WO2024114680A1 - Heterocyclic compound, pharmaceutical composition, and application thereof - Google Patents

Abstract

Disclosed are a class of heterocyclic compounds acting as FGFR inhibitors, and specifically disclosed are a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same, and an application thereof in the preparation of a drug for treating cancer.

Description

Heterocyclic compound, pharmaceutical composition and application thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority and rights of Chinese Patent Application No. 202211520746.6 filed with the State Intellectual Property Office of China on November 30, 2022, Chinese Patent Application No. 202311028759.6 filed with the State Intellectual Property Office of China on August 15, 2023, and Chinese Patent Application No. 202311487332.2 filed with the State Intellectual Property Office of China on November 8, 2023. The contents disclosed in the above applications are incorporated herein by reference in their entirety.

Technical Field

The present disclosure belongs to the field of medical technology, and specifically relates to heterocyclic compounds of FGFR inhibitors, pharmaceutical compositions and applications thereof.

Background technique

FGFR (Fibroblast Growth Factor Receptor) is a transmembrane receptor-type tyrosine kinase, and the family mainly includes four members FGFR1, 2, 3 and 4. After binding to its ligand FGF (Fibroblast growth factor), FGFR causes receptor dimerization and then phosphorylates the tyrosine residues in the kinase region to activate the receptor. Subsequently, the activated FGFR further activates downstream RAS/RAF, PI3K/AKT, JAK/STAT and PLCγ signaling pathways, and participates in regulating multiple processes such as cell proliferation, apoptosis, migration, repair of damaged tissues and angiogenesis. Under normal physiological conditions, the FGFR signaling pathway is strictly regulated and is at a weak activation level. However, its overactivation often leads to the occurrence and development of tumors. The molecular mechanisms of abnormal FGFR activation mainly include 1) gene amplification; 2) gene mutation; 3) gene fusion caused by gene translocation, etc. For example, FGFR2 gene amplification occurs in gastric cancer (5-10%), FGFR2 gene translocation occurs in intrahepatic bile duct cancer (14%), and FGFR2 gene mutation occurs in endometrial cancer (12-14%). FGFR3 gene abnormalities are most common in bladder cancer, including gene mutations (60-80% of non-muscle invasive bladder cancer and 15-20% of muscle invasive bladder cancer), gene translocation (3-6%), and gene amplification (the incidence has not been reported); followed by myeloma, 15-20% of myeloma patients have FGFR3 gene translocation. Some of the above FGFR gene abnormalities have been proven to be associated with poor prognosis of patients.

Given the importance of the FGFR signaling pathway in tumor treatment, targeted therapy for the FGFR signaling pathway has become a research hotspot in the field of tumor treatment in recent years.

Summary of the invention

The present disclosure provides a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

in,

X ₁ and X ₂ are independently selected from N or C;

Z is selected from O, S, NH, a bond, OCR ⁶ R ⁷ , SCR ⁶ R ⁷ , NHCR ⁶ R ⁷ or CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently selected from H and C ₁ -C ₆ alkyl;

R ¹ is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted with R ^1a ;

R ^1a is selected from halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted by R ^1b ;

R ^1b is selected from halogen, OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ² is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R ^2a ;

R ^2a is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl;

R ³ is selected from H, CN, OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

Ring A is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the C ₃ -C 6 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C ₁₀ aryl or 5-10 membered heteroaryl The cyclic group, C ₆ -C ₁₀ aryl group or 5-10 membered heteroaryl group is optionally substituted by ^Ra ;

Ring B is selected from a C ₆ -C ₁₀ aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C ₆ -C ₁₀ aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R ^b ;

Ring C is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or C ₆ -C ₁₀ aryl, and the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or C ₆ -C ₁₀ aryl is optionally substituted by R ^c ;

Each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, CN, OH, _NH2 , -S(=O) _-C1 - _C4 alkyl, -S(=O) ₂ - _C1 - _C4 alkyl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, or 4-10 membered heterocyclyl;

L is selected from a bond, -CH ₂ -, -C(=O)-, -NHC(=O)-, a C ₃ -C ₆ carbocyclic ring, a 4-6 membered heterocyclic ring, a C ₆ -C ₁₀ aromatic ring or a 5-6 membered heteroaromatic ring;

W is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 4-6 membered heterocyclyl, -S(═O) ₂ -C ₁ -C ₄ alkyl, -C(═O)-RT, -C(═O)CR ^{4 ═C} (R ⁵ ) ₂ , -C(═O)C≡CR ⁵ , -NHC(═O)CR ⁴ ═C(R ⁵ ) ₂ , -NHC(═O)C≡CR ⁵ , -S(═O)CR ⁴ ═C(R ⁵ ) ₂ , -S(═O) ₂ CR ⁴ ═C(R ⁵ ) ₂ , -NHS(═O)CR ⁴ ═C(R ⁵ ) ₂ , or -NHS(═O) ₂ CR ⁴ ═C(R ⁵ ) ₂ ;

^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclyl, -N( _C1 - _C6 alkyl) ₂ , _C1 - _C6 alkyl-CN or _C3 - _C6 cycloalkyl;

R ⁴ is selected from H, CN, halogen or C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^5a ;

R ^5a is independently selected from halogen, CN, OH, NH ₂ , —NH—C ₁ -C ₆ alkyl, —N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₈ cycloalkyl or 4-9 membered heterocyclyl.

In some embodiments, in Formula (I),

X ₁ and X ₂ are independently selected from N or C;

Z is selected from O, S, NH or a bond;

R ¹ is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted with R ^1a ;

R ^1a is selected from halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted by R ^1b ;

R ^1b is selected from halogen, OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ² is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R ^2a ;

R ^2a is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl;

R ³ is selected from H, CN, OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

Ring A is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by ^Ra ;

Ring B is selected from a C ₆ -C ₁₀ aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C ₆ -C ₁₀ aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R ^b ;

Ring C is selected from C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl, and the C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ^c ;

Each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, CN, OH, _NH2 , -S(=O) _-C1 - _C4 alkyl, -S(=O) ₂ - _C1 - _C4 alkyl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, or 4-10 membered heterocyclyl;

L is selected from a bond, -CH ₂ -, -C(=O)-, -NHC(=O)-, a C ₃ -C ₆ carbocyclic ring, a 4-6 membered heterocyclic ring, a C ₆ -C ₁₀ aromatic ring or a 5-6 membered heteroaromatic ring;

W is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 4-6 membered heterocyclyl, -S(═O) ₂ -C ₁ -C ₄ alkyl, -C(═O)-RT, -C(═O)CR ^{4 ═C} (R ⁵ ) ₂ , -C(═O)C≡CR ⁵ , -NHC(═O)CR ⁴ ═C(R ⁵ ) ₂ , -NHC(═O)C≡CR ⁵ , -S(═O)CR ⁴ ═C(R ⁵ ) ₂ , -S(═O) ₂ CR ⁴ ═C(R ⁵ ) ₂ , -NHS(═O)CR ⁴ ═C(R ⁵ ) ₂ , or -NHS(═O) ₂ CR ⁴ ═C(R ⁵ ) ₂ ;

^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclyl or _C3 - _C6 cycloalkyl;

R ⁴ is selected from H, CN, halogen or C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^5a ;

R ^5a is independently selected from halogen, CN, OH, NH ₂ , —NH—C ₁ -C ₆ alkyl, —N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₈ cycloalkyl or 4-9 membered heterocyclyl.

In some embodiments, in Formula (I),

X ₁ and X ₂ are independently selected from N or C;

Z is selected from O, S, NH or a bond;

R ¹ is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted with R ^1a ;

R ^1a is selected from halogen, OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ² is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R ^2a ;

R ^2a is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl;

R ³ is selected from H, CN, OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

Ring A is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by ^Ra ;

Ring B is selected from a C ₆ -C ₁₀ aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C ₆ -C ₁₀ aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R ^b ;

Ring C is selected from C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl, and the C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ^c ;

Each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, CN, OH, _NH2 , -S(=O) _-C1 - _C4 alkyl, -S(=O) ₂ - _C1 - _C4 alkyl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, or 4-10 membered heterocyclyl;

L is selected from a bond, -CH ₂ -, -C(=O)-, -NHC(=O)-, a C ₃ -C ₆ carbocyclic ring, a 4-6 membered heterocyclic ring, a C ₆ -C ₁₀ aromatic ring or a 5-6 membered heteroaromatic ring;

W is selected from -C(＝O)CR ⁴ ＝C(R ⁵ ) ₂ , -C(＝O)C≡CR ⁵ , -NHC(＝O)CR ⁴ ＝C(R ⁵ ) ₂ , -NHC(＝O)C≡CR ⁵ , -S(＝O)CR ⁴ ＝C(R ⁵ ) ₂ , -S(＝O) ₂ CR ⁴ ＝C(R ⁵ ) ₂ , -NHS(＝O)CR ⁴ ＝C(R ⁵ ) ₂ or -NHS(＝O) ₂ CR ⁴ ＝C(R ⁵ ) ₂ ;

R ⁴ is selected from H, CN, halogen or C ₁ -C ₆ alkyl;

each R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl, said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl being optionally substituted with R ^5a ;

R ^5a is independently selected from halogen, CN, OH, NH ₂ , —NH—C ₁ -C ₆ alkyl, —N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₈ cycloalkyl or 4-9 membered heterocyclyl.

In some embodiments, at least one of _X1 or _X2 is selected from N.

In some embodiments, _X1 is selected from C and _X2 is selected from N.

In some embodiments, _X1 is selected from N, and _X2 is selected from C.

In some embodiments, Z is selected from O, S, NH, a bond, OCR ⁶ R ⁷ , SCR ⁶ R ⁷ , NHCR ⁶ R ⁷ , or CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently selected from H and C ₁ -C ₃ alkyl.

In some embodiments, Z is selected from O, S, NH, a bond, OCH ₂ , SCH ₂ , NHCH ₂ , or CH ₂ .

In some embodiments, Z is selected from O, S, NH, or a bond.

In some embodiments, Z is O or _OCH2 .

In some embodiments, Z is selected from O.

In some embodiments, Z is _OCH2 .

In some embodiments, R ¹ is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy or C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy or C ₃ -C ₆ cycloalkyl is optionally substituted with R ^1a .

In some embodiments _, R ¹ is selected from CN, OH, halogen, C _{1 -C 6} alkyl, C _{2 -C 6} alkynyl, or C ₃ -C _{6 cycloalkyl , which} is optionally substituted with R ^1a .

In some embodiments, R ¹ is selected from CN, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, or C ₃ -C ₆ cycloalkyl, said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl, or C ₃ -C ₆ cycloalkyl being optionally substituted with R ^1a .

In some embodiments, R ¹ is selected _from C ₂ -C ₆ alkynyl or C _{3 -C 6} cycloalkyl, which _is optionally substituted with ^{R 1a} _.

In some embodiments, R ¹ is selected _from C _{2 -C 6} alkynyl, which is optionally substituted with R ^1a .

In some embodiments, R ¹ is selected _from C _{2 -C 4} alkynyl, which is optionally substituted with R ^1a .

In some embodiments, R ^1a is selected from OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with R ^1b .

In some embodiments, R ^1a is selected from OH, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with R ^1b .

In some embodiments, the 4-6 membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 4-6 membered heterocyclyl contains 1 O or S atom.

In some embodiments, the 5-6 membered heteroaryl group contains 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 5-6 membered heteroaryl contains 1 or 2 N atoms.

In some embodiments, R ^1a is selected from OH, -CH ₃ , -OCH ₃ , cyclopropyl, cyclobutyl, 3-oxetanyl, 2-tetrahydrofuranyl, tetrahydro-2H-thiopyranyl-4-yl, phenyl, 3-pyridyl or 5-pyrimidinyl, and the cyclopropyl, cyclobutyl, 3-oxetanyl, 2-tetrahydrofuranyl, tetrahydro-2H-thiopyranyl-4-yl, phenyl, 3-pyridyl or 5-pyrimidinyl is optionally substituted with R ^1b .

In some embodiments, R ^1a is selected from OH, -OCH ₃ , cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-thiopyranyl, phenyl, pyridinyl, or pyrimidinyl, which is optionally substituted with R ^1b .

In some embodiments, R ^1a is selected from halogen, OH, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, R ^1a is selected from OH, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, R ^1b is selected from halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, R ^1b is selected from F, Cl, CH ₃ or -OCH ₃ .

In some embodiments, R ¹ is selected from -CN, -Cl, -CH ₃ , -CH ₂ OH,

In some embodiments, R ¹ is In some embodiments, R ¹ is In some embodiments, R ¹ is

In some embodiments, R ² is selected _from CN, OH, NH ₂ , halogen, C _{1 -C 6} alkyl or C _{1 -C 6} alkoxy, _which is optionally substituted with R ^2a .

In some embodiments, R ^2a is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl.

In some embodiments, ^R2 is selected from _CH3 , _{CH2OH , CH2O} (cyclopropyl), _CF3 , _CH2OCH3 , _{CH2OCF3 , C2H5} , _OCH3 , or _OH .

In some embodiments, ^R2 is selected from _CH2OH , methyl _{, CH2OCH3} , _OCH3 , or OH.

In some embodiments, R ² is selected from CH ₂ OH or methyl.

In some embodiments, R ² is selected from CH ₂ OH.

In some embodiments, ^R3 is selected from H.

In some embodiments, one of R ² and R ³ is H.

In some embodiments _, ^R2 is selected from _CH3 , _{CH2OH , CH2O} (cyclopropyl), _CF3 , _CH2OCH3 , _{CH2OCF3 , C2H5} , _OCH3 , or OH; ^R3 is H.

In some embodiments, ^R2 is _CH2OH and ^R3 is H. In some embodiments, ^R2 is methyl _and ^R3 is H. In some embodiments, ^R2 is _CH2OCH3 and ^R3 is H.

In some embodiments, Ring A is selected from C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, and the C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl is optionally substituted with ^Ra .

In some embodiments, Ring A is selected from C ₃ -C ₆ cycloalkyl or 5-10 membered heteroaryl, wherein the C ₃ -C ₆ cycloalkyl or 5-10 membered heteroaryl is optionally substituted with ^Ra .

In some embodiments, Ring A is selected from C ₃ -C ₆ cycloalkyl or 5-6 membered heteroaryl, and the C ₃ -C ₆ cycloalkyl or 5-6 membered heteroaryl is optionally substituted with ^Ra .

In some embodiments, the 5-10 membered heteroaryl and the 5-6 membered heteroaryl each independently contain 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 5-10 membered heteroaryl and the 5-6 membered heteroaryl each independently contain 1 or 2 N atoms.

In some embodiments, Ring A is selected from cyclopropyl, pyridinyl (including 2-pyridinyl, 3-pyridinyl) or pyrimidinyl (including 2-pyrimidinyl), and the cyclopropyl, pyridinyl or pyrimidinyl is optionally substituted with ^Ra .

In some embodiments, Ring A is selected from cyclopropyl or pyridinyl, which is optionally substituted with ^Ra .

In some embodiments, Ring A is selected from pyridinyl, which is optionally substituted with ^Ra .

In some embodiments, Ra ^is selected from halogen.

In some embodiments, Ra ^is selected from F.

In some embodiments, Ring A is selected from

In some embodiments, Ring A is

In some embodiments, Ring B is selected from a 5-10 membered heteroaryl ring, which is optionally substituted with R ^b .

In some embodiments, Ring B is selected from a 5-6 membered heteroaromatic ring containing 1, 2, or 3 N heteroatoms, which is optionally substituted with R ^b .

In some embodiments, Ring B is selected from a triazole ring, which is optionally substituted with R ^b .

In some embodiments, Ring B is selected from a 1,2,3-triazole ring, which is optionally substituted with R ^b .

In some embodiments, R ^b is selected from C ₁ -C ₆ alkyl.

In some embodiments, R ^b is selected from CH ₃ .

In some embodiments, Ring B is

In some embodiments, ring C is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or phenyl, and the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or phenyl is optionally substituted with R ^c ;

In some embodiments, Ring C is selected from C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl, wherein the C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^c .

In some embodiments, Ring C is selected from 4-10 membered heterocyclyl or phenyl, which is optionally substituted with R ^c .

In some embodiments, Ring C is selected from 4-6 membered heterocyclyl or phenyl, which is optionally substituted with R ^c .

In some embodiments, Ring C is selected from 4-10 membered heterocyclyl, which is optionally substituted with R ^c .

In some embodiments, Ring C is selected from 4-6 membered heterocyclyl, which is optionally substituted with R ^c .

In some embodiments, the 4-10 membered heterocyclyl or the 4-6 membered heterocyclyl each contains 1, 2 or 3 heteroatoms independently selected from N, O or S. In some embodiments, the 4-10 membered heterocyclyl or the 4-6 membered heterocyclyl each contains 1, 2 or 3 N atoms.

In some embodiments, Ring C is selected from Said Optionally substituted with R ^c .

In some embodiments, Ring C is selected from piperidinyl, which is optionally substituted with R ^c .

In some embodiments, R ^c is selected from halogen or C ₁ -C ₆ alkyl.

In some embodiments, R ^c is F.

In some embodiments, Ring C is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, or C ₆ -C ₁₀ aryl.

In some embodiments, Ring C is selected from C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl.

In some embodiments, Ring C is selected from a 4-10 membered heterocyclyl or a C ₆ -C ₁₀ aryl.

In some embodiments, Ring C is selected from 6-9 membered heterocyclyl or phenyl.

In some embodiments, Ring C is selected from a 4-10 membered heterocyclyl.

In some embodiments, Ring C is selected from a 4-6 membered heterocyclyl.

In some embodiments, Ring C is selected from

In some embodiments, Ring C is selected from

In some embodiments, Ring C is selected from In some embodiments, W is selected from -C(=O) ^CR4 =C( ^R5 ) ₂ , -C(=O) ^C≡CR5 , -NHC(=O) ^CR4 =C( ^R5 ) ₂ , -NHC(=O) ^C≡CR5 , -S(=O) ^CR4 =C( ^R5 ) ₂ , -S(=O) ^2CR4 =C( ^R5 ) ₂ , -NHS(=O) ^CR4 =C( ^R5 ) ₂ , or -NHS(=O) _2CR4 ⁼ C( ^R5 ) _{2 .}

In some embodiments, W is selected from -C(=O)CR ⁴ =C(R ⁵ ) ₂ .

