selected from an alkynylene group, a 6-10 membered arylene group, a 5-12 membered heteroarylene group, a 3-12 membered carbocycle, or a 3-12 membered heterocycle, wherein the arylene group, heteroarylene group, carbocycle and heterocycle may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6, wherein R3, R5 and R6 are as defined in claim 1.

10. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R 10 、R 11 and R 12 Each independently selected from H or C 1-6 Alkyl, which may be optionally substituted with halogen, -CN, -OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, -O-R5, -S-R5, -NR5R6, -(CO)-R3, -(CO)OR5, -(CO)NR5R6, -SO2-R3, or -(SO2)NR5R6.

11. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, wherein R3 is independently selected from C 1-6 Alkyl, 3-12 membered cycloalkyl, or 3-12 membered heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl may be optionally substituted by halogen, -CN, -OH or -NH2.

12. The following compounds or their pharmaceutically acceptable salts, solvates, polymorphs or isomers 13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, and a pharmaceutically acceptable carrier.

14. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof, or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a disease associated with FGFR. The use according to claim 14 , wherein the disease associated with FGFR is a tumor.

16. The use according to claim 14, wherein the disease associated with FGFR is bile duct cancer, urothelial carcinoma, lung cancer, bladder cancer, cervical cancer, endometrial cancer, breast cancer, thyroid cancer, intestinal cancer, gastric cancer, liver cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gallbladder cancer, leukemia, multiple myeloma, Hodgkin's lymphoma, or melanoma.

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