In some embodiments, W is selected from -C(=O) _CCH3 = _CH2 or -C(=O)CH= _CH2 .

In some embodiments, W is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 4-6 membered heterocyclyl, -S(═O) ₂ -C ₁ -C ₄ alkyl, -C(═O)N(CH ₃ ) ₂ , -C(═O)CH ₂ CN, -C(═O) ^-RT , or -C(═O)CR ⁴ ═C(R ⁵ ) ₂ .

In some embodiments, ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclyl, or _C3 - _C6 cycloalkyl.

In some embodiments, ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, or 4-6 membered heterocyclyl.

In some embodiments, the 4-6 membered heterocyclyl contains 1, 2 or 3 heteroatoms independently selected from N, O or S.

In some embodiments, W is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 4-6 membered heterocyclyl, -S(═O) ₂ -C ₁ -C ₄ alkyl, -C(═O) ^-RT , or C(═O)CR ⁴ ═C(R ⁵ ) ₂ .

In some embodiments, ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, or 4-6 membered heterocyclyl.

In some embodiments, R ⁴ is selected from H or CH ₃ .

In some embodiments, each R ⁵ is independently selected from H or CH ₂ N(CH ₃ ) ₂ .

In some embodiments, ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclyl, -N( _C1 - _C6 alkyl) ₂ , or _C1 - _C6 alkyl-CN.

In some embodiments, ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, or 4-6 membered heterocyclyl. In some embodiments, the 4-6 membered heterocyclyl contains 1, 2, or 3 heteroatoms independently selected from N, O, or S.

In some embodiments, ^RT is selected from _CH3 , _{C2H5 , OCH3 , OC2H5} , _CF3 , or

In some embodiments, W is selected from H, methyl, ethyl _, isopropyl, _-CH2CF3 , _oxetanyl , -S(=O) _2CH3 , -C ₍ =O)C( _CH3 )=CH2, -C(=O)CH= _CH2 , -C(=O)CH= _CHCH2N ( _CH3 ) ₂ , -C(=O) _CH2CN , -C(=O)N( _CH3 ) ₂ , -C(=O) _{CH2CH3 ,} -C(=O) _CH3 , -C(=O) _CF3 , -C(=O) _{OCH2CH3 ,} or -C(=O) _OCH3 .

In some embodiments, W is selected from H, methyl, ethyl, isopropyl, _-CH2CF3 , ₃ -oxetanyl, -S(=O) _{2CH3 ,} -C(=O)C( _CH3 )=CH2, -C(=O)CH= _{CH2 , -C} (=O)CH= _CHCH2N ( _CH3 ) ₂ , -C(=O)CH2CN, _{-C (} =O)N( _CH3 ) ₂ , -C(=O) _CH2CH3 , -C(=O)CH3, -C(=O) _{CF3 ,} -C(=O) _OCH2CH3 , -C(=O) _OCH3 , or

In some embodiments, W is selected from -C(=O)CH= _CH2 .

In some embodiments, W is selected from 3-oxetanyl.

In some embodiments, W is attached to the N atom of ring C. In some embodiments, ring C is selected from W is connected to the N atom on the ring C; optionally, W is selected from H, methyl, ethyl, isopropyl, _-CH2CF3 , ₃ -oxetanyl, -S(=O) _2CH3 , -C(=O)C( _CH3 )= _{CH2 ,} -C ₍ =O)CH= _CH2 , -C(=O)CH=CHCH2N _{( CH3} ) ₂ , -C ₍ =O)CH2CN, -C(=O)N( _CH3 ) ₂ , -C(=O) _CH2CH3 , -C(=O) _CH3 , -C(=O) _CF3 , -C(=O) _{OCH2CH3 ,} -C(=O) _OCH3 , or

In some embodiments, Ring C is And W is connected to the N atom on the ring C.

In some embodiments, Ring C is W is connected to the N atom on the ring C, and W is selected from H, methyl, ethyl, isopropyl, _-CH2CF3 , ₃ -oxetanyl, -S(=O) _{2CH3 ,} -C(=O)C( _CH3 )= _CH2 , -C ₍ =O)CH= _CH2 , -C(=O)CH= _CHCH2N ( _CH3 ) ₂ , -C ₍ =O)CH2CN, -C(=O)N( _CH3 ) ₂ , -C(=O)CH2CH3 _, -C(=O) _CH3 , -C(=O) _{CF3 ,} -C(=O) _OCH2CH3 , -C(=O) _OCH3 , or

In some embodiments, ring C and W together form a structural fragment

In some embodiments, ring C and W together form a structural fragment

In some embodiments, L is selected from a bond.

In some embodiments, each R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, said C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy being optionally substituted with R ^5a .

In some embodiments, R ^5a is independently selected from halogen, CN, OH, NH ₂ , -NH-C ₁ -C ₆ alkyl, or -N(C ₁ -C ₆ alkyl) ₂ .

In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt:

wherein Ring A, Ring B, Ring C, R ¹ , R ² , R ³ , Z, L, and W are as defined above.

In some embodiments, the compound represented by formula (I) or its stereoisomer or pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein Ring A, Ring B, Ring C, R ¹ , R ² , R ³ , Z, L, and W are as defined above.

In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (IV) or its stereoisomer or its pharmaceutically acceptable salt:

wherein Ring A, Ring C, R ¹ , R ² , R ³ , R ^b , X ₁ , X ₂ and W are as defined above.

In some embodiments, the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:

Furthermore, the present disclosure also provides a pharmaceutical composition, which comprises a compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Furthermore, the present disclosure relates to the use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a disease mediated by FGFR.

Furthermore, the present disclosure relates to the use of the compound of formula (I) or its stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof in preventing or treating diseases mediated by FGFR.

Furthermore, the present disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease mediated by FGFR.

The present disclosure also relates to a method for preventing or treating a disease mediated by FGFR, which comprises administering to an individual a therapeutically effective amount of a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, or a pharmaceutical preparation comprising a compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof as described in the present disclosure.

Furthermore, the disease mediated by FGFR is selected from cancer.

Preferably, the disease mediated by FGFR is a disease mediated by FGFR2 or FGFR3. More preferably, the disease mediated by FGFR The disease is a disease mediated by FGFR3.

In some embodiments, the cancer is, for example, a solid tumor. In some embodiments, the cancer is, for example, gastric cancer or bladder cancer.

Any embodiment of any aspect of the present disclosure can be combined with other embodiments without contradiction. In addition, in any embodiment of any aspect of the present disclosure, any technical feature can be applied to the technical feature in other embodiments without contradiction.

The compounds disclosed herein have one or more of the following beneficial effects:

The heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt thereof provided by the present disclosure can selectively inhibit FGFR protein, such as FGFR3, and has a killing effect on related tumor cells;

The heterocyclic compound or its stereoisomer or its pharmaceutically acceptable salt provided by the present disclosure has good inhibitory activity against FGFR, especially FGFR3. Compared with FGFR1 and/or FGFR2, the heterocyclic compound or its stereoisomer or its pharmaceutically acceptable salt provided by the present disclosure has higher selectivity for FGFR3;

The heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt thereof provided by the present disclosure has good inhibitory activity on tumor cells (eg, cells JMSU-1, cells SNU16, cells RT112).

The heterocyclic compound or stereoisomer thereof or pharmaceutically acceptable salt thereof provided by the present disclosure has good pharmacokinetic properties, for example, good plasma clearance rate.

The heterocyclic compound or its stereoisomer or its pharmaceutically acceptable salt provided by the present disclosure has good permeability, for example, good permeability to caco2 cells.

Definitions and explanations of terms

Unless otherwise specified, the terms used in this disclosure have the following meanings, and the groups and term definitions recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

The graphic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dashed wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

In the ring Indicates that the corresponding ring is an aromatic ring.

Indicates the attachment site on a substituent.

The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced, and the oxo group will not occur in Aromatic base.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence and non-occurrence of the event or circumstance. For example, an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH ₂ CH ₃ ), monosubstituted (CH ₂ CH ₂ F, CH ₂ CH ₂ Cl, etc.), polysubstituted (CHFCH ₂ F, CH ₂ CHF ₂ , CHFCH ₂ Cl, CH ₂ CHCl ₂ , etc.) or fully substituted (CF ₂ CF ₃ , CF ₂ CCl ₃ , CCl ₂ CCl ₃ , 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 is sterically impossible to exist and/or cannot be synthesized will be introduced.

When any variable (eg, ^Ra , ^Rb ) occurs more than once in a compound's composition or structure, its definition is independent at each occurrence. For example, if a group is substituted with 2 ^Rb , each ^Rb has an independent option.

In the embodiments of the present disclosure, the substituent "X" is optionally substituted by a substituent "Y", which means that the substituent "X" is optionally substituted by one or more (e.g., 1, 2, 3 or 4) substituents "Y", and the options for each substituent "Y" are independent of each other. For example, "the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl is optionally substituted by R ^1a " means that the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl is optionally substituted by one or more R ^1a , and the options for each R ^1a are independent.

When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in A-L-Z represents a bond, it means that the structure is actually A-Z.

When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. When L ¹ is selected from "C ₁ -C ₃ alkylene-O", L ¹ can connect ring Q and R ¹ from left to right to form "ring QC ₁ -C ₃ alkylene-OR ¹ ", or connect ring Q and R ¹ from right to left to form "ring QOC ₁ -C ₃ alkylene-R ¹ ".

When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. It means that R ⁵ can be substituted at any position on the benzene ring.

_Cm - _Cn herein refers to an integer number of carbon atoms in the range of mn. For example, " _C1 - _C10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

The term "alkyl" refers to a hydrocarbon group of the general formula _{CnH2n +1} , which may be linear or branched and generally has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The term " _C1 - _C10 alkyl" is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C _{1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1} -C "C 1 -C ₆ alkyl" may be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like. The term "C ₁ -C ₃ alkyl" may be understood to mean a straight or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C ₁ -C ₁₀ alkyl" may include a range of "C ₁ -C ₆ alkyl", "C ₁ -C ₄ alkyl" or "C ₁ -C ₃ alkyl", and the "C ₁ -C ₆ alkyl" may further include "C ₁ -C ₄ alkyl" or "C ₁ -C ₃ alkyl".

The term "haloalkyl" refers to monohaloalkyl and polyhaloalkyl, usually having 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. For example, the term "C _1-6 haloalkyl" refers to C _1-6 alkyl as defined above substituted by one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl, etc. "C _1-6 haloalkyl" may further include "C _1-3 haloalkyl".

The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, which can be understood as "alkyloxy" or "alkyl-O-", and usually has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms. The term "C ₁ -C ₆ alkoxy" can be understood as "C ₁ -C ₆ alkyloxy" or "C ₁ -C ₆ alkyl-O-". The "C ₁ -C ₆ alkoxy" may further include a "C ₁ -C ₃ alkoxy".

The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond, usually having 2 to 10, 2 to 8, 2 to 6, 2 to 4, 2 to 3 carbon atoms. The term "C ₂ -C ₁₀ alkenyl" is understood to mean a straight-chain or branched unsaturated aliphatic hydrocarbon group having at least one double bond. or branched unsaturated hydrocarbon group, which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, " _C2 - _C10 alkenyl" is preferably " _C2 - _C6 alkenyl", further preferably " _C2 - _C4 alkenyl", and further preferably _C2 or _C3 alkenyl. It is understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond, and generally having 2 to 10, 2 to 8, 2 to 6, 2 to 4, 2 to 3 carbon atoms. The term "C ₂ -C ₁₀ alkynyl" may be understood to mean a straight or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C ₂ -C ₁₀ alkynyl" may include "C ₂ -C ₆ alkynyl". Examples of "C ₂ -C ₁₀ alkynyl" include, but are not limited to, ethynyl (-C≡CH _3, -CH ₂ C≡CH 3), but-1-ynyl, but-2-ynyl or but-3-ynyl. The "C ₂ -C ₁₀ alkynyl group" may include a "C ₂ -C ₃ alkynyl group", and examples of the "C ₂ -C ₃ alkynyl group" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH ₃ ), prop-2-ynyl (-CH ₂ C≡CH).

The term "cycloalkyl" refers to a fully saturated carbocyclic ring in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3-10 ring, a 3-8 ring, a 4-8 ring, a 5-8 ring, a 5-6 ring or a 3-6 ring. The term "C ₃ -C ₁₀ cycloalkyl" is understood to mean a saturated monocyclic, cyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc. The term "C ₃ -C ₁₀ cycloalkyl" may include "C ₃ -C ₆ cycloalkyl" or "C ₃ -C ₈ cycloalkyl". The term "C ₃ -C ₆ cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "heterocyclyl" refers to a fully saturated or partially saturated (not a heteroaromatic group having aromaticity as a whole) monocyclic, fused, spirocyclic or bridged ring group, which contains 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (i.e., an atom group containing heteroatoms) in the ring atoms. The "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(＝O) ₂ -, -S(＝O)-, -P(＝O) ₂ -, -P(＝O)-, -NH-, -S(＝O)(＝NH)-, -C(＝O)NH- or -NHC(＝O)NH-, etc. Unless otherwise indicated, the heterocyclic ring is typically a 4- to 10-membered, 3- to 10-membered, 3- to 8-membered, 4- to 9-membered, 5- to 8-membered, 5- to 6-membered, 6- to 9-membered, 3- to 7-membered, or 4- to 6-membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen, or nitrogen. The term "3- to 10-membered heterocyclyl" refers to a heterocyclyl having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5 heteroatoms or heteroatoms independently selected from the above-described heteroatoms in its ring atoms. The term "4- to 10-membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and containing 1, 2, 3, 4, or 5 heteroatoms or heteroatoms independently selected from the above-described heteroatoms in its ring atoms. The term "4- to 10-membered heterocyclyl" may contain 1, 2, or 3 heteroatoms independently selected from N, O, or S. “4-10 membered heterocyclyl” includes “4-9 membered heterocyclyl”, “6-9 membered heterocyclyl” or “4-6 membered heterocyclyl”, each of which independently contains 1, 2 or 3 heteroatoms independently selected from N, O or S, or each of which independently contains 1, 2 or 3 N atoms. “3-10 membered heterocyclic group” includes “4-7 membered heterocyclic group”, wherein specific examples of 4 membered heterocyclic group include but are not limited to azetidinyl, thietanyl or oxetanyl; specific examples of 5 membered heterocyclic group include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic group include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, 4H-[1,3,4]thiadiazinyl, Specific examples of 7-membered heterocyclic groups include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl, Heterocyclic Examples include but are not limited to Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolinyl and the like. "4-10-membered heterocyclic group" may include "5-10-membered heterocyclic group", "4-7-membered heterocyclic group", "5-6-membered heterocyclic group", "6-8-membered heterocyclic group", "4-10-membered heterocycloalkyl", "5-10-membered heterocycloalkyl", "4-7-membered heterocycloalkyl", "5-6-membered heterocycloalkyl", "6-8-membered heterocycloalkyl", and the like, and "4-7-membered heterocyclic group" may further include "4-6-membered heterocyclic group", "5-6-membered heterocyclic group", "4-7-membered heterocycloalkyl", "4-6-membered heterocycloalkyl", "5-6-membered heterocycloalkyl", "5-6-membered heterocycloalkyl", and the like. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms. The term "C ₆ -C ₂₀ aryl" is understood to mean an aryl group having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring having 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl; or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. The term "C ₆ -C ₁₀ aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. In particular, it refers to a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "C ₆ -C ₂₀ aryl" may include "C ₆ -C ₁₀ aryl"

The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: which have 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) inhibiting a disease or disease state, i.e. arresting its development;

(ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease. The invention relates to preventing a disease or disease state in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

The amount of a compound of the disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on his or her knowledge and this disclosure.

The term "individual" includes 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, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal can be a human.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid addition or base addition salts, including salts formed between a compound and an inorganic acid or an organic acid, and salts formed between a compound and an inorganic base or an organic base.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be construed as having an open, non-exclusive meaning, ie, "including but not limited to".

The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ^{13 N, 15} N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I, and ³⁶ Cl ^, etc., respectively.

Certain isotopically labeled compounds of the present disclosure (e.g., labeled with ³ H and ¹⁴ C) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.

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

Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or sugar-coated core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

In all methods of administration of the compounds of formula I described herein, the dosage administered is from 0.01 mg/kg to 200 mg/kg body weight per day, in single or divided doses.

Detailed ways

The present disclosure is described in detail below in conjunction with examples and drawings, but the following examples should not be construed as limiting the scope of the present disclosure.

Unless otherwise specified, the experimental methods used in the following embodiments and test examples are conventional methods; the materials, reagents, etc. used are reagents and materials that can be obtained from commercial channels unless otherwise specified.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC ₅₀ " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio is the volume ratio of each solvent. For example, "the elution phase is a mixed solvent of petroleum ether containing 0 to 15% ethyl acetate" means that during the gradient elution process, the volume ratio of ethyl acetate to petroleum ether in the mixed eluent is 0:100 to 15:85.

Abbreviations:

n-BuOH: n-butanol; NIS: N-iodosuccinimide; DCM: dichloromethane; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium; Dioxane: dioxane; Xphos-Pd G ₂ : chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); TFA: trifluoroacetic acid; DIEA or DIPEA: N,N-diisopropylethylamine; Pd(dppf)Cl ₂ ：[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); NCS: N-chlorosuccinimide; PPTS: pyridinium p-toluenesulfonate; DMA: N,N-dimethylacetamide; NDM: n-dodecyl mercaptan; Et ₃ N or TEA: triethylamine; PPh ₃ : triphenylphosphine; DIAD: diisopropyl azodicarboxylate; B ₂ Pin ₂ : bis(pinacol borate) or 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane); NMP: N-methylpyrrolidone; Pd(PPh ₃ ) ₂ Cl ₂ : bis(triphenylphosphine)palladium dichloride; TBS: tert-butyldimethylsilyl; TMS: tetramethylsilyl; Boc: tert-butyloxycarbonyl; i-PrMgCl: isopropylmagnesium chloride; toluene: toluene; Pd(PPh 3 ) 2 Cl 2 ₃ ) ₄ : tetrakis(triphenylphosphine)palladium; TBAF: tetrabutylammonium fluoride; HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate; KN ₃ : potassium azide; Et ₂ NH: diethylamine; DMSO: dimethyl sulfoxide; DMAP: 4-dimethylaminopyridine; TsCl: p-toluenesulfonyl chloride.

Example 1 7-(1-acryloylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 1)

Step 1: 5,7-Dichloroimidazo[1,2-a]pyridine (1B)

2-amino-4,6-dichloropyridine (3.2 g, 20 mmol, 1 eq), chloroacetaldehyde (7.8 g, 40 mmol, 2 eq, 40% aqueous solution) and sodium bicarbonate were added. (5.04g, 60mmol, 3eq) was dissolved in n-butanol (50mL) and stirred at 80°C for 16 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and water (100mL) was added to the residue. The resulting mixture was extracted with ethyl acetate (100mL x 3 times). The organic phases were mixed, washed with saturated brine (100mL x 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled under reduced pressure. The resulting residue was purified by silica gel column (eluting phase was a petroleum ether mixed solvent containing 16-18% ethyl acetate) to obtain the title compound 1B (2.22g, 12mmol, yield: 60%).

MS (ESI+) m/z = 187.2 [M + H] ⁺ .

Step 2: 5,7-Dichloro-3-iodoimidazo[1,2-a]pyridine (1C)

5,7-Dichloroimidazo[1,2-a]pyridine (1.86 g, 10 mmol, 1.0 eq) and N-iodosuccinimide (2.7 g, 12 mmol, 1.2 eq) were dissolved in dichloromethane (30 mL). The reaction solution was stirred at 25 °C for 2 hours and then cooled. Water (100 mL) was added and extracted with dichloromethane (100 mL x 3 times). The obtained organic phases were mixed, washed with saturated brine (100 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column (eluting phase was a petroleum ether mixed solvent containing 0-15% ethyl acetate) to obtain the title compound 1C (3.2 g, 10.32 mmol, yield: 86%).

MS (ESI+) m/z = 312.9 [M + H] ⁺ .

Step 3: 5,7-Dichloroimidazo[1,2-a]pyridine-3-carbonitrile (1D)

Compound 1C (1.6 g, 5 mmol, 1.0 eq) and cuprous cyanide (1.8 g, 20 mmol, 4 eq) were mixed in N,N-dimethylformamide (10 mL). The mixture was stirred at 100 ° C under nitrogen atmosphere for 3 hours. Water (100 mL) was added to the mixture, and ethyl acetate was used for extraction. The residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1D (660 mg, 3.15 mmol, yield: 63%).

MS (ESI+) m/z = 212.2 [M + H] ⁺ .

Step 4: 7-Chloro-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (1E)

Compound 1J (670 mg, 4.73 mmol, 1.5 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (380 mg, 9.46 mmol, 3 eq) was added at 0°C. After stirring for 30 minutes, 1D (660 mg, 3.15 mmol, 1.0 eq) was added, and the reaction solution was reacted for 3 hours. An aqueous solution of ammonium chloride was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the organic phase was distilled under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 33-100% ethyl acetate) to obtain the title compound 1E (726 mg, 2.3 mmol, yield: 73%).

MS (ESI+) m/z = 317.3 [M + H] ⁺ .

Step 5: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1F)

Compound 1E (100 mg, 0.315 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (118 mg, 0.46 mmol, 1.5 eq), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (13 mg, 0.03 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium (28 mg, 0.03 mmol, 0.2 eq), potassium acetate (130 mg, 1.5 mmol, 5 eq) were mixed in dioxane (3 mL). The mixture was stirred at 90° C. under nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was filtered and dried to obtain the title compound 1F (150 mg, crude product).

MS (ESI+) m/z = 409.2 [M + H] ⁺ .

Step 6: 4-(4-(3-cyano-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1G)

Compound 1F (150 mg, 1.0 eq), compound 1K (217 mg, 0.63 mmol, 2 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (47 mg, 0.06 mmol, 0.2 eq), potassium carbonate (195 mg, 1.5 mmol, 5 eq) were mixed in dioxane (5 mL) and water (1 mL). The mixture was stirred at 100 ° C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 33-100% ethyl acetate) to obtain the title compound 1G (84.3 mg, 0.16 mmol, yield: 50%).

MS (ESI+) m/z = 547.2 [M + H] ⁺ .

Step 7: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(4-piperidinyl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile (1H)

Compound 1G (84.3 mg, 0.16 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at 25 °C under nitrogen atmosphere for 2 hours. The residue was purified by silica gel column (eluting phase was a mixed solvent of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 1H (44.3 mg, 0.1 mmol, yield: 62.5%) as a yellow solid.

MS (ESI+) m/z = 447.2 [M + H] ⁺ .

Step 8: 7-(1-acryloylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 1)

Compound 1H (44.3 mg, 0.1 mmol, 1.0 eq) and N,N-diisopropylethylamine (26 mg, 0.2 mmol, 2.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 1.0 eq) was added to the mixture at 0°C under nitrogen atmosphere and stirred for 0.2 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-75% acetonitrile-water) to obtain the title compound 1 (12 mg, 0.024 mmol, yield: 24%). MS (ESI+) m/z = 501.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d, J = 2.9 Hz, 1H), 8.47 (s, 1H), 7.86–7.72 (m, 2H), 7.58 (d, J = 1.2 Hz, 1H), 6.97–6.86 (m, 1H), 6.86–6.81 (m, 1H), 6.14 (dd, J = 16.7, 2.5 Hz, 1H), 6.07 (q, J = 6.3 Hz, 1H) ,5.71(dd,J＝10.4,2.5Hz,1H),4.75(m,1H),4.55(m,1H),4.22(m,1H),3.28(m,1H),2.90(m,1H), 2.50 (s, 3H), 2.12–2.03 (m, 2H), 1.99–1.84 (m, 2H), 1.79 (d, J=6.4 Hz, 3H).

Example 2: 1-(4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 2)

Step 1: 4-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (2B)

6-Bromo-3-chloro-4-methoxypyrazolo[1,5-a]pyridine (Compound 2A, 500 mg, 1.91 mmol, 1.0 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (631 mg, 2.48 mmol, 1.3 eq.) were dissolved in 1,4-dioxane (10 mL) at room temperature. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (139 mg, 0.19 mmol, 0.1 eq.) and potassium acetate (374 mg, 3.82 mmol, 2.0 eq.) were added under argon atmosphere. The reaction solution was stirred at 80°C under argon atmosphere for 2 hours, and concentrated under reduced pressure to obtain a residue, which was chromatographed on a silica gel column (the eluting phase was a petroleum ether mixed solvent containing 30-70% ethyl acetate) to obtain the target product 2B (450 mg, yield: 86%). m/z (ESI): 275.2 [M+H] ⁺ .

Step 2: tert-Butyl 4-(4-(4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2C)

Compound 2B (80 mg, 0.29 mmol, 1.0 eq.) and 1K (110 mg, 0.32 mmol, 1.1 eq.) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL) at room temperature. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (22 mg, 0.03 mmol, 0.1 eq.) and potassium carbonate (80 mg, 0.58 mmol, 2.0 eq.) were added under argon atmosphere. The reaction solution was stirred at 90 ° C under argon atmosphere for 2 hours, and concentrated under reduced pressure to obtain a residue. The residue was chromatographed on a silica gel column (the eluting phase was a petroleum ether mixed solvent containing 20-50% ethyl acetate) to obtain the target product 2C (80 mg, yield: 67%). m/z (ESI): 413.3 [M+H] ⁺ .

Step 3: tert-Butyl 4-(4-(3-chloro-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2D)

Compound 2C (80 mg, 0.19 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL) at room temperature, and then N-chlorosuccinimide (28 mg, 0.21 mmol, 1.1 eq.) and pyridine p-toluenesulfonate (5 mg, 0.02 mmol, 0.1 eq.) were added. The reaction solution was stirred at 40°C for 1.5 hours and concentrated under reduced pressure to obtain a residue. The residue was chromatographed on a silica gel column (the eluting phase was a petroleum ether mixed solvent containing 30-50% ethyl acetate) to obtain the target product. 2D (50 mg, yield: 57%). m/z (ESI): 447.2 [M+H] ⁺ .

Step 4: tert-Butyl 4-(4-(3-chloro-4-hydroxypyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2E)

Compound 2D (50 mg, 0.11 mmol, 1.0 eq.) and 50% sodium hydroxide aqueous solution (26 mg, 0.33 mmol, 3.0 eq.) were dissolved in N,N-dimethylacetamide (3 mL) at room temperature, and then n-dodecyl mercaptan (45 mg, 0.22 mmol, 2.0 eq.) was added. The reaction solution was stirred at 50 ° C in an argon atmosphere for 2 hours, cooled to room temperature, and formic acid was added to adjust the pH to 4, and the residue was concentrated under reduced pressure. The residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-75% acetonitrile-water) to obtain the target product 2E (30 mg, yield: 63%). m/z (ESI): 433.2 [M+H] ⁺ .

Step 5: tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-chloropyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (2F)

Compound 2E (30 mg, 0.07 mmol, 1.0 eq.) and compound 2H (38 mg, 0.11 mmol, 1.5 eq.) were dissolved in N,N-dimethylformamide (3 mL) at room temperature, and then cesium carbonate (46 mg, 0.14 mmol, 2.0 eq.) was added. The reaction solution was stirred at 80°C for 2 hours, cooled to room temperature, added with water, extracted with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (the elution phase was a petroleum ether mixed solvent containing 30-50% ethyl acetate) to obtain the target product 2F (20 mg, yield: 42%). m/z (ESI): 686.3 [M + H] ⁺ .

Step 6: 2-((3-chloro-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethan-1-ol (2G)

Compound 2F (20 mg, 0.03 mmol) was dissolved in dichloromethane (3 mL) at room temperature, and trifluoroacetic acid (3 mL) was added. The reaction solution was stirred at room temperature for 16 hours and concentrated under reduced pressure to obtain crude product 2G, which was used directly in the next step without purification.

Step 7: 1-(4-(4-(3-chloro-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 2)

Under ice bath, compound 2G was dissolved in dichloromethane (3 mL), and then triethylamine (15 mg, 0.15 mmol, 5.0 eq.) and acryloyl chloride (3.6 mg, 0.04 mmol, 1.2 eq.) were added in sequence. The reaction solution was stirred under ice bath for 30 minutes, quenched with water, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-75% acetonitrile-water) to obtain the title compound 2 (10 mg, yield: 67%). m/z (ESI): 526.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 8.45 (s, 1H), 8.13 (s, 1H), 7.80–7.75 (m, 1H), 7.66–7.63 (m, 1H), 6.93–6.86 (m, 3H), 4.17–6.13 (m, 1H), 5.77–5.76 (m, 1H) 5.73–5.70 (m, 1H), 5.65–5.62 (m, 1H), 5.20–5.15 (m, 1H), 4.76–4.70 (m, 1H), 4.58–4.53 (m, 1H), 4.25–4.21 (m, 1H), 3.95 (s, 3H), 2.42–2.41 (m, 6H).

Intermediate: Synthesis of ethyl 2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)methanesulfonate

Step 1: 2-[(tert-butyldimethylsilyl)oxy]-1-(5-fluoropyridin-2-yl)ethan-1-ol (2Y)

Compound 2-bromo-5-fluoropyridine (compound 2X, 2 g, 11.49 mmol) was dissolved in toluene (10 mL), and isopropylmagnesium chloride (2M, 8.5 mL) was added dropwise at 0°C and stirred for half an hour. Subsequently, 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (2.9 g, 17.1 mmol) was added to the reaction system and stirred at 0°C for three hours until the reaction was complete. Saturated ammonium chloride solution (10 mL) was added at 0°C to quench the reaction, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 0-10% tetrahydrofuran) to obtain the title compound 2Y (1 g, 3.66 mmol, yield: 31.8%) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d6) δ = 8.55 (d, J = 2.9 Hz, 1H), 7.86-7.71 (m, 1H), 7.65-7.54 (m, 1H), 5.61-5.43 (m, 1H), 4.74-4.63 (m, 1H), 3.96-3.74 (m, 2H), 0.86-0.83 (m, 9H), 0.02-0.04 (m, 6H).

Step 2: Ethyl 2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)methanesulfonate (2H)

Compound 2Y (1 g, 3.66 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and methylsulfonic anhydride (1.27 g, 7.32 mmol, 2.0 eq) and triethylamine (740 mg, 7.32 mmol, 2.0 eq) were added at room temperature. The reaction was stirred for 2 hours, and the organic solvent was removed by rotary evaporation. The residue was purified by silica gel column (the elution phase was a mixed solvent containing 0-20% ethyl acetate and petroleum ether) to obtain the title compound 2H (868.6 mg, 2.49 mmol, Yield: 68%).

Example 3: 1-[4-[4-[3-(2-cyclopropylethynyl)-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]prop-2-en-1-one (Compound 3)

Step 1: 6-Bromopyrazolo[1,5-a]pyridine-4-ol (3B)

Compound 3A (25 g, 110.10 mmol, 1.0 eq) was dissolved in N, N-dimethylacetamide (130 mL), and sodium hydroxide (4.40 g, 110.10 mmol, 1.0 eq)/water (8 mL) solution was added. The reaction system was heated to 30 ° C, and then dodecyl mercaptan (33.43 g, 165.16 mmol, 1.5 eq) was added. The mixture was stirred at 60 ° C for 6 hours. After the reaction was completed, the reaction mixture was diluted with water (300 mL), and aqueous hydrochloric acid was added until pH <7, and the residue was filtered to obtain a filter residue. The filtrate was extracted with ethyl acetate (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by vacuum filtration to obtain a concentrate. The concentrate and the filter residue were purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 30-50% tetrahydrofuran) to obtain the title compound 3B (20 g, 93.88 mmol, yield: 85%).

MS (ESI+) m/z = 213.0 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝11.06(s,1H),8.55(s,1H),7.91(d,J＝2.2Hz,1H),6.69(d,J＝1.7Hz,1H),6.56(d,J＝1.1Hz,1H)

Step 2: 6-bromo-4-(2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridine (3C)

Compound 3B (10 g, 46.94 mmol, 1.0 eq), compound 3I (15.29 g, 56.33 mmol, 1.2 eq) and triphenylphosphine (18.47 g, 70.41 mmol, 1.5 eq) were dissolved in tetrahydrofuran (200 mL), the reaction system was cooled to 0°C, diisopropyl azodicarboxylate (11.39 g, 56.33 mmol, 1.2 eq) was added, and the mixture was stirred at 0°C for 6 hours. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to obtain a concentrate. The concentrate was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 0-5% tetrahydrofuran) to obtain the title compound 3C (9 g, 19.30 mmol, yield: 41%).

MS (ESI+) m/z = 466.2 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝8.66(s,1H),8.62(d,J＝2.9Hz,1H),7.99(d,J＝2.2Hz,1H),7.77(dt,J＝3.0,8.7Hz,1H),7.63(dd,J＝4.6,8.8Hz,1H),6.74(s,2H),5.76(t,J＝4.8Hz,1H),4.14–4.10(m,2H),0.79(s,9H),0.03(s,3H),-0.03(s,3H)

Step 3: 4-(2-(tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (3D)

Compound 3C (9 g, 19.30 mmol, 1.0 eq), bis-naphthalene borate (14.70 g, 57.89 mmol, 3 eq), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (700 mg, 964.80 umol, 0.05 eq) and potassium acetate (3.79 g, 38.59 mmol, 2 eq) were mixed in dioxane (90 mL). The mixture was stirred at 70 ° C under nitrogen atmosphere for 6 hours. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 0-15% tetrahydrofuran) to obtain a red colloid title compound crude product 3D (10.5 g, 19 mmol, yield: 98%).

MS (ESI+) m/z = 513.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝8.62(d, J＝2.9 Hz, 1H),8.35(s, 1H),8.05(d, J＝2.0 Hz, 1H),7.74(dt, J＝2.9,8.7 Hz, 1H),7.57(dd, J＝4.5,8.7 Hz, 1H),6.72(d, J＝2.2 Hz, 1H),6.57(s, 1H),5.68–5.64(m, 1H),4.16–4.05(m, 2H),1.28(d, J＝2.9 Hz, 12H),0.80(s, 9H),0.04(s, 3H),-0.03(s, 3H)

Step 4: tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (3E)

Compound 3D (1.026 g, 2 mmol, 1.0 eq), compound 1K (826 mg, 2.4 mmol, 1.2 eq), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (74.1 mg, 0.1 mmol, 0.05 eq), potassium carbonate (415 mg, 3 mmol, 1.5 eq) were mixed in dioxane (10 mL) and water (1 mL). The mixture was stirred at 90 ° C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 40-70% ethyl acetate) to obtain the title compound 3E (1.08 g, 1.66 mmol, yield: 83%). MS (ESI+) m/z = 652.3 [M + H] ⁺ .

Step 5: 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (3F)

Compound 3E (1.08 g, 1.66 mmol, 1.0 eq) was dissolved in methanol (10 mL), and 4 M hydrochloric acid-dioxane (10 mL) was added at room temperature. The mixture was stirred at room temperature for 6 hours, then filtered and dried to obtain the title compound 3F (651 mg, 1.49 mmol, yield: 90%).

MS (ESI+) m/z = 438.2 [M + H] ⁺ .

Step 6: 1-(4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (3G)

Compound 3F (651 mg, 1.49 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (2 mL), and N,N-diisopropylethylamine (388 mg, 2.98 mmol, 2.0 eq) and acryloyl chloride (162 mg, 1.79 mmol, 1.2 eq) were added at 0°C. After the mixture was stirred at room temperature for 1 hour, the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-75% acetonitrile-water) to obtain the title compound 3G (613 mg, 1.25 mmol, yield: 84%).

MS (ESI+) m/z = 492.3 [M + H] ⁺ .

Step 7: 1-(4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (3H)

Compound 3G (613 mg, 1.25 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (562.5 mg, 2.50 mmol, 2.0 eq) was added at room temperature. After the mixture was stirred at room temperature for 3 hours, the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-60% acetonitrile-water) to obtain the title compound 3H (678.7 mg, 1.10 mmol, yield: 88%).

MS (ESI+) m/z = 618.2 [M + H] ⁺ .

Step 8: 1-[4-[4-[3-(2-cyclopropylethynyl)-4-[1-(5-fluoro-2-pyridinyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]prop-2-en-1-one (Compound 3)

Compound 3H (61.8 mg, 0.1 mmol, 1.0 eq), cyclopropylacetylene (33 mg, 0.5 mmol, 5 eq), bistriphenylphosphine palladium dichloride (7 mg, 0.01 mmol, 0.1 eq), cuprous iodide (2 mg, 0.01 mmol, 0.1 eq), triethylamine (50 mg, 0.5 mmol, 5 eq) were mixed in tetrahydrofuran (2 mL). The mixture was heated to 50 ° C and stirred for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 3 (39.4 mg, 0.071 mmol, yield: 71%).

MS (ESI+) m/z = 556.4 [M + H] ⁺ .

Step 9: (R)-1-[4-[4-[3-(2-cyclopropylethynyl)-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]prop-2-en-1-one and (S)-1-[4-[4-[3-(2-cyclopropylethynyl)-4-[1-(5-fluoro-2-pyridyl)-2-hydroxy-ethoxy]pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl]prop-2-en-1-one Oxy] pyrazolo[1,5-a]pyridin-6-yl]-5-methyl-triazol-1-yl]-1-piperidinyl] prop-2-en-1-one (Compound 3-1 and Compound 3-2)

Compound 3 was subjected to chiral separation (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 55%-55%; flow rate: 80 ml/min) to obtain two single-configuration compounds 3-1 and 3-2.

3-1SFC retention time: 3.301min

¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝8.60(d, J＝2.8 Hz, 1H),8.45(d, J＝0.9 Hz, 1H),8.10(s, 1H),7.84-7.70(m, 2H), 6.98 (s, 1H), 6.89 (dd, J = 10.5, 16.7 Hz, 1H), 6.15 (dd, J = 2.4, 16.7 Hz, 1H), 5.76-5.69 (m, 1H), 5.65 (t ,J＝5.3Hz,1H),5.13(t,J＝5.7Hz,1H),4.78-4.67(m ,1H),4.56(d,J＝12.7Hz,1H),4.23(d,J＝12.3Hz,1H),4.02-3.89(m,2H),3.33-3.29(m,1H),2.91(t, J＝11.6Hz,1H),2.44(s,3H),2.12-2.03(m,2H),2.03-1.85(m,2H),1.60(tt,J＝5.0,8.2Hz,1H),0.93-0.85 (m,2H),0.79-0.72(m,2H)

MS m/z (ESI): =556.4 [M+H] ⁺ .

3-2SFC retention time: 5.385min

¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝8.60(d, J＝2.8 Hz, 1H),8.45(d, J＝0.9 Hz, 1H),8.10(s, 1H),7.84-7.69(m, 2H), 6.98 (s, 1H), 6.89 (dd, J = 10.6, 16.7 Hz, 1H), 6.15 (dd, J = 2.4, 16.7 Hz, 1H), 5.76-5.62 (m, 2H), 5.12 (t ,J＝5.7Hz,1H),4.80-4.67(m, 1H), 4.56 (d, J = 12.8 Hz, 1H), 4.23 (d, J = 12.8 Hz, 1H), 4.02-3.87 (m, 2H), 3.29-3.25 (m, 1H), 2.97-2.84 (m ,1H),2.44(s,3H),2.06(s,2H),2.01-1.85(m,2H),1.65-1.56(m,1H),0.93-0.84(m,2H),0.80-0.71(m ,2H)

MS m/z (ESI): =556.4 [M+H] ⁺ .

Example 4: 7-(1-(1-acryloylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 4)

Step 1: 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-chloroimidazo[1,2-a]pyridine-3-carbonitrile (4B)

Compound 3I (813 mg, 3.0 mmol, 1.5 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (240 mg, 6.0 mmol, 3 eq) was added at 0°C. After stirring for 30 minutes, 1D (422 mg, 2.0 mmol, 1.0 eq) was added, and the reaction solution was reacted for 3 hours. An aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the mixture was filtered, and the organic phase was distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 33-100% ethyl acetate) to obtain the title compound 4B (670.5 mg, 1.5 mmol, yield: 75%).

MS (ESI+) m/z = 447.3 [M + H] ⁺ .

Step 2: 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-3-carbonitrile (4C)

Compound 4B (447 mg, 1.0 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (385 mg, 1.5 mmol, 1.5 eq), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (39 mg, 0.1 mmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium (91.5 mg, 0.1 mmol, 0.1 eq), potassium acetate (433 mg, 5.0 mmol, 5 eq) were mixed in dioxane (5 mL). The mixture was heated at 90 °C under nitrogen atmosphere. After stirring for 3 hours at room temperature, the mixture was cooled to room temperature, filtered and dried to obtain the title compound 4C (470 mg, crude product).

MS (ESI+) m/z = 539.2 [M + H] ⁺ .

Step 3: tert-butyl 4-(4-(5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-cyanoimidazolo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (4D)

Compound 4C (470 mg, 1.0 eq), compound 1K (686 mg, 2.0 mmol, 2 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (95 mg, 0.1 mmol, 0.1 eq), potassium carbonate (650 mg, 5.0 mmol, 5 eq) were mixed in dioxane (5 mL) and water (1 mL). The mixture was stirred at 90 ° C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 33-100% ethyl acetate) to obtain the title compound 4D (419 mg, 0.62 mmol, yield: 62%).

MS (ESI+) m/z = 677.3 [M + H] ⁺ .

Step 4: 5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-3-carbonitrile (4E)

Compound 4D (67.8 mg, 0.1 mmol, 1.0 eq) was dissolved in methanol (2 mL), and 4 M hydrochloric acid-dioxane (2 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours, then filtered and dried to obtain the title compound 4E (41.6 mg, 0.09 mmol, yield: 90%).

MS (ESI+) m/z = 463.3 [M + H] ⁺ .

Step 5: 7-(1-(1-acryloylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)imidazo[1,2-a]pyridine-3-carbonitrile (Compound 4)

Compound 4E (41.6 mg, 0.09 mmol, 1.0 eq) and N,N-diisopropylethylamine (23.4 mg, 0.18 mmol, 2.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (9 mg, 0.1 mmol, 1.1 eq) was added to the mixture under nitrogen atmosphere at 0°C and stirred for 0.2 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 4 (20 mg, 0.038 mmol, yield: 43%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝8.62(d, J＝2.8 Hz, 1H),8.47(s, 1H),7.85–7.80(m, 1H),7.80–7.75(m, 1H), 7.59 (d, J = 1.3 Hz, 1H), 6.97 (d, J = 1.3 Hz, 1H), 6.93–6.84 (m, 1H), 6.14 (dd, J = 16.6, 2.4 Hz, 1H), 5.95–5.91 (m,1H),5.7 1(dd,J＝10.4,2.4Hz,1H),5.24(t,J＝5.7Hz,1H),4.81–4.71(m,1H),4.60–4.52(m,1H),4.26–4.20(m, 1H), 4.10–4.02 (m, 2H), 4.01–3.94 (m, 2H), 2.52 (s, 3H), 2.12–2.04 (m, 2H), 2.03–1.85 (m, 2H).

MS (ESI+) m/z = 517.2 [M + H] ⁺ .

Example 5: 1-(4-(4-(3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 5)

Step 1: 7-Chloro-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridine (5A)

1-(5-Fluoropyridin-2-yl)ethane-1-ol (Compound 1J, 846 mg, 6.0 mmol, 1.5 eq) was dissolved in tetrahydrofuran (10 mL), and sodium hydride (480 mg, 12.0 mmol, 3 eq) was added at 0°C. After stirring for 30 minutes, 1B (748 mg, 4.0 mmol, 1.0 eq) was added, and the reaction solution was reacted for 3 hours. An aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the mixture was filtered, and the organic phase was distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 33-100% ethyl acetate) to obtain the title compound 5A (850 mg, 2.92 mmol, yield: 73%).

MS (ESI+) m/z = 292.3 [M + H] ⁺ .

Step 2: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (5B)

Compound 5A (850 mg, 2.92 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.12 g, 4.38 mmol, 1.5 eq), 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (117 mg, 0.3 mmol, 0.1 eq), tris(dibenzylideneacetone)dipalladium (136 mg, 0.15 mmol, 0.05 eq), potassium acetate (858 mg, 8.76 mmol, 3 eq) were mixed in dioxane (10 mL). The mixture was stirred at 90 ° C under nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was filtered and dried to obtain the title compound 5B (900 mg, crude product).

MS (ESI+) m/z = 384.2 [M + H] ⁺ .

Step 3: tert-butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5C)

Compound 5B (400 mg, 1.0 eq), compound 1K (680 mg, 2 mmol, 2 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (95 mg, 0.1 mmol, 0.1 eq), potassium carbonate (650 mg, 5.0 mmol, 5 eq) were mixed in dioxane (5 mL) and water (1 mL). The mixture was stirred at 90 ° C under nitrogen atmosphere for 2 hours. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 33-100% ethyl acetate) to obtain the title compound 5C (345 mg, 0.67 mmol, yield: 67%).

MS (ESI+) m/z = 522.3 [M + H] ⁺ .

Step 4: tert-butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5D)

Compound 5C (345 mg, 0.67 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (301.5 mg, 1.34 mmol, 2.0 eq) was added at room temperature. The mixture was stirred at room temperature for 2 hours and then purified by chromatography (Phenomenex Luna C18 150*25 mm*10 um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 5D (360.3 mg, 0.56 mmol, yield: 83%). MS (ESI+) m/z = 648.2 [M+H] ⁺ .

Step 5: tert-Butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5E)

Compound 5D (360.3 mg, 0.56 mmol, 1.0 eq), trimethylsilyl acetylene (151.8 mg, 2.3 mmol, 5 eq), bistriphenylphosphine palladium dichloride (45 mg, 0.06 mmol, 0.1 eq), cuprous iodide (10 mg, 0.06 mmol, 0.1 eq), triethylamine (250 mg, 2.5 mmol, 5 eq) were mixed in tetrahydrofuran (20 mL). The mixture was heated to 50 ° C and stirred for 6 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 5E (200 mg, 0.33 mmol, yield: 58%).

MS (ESI+) m/z = 618.3 [M + H] ⁺ .

Step 6: tert-Butyl 4-(4-(3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (5F)

Compound 5E (200 mg, 0.33 mmol, 1.0 eq) was dissolved in methanol (10 mL), and potassium carbonate (455 mg, 3.3 mmol, 10.0 eq) was added at room temperature. Stir for 5 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the residue was purified by preparative chromatography (Phenomenex Luna C18 150*25 mm*10 um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 5F (113 mg, 0.21 mmol, yield: 63%). MS (ESI+) m/z = 546.2 [M+H] ⁺ .

Step 7: 3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (5G)

Dissolve compound 5F (113 mg, 0.21 mmol, 1.0 eq) in dichloromethane (2 mL), add trifluoroacetic acid (2 mL) at room temperature. Stir for 3 hours. Distill the reaction solution under reduced pressure to remove the solvent, and purify the residue by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase is 5%-50% acetonitrile-water) to obtain the title compound 5G (49 mg, 0.11 mmol, yield: 54%).

MS (ESI+) m/z = 446.2 [M + H] ⁺ .

Step 8: 1-(4-(4-(3-ethynyl-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 5)

Compound 5G (49 mg, 0.11 mmol, 1.0 eq) and N,N-diisopropylethylamine (28.6 mg, 0.22 mmol, 2.0 eq) were dissolved in dichloromethane (1 mL). Acryloyl chloride (10 mg, 0.12 mmol, 1.1 eq) was added to the mixture under nitrogen atmosphere at 0°C and stirred for 0.5 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the resulting residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 5 (28 mg, 0.06 mmol, yield: 51%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (d, J = 3.0 Hz, 1H), 7.91 (s, 1H), 7.83–7.77 (m, 1H), 7.73–7.69 (m, 1H), 7.41 (d, J = 1.3 Hz, 1H), 6.88 (dd, J = 16.7, 10.5 Hz, 1H), 6.63 (s, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.97–5.9 2(m,1H),5.71(dd,J＝10.4,2.4Hz,1H),4.75–4.72(m,1H),4.71(s,1H),4.60–4.48(m,2H),4.28–4.16( m, 2H), 2.47 (s, 3H), 2.10–2.04 (m, 2H), 1.99–1.89 (m, 2H), 1.75 (d, J＝6.4 Hz, 3H).

MS (ESI+) m/z = 500.2 [M + H] ⁺ .

Example 6: 1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 6)

Step 1: 1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 6)

Compound 3H (61.8 mg, 0.1 mmol, 1.0 eq), 3,3-dimethyl-1-butyne (41 mg, 0.5 mmol, 5 eq), bistriphenylphosphine dichloride Palladium (7 mg, 0.01 mmol, 0.1 eq), cuprous iodide (2 mg, 0.01 mmol, 0.1 eq), triethylamine (50 mg, 0.5 mmol, 5 eq) were mixed in tetrahydrofuran (2 mL). The mixture was heated to 50 ° C and stirred for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-70% acetonitrile-water) to obtain the title compound 6 (36 mg, 0.063 mmol, yield: 63%).

MS (ESI+) m/z = 572.2 [M + H] ⁺ .

Step 2: (R)-1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one and (S)-1-(4-(4-(3-(3,3-dimethylbut-1-yn-1-yl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 6-1 and Compound 6-2)

Compound 6 was separated by chiral separation (column: DAICEL CHIRALCEL OD (250mm*30mm, 10um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 40%-40%; flow rate: 80 ml/min) to obtain two single-configuration compounds 6-1 and 6-2.

6-1SFC retention time: 0.496min

¹ H NMR (400 MHz, DMSO-d6) δ = 8.60 (d, J = 2.8 Hz, 1H), 8.44 (s, 1H), 8.08 (s, 1H), 7.78 (dt, J = 3.0, 8.7 Hz, 1H ),7.64(dd,J＝4.4,8.7Hz,1H),6.96-6.82(m,2H),6.15(dd,J＝2.4,16.7Hz,1H),5.76(s,1H),5.74- 5.69 (m, 1H), 5.66 (t, J = 5.4 Hz, 1H), 5.14 (t, J = 5.7 Hz, 1H), 4.72 (t, J = 11.2 Hz, 1H), 4.54 (s, 1H), 4.21(s,1H),4.00-3.91(m,2H),2.90(s,1H),2.42(s,3H),2.06(s,2H),2.03-1.89(m,2H),1.33(s, 9H).

MS (ESI+) m/z = 572.2 [M + H] ⁺ .

6-2SFC retention time: 0.377min

¹ H NMR (400 MHz, DMSO-d6) δ＝8.60 (d, J＝2.8 Hz, 1H), 8.44 (s, 1H), 8.08 (s, 1H), 7.84-7.74 (m, 1H), 7.64 (dd , J = 4.5, 8.6 Hz, 1H), 6.95-6.83 (m, 2H), 6.15 (dd, J = 2.3, 16.8 Hz, 1H), 5.72 (dd, J = 2.3, 10.4 Hz, 1H), 5.66 ( t, J = 5.8 Hz, 1H), 5.14 (t, J = 5.7 Hz, 1H), 4.78-4.66 (m, 1H), 4.56 (d, J = 13.9 Hz, 1H), 4.23 (d, J = 12.6 Hz, 1H), 3.96 (t, J = 6.1 Hz, 2H), 2.97-2.84 (m, 1H), 2.42 (s, 3H), 2.06 (s, 2H), 2.03-1.88 (m, 2H), 1.33 (s,9H).

MS (ESI+) m/z = 572.2 [M + H] ⁺ .

Embodiment 7-11

Using a synthetic route and steps similar to Example 6, the following compounds 7-10 were synthesized by replacing raw material 6B with raw material A in the following table.

Example 11: 1-(4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one (Compound 11)

Step 1: tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodopyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (11A)

Compound 3E (1.3 g, 2.0 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (5 mL), and N-iodosuccinimide (540 mg, 2.40 mmol, 1.2 eq) was added at room temperature. After the mixture was stirred at room temperature for 3 hours, the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 15%-99% acetonitrile-water) to obtain the title compound 11A (1.46 g, 1.88 mmol, yield: 94%).

MS (ESI+) m/z = 778.2 [M + H] ⁺ .

Step 2: tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-(cyclopropylethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (11C)

Compound 11A (778 mg, 1.0 mmol, 1.0 eq), cyclopropylacetylene (200 mg, 3.0 mmol, 3 eq), bistriphenylphosphine palladium dichloride (70 mg, 0.1 mmol, 0.1 eq), cuprous iodide (19 mg, 0.1 mmol, 0.1 eq), triethylamine (505 mg, 5 mmol, 5 eq) were mixed in tetrahydrofuran (10 mL). The mixture was heated to 60 ° C and stirred for 5 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 20%-100% acetonitrile-water) to obtain the title compound 11C (486.8 mg, 0.68 mmol, yield: 68%).

MS (ESI+) m/z = 716.3 [M + H] ⁺ .

Step 3: tert-butyl 4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (11D)

Compound 11C (486.8 mg, 0.68 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL). 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.82 mL, 1.2 eq) was added at room temperature, stirred for 1 hour, filtered and dried, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 20%-90% acetonitrile-water) to obtain the title compound 11D (337.7 mg, 0.56 mmol, yield: 83%).

MS (ESI+) m/z = 602.3 [M + H] ⁺ .

Step 4: 2-((3-(cyclopropylethynyl)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (11E)

Compound 11D (337.7 mg, 0.56 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Zinc bromide (378 mg, 1.68 mmol, 3.0 eq) was added at room temperature, stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-80% acetonitrile-water) to obtain the title compound 11E (225.1 mg, 0.45 mmol, yield: 81%).

MS (ESI+) m/z = 502.3 [M + H] ⁺ .

Step 5: 1-(4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-2-methylprop-2-en-1-one (11)

Compound 11E (26 mg, 0.05 mmol, 1.0 eq) was dissolved in N-methylpyrrolidone (2 mL), and triethylamine (11 mg, 0.1 mmol, 2.0 eq) and methacryloyl chloride (0.55 mg, 0.06 mmol, 1.2 eq) were added at 0°C. After the mixture was stirred at room temperature for 1 hour, the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-80% acetonitrile-water) to obtain the title compound 11 (15 mg, 0.026 mmol, yield: 53%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.80 (dd, J = 8.7 ,2.9Hz,1H),7.78–7.69(m,2H),6.97(d,J＝1.1Hz,1H),5.67–5.62(m,1H),5.21–5.19(m,1H),5.09(t, J＝5.7 Hz,1H),5.05–5.01(m,1H),4.80–4.66(m,2H),4.50–4.39(m,1H),3.99–3.91(m,3H),2.43(s,3H),2.09– 2.04(m,2H),2.00–1.94(m,2H),1.90(s,3H),1.62–1.57(m,1H),0.90–0.86(m,2H),0.78–0.73(m,2H).

MS (ESI+) m/z = 570.3 [M+H] ⁺ . Example 12-14

Using a synthetic route and steps similar to Example 11, replacing raw material 11F with raw material B in the table below, replacing triethylamine with potassium carbonate, and replacing N-methylpyrrolidone with N,N-dimethylformamide, the following compounds 12-14 were synthesized.

Example 15: (E)-1-(4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Compound 15)

Compound 11E (25 mg, 0.05 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and trans-4-dimethylaminocroton hydrochloride (16.5 mg, 0.1 mmol, 2 eq), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (38 mg, 0.1 mmol, 2 eq), and triethylamine (11 mg, 0.1 mmol, 2 eq) were added at room temperature. The mixture was stirred at room temperature for 3 hours, and the organic solvent was removed by rotary evaporation. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 15%-80% acetonitrile-water) to obtain the title compound 15 (13 mg, 0.021 mmol, yield: 43%).

¹ H NMR (400 MHz, DMSO-d6) δ8.59 (d, J = 2.9 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.08 (s, 1H), 7.81–7.76 (m, 1H ),7.75–7.69(m,1H),6.97(s,1H),6.72–6.59(m,2H),5.66–5.60(m,1H),5.11(t,J＝5.7Hz,1H),4.77– 4.67(m,1H),4 .58–4.50(m,1H),4.25–4.14(m,1H),3.99–3.90(m,2H),3.41–3.38(m,2H),3.15–3.11(m,2H),2.43(s, 3H),2.22(s,6H),2.09–2.04(m,2H),2.01–1.96(m,2H),1.62–1.56(m,1H),0.89–0.86(m,2H),0.78–0.73( m,2H).

MS (ESI+) m/z = 613.3 [M + H] ⁺ .

Example 16: 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 16)

Step 1: tert-Butyl 4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (16B)

Compound 11A (778 mg, 1.0 mmol, 1.0 eq), 1-(trimethylsilyl)propyne (336 mg, 3.0 mmol, 3 eq), tetrakis(triphenylphosphine)palladium (115 mg, 0.1 mmol, 0.1 eq), cuprous iodide (19 mg, 0.1 mmol, 0.1 eq), triethylamine (505 mg, 5 mmol, 5 eq) were mixed and dissolved in toluene (10 mL). 1 M tetrabutylammonium fluoride tetrahydrofuran solution (3 mL) was added under nitrogen atmosphere, and the mixture was stirred at room temperature for 5 hours. Filter and dry, and the obtained residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase is 10%-90%) acetonitrile-water) to give the title compound 16B (414 mg, 0.72 mmol, yield: 72%).

MS (ESI+) m/z = 576.3 [M + H] ⁺ .

Step 2: 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (16C)

Compound 16B (414 mg, 0.72 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Zinc bromide (486.4 mg, 2.16 mmol, 3.0 eq) was added at room temperature, stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-80% acetonitrile-water) to obtain the title compound 16C (283.8 mg, 0.60 mmol, yield: 83%).

¹ H NMR (400 MHz, DMSO-d6) δ8.59 (d, J = 2.9 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.08 (s, 1H), 7.83–7.77 (m, 1H ),7.77–7.72(m,1H),6.99(d,J＝1.1Hz,1H),5.64(t,J＝5.1Hz,1H),5.08(t, J＝5.6Hz,1H),4.46–4.40(m,1H),4.00–3.93(m,2H),3.28–3.26(m,1H),3.10–3.04(m,2H),2.68–2.64(m, 2H), 2.41(s, 3H), 2.10(s, 3H), 2.00–1.95(m, 2H), 1.94–1.90(m, 2H).

MS (ESI+) m/z = 476.2 [M + H] ⁺ .

Step 3: 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 16)

Compound 16C (47.6 mg, 0.1 mmol, 1.0 eq) was dissolved in methanol (2 mL). Paraformaldehyde (60 mg, 2.0 mmol, 20.0 eq), acetic acid (6 mg, 0.1 mmol, 1.0 eq), and sodium cyanoborohydride (31.5 mg, 0.5 mmol, 5.0 eq) were added at room temperature. The reaction solution was stirred for 5 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-90% acetonitrile-water) to obtain the title compound 16 (25.4 mg, 0.052 mmol, yield: 52%).

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.59(d,J＝2.8Hz,1H),8.43(s,1H),8.08(s,1H),7.80(td,J＝8.7,2.8Hz,1H),7.74(dd,J＝8.8,4.6Hz,1H),6.99(s,1H),5.64(t,J＝5.1Hz,1H),5.08(t,J＝5.6Hz,1H),4.38–4.31(m,1H),3.99–3.91(m,2H),2.92–2.88(m,2H),2.41(s,3H),2.23(s,3H),2.14–2.11(m,3H),2.10(s,3H),2.08–2.01(m,1H),1.99–1.93(m,2H).

MS (ESI+) m/z = 490.3 [M + H] ⁺ .

Example 17: 2-((6-(1-(1-ethylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (Compound 17)

Compound 16C (47.6 mg, 0.1 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (2 mL), and iodoethane (19 mg, 0.12 mmol, 1.2 eq) and potassium carbonate (27.6 mg, 0.2 mmol, 2 eq) were added at room temperature. After the mixture was stirred at room temperature for 1 hour, the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 15%-80% acetonitrile-water) to obtain the title compound 17 (24 mg, 0.048 mmol, yield: 48%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 2.8 Hz, 1H), 8.44 (s, 1H), 8.08 (s, 1H), 7.80 (td, J = 8.8, 2.9 Hz, 1H),7.74(dd,J＝8.7,4.6Hz,1H),6.99(s,1H),5.66–5.62(m,1H),5.14–5.05(m,1H),4.39–4.33 (m, 1H), 4.01–3.91 (m, 3H), 3.03–2.99 (m, 2H), 2.41 (s, 3H), 2.40–2.37 (m, 2H), 2.13–2.11 (m, 1H), 2.10 (s, 3H), 2.09–2.00 (m, 2H), 2.00–1.94 (m, 2H), 1.03 (t, J＝7.2 Hz, 3H).

MS (ESI+) m/z = 504.2 [M + H] ⁺ .

Example 18: 2-(5-fluoropyridin-2-yl)-2-((6-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 18)

Compound 16C (47.6 mg, 0.1 mmol, 1.0 eq) was dissolved in methanol (2 mL). Acetone (116 mg, 2.0 mmol, 20.0 eq), acetic acid (6 mg, 0.1 mmol, 1.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 10.0 eq) were added at room temperature. The reaction solution was stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25 mm*10 um, elution phase was 5%-90% acetonitrile-water) to obtain the title compound 18 (34.7 mg, 0.067 mmol, yield: 67%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 8.08 (s, 1H), 7.80 (td, J = 8.7,2.9Hz,1H),7.74(dd,J＝8.8,4.6Hz,1H),6.99(d,J＝1.1Hz,1H),5.64(dd,J＝5.9,4.3Hz,1H),4.36– 4.28(m,1H),4.00–3.92(m,2H),2.94–2.89(m,2H),2.80–2.75(m,1H),2.41(s,3H),2.36–2.30(m,2H), 2.10 (s, 3H), 2.08–2.02 (m, 2H), 2.01–1.93 (m, 3H), 1.00 (d, J＝6.6 Hz, 6H).

MS (ESI+) m/z = 518.2 [M + H] ⁺ .

Example 19: 2-((3-ethynyl-6-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (Compound 19)

Step 1: tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (19B)

Compound 11A (778 mg, 1.0 mmol, 1.0 eq), trimethylethynylsilane (300 mg, 3.0 mmol, 3 eq), bistriphenylphosphine palladium dichloride (70 mg, 0.1 mmol, 0.1 eq), cuprous iodide (19 mg, 0.1 mmol, 0.1 eq), triethylamine (505 mg, 5 mmol, 5 eq) were mixed in tetrahydrofuran (10 mL). The mixture was heated to 60 ° C and stirred for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and dried, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-100% acetonitrile-water) to obtain the title compound 19B (546 mg, 0.73 mmol, yield: 73%).

MS (ESI+) m/z = 748.3 [M + H] ⁺ .

Step 2: tert-butyl 4-(4-(4-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-ethynylpyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (19C)

Compound 19B (546 mg, 0.73 mmol, 1.0 eq) was dissolved in methanol (5 mL). Potassium carbonate (302 mg, 2.19 mmol, 3.0eq), stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-95% acetonitrile-water) to obtain the title compound 19C (444 mg, 0.66 mmol, yield: 90%).

MS (ESI+) m/z = 676.3 [M + H] ⁺ .

Step 3: tert-butyl 4-(4-(3-ethynyl-4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (19D)

Compound 19C (444 mg, 0.66 mmol, 1.0 eq) was dissolved in tetrahydrofuran (2 mL). 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (2 mL, 2.0 mmol, 3.0 eq) was added at room temperature, stirred for 1 hour, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-95% acetonitrile-water) to obtain the title compound 19D (312 mg, 0.54 mmol, yield: 84%).

MS (ESI+) m/z = 562.2 [M + H] ⁺ .

Step 4: 2-((3-ethynyl-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (19E)

Compound 19D (312 mg, 0.54 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Zinc bromide (370 mg, 1.62 mmol, 3.0 eq) was added at room temperature, stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-80% acetonitrile-water) to obtain the title compound 19E (132 mg, 0.29 mmol, yield: 53%).

MS (ESI+) m/z = 462.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.58 (d, J = 2.6 Hz, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 7.81–7.72 (m, 2H), 7.05 (s, 1H), 5.67 (t, J = 5.2 Hz, 1H), 5.10–5.04 (m, 1H), 4.46–4.44 (m, 1H), 4.19 (s, 1H), 3.97–3.93 (m, 2H), 3.18–3.14 (m, 2H), 3.09–3.03 (m, 2H), 2.67–2.65 (m, 1H), 2.42 (s, 3H), 2.02–1.94 (m, 2H), 1.93–1.90 (m, 2H).

Step 5: 2-((3-ethynyl-6-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)-2-(5-fluoropyridin-2-yl)ethane-1-ol (Compound 19)

Compound 19E (46 mg, 0.1 mmol, 1.0 eq) was dissolved in methanol (2 mL). Acetone (116 mg, 2.0 mmol, 20.0 eq), acetic acid (6 mg, 0.1 mmol, 1.0 eq), and sodium cyanoborohydride (63 mg, 1 mmol, 10.0 eq) were added at room temperature. The reaction solution was stirred at room temperature for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-90% acetonitrile-water) to obtain the title compound 19 (24 mg, 0.048 mmol, yield: 48%).

MS (ESI+) m/z = 504.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.59–8.57 (m, 1H), 8.48 (d, J = 1.0 Hz, 1H), 8.21 (s, 1H), 7.78–7.74 (m, 2H), 7.05 (d, J = 1.1 Hz, 1H), 5.67 (t, J = 5.2 Hz, 1H), 5.09–5.04 (m, 1H), 4.36–4.28 (m, 1H), 4.19 (s, 1H), 3.98–3.93 (m, 2H), 2.94–2.88 (m, 2H), 2.81–2.74 (m, 1H), 2.41 (s, 3H), 2.37–2.30 (m, 2H), 2.11–2.04 (m, 2H), 2.02–1.97 (m, 2H), 1.01 (d, J = 6.5 Hz, 6H).

Example 20: 1-(4-(4-(3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 20)

Step 1: tert-Butyl 4-(4-(3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (Compound 20A)

Compound 5D (647 mg, 1.0 mmol, 1.0 eq), cyclopropylacetylene (200 mg, 3.0 mmol, 3 eq), bistriphenylphosphine palladium dichloride (70 1,4-dihydro-1,4-dihydro-2-nitropropene (2,4-dihydro-1,4-dihydro-2-nitropropene) (4,4-dihydro-1,4-dihydro-2-nitropropene) (5,4-dihydro-1,4-dihydro-2-nitropropene) (6,4-dihydro-1,4-dihydro-2-nitropropene) (2,4-dihydro-1,4-dihydro-2-nitropropene) (6,4-dihydro-1,4-dihydro-2-nitropropene) (4,4-dihydro-1,4-dihydro-2-nitropropene) (6,4-dihydro-1,4-dihydro-2-nitropropene) (6,4-dihydro-1,4-dihydro-2-nitropropene) (2,4-dihydro-1,4-dihydro-2-nitropropene) (6 ...

MS (ESI+) m/z = 586.3 [M + H] ⁺ .

Step 2: 3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (20B)

Compound 20A (380 mg, 0.65 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Zinc bromide (439 mg, 1.95 mmol, 3.0 eq) was added at room temperature, stirred for 4 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-80% acetonitrile-water) to obtain the title compound 20B (193 mg, 0.39 mmol, yield: 61%).

MS (ESI+) m/z = 486.2 [M + H] ⁺ .

Step 3: 1-(4-(4-(3-(cyclopropylethynyl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Compound 20)

Compound 20B (25 mg, 0.05 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (13 mg, 0.1 mmol, 2.0 eq) and acryloyl chloride (0.54 mg, 0.06 mmol, 1.2 eq) were added at 0°C. After the mixture was stirred at room temperature for 1 hour, the organic solvent was removed by rotary evaporation, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-80% acetonitrile-water) to obtain the title compound 20 (11.6 mg, 0.021 mmol, yield: 43%).

MS (ESI+) m/z = 540.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 2.8 Hz, 1H), 7.81 (td, J = 8.7, 2.9 Hz, 1H), 7.74 (s, 1H), 7.70 (dd, J＝8.8,4.5Hz,1H),7.36(d,J＝1.3Hz,1H),6.88(dd,J＝16.7,10.5Hz,1H),6.59(d,J＝1.4Hz,1H),6.14( dd, J = 16.7, 2.4 Hz, 1H), 5.92 (q, J = 6.4 Hz, 1H), 5.71 ( dd, J = 10.4, 2.4 Hz, 1H), 4.77–4.68 (m, 1H), 4.75–4.71 (m, 1H), 4.25–4.19 (m, 1H), 3.31–3.20 (m, 2H), 2.46 ( s, 3H), 2.08–2.05 (m, 2H), 1.98–1.91 (m, 2H), 1.77 (d, J＝6.4 Hz, 3H), 1.67–1.60 (m, 1H), 0.93–0.88 (m, 2H), 0.76–0.70 (m, 2H).

Example 21: Ethyl 4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (Compound 21)

Compound 16C (47.6 mg, 0.1 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL). Ethyl chloroformate (22 mg, 0.2 mmol, 2.0 eq) and triethylamine (55 mg, 0.5 mmol, 5.0 eq) were added at 0°C, the reaction solution was stirred for 5 hours, the organic solvent was removed by spin drying, and the residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 5%-90% acetonitrile-water) to obtain the title compound 21 (18.6 mg, 0.034 mmol, yield: 34%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 2.9 Hz, 1H), 8.45 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.83–7.79 (m, 1H),7.77–7.70(m,1H),6.99(s,1H),5.64(t,J＝5.1Hz,1H),5.08(t,J＝5.6Hz,1H),4.67–4.60( m,1H),4.15–4.11(m,2H),4.09–4.05(m,2H),3.98–3.93(m,2H),3.08–3.03(m,2H),2.43(s,3H),2.10( s, 3H), 2.04–2.00 (m, 2H), 1.99–1.92 (m, 2H), 1.20 (t, J＝7.1 Hz, 3H).

MS (ESI+) m/z = 548.3 [M + H] ⁺ .

Example 22: 2-(5-fluoropyridin-2-yl)-2-((7-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (Compound 22)

Step 1: 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-chloroimidazo[1,2-a]pyridine (22A)

2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)-1-ethanol (6.53 g, 24.1 mmol, 1.5 eq) was dissolved in tetrahydrofuran (25 mL), sodium hydride (1.6 g, 4400.1 mmol, 2.5 eq) was added at 0°C, stirred for 40 minutes, and 5,7-dichloroimidazo[1,2-a]pyridine (3 g, 16 mmol, 1 eq) was added. Stirred at 45°C for 12 hours, saturated ammonium chloride was added, extracted with ethyl acetate, the organic phases were mixed, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 16-18% ethyl acetate) to obtain the title compound 22A (1.2 g, 2.84 mmol, yield: 18%).

MS (ESI+) m/z = 422.1 [M + H] ⁺ .

Step 2: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (22B)

Compound 22A (600 mg, 1.42 mmol, 1.0 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (111.7 mg, 0.142 mmol, 0.1 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (33.9 mg, 0.07 mmol, 0.05 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (541.6 mg, 2.13 mmol, 1.5 eq), potassium acetate (418.5 mg, 4.27 mmol, 3 eq) were mixed in dioxane (5 mL). The mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours. After cooling to room temperature, the product was filtered and used directly in the next step.

MS (ESI+) m/z = 514.2 M + H] ⁺ .

Step 3: 4-(4-(5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (22C)

Compound 1K (736.2 mg, 2.13 mmol, 1.5 eq), potassium carbonate (589.4 mg, 4.26 mmol, 3 eq) and water (1 ml) were added to a dioxane solution (10 mL) of compound 22B (730 mg, 1.42 mmol, 1.0 eq) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (111.7 mg, 0.142 mmol, 0.1 eq). The mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 22C (490 mg, 0.75 mmol, yield: 53%).

MS (ESI+) m/z = 652.4 [M+H] ⁺ .

Step 4: 4-(4-(5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (22D)

Compound 22C (490 mg, 0.75 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (182 mg, 0.81 mmol, 1.05 eq) was added. The reaction was continued for 3 hours. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 22D (500 mg, 0.66 mmol, yield: 85%).

MS (ESI+) m/z = 778.2 [M + H] ⁺ .

Step 5: 4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (22E)

Compound 22D (250 mg, 0.32 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (37.2 mg, 0.032 mmol, 0.1 eq), cuprous iodide (12.2 mg, 0.064 mmol, 0.2 eq), trimethyl(1-propynyl)silane (72.2 mg, 0.64 mmol, 2 eq), triethylamine (97.4 mg, 0.96 mmol, 3 eq), 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (1.6 ml, 1.6 mmol, 5 eq) were mixed in toluene (3 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-90% acetonitrile) to obtain the title compound 22E (150 mg, 0.26 mmol, yield: 81%).

MS (ESI+) m/z = 576.3 [M + H] ⁺ .

Step 6: 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (22F)

To a dichloromethane solution (2 mL) of compound 22E (60 mg, 0.1 mmol, 1.0 eq), 2 mL of 6 M hydrochloric acid dioxane solution was added, the mixture was stirred at room temperature for 2 hours, and then dried to give the title compound 22F (53 mg, 0.1 mmol, yield: 99%).

MS (ESI+) m/z = 476.3 [M + H] ⁺ .

Step 7: 2-(5-fluoropyridin-2-yl)-2-((7-(1-(1-isopropylpiperidin-4-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (22)

Compound 22F (20 mg, 0.04 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 4.2 eq), acetone (24 mg, 0.4 mmol, 10 eq) were mixed in methanol (3 mL), and then sodium cyanoborohydride (24.6 mg, 0.4 mmol, 10 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 22 (3 mg, 0.05 mmol, yield: 14%).

¹ H NMR (400 MHz, DMSO-d6) δ8.54 (d, J＝2.9 Hz, 1H), 7.82–7.75 (m, 1H), 7.74–7.71 (m, 1H), 7.67 (s, 1H), 7.37 (d, J = 1.3 Hz, 1H), 6.79 (d, J = 1.3 Hz, 1H), 5.97 (d, J = 5.1 Hz, 1H), 5.16–5.12 (m, 1H) ,4.69–4.64(m,1H),4.58–4.54(m,1H),4.41–4.33(m,1H),2.96–2.92(m,2H),2.80–2.76(m,1H),2.55(s, 3H), 2.39–2.31 (m, 3H), 2.09 (s, 3H), 2.04–1.98 (m, 3H), 1.01 (d, J＝6.5 Hz, 6H).

MS (ESI+) m/z = 518.3 [M + H] ⁺ .

Example 23: 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-(1-(oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (Compound 23)

Compound 22F (20 mg, 0.04 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 4.2 eq), 3-oxetanone (28.2 mg, 0.4 mmol, 10 eq) were mixed in methanol (3 mL), and then sodium cyanoborohydride (24.6 mg, 0.4 mmol, 10 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 23 (6 mg, 0.11 mmol, yield: 28%).

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.54(d,J＝2.9Hz,1H),7.82–7.77(m,1H),7.75–7.71(m,1H),7.67(s,1H),7.37(d,J＝1.3Hz,1H),6.79(d,J＝1.4Hz,1H),5.97(d,J＝5.1Hz,1H),5.16–5.11(m,1H),4.68–4.65(m,1H),4.59–4.54(m,3H),4.48–4.44(m,3H),3.48–3.45(m,1H),2.88–2.84(m,2H),2.56(s,3H),2.18–2.11(m,2H),2.09(s,3H),2.06–1.98(m,4H).

MS (ESI+) m/z = 532.2 [M + H] ⁺ .

Example 24: 4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid methyl ester (Compound 24)

Compound 22F (20 mg, 0.04 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL), and methyl chloroformate (37 mg, 0.4 mmol, 10 eq) and triethylamine (39.5 mg, 0.4 mmol, 10 eq) were added at 0°C. The mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, eluting phase was a water mixed solvent containing 20-95% acetonitrile) to obtain the title compound 24 (5 mg, 0.09 mmol, yield: 23%).

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.54(d,J＝2.9Hz,1H),7.82–7.77(m,1H),7.75–7.71(m,1H),7.67(s,1H),7.38(d,J＝1.3Hz,1H),6.78(d,J＝1.3Hz,1H),5.97(d,J＝5.1Hz,1H),5.17–5.11(m,1H),4.69–4.65(m,2H),4.59–4.53(m,1H),4.15–4.09(m,2H),3.64(s,3H),3.09–3.05(m,2H),2.58(s,3H),2.09(s,3H),2.05–2.00(m,2H),1.98–1.92(m,2H).

MS (ESI+) m/z = 534.2 [M + H] ⁺ .

Example 25: 3-(4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-hydroxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-3-oxopropionitrile (Compound 25)

Compound 22F (60 mg, 0.11 mmol, 1.0 eq) and 2-cyanoacetic acid (12 mg, 0.14 mmol, 1.2 eq) were dissolved in N,N-dimethylformamide (1 mL), and N,N-diisopropylethylamine (38 mg, 0.29 mmol, 2.5 eq) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (53.2 mg, 0.14 mmol, 1.2 eq) were added. The mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The product was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 25 (10 mg, 0.18 mmol, yield: 15%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (d, J = 2.9 Hz, 1H), 7.82–7.77 (m, 1H), 7.75–7.71 (m, 1H), 7.67 (s, 1H), 7.38 (d, J = 1.3 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 5.96 (d, J = 4.9 Hz, 1H), 5.17–5.12 (m, 1H), 4.77–4.71 (m ,1H),4.69 –4.65(m,1H),4.60–4.52(m,1H),4.49–4.43(m,1H),4.15–4.11(m,2H),3.85–3.80(m,1H),3.31(s,2H) ,2.95–2.90(m,1H),2.58(s,3H),2.19–2.14(m,1H),2.09(s,3H),2.07–2.01(m,2H).

MS (ESI+) m/z = 543.2 [M + H] ⁺ .

Example 26: 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-ylimidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (Compound 26)

Step 1 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (26A)

Compound 26D (84.5 mg, 0.36 mmol, 1.5 eq), potassium carbonate (98.2 mg, 0.71 mmol, 3 eq) and water (1 ml) were added to a dioxane solution (10 mL) of compound 22B (121.6 mg, 0.24 mmol, 1.0 eq) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (18.6 mg, 0.024 mmol, 0.1 eq). The mixture was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 26A (100 mg, 0.18 mmol, yield: 77%).

MS (ESI+) m/z = 545.2 [M+H]+.

Step 2: 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodo-7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (26B)

Compound 26A (100 mg, 0.18 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (182 mg, 0.22 mmol, 1.2 eq) was added. The reaction was continued for 3 hours. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 26B (100 mg, 0.15 mmol, yield: 81%).

MS (ESI+) m/z = 671.1 [M+H]+.

Step 3: 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (26)

Compound 26B (50 mg, 0.07 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (8.6 mg, 0.007 mmol, 0.1 eq), cuprous iodide (2.8 mg, 0.014 mmol, 0.2 eq), trimethyl(1-propynyl)silane (25.2 mg, 0.21 mmol, 3 eq), triethylamine (22.4 mg, 0.21 mmol, 3 eq), 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (0.35 ml, 0.35 mmol, 5 eq) were mixed in toluene (1 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 26 (10 mg, 0.02 mmol, 28%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (d, J = 2.8 Hz, 1H), 7.83–7.78 (m, 1H), 7.76–7.72 (m, 1H), 7.70 (s, 1H), 7.69–7.62 (m, 5H), 7.47 (d, J = 1.4 Hz, 1H), 6.88 (d, J = 1.4 Hz, 1H), 6.00 (d, J = 5.1 Hz, 1H), 5.19–5.14 (m, 1H), 4.73–4.68 (m, 1H), 4.63–4.57 (m, 1H), 2.54 (s, 3H), 2.10 (s, 3H).

MS (ESI+) m/z = 469.2 [M + H] ⁺ .

Intermediate 26D: 4-Bromo-5-methyl-1-phenyl-1H-1,2,3-triazole (Compound 26D)

The first step is phenylazide (26F)

Compound 26E (2 g, 21.48 mmol, 1.0 eq) was dissolved in 4N hydrochloric acid (12 mL), and a 10 mL aqueous solution of sodium nitrite (1.93 g, 27.92 mmol, 1.3 eq) was added at 0°C. After stirring for 30 minutes, a 20 mL aqueous solution of potassium azide (3.26 g, 40.15 mmol, 1.87 eq) was added. The mixture was stirred at room temperature for 3 hours. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain the title compound 26F (2.1 g, 17 mmol, yield: 82%).

Step 2: 5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (26G)

Compound 26F (2.1 g, 17 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (4 mL), and ethyl acetoacetate (2.3 g, 17 mmol, 1 eq) and diethylamine (128 mg, 1.7 mmol, 0.1 eq) were added. The mixture was stirred at 70°C for 12 hours. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 5-50% ethyl acetate) to obtain the title compound 26G (2.65 g, 11 mmol, yield: 65%).

MS (ESI+) m/z = 232.1 [M+H] ⁺ .

Step 3: 5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (26H)

Compound 26G (2.65 g, 11 mmol, 1.0 eq) was added to a 25 mL aqueous solution of potassium hydroxide (1.29 g, 22 mmol, 2 eq), and the mixture was stirred at 50° C. for 4 h. The aqueous solution of 26H was used directly in the next step.

MS (ESI+) m/z = 204.1 [M + H] ⁺ .

Step 4: 4-Bromo-5-methyl-1-phenyl-1H-1,2,3-triazole (26D)

Potassium hydroxide (650 mg, 11 mmol, 1 eq) was added to the aqueous solution of compound 26H, and liquid bromine (3.66 g, 22 mmol, 2 eq) was added dropwise. The mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 5-50% ethyl acetate) to obtain the title compound 26D (2.5 g, 10 mmol, yield: 90%). MS (ESI+) m/z = 238.0 [M + H] ⁺ .

Example 27: 2-(5-fluoropyridin-2-yl)-2-((6-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-4-yl)oxy)ethane-1-ol (Compound 27)

Compound 16C (20 mg, 0.04 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 4.2 eq), 3-oxetanone (28.2 mg, 0.4 mmol, 10 eq) were mixed in methanol (2 mL), and then sodium cyanoborohydride (24.6 mg, 0.4 mmol, 10 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 10 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 27 (11 mg, 0.11 mmol, yield: 52%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 2.8 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.08 (s, 1H), 7.84–7.77 (m, 1H), 7.76–7.71 (m, 1H), 7.00 (s, 1H), 5.67–5.61 (m, 1H), 5.07 (t, J = 5.7 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H ),4.47(t,J＝6 .1Hz,2H),4.43–4.37(m,1H),3.99–3.93(m,2H),3.49–3.43(m,1H),2.88–2.83(m,2H),2.42(s,3H),2.16 –2.11(m,1H),2.10(s,3H),2.09–2.06(m,1H),2.05–2.01(m,2H),2.05–1.97(m,2H).

MS (ESI+) m/z = 532.3 [M + H] ⁺ .

Embodiment 28:

Using a synthetic route and steps similar to Example 11, compound 28 was synthesized by replacing raw material 11F with raw material C in the table below.

Embodiment 29:

Using a synthetic route and steps similar to Example 22, compound 29 was synthesized by replacing raw material 22F with raw material 11E.

Embodiment 30:

The synthetic route and steps of intermediate 22F in Example 22 were adopted, and cyclopropylacetylene was used to replace trimethyl(1-propynyl)silane to synthesize the required intermediate 30A. A synthetic route and steps similar to Example 27 were adopted, and raw material 30A in the table below was used to replace raw material 16C to synthesize compound 30.

Embodiment 31:

Using a synthetic route and steps similar to Example 24, compound 31 was synthesized by replacing raw material 22F with raw material 30A in the table below.

Embodiment 32:

Using a synthetic route and steps similar to that of intermediate 5G in Example 5, trimethyl(1-propynyl)silane was used to replace trimethylsilylacetylene to synthesize the desired intermediate 32A. Using a synthetic route and steps similar to that of Example 25, raw material 32A in the table below was used to replace raw material 22F to synthesize compound 32.

Example 33: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(1-(oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Compound 33)

Using the similar synthetic route and steps as Example 27, compound 33 was synthesized by replacing 16C with 32A.

MS (ESI+) m/z = 516.3

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 2.9 Hz, 1H), 7.85–7.80 (m, 1H), 7.73 (s, 1H), 7.72–7.68 (m, 1H), 7.36 (d, J = 1.3 Hz, 1H), 6.59 (d, J = 1.4 Hz, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.43–4.34 (m, 1H), 3.49–3.43 (m, 1H), 2.87–2.81 (m, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 2.11–2.07 (m, 2H), 2.05–1.99 (m, 4H), 1.75 (d, J＝6.4 Hz, 3H).

Compound 33 was subjected to chiral separation (column: DAICEL CHIRALCEL AD (250 mm*30 mm, 10 um); mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia water); B%: 60%-60%; flow rate: 80 ml/min) to obtain two single-configuration compounds 33-1 and 33-2.

33-1 SFC retention time: 0.541min

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J = 2.9 Hz, 1H), 7.86–7.81 (m, 1H), 7.73 (s, 1H), 7.72–7.67 (m, 1H), 7.35 (d, J = 1.3 Hz, 1H), 6.59 (d, J = 1.4 Hz, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.43–4.33 (m, 1H), 3.48–3.43 (m, 1H), 2.87–2.81 (m, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 2.11–2.08 (m, 2H), 2.05–1.99 (m, 4H), 1.75 (d, J＝6.4 Hz, 3H).

MS (ESI+) m/z = 516.3 [M + H] ⁺ .

33-2 SFC retention time: 1.192min

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 2.9 Hz, 1H), 7.87–7.81 (m, 1H), 7.73 (s, 1H), 7.72–7.67 (m, 1H), 7.36 (d, J = 1.3 Hz, 1H), 6.58 (d, J = 1.4 Hz, 1H), 5.91 (q, J = 6.4 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.46 (t, J = 6.1 Hz, 2H), 4.43–4.33 (m, 1H), 3.48–3.43 (m, 1H), 2.87–2.81 (m, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 2.11–2.08 (m, 2H), 2.06–1.98 (m, 4H), 1.74 (d, J＝6.4 Hz, 3H).

MS (ESI+) m/z = 516.3 [M + H] ⁺ .

Example 34: 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethan-1-ol (Compound 34)

Step 1 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (34A)

Compound 34E (88.5 mg, 0.36 mmol, 1.5 eq), potassium carbonate (98.2 mg, 0.71 mmol, 3 eq) and water (1 ml) were added to a dioxane solution (10 mL) of compound 22B (121.6 mg, 0.24 mmol, 1.0 eq) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (18.6 mg, 0.024 mmol, 0.1 eq). The mixture was stirred at 80°C under nitrogen atmosphere for 2 hours. The reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 34A (120 mg, 0.18 mmol, yield: 90%).

MS (ESI+) m/z = 553.3 [M + H] ⁺ .

Step 2 5-(2-((tert-butyldimethylsilyl)oxy)-1-(5-fluoropyridin-2-yl)ethoxy)-3-iodo-7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (34B)

Compound 34A (120 mg, 0.22 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (182 mg, 0.22 mmol, 1.2 eq) was added. The reaction was continued for 3 hours. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 34B (128 mg, 0.19 mmol, yield: 86%).

MS (ESI+) m/z = 679.2 [M+H] ⁺ .

Step 3: 2-(5-fluoropyridin-2-yl)-2-((7-(5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-5-yl)oxy)ethane-1-ol (34)

Compound 34B (47 mg, 0.07 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (8.6 mg, 0.007 mmol, 0.1 eq), cuprous iodide (2.8 mg, 0.014 mmol, 0.2 eq), trimethyl(1-propynyl)silane (25.2 mg, 0.21 mmol, 3 eq), triethylamine (22.4 mg, 0.21 mmol, 3 eq), 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (0.35 ml, 0.35 mmol, 5 eq) were mixed in toluene (1 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 34 (12 mg, 0.025 mmol, 36%).

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.54(d,J＝2.9Hz,1H),7.84–7.78(m,1H),7.75–7.70(m,1H),7.68(s,1H),7.38(d,J＝1.3Hz,1H),6.79(d,J＝1.4Hz,1H),5.99(d,J＝5.1Hz,1H),5.16–5.11(m,1H),4.77–4.63(m,2H),4.59–4.53(m,1H),4.05–3.95(m,2H),3.59–3.49(m,2H),2.58(s,3H),2.17–2.11(m,2H),2.09(s,3H),2.01–1.96(m,2H).

MS (ESI+) m/z = 477.2 [M + H] ⁺ .

Intermediate 34E: 4-bromo-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole (Compound 34E)

Step 1: 4-azidotetrahydro-2H-pyran (34B)

Compound 34A (5 g, 23.6 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), potassium azide (3.58 g, 35.4 mmol, 1.5 eq) was added, stirred at 60°C for 5 h, saturated sodium bicarbonate was added, extracted with ethyl acetate, the organic phases were mixed, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dimethyl sulfoxide (20 mL) was added, and the solvent was removed by distillation under reduced pressure to obtain a dimethyl sulfoxide solution of the title compound 34B.

Step 2: 5-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxylic acid ethyl ester (34C)

Potassium carbonate (9.8 g, 70.8 mmol, 3 eq) was added to a solution of compound 34B (3 g, 23.6 mmol, 1 eq) in dimethyl sulfoxide (20 mL). The mixture was stirred at 80 ° C under nitrogen atmosphere for 12 hours. After cooling to room temperature, it was extracted with water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column (eluting phase was a mixed solvent of petroleum ether containing 5-50% ethyl acetate) to obtain the title compound 34C (3.6 g, 15 mmol, yield: 63%).

MS (ESI+) m/z = 240.2 [M + H] ⁺ .

Step 3: 5-Methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxylic acid (34D)

Compound 34C (3.6 g, 15 mmol, 1.0 eq) was added to 30 mL of an aqueous solution of potassium hydroxide (1.69 g, 30 mmol, 2 eq), and the mixture was stirred at 50° C. for 2 hours to obtain an aqueous solution of 34D which was used directly in the next step.

MS (ESI+) m/z = 212.1 [M + H] ⁺ .

Step 4: 4-Bromo-5-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole (34E)

Potassium hydroxide (850 mg, 15 mmol, 1 eq) was added to the aqueous solution of compound 34D, and liquid bromine (4.81 g, 30 mmol, 2 eq) was added dropwise. The mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The crude product was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 5-50% ethyl acetate) to obtain the title compound 34E (2.8 g, 11 mmol, yield: 75%). MS (ESI+) m/z = 246.0 [M + H] ⁺ .

Example 35: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(8-(oxabutane-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Compound 35)

The first step: 3-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35D)

Compound 35C (172 mg, 0.46 mmol, 1.5 eq), potassium carbonate (128.3 mg, 0.93 mmol, 3 eq) and water (1 ml) were added to a dioxane solution (10 mL) of compound 5B (120 mg, 0.31 mmol, 1.0 eq) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (24 mg, 0.024 mmol, 0.1 eq). The mixture was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 35D (137 mg, 0.25 mmol, yield: 81%).

MS (ESI+) m/z = 548.3 [M + H] ⁺ .

Step 2: 3-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35E)

Compound 35D (137 mg, 0.25 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (248 mg, 0.3 mmol, 1.2 eq) was added. The reaction was continued for 3 hours. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 35E (148 mg, 0.22 mmol, yield: 88%).

MS (ESI+) m/z = 674.2 [M+H] ⁺ .

Step 3: 3-(4-(5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35F)

Compound 35E (94.3 mg, 0.14 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (17.2 mg, 0.014 mmol, 0.1 eq), cuprous iodide (2.8 mg, 0.014 mmol, 0.1 eq), trimethyl(1-propynyl)silane (50.4 mg, 0.42 mmol, 3 eq), triethylamine (45 mg, 0.42 mmol, 3 eq), 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (0.7 ml, 0.7 mmol, 5 eq) were mixed in toluene (1 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 35F (39 mg, 0.067 mmol, 48%).

MS (ESI+) m/z = 586.3 [M + H] ⁺ .

Step 4: 7-(1-(8-azabicyclo[3.2.1]octan-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl)-5-(1-(5-fluoropyridin-2-yl)ethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (35G)

To a dichloromethane solution (1 mL) of compound 35F (39 mg, 0.067 mmol, 1.0 eq) was added 1 mL of 4 M hydrochloric acid dioxane solution. The mixture was stirred at room temperature for 2 hours and then dried to give the title compound 35G (34.7 mg, 0.066 mmol, yield: 99%).

MS (ESI+) m/z = 486.3 [M + H] ⁺ .

Step 5: 5-(1-(5-fluoropyridin-2-yl)ethoxy)-7-(5-methyl-1-(8-(oxabutane-3-yl)-8-azabicyclo[3.2.1]octan-3-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (35)

Compound 35G (34.7 mg, 0.066 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 2.4 eq), 3-oxetanone (46.5 mg, 0.66 mmol, 10 eq) were mixed in methanol (2 mL), and then sodium cyanoborohydride (40.6 mg, 0.66 mmol, 10 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 10 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 35 (19 mg, 0.036 mmol, yield: 55%).

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.61(d,J＝2.9Hz,1H),7.83–7.78(m,1H),7.74(s,1H),7.73–7.70(m,1H),7.37–7.33(m,1H),6.61–6.55(m,1H),5.92(d,J＝6.7Hz,1H),5.32(t,J＝4.8Hz,2H),4.61–4.56(m,2H),4.41–4.35(m,2H),2.44(s,3H),2.12(s,3H),2.03–1.97(m,4H),1.92–1.87(m,1H),1.82–1.77(m,1H),1.75(d,J＝6.4Hz,3H),1.48–1.42(m,4H).

MS (ESI+) m/z = 542.3 [M + H] ⁺ .

Intermediate 35C: tert-butyl 3-(4-bromo-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Compound 35C)

Step 1: tert-butyl 3-(tosyloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (35B)

Compound 35A (2.28 g, 10 mmol, 1 eq) was dissolved in dichloromethane (20 mL), and 4-dimethylaminopyridine (122 mg, 1 mmol, 0.1 eq), p-toluenesulfonyl chloride (2.85 g, 15 mmol, 1.5 eq), and triethylamine (3.03 g, 30 mmol, 3 eq) were added. The mixture was stirred at room temperature for 20 hours, filtered, and dried by rotation. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 10-80% acetonitrile) to give the title compound 35B (1.33 g, 3.5 mmol, yield: 35%).

MS (ESI+) m/z = 382.2 [M + H] ⁺ .

Step 2: 3-(4-Bromo-5-methyl-1H-1,2,3-triazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (35C)

Compound 35B (1.33 g, 3.5 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL) and 5-bromo-4-methyl-1H-1H- 1,2,3-Triazole (563 mg, 3.5 mmol, 1 eq), cesium carbonate (1.71 g, 5.25 mmol, 1.5 eq), stirred at 80 ° C for 5 h, cooled to room temperature and diluted with water (30 mL), extracted with ethyl acetate, the organic phases were mixed, washed with saturated brine, and dried over anhydrous sodium sulfate, filtered, and spin-dried. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 20-90% acetonitrile) to give the title compound 35C (233.7 mg, 0.63 mmol, yield: 18%).

MS (ESI+) m/z = 371.2 [M + H] ⁺ .

Example 36: 3-(Cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (Compound 36)

Step 1: tert-Butyl 4-(4-(3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (36A)

Compound 11D (240 mg, 0.4 mmol, 1 eq) was dissolved in tetrahydrofuran (5 mL), sodium hydride (24 mg, 0.6 mmol, 1.5 eq) was added at 0°C and stirred for 0.5 h, then iodomethane (85.2 mg, 0.6 mmol, 1.5 eq) was added and stirring was continued for 2 h, water was added to quench the mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic solvent was dried and the mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 10-80% acetonitrile) to give the title compound 36A (187 mg, 0.3 mmol, yield: 76%).

MS (ESI+) m/z = 616.3 [M + H] ⁺ .

Step 2: 3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (36B)

Compound 36A (187 mg, 0.3 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Zinc bromide (337.5 mg, 1.5 mmol, 5.0 eq) was added at room temperature, stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-90% acetonitrile water mixed solvent) to obtain the title compound 36B (128.3 mg, 0.25 mmol, yield: 83%).

MS (ESI+) m/z = 516.3 [M + H] ⁺ .

Step 3: 3-(cyclopropylethynyl)-4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)pyrazolo[1,5-a]pyridine (36)

Compound 36B (51.5 mg, 0.1 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 1.6 eq), 3-oxetanone (72.0 mg, 1.0 mmol, 10 eq) were mixed in methanol (2 mL), and then sodium cyanoborohydride (24.6 mg, 0.4 mmol, 4 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 10 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 36 (34 mg, 0.061 mmol, yield: 61%).

MS (ESI+) m/z = 572.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.0 Hz, 1H), 8.09 (s, 1H), 7.79 (td, J = 8.7,2.9Hz,1H),7.69(dd,J＝8.8,4.5Hz,1H),6.92(d,J＝1.1Hz,1H),5.83(t,J＝5.0Hz,1H),4.56(t, J＝6.5Hz,2H),4.46(t,J＝6.1Hz,2H),4.4 3–4.34(m,1H),3.94–3.88(m,2H),3.50–3.44(m,1H),3.37(s,3H),2.88–2.82(m,2H),2.38(s,3H), 2.14–2.08(m,2H),2.06–2.01(m,2H),2.00–1.96(m,2H),1.62–1.56(m,1H),0.92–0.86(m,2H),0.78–0.71(m ,2H).

Example 37: 4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridine (Compound 37)

Step 1: tert-Butyl 4-(4-(4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridin-6-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (37A)

Compound 16B (57.5 mg, 0.1 mmol, 1 eq) was dissolved in tetrahydrofuran (3 mL). Sodium hydride (6 mg, 0.15 mmol, 1.5 eq) was added at 0°C and stirred for 0.5 h. Then iodomethane (21.3 mg, 0.15 mmol, 1.5 eq) was added and stirring was continued for 2 h. Water was added to quench the mixture, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried by rotary evaporation. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 5-85% acetonitrile) to give the title compound 37A (47.2 mg, 0.08 mmol, yield: 80%).

MS (ESI+) m/z = 590.3 [M + H] ⁺ .

Step 2: 4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridine (37B)

Compound 37A (47.2 mg, 0.08 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). Zinc bromide (90 mg, 0.4 mmol, 5.0 eq) was added at room temperature, stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25 mm*10 um, elution phase was 10%-90% acetonitrile water mixed solvent) to obtain the title compound 37B (30.2 mg, 0.06 mmol, yield: 77%).

MS (ESI+) m/z = 490.3 [M + H] ⁺ .

Step 3: 4-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-6-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)pyrazolo[1,5-a]pyridine (37)

Compound 37B (30.2 mg, 0.06 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 2.7 eq), 3-oxetanone (43.2 mg, 0.6 mmol, 10 eq) were mixed in methanol (2 mL), and then sodium cyanoborohydride (18.8 mg, 0.3 mmol, 5 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 10 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 37 (21.3 mg, 0.039 mmol, yield: 65%).

MS (ESI+) m/z = 546.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ8.61 (d, J = 2.9 Hz, 1H), 8.44 (d, J = 1.0 Hz, 1H), 8.10 (s, 1H), 7.80 (td, J = 8.7 ,2.9Hz,1H),7.69(dd,J＝8.8,4.5Hz,1H),6.91(s,1H),5.80(t,J＝4.8Hz,1H),4.56(t,J＝6.5Hz,2H ),4.46(t, J＝6.1Hz,2H),4.42–4.37(m,1H),3.94–3.89(m,2H),3.50–3.45(m,1H),3.37(s,3H),2.87–2.82(m,2H) ,2.38(s,3H),2.15–2.12(m,1H),2.10(s,3H),2.08–2.05(m,1H),2.04–2.00(m,2H),1.99–1.95(m,2H) .

Example 38: 5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(1-(oxabutan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Compound 38)

Step 1: tert-butyl 4-(4-(5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate (38A)

Compound 22E (57.5 mg, 0.1 mmol, 1 eq) was dissolved in tetrahydrofuran (3 mL), sodium hydride (6 mg, 0.15 mmol, 1.5 eq) was added at 0°C and stirred for 0.5 h, then iodomethane (21.3 mg, 0.15 mmol, 1.5 eq) was added and stirring was continued for 2 h, water was added to quench the mixture, ethyl acetate was extracted, the mixture was dried over anhydrous sodium sulfate, filtered, the organic solvent was dried, and the mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 10-85% acetonitrile) to give the title compound 38A (49.6 mg, 0.084 mmol, yield: 84%).

MS (ESI+) m/z = 590.3 [M + H] ⁺ .

Step 2: 5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (38B)

Compound 38A (49.6 mg, 0.084 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL). 4 M hydrochloric acid dioxane solution (2 mL) was added at room temperature, stirred for 3 hours, and the organic solvent was removed by spin drying. The residue was purified by reverse phase chromatography (Phenomenex Luna C18 150*25mm*10um, elution phase was 10%-90% acetonitrile water mixed solvent) to obtain the title compound 38B (28.8 mg, 0.058 mmol, yield: 70%).

MS (ESI+) m/z = 490.3 [M + H] ⁺ .

Step 3: 5-(1-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (38)

Compound 38B (28.8 mg, 0.058 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 2.7 eq), 3-oxetanone (43.2 mg, 0.6 mmol, 10 eq) were mixed in methanol (2 mL), and then sodium cyanoborohydride (18.8 mg, 0.3 mmol, 5 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 10 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, eluting phase was a water mixed solvent containing 10-95% acetonitrile) to obtain the title compound 38 (14.6 mg, 0.027 mmol, yield: 46%).

MS (ESI+) m/z = 546.3 [M + H] ⁺ .

1H NMR (400MHz, DMSO-d6) δ8.60 (d, J＝2.9Hz, 1H), 7.85–7.80 (m, 1H), 7.72–7.68 (m, 2H), 7.38 (d, J＝1.3Hz, 1H), 6.77 (d, J＝1.3Hz, 1H), 4.85 (t, J＝5.1Hz, 1H), 4.68–4. 63(m,2H),4.58–4.54(m,2H),4.50–4.44(m,3H),3.50–3.45(m,1H),3.39(s,3H),2.88–2.82(m,2H),2.55(s,3H),2.15(s,3H),2.13–2.04(m,3H),2.03–1.97(m,3H).

Example 39: 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(1-(oxabutan-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (Compound 39)

Step 1: 7-Chloro-5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)imidazo[1,2-a]pyridine (39A)

Compound 39G (2.56 g, 15 mmol, 1.5 eq) was dissolved in tetrahydrofuran (25 mL), sodium hydride (1.0 g, 25 mmol, 2.5 eq) was added at 0°C, stirred for 40 minutes, and 5,7-dichloroimidazo[1,2-a]pyridine (1.85 g, 10 mmol, 1 eq) was added. The mixture was stirred at 65°C for 12 hours, saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phases were mixed, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column (the elution phase was a petroleum ether mixed solvent containing 16-45% ethyl acetate) to obtain the title compound 39A (1.64 g, 5.1 mmol, yield: 51%).

MS (ESI+) m/z = 322.1 [M+H] ⁺ .

Step 2: 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (39B)

Compound 39A (1.64 g, 5.1 mmol, 1.0 eq), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (401 mg, 0.51 mmol, 0.1 eq), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (121 mg, 0.25 mmol, 0.05 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.94 g, 7.65 mmol, 1.5 eq), potassium acetate (1.53 g, 15.3 mmol, 3 eq) were mixed in dioxane (15 mL). The mixture was stirred at 90 ° C under nitrogen atmosphere for 2 hours. After cooling to room temperature, it was filtered and directly Used in the next step.

MS (ESI+) m/z = 414.2 M + H] ⁺ .

Step 3: 4-(4-(5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (39C)

Compound 1K (1035 mg, 3.0 mmol, 1.5 eq), potassium carbonate (828 mg, 6.0 mmol, 3 eq) and water (1 ml) were added to a dioxane solution (10 mL) of compound 39B (828 mg, 2.0 mmol, 1.0 eq) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (156 mg, 0.2 mmol, 0.1 eq). The mixture was stirred at 85 °C under nitrogen atmosphere for 2 hours. The reaction solution was spin-dried and the obtained residue was purified by reverse phase column (Phenomenex Luna C18 150*25mm*10um, elution phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 39C (674.6 mg, 1.22 mmol, yield: 61%).

MS (ESI+) m/z = 552.3 [M + H] ⁺ .

Step 4: 4-(4-(5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-iodoimidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (39D)

Compound 39C (674.6 mg, 1.22 mmol, 1 eq) was dissolved in N,N-dimethylformamide (2 mL), and N-iodosuccinimide (288 mg, 1.28 mmol, 1.05 eq) was added. The reaction was continued for 3 hours. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 39D (728 mg, 1.07 mmol, yield: 88%).

MS (ESI+) m/z = 678.2 [M+H] ⁺ .

Step 5: 4-(4-(5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (39E)

Compound 39D (217 mg, 0.32 mmol, 1.0 eq), tetrakis(triphenylphosphine)palladium (37.2 mg, 0.032 mmol, 0.1 eq), cuprous iodide (12.2 mg, 0.064 mmol, 0.2 eq), trimethyl(1-propynyl)silane (72.2 mg, 0.64 mmol, 2 eq), triethylamine (97.4 mg, 0.96 mmol, 3 eq), 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (1.6 ml, 1.6 mmol, 5 eq) were mixed in toluene (3 mL). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25 mm*10 um, eluting phase was a water mixed solvent containing 5-90% acetonitrile) to obtain the title compound 39E (137.8 mg, 0.23 mmol, yield: 73%).

MS (ESI+) m/z = 590.3 [M + H] ⁺ .

Step 6: 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (39F)

To a dichloromethane solution (2 mL) of compound 39E (59 mg, 0.1 mmol, 1.0 eq) was added 2 mL of 4 M hydrochloric acid dioxane solution. The mixture was stirred at room temperature for 2 hours and then dried to give the title compound 39F (51 mg, 0.1 mmol, yield: 99%).

MS (ESI+) m/z = 490.3 [M + H] ⁺ .

Step 7: 5-(2-(5-fluoropyridin-2-yl)-2-methoxyethoxy)-7-(5-methyl-1-(1-(oxabutane-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-3-(prop-1-yn-1-yl)imidazo[1,2-a]pyridine (39)

Compound 39F (49 mg, 0.1 mmol, 1.0 eq), acetic acid (10 mg, 0.16 mmol, 1.6 eq), 3-oxetanone (72 mg, 1 mmol, 10 eq) were mixed in methanol (2 mL), and then sodium cyanoborohydride (32 mg, 0.5 mmol, 5 eq) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 12 hours. The mixture was spin-dried and purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, eluting phase was a water mixed solvent containing 5-95% acetonitrile) to obtain the title compound 39 (33.8 mg, 0.062 mmol, yield: 62%).

MS (ESI+) m/z = 546.3 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ8.60 (d, J = 2.9 Hz, 1H), 7.85–7.80 (m, 1H), 7.73–7.66 (m, 2H), 7.38 (d, J = 1.3 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 4.86 (t, J = 5.1 Hz, 1H), 4.72–4.62 (m, 2H), 4.57 (t, J = 6.5 Hz, 2H), 4.49–4.38 (m, 3H), 3.50–4.44 (m, 1H), 3.39 (s, 3H), 2.91–2.81 (m, 2H), 2.55 (s, 3H), 2.15 (s, 3H), 2.14–2.04 (m, 3H), 2.02–1.96 (m, 3H).

Intermediate 39G: 2-(5-fluoropyridin-2-yl)-2-methoxyethane-1-ol (Compound 39G)

Step 1: 2-(2-((tert-Butyldimethylsilyl)oxy)-1-methoxyethyl)-5-fluoropyridine (39-Int)

Compound 2Y (8.13 g, 30 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL). Sodium hydride (1.8 g, 15 mmol, 1.5 eq) was added at 0°C and stirred for 0.5 h. Then iodomethane (6.4 g, 45 mmol, 1.5 eq) was added and stirred for 5 h. Water was added to quench the mixture. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The mixture was filtered and the organic solvent was dried. The mixture was purified by reverse phase silica gel column (Phenomenex Luna C18 150*25mm*10um, the elution phase was a water mixed solvent containing 10-95% acetonitrile) to give the title compound 39-Int (7.2 g, 25.2 mmol, yield: 84%).

MS (ESI+) m/z = 286.2 [M + H] ⁺ .

Step 2 2-(5-Fluoropyridin-2-yl)-2-methoxyethane-1-ol (39G)

100 mL of 4M hydrochloric acid dioxane solution was added to a dichloromethane solution (30 mL) of compound 39-Int (7.2 g, 25.2 mmol, 1.0 eq). The mixture was stirred at room temperature for 5 hours, dried by spin drying, washed with saturated brine (50 mL), extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic solvent was dried by spin drying to obtain the title compound 39G (3.12 g, 18.3 mmol, yield: 73%).

MS (ESI+) m/z = 172.1 [M + H] ⁺ .

Biological evaluation

The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

Test Example 1: FGFR enzyme inhibition experiment of the disclosed compounds

The test samples were dissolved in DMSO to prepare a 10 mM storage solution and stored at -30°C.

The enzyme reaction was performed using the enzyme reaction kit produced by Promega (FGFR1Kit Catalog No. V2991, FGFR2Kit Catalog No. V4060, FGFR3Kit Catalog No. VA7459, the reaction substrate was Poly E4Y1) according to the method recommended by the manufacturer. The reaction product was detected using the ADP detection kit produced by Promega (ADP-Glo ^TM Kinase Assay, Catalog No. V9101).

The 5μL reaction system contains 0.4ng/μL FGFR1 kinase (or 1.4ng/μL FGFR2 kinase, or 1ng/μL FGFR3 kinase), 0.2μg/μL Poly E4Y1, 5μM ATP (Poly E4Y1 and ATP are both from the enzyme reaction kit) and gradient dilutions (starting concentration 10000nM, 3× gradient dilution, 10 concentrations) of the test compound. The final concentration of DMSO in the reaction system is 1%. The reaction is carried out in a 384-well plate (Perkinelmer, Cat. 6007290), and all tests are performed in duplicate. In the above system, ATP is added at the end to start the reaction. The above 384-well reaction plate is reacted at 25℃ for 60 minutes, and then 5μL ADP-Glo (from the ADP detection kit) is added, and the reaction is carried out at 25℃ for 40 minutes. Then 10μL detection buffer is added and the reaction is carried out at 25℃ for 30 minutes. After the reaction, the luminescence value (Lum) is measured using an enzyme reader (Perkinelmer Envision). Luminescence value represents the amount of ADP generated. The inhibition rate of kinase activity was calculated by high signal (Luminescence value with enzyme added but no test compound), low signal (Luminescence value without enzyme added), and sample signal (Luminescence value with enzyme added and test compound added). The half-maximal inhibitory concentration (IC ₅₀ ) was calculated by XLfit2.0 software (ID Business Solutions Ltd).

Inhibition rate (%) = ((high Lum-sample Lum)/(high Lum-low Lum)) × 100%. The in vitro activity of the compounds of the present disclosure on the wild-type FGFR3/2/1 enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 1.

Test results: Under the experimental conditions, the compounds of the present disclosure were tested to have good inhibitory activity against FGFR3. Compared with FGFR1 and/or FGFR2, the compounds of the present disclosure have higher selectivity for FGFR3.

Table 1 Results of in vitro activity assay of the disclosed compounds on FGFR3/2/1 enzyme

Test Example 2: Experiment on the inhibition of cell proliferation by the disclosed compounds

The test samples were dissolved in DMSO to prepare a 10 mM stock solution and stored at -30°C. During the assay, the compound was diluted in serum-free medium containing 5% DMSO to a concentration 10 times the assay concentration.

The cells used in the experiment were purchased from ATCC (American Type Culture Collection, USA, catalog number CRL-5974), JMSU-1 cells were purchased from DSMZ, and RT112 cells were purchased from DSMZ. The culture medium IMDM was purchased from Gibco (Cat. No. 12440-061), the culture medium 1640 was purchased from Gibco (Cat. No. 12634-010), and the serum was purchased from Gibco (Cat. No. 10099-141C). Cell-counting kit-8 (CK04) was purchased from Tongren Chemical Co., Ltd. Luminescent Cell Viability Assay was purchased from Promega (Cat. No. G7570).

Cells in the logarithmic growth phase were inoculated in a 96-well cell culture plate with a volume of 100 μL. Cultured overnight at 37°C in an incubator containing 5% carbon dioxide. The next day, 10 μL/well gradient dilutions (starting concentration: 5000nM, 3× gradient dilutions, 10 concentration points) of the test compound were added, and 10 μL/well serum-free medium containing 5% DMSO was added to the control group instead of the test compound dilution solution, and the final concentration of DMSO was 0.5%. Incubate in an incubator for 72 hours. Add 10 μL/well Cell-counting kit-8 reagent (or 50 μL/well CTG). Incubate at 37°C in a carbon dioxide incubator for 40 minutes, and read the light absorption value at 450nm (CTG reads Luminescence) on a microplate reader (Perkinelmer Envision). The inhibition rate of cell growth by the disclosed compounds was calculated according to the following formula, and the half-maximum proliferation inhibition concentration (GI ₅₀ ) of the drug was calculated using XLFit2.0 software.

Inhibition rate (%) = [1-([OD ₄₅₀ ] _compound- [OD ₄₅₀ ] _background )/([OD ₄₅₀ ] _cell- [OD ₄₅₀ ] _background )]×100%

Where: [OD ₄₅₀ ] _compound represents the light absorbance value of the compound-treated wells;

[OD ₄₅₀ ] _cells represent the light absorption value of the wells with DMSO instead of the compound on day 3;

[OD ₄₅₀ ] _Background represents the light absorbance value of the wells with DMSO instead of compound on day 0;

The cell proliferation experiment of the disclosed compounds was determined by the above test, and the measured GI ₅₀ values are shown in Table 2.

Table 2 Results of the cell proliferation assay of the disclosed compounds

Test Example 3: Pharmacokinetics test in BALB/c mice

Experimental purpose: BALB/c mice were used as test animals, and the drug concentration in plasma at different times after injection of the test compound was determined by LC/MS/MS. The pharmacokinetic behavior of the compound in mice was studied and its pharmacokinetic characteristics were evaluated.

Test reagents:

BALB/c mice, NMP (N-methylpyrrolidone), and solutol HS15 (polyethylene glycol-15 hydroxystearate) are all commercially available.

experimental method:

1. Animal testing

Three healthy female BALB/c mice were taken and administered via the tail vein at a dose of 5 mg/kg. The tail vein administration group used a complete solvent solution of 5% (v/v) NMP + 95% (v/v) solutol HS15 (10%, v/v) in water, and the individual dosage was calculated according to the weight of the mouse. The tail vein administration group underwent orbital blood sampling before and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24h after administration. About 30u L of whole blood was collected at each time point and placed in a 1.5mL centrifuge tube anticoagulated with EDTA-2K, followed by centrifugation at 8000r/min for 5min, and the plasma was removed and stored at -80℃.

2. Sample processing and bioanalysis

Take 10uL of mouse plasma sample, add 150uL acetonitrile solvent (containing internal standard compound verapamil) to precipitate protein, vortex for 5min and centrifuge (14000rpm) for 5min, take the supernatant and dilute it 2 times with water containing 0.1% (v/v) formic acid, and perform quantitative detection on LC-MS/MS system (AB Sciex Triple Quad 6500+). When determining the sample concentration, carry out Balbc mouse plasma standard curve and quality control sample. For the 20x diluted sample, take 2uL sample and add 38uL blank plasma, vortex for 0.5min, add 600uL acetonitrile solvent (containing internal standard compound verapamil) to precipitate protein, and the rest of the processing steps are the same as the undiluted sample.

3. Data processing

The pharmacokinetic parameters were calculated by non-compartmental statistical moment method using Phoenix WinNonlin 8.0 software (Certara, USA). The experimental results are shown in Table 3.

Table 3 Pharmacokinetics of the compounds of the present disclosure in mice

Claims (20)

A compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
in, X ₁ and X ₂ are independently selected from N or C; Z is selected from O, S, NH, a bond, OCR ⁶ R ⁷ , SCR ⁶ R ⁷ , NHCR ⁶ R ⁷ or CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are each independently selected from H and C ₁ -C ₆ alkyl; R ¹ is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted with R ^1a ; R ^1a is selected from halogen, OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl is optionally substituted by R ^1b ; R ^1b is selected from halogen, OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ² is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted with R ^2a ; R ^2a is selected from halogen, OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the OH, NH ₂ , C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted with halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or C ₃ -C ₆ cycloalkyl; R ³ is selected from H, CN, OH, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; Ring A is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, wherein the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by ^Ra ; Ring B is selected from a C ₆ -C ₁₀ aromatic ring or a 5-10 membered heteroaromatic ring, wherein the C ₆ -C ₁₀ aromatic ring or the 5-10 membered heteroaromatic ring is optionally substituted by R ^b ; Ring C is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or C ₆ -C ₁₀ aryl, and the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or C ₆ -C ₁₀ aryl is optionally substituted by R ^c ; Each of ^Ra , ^Rb , and ^Rc is independently selected from halogen, CN, OH, _NH2 , -S(=O) _-C1 - _C4 alkyl, -S(=O) ₂ - _C1 - _C4 alkyl, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, or 4-10 membered heterocyclyl; L is selected from a bond, -CH ₂ -, -C(=O)-, -NHC(=O)-, a C ₃ -C ₆ carbocyclic ring, a 4-6 membered heterocyclic ring, a C ₆ -C ₁₀ aromatic ring or a 5-6 membered heteroaromatic ring; W is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, 4-6 membered heterocyclyl, -S(═O) ₂ -C ₁ -C ₄ alkyl, -C(═O)-RT, -C(═O)CR ^{4 ═C} (R ⁵ ) ₂ , -C(═O)C≡CR ⁵ , -NHC(═O)CR ⁴ ═C(R ⁵ ) ₂ , -NHC(═O)C≡CR ⁵ , -S(═O)CR ⁴ ═C(R ⁵ ) ₂ , -S(═O) ₂ CR ⁴ ═C(R ⁵ ) ₂ , -NHS(═O)CR ⁴ ═C(R ⁵ ) ₂ , or -NHS(═O) ₂ CR ⁴ ═C(R ⁵ ) ₂ ; ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclyl, -N( _C1 - _C6 alkyl) ₂ , _C1 - _C6 alkyl-CN or _C3 - _C6 cycloalkyl; R ⁴ is selected from H, CN, halogen or C ₁ -C ₆ alkyl; each R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted with R ^5a ; R ^5a is independently selected from halogen, CN, OH, NH ₂ , —NH—C ₁ -C ₆ alkyl, —N(C ₁ -C ₆ alkyl) ₂ , C ₃ -C ₈ cycloalkyl or 4-9 membered heterocyclyl. The compound of formula (I) according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, wherein at least one of _X1 or _X2 is selected from N; Or _X1 is selected from C, _X2 is selected from N; Alternatively, _X1 is selected from N, and _X2 is selected from C. The compound of formula (I) according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z is selected from O, S, NH, a bond, OCR ⁶ R ⁷ , SCR ⁶ R ⁷ , NHCR ⁶ R ⁷ or CR ⁶ R ⁷ , and R ⁶ and R ⁷ are each independently selected from H and C ₁ -C ₃ alkyl; Alternatively, Z is selected from O, S, NH, a bond, _OCH2 , _SCH2 , _NHCH2 , or _CH2 ; alternatively, Z is selected from O, S, NH, or a bond; alternatively, Z is O or _OCH2 ; alternatively, Z is selected from O; or alternatively, Z is _OCH2 . The compound represented by formula (I) according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from H, CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy or C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy or C ₃ -C ₆ cycloalkyl is optionally substituted by R ^1a ; or R ¹ is selected from CN, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl, and the C ₁ -C ₆ alkyl, C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl is optionally substituted by R ^1a ; Alternatively, R ¹ is selected from C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl, and the C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl is optionally substituted by R ^1a ; or R ¹ is selected from C ₂ -C ₆ alkynyl, said C ₂ -C ₆ alkynyl being optionally substituted by R ^1a ; Alternatively, R ¹ is selected from -CN, -Cl, -CH ₃ , -CH ₂ OH, The compound represented by formula (I) according to any one of claims 1 to 4, or its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R ^1a is selected from OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by R ^1b ; or R ^1a is selected from OH, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, and the C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by R ^1b ; or R ^1a is selected from halogen, OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; or R ^1a is selected from OH, -CH ₃ , -OCH ₃ , cyclopropyl, cyclobutyl, 3-oxetanyl, 2-tetrahydrofuranyl, tetrahydro-2H-thiopyranyl-4-yl, phenyl, 3-pyridyl or 5-pyrimidyl, and the cyclopropyl, cyclobutyl, 3-oxetanyl, 2-tetrahydrofuranyl, tetrahydro-2H-thiopyranyl-4-yl, phenyl, 3-pyridyl or 5-pyrimidyl is optionally substituted with R ^1b ; Optionally, R ^1b is selected from halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; or R ^1b is selected from F, Cl, CH ₃ or -OCH ₃ . The compound represented by formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from CN, OH, NH ₂ , halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted by R ^2a ; or R ² is selected from CH ₃ , CH ₂ OH, CH ₂ O(cyclopropyl), CF ₃ , CH ₂ OCH ₃ , CH ₂ OCF ₃ , C ₂ H ₅ , OCH ₃ or OH; Optionally, one of R ² and R ³ is H; Optionally, ^R3 is H. The compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring A is selected from C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, and the C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl is optionally substituted by ^Ra ; Or ring A is selected from C ₃ -C ₆ cycloalkyl or 5-6 membered heteroaryl, and the C ₃ -C ₆ cycloalkyl or 5-6 membered heteroaryl is optionally substituted by ^Ra ; Or ring A is selected from cyclopropyl, pyridyl or pyrimidinyl, and the cyclopropyl, pyridyl or pyrimidinyl is optionally substituted by ^Ra ; Optionally, Ra ^is selected from halogen; Or ring A is selected from The compound represented by formula (I) according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from a 5-10 membered heteroaromatic ring, and the 5-10 membered heteroaromatic ring is optionally substituted by R ^b ; or Ring B is selected from a 5-6 membered heteroaromatic ring containing 1, 2 or 3 N heteroatoms, wherein the 5-6 membered heteroaromatic ring containing 1, 2 or 3 N heteroatoms is optionally substituted by R ^b ; or Ring B is selected from a 1,2,3-triazole ring, wherein the 1,2,3-triazole ring is optionally substituted by R ^b ; Optionally, R ^b is selected from C ₁ -C ₆ alkyl, or R ^b is selected from CH ₃ ; Or ring B is The compound represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein ring C is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or phenyl, and the C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or phenyl is optionally substituted by R ^c ; Alternatively, Ring C is selected from C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl, wherein the C ₃ -C ₆ cycloalkyl or 4-10 membered heterocyclyl is optionally substituted by R ^c ; Alternatively, Ring C is selected from a 4-10 membered heterocyclyl group, wherein the 4-10 membered heterocyclyl group is optionally substituted by R ^c ; Alternatively, ring C is selected from C ₃ -C ₆ cycloalkyl, 4-10 membered heterocyclyl or C ₆ -C ₁₀ aryl; Alternatively, ring C is selected from a 4-10 membered heterocyclic group or a C ₆ -C ₁₀ aryl group; Optionally, R ^c is selected from halogen or C ₁ -C ₆ alkyl; or R ^c is F; Alternatively, ring C is selected from The compound represented by formula (I) according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein W is selected from H, methyl, ethyl, isopropyl, -CH ₂ CF ₃ , oxetanyl, -S(＝O) ₂ CH ₃ , -C(＝O)C(CH ₃ )＝CH ₂ , -C(＝O)CH＝CH ₂ , -C(＝O)CH＝CHCH ₂ N(CH ₃ ) ₂ , -C(＝O)CH ₂ CN, -C(＝O)N(CH ₃ ) ₂ , -C(＝O)CH ₂ CH ₃ , -C(＝O)CH ₃ , -C(＝O)CF ₃ , -C(＝O)OCH ₂ CH ₃ or -C(＝O)OCH ₃ ; Alternatively, W is selected from -C(=O)CR ⁴ =C(R ⁵ ) ₂ , -C(=O)C≡CR ⁵ , -NHC(=O)CR ⁴ =C(R ⁵ ) ₂ , -NHC(=O)C≡CR ⁵ , -S(=O)CR ⁴ =C(R ⁵ ) ₂ , -S(=O) ₂ CR ⁴ =C(R ⁵ ) ₂ , -NHS(=O)CR ⁴ =C(R ⁵ ) ₂ or -NHS(=O) ₂ CR ⁴ =C(R ⁵ ) ₂ ; or W is selected from -C(=O)CR ⁴ =C(R ⁵ ) ₂ ; Alternatively, W is selected from 3-oxetanyl. The compound represented by formula (I) according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclic group or _C3 - _C6 cycloalkyl; Alternatively, ^RT is selected from _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, 4-6 membered heterocyclyl, -N( _C1 - _C6 alkyl) ₂ or _C1 - _C6 alkyl-CN; Alternatively, ^RT is selected _{from CH3} , _C2H5 , _{OCH3 , OC2H5} , _CF3 or The compound represented by formula (I) according to any one of claims 1 to 11, or its stereoisomer, or its pharmaceutically acceptable salt, wherein L is selected from a bond. The compound represented by formula (I) according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, and the C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy is optionally substituted by R ^5a ; optionally, R ^5a is independently selected from halogen, CN, OH, NH ₂ , -NH-C ₁ -C ₆ alkyl or -N(C ₁ -C ₆ alkyl) ₂ . The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (II) or its stereoisomer or its pharmaceutically acceptable salt:
Wherein, Ring A, Ring B, Ring C, R ¹ , R ² , R ³ , Z, L, and W are as defined in any one of claims 1-13. The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt according to any one of claims 1 to 13, wherein the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound represented by formula (III) or its stereoisomer or its pharmaceutically acceptable salt:
Wherein, Ring A, Ring B, Ring C, R ¹ , R ² , R ³ , Z, L, and W are as defined in any one of claims 1-13. The compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the compound represented by formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts:










A pharmaceutical composition comprising a compound represented by formula (I) according to any one of claims 1 to 16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compound represented by formula (I) according to any one of claims 1 to 16, or its stereoisomer or its pharmaceutically acceptable salt, or the claim Request 17 for the use of the pharmaceutical composition described in claim 17 in the preparation of drugs for preventing or treating diseases mediated by FGFR. A method for preventing or treating a disease mediated by FGFR, the method comprising administering to an individual a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17. The use according to claim 18 or the method according to claim 19, wherein the disease mediated by FGFR is selected from cancer